EMA-HMPC-228759. Assessment Report On Senna Alexandrina Mill. (Cassia Senna L. Cassia Angustifolia Vahl) Folium and Fructus, 2016

25 September 2018
EMA/HMPC/228759/2016
Committee on Herbal Medicinal Products (HMPC)
Assessment report on Senna alexandrina Mill. (Cassia

senna L.; Cassia angustifolia Vahl) 1, folium and fructus
Final
Based on Article 10a of Directive 2001/83/EC (well-established use)
Herbal substance(s) (binomial scientific name of Senna alexandrina Mill. (Cassia senna L.; Cassia
the plant, including plant part) angustifolia Vahl), folium and fructus
Herbal preparation(s) Comminuted herbal substance or herbal

preaparations thereof, standardised
Pharmaceutical form(s) Standardised herbal substance as herbal tea for

oral use. Standardised herbal preparations in
liquid or solid dosage forms for oral use.
Rapporteur(s) W. Knoess (revision), C. Werner (first version)
Assessor(s) C. Werner (revision), B. Merz (first version)
Peer-reviewer I. Chinou
1 The botanical name of the herbal substance has been changed, see section 1 of the assessment report for further details.
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Table of contents
Table of contents ................................................................................................................... 2
1. Introduction ....................................................................................................................... 4
1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof .. 4
1.2. Search and assessment methodology ..................................................................... 5
2. Data on medicinal use ........................................................................................................ 6
2.1. Information about products on the market .............................................................. 6
2.1.1. Information about products on the market in the EU/EEA Member States ................. 6
2.1.2. Information on products on the market outside the EU/EEA .................................. 17
2.2. Information on documented medicinal use and historical data from literature ............ 17
2.3. Overall conclusions on medicinal use .................................................................... 21
3. Non-Clinical Data ............................................................................................................. 23
3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal
preparation(s) and relevant constituents thereof ........................................................... 23
3.1.1. Primary pharmacodynamics .............................................................................. 23
3.1.2. Secondary pharmacodynamics .......................................................................... 27
3.1.3. Safety pharmacology ....................................................................................... 28
3.1.4. Pharmacodynamic interactions .......................................................................... 29
3.1.5. Conclusions .................................................................................................... 29
3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal
preparation(s) and relevant constituents thereof ........................................................... 29
3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal
preparation(s) and constituents thereof ....................................................................... 33
3.3.1. Single dose toxicity .......................................................................................... 33
3.3.2. Repeat dose toxicity......................................................................................... 34
3.3.3. Genotoxicity ................................................................................................... 36
3.3.4. Carcinogenicity ................................................................................................ 40
3.3.5. Reproductive and developmental toxicity ............................................................ 42
3.3.6. Local tolerance ................................................................................................ 42
3.3.7. Other special studies ........................................................................................ 43
3.3.8. Conclusions .................................................................................................... 43
3.4. Overall conclusions on non-clinical data ................................................................ 44
4. Clinical Data ..................................................................................................................... 44
4.1. Clinical pharmacology ......................................................................................... 44
4.1.1. Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s)
including data on relevant constituents ........................................................................ 44
4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s)
including data on relevant constituents ........................................................................ 45
4.2. Clinical efficacy .................................................................................................. 47
4.2.1. Dose response studies...................................................................................... 47
4.2.2. Clinical studies (case studies and clinical trials) ................................................... 47
4.3. Clinical studies in special populations (e.g. elderly and children) .............................. 88
4.4. Overall conclusions on clinical pharmacology and efficacy ........................................ 93
Assessment report on Senna alexandrina Mill. (Cassia senna L.; Cassia angustifolia
Vahl), folium and fructus
EMA/HMPC/228759/2016 Page 2/133
5. Clinical Safety/Pharmacovigilance ................................................................................... 94
5.1. Overview of toxicological/safety data from clinical trials in humans ........................... 94
5.2. Patient exposure .............................................................................................. 110
5.3. Adverse events, serious adverse events and deaths .............................................. 112
5.4. Laboratory findings ........................................................................................... 117
5.5. Safety in special populations and situations ......................................................... 117
5.5.1. Use in children and adolescents ....................................................................... 117
5.5.2. Contraindications ........................................................................................... 117
5.5.3. Special warnings and precautions for use ......................................................... 118
5.5.4. Drug interactions and other forms of interaction ................................................ 119
5.5.5. Fertility, pregnancy and lactation ..................................................................... 120
5.5.6. Overdose ...................................................................................................... 121
5.5.7. Effects on ability to drive or operate machinery or impairment of mental ability .... 121
5.5.8. Safety in other special situations ..................................................................... 121
5.6. Overall conclusion on clinical safety .................................................................... 121
6. Overall conclusions (benefit-risk assessment) ............................................................... 122
Annex ................................................................................................................................ 123

List of references .................................................................................................... 123
EMA/HMPC/228759/2016 Page 3/133
1. Introduction
Senna alexandrina Mill. has recently been identified as the correct name of a plant species
(www.theplantlist.org; Wichtl, 2016), which had been classified before as two different species, Cassia
senna L. and Cassia angustifolia Vahl. These two species had already been known as very closely
related. It is also intended to use Senna alexandrina Mill. in the respective monographs of the
European Pharmacopeia and therefore the European monographs have been renamed accordingly.
Leaves and fruits of both species contain a similar spectrum of hydroxyanthracene derivatives, which
are accepted as the active constituents.
This assessment report includes data relevant for the European Union herbal monographs on senna
leaves and senna pods. Whenever reference is made to literature, this assessment report displays the
species name which had been originally used in the reference document.
In addition, in this assessment report the English common names “senna fruits” and “senna pods” are
used for the herbal substance “Sennae fructus”. Citations based on references may use the term from
the original publication.
1.1. Description of the herbal substance(s), herbal preparation(s) or

combinations thereof
• Herbal substance(s)
Senna leaves
The herbal substance senna leaves consist of the dried leaflets of Cassia senna L. (Cassia acutifolia
Del.), known as Alexandrian or Khartoum senna, or Cassia angustifolia Vahl, known as Tinnevelly
senna, or a mixture of the two species, now collectively subsumed under the item Senna alexandrina
Mill. The herbal substance contains not less than 2.5% of hydroxyanthracene glycosides, calculated as
sennoside B (C42H38O20; Mr 863). The material complies with the European Pharmacopoiea monograph
“Senna leaf” (Ph. Eur. 9: 0206). The active constituents are the anthranoids that are present in the
leaf of the herbal substance as dianthrones (75–80%) and as anthrones (20–25%).
The herbal substance also contains small quantities of other dianthrone diglycosides,
monoanthraquinone glycosides and aglycones. The amount of aglycones increases during storage. The
naphthalene glycosides are without pharmacological significance but have been used to differentiate
the two species of senna, when this was reflecting the taxonomic status: tinnevellin glycoside was
found only in Cassia angustifolia Vahl, and 6-hydroxymusizin glycoside only in the mature plants of
Cassia senna L. (Lemli et al., 1981, Lemli et al., 1983).
Senna pods
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 (C42H38O20; Mr 863) with reference to the dried herbal substance. The material complies
with the European Pharmacopoiea monograph “Senna pods, Alexandrian” (Ph. Eur. 9: 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
aglycones are also present.
Historically, 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
EMA/HMPC/228759/2016 Page 4/133
sennoside B (C42H38O20; Mr 863) with reference to the dried herbal substance. The material complies
with the European Pharmacopoiea monograph “Senna pods, Tinnevelly” (Ph. Eur.: 0208).
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 aglycones.
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, A1 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, A1 and B, and 20% are sennosides C and
D. In the leaves tinnevellin glycoside is present at 0.4% (Westendorf 1993).
The amount of anthranoids of the emodin and aloe emodin type is generally higher in the leaves than
in the fruits (Kommission E, 1993).
• Herbal preparation(s)
Senna leaves and fruits are commonly used as comminuted herbal substance. Additionally, there
are some extracts which are also standardised on a defined content of hydroxyl anthracene
glycosides. There is also a standardised dry extract of senna leaves described in the European
Pharmacopeia. Standardised senna leaf dry extract is produced from Senna leaf (Ph. Eur.: 0206).
The extract is produced from the herbal substance by a suitable procedure using ethanol (50-80
per cent V/V). It contains not less than 5.5% and not more than 8.0% of hydroxyanthracene
glycosides, calculated as sennoside B (C42H38O20; Mr 863) with reference to the dried extract. The
measured content does not deviate from the value stated on the label by more than±10%. (Ph.
Eur.: 1261)
• Combinations of herbal substance(s) and/or herbal preparation(s) including a description of

vitamin(s) and/or mineral(s) as ingredients of traditional combination herbal medicinal products
assessed, where applicable.
There are manifold combinations of senna leaves or fruits with other herbal substances or herbal
preparations with a laxative effect. With respect to the diverse nature of these products they are
not described in detail in the AR. There are combinations of senna leaves and senna fruits because
the combination is facilitating adjustment to a defined content of hydroxy anthraquinone
derivatives. Such combinations can be evaluated in analogy to the monographs on senna leaves
and senna pods as the therapeutic principle is identical and overall composition of natural
compounds of these herbal substances is similar.
1.2. Search and assessment methodology
Literature search was done via PubMed, DIMDI and SciFinder in medical and scientific databases as
MEDLINE, National Center for Biotechnology Information (NCBI), Cochrane Database of Systematic
Reviews TOXLINE (date of search: September 2015). For the unqualified terms (Cassia, Senn*, Aloe,
Cassia clinical trials; senn* and cassia and in vitro; *anthroquinones and in vitro, rhein and in vitro,
aloe emodin and in vitro, senn* and cassia and in vivo; anthroquinones and in vivo, rhein and in vivo
EMA/HMPC/228759/2016 Page 5/133
aloe emodin and in vivo, senn* and cassia and preclin*; senn* and cassia, rhein, aloe emodin
hydroxyanthracen* and safety; senn* and cassia, rhein, aloe emodin hydroxyanthracen* and the
different indications) as text words in the title, abstract, and full journal article. The search strategy
included the terms for senn* and cassia, rhein, aloe, and terms for the specific diseases or conditions
derived from its traditional use and current indications, supplemented with those expected from non-
clinical studies with aloe. In addition to the PubMed and SciFinder literature search, bibliographies of
review articles and eligible articles were examined in an effort to identify all available literature that
may not have been identified by the database research. Randomised studies that used combination
products with senn* and cassia as one of its ingredients are not included.
Search engines used: Google
Scientific databases: PubMed, DIMDI, SciFinder
Medical databases: MEDLine, Cochrane Database of Systematic Reviews, EMBASE, BioMed Central
Toxicological databases: ToxLine
Pharmacovigilance resources: Vigilance central
Data from EU and non-EU regulatory authorities: WHO Monograph; NTP Technical Reports on Aloe vera
whole leaf extract and Emodin; IARC Monograph Aloe vera; NTP Technical Reports on Cassia Senna
whole leaf extract and Rhein; IARC Monograph Cassia senna;
Other resources: Historical literature according to list of references
2. Data on medicinal use
2.1. Information about products on the market
2.1.1. Information about products on the market in the EU/EEA Member

States
Table 1: Overview of data obtained from marketed medicinal products
Active substance Indication Pharmaceutical form Regulatory Status

Posology
Duration of use
Senna leaf
Dry extract (DER Constipation Coated tablet WEU since 2013; AT
84.4:1) from Sennae
Adults and adolescents:
folium, extraction
1-2 coated tablets per
solvent methanol 75%
day
V/V, standardised to
47.5-52.5%
hydroxyanthracene
derivatives
corresponding to 12
mg per coated tablet
Dry extract (DER Constipation Chocolate like bar WEU since 1985; AT
84.4:1) from Sennae
Adults and adolescents:
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Posology
Duration of use
folium, extraction ¼-½ bar per day

V/V, standardised to
47.5-52.5%
hydroxyanthracene
derivatives corresp. to
48 mg per ‘Täfelchen’
(=chocolate like bar)
Cassiae Sennae L. folii Symptomatic Coated tablets 28/10/2002;

(C. acutifolia Delile) treatment of Bibliographical; BE
2-3 tablets per day
extractum siccum constipation, after
hydro-alcoholicum exclusion of serious Maximal 2 weeks
(ethanolum 60 per disorders
Contra-indicated for
centum) 66.6 mg (eq.
children younger than
10 mg sennoside B)
12 years
Sennae folium Symptomatic Powder for oral use 01/11/1977;

(Sennablad) 60 g treatment of Complete registration;
The maximal daily dose
constipation, except BE
corresponds to 30 mg
from mechanical
hydroxyanthracene
origin, with a
glycosides (1
contactlaxativum. Only
measuring spoon)
for occasional use
¼-1 measuring spoon 2
-3 times per week
Maximal 2 weeks
Contra-indicated for
children younger than
12 years
Sennae folium Herbal medicinal Herbal tea for oral use WEU, 1995; CZ
product for short-term
1 tea bag (1 g of the
use in cases of
herbal substance)
occasional constipation
equivalent to 15–30 mg
Cleaning of bowel of hydroxyanthracene
before diagnostic derivatives, calculated
endoscopic and as sennoside B, to be
radiological taken once daily at
examination night. Normally it is
sufficient to take this
medicinal product up to
two to three times a
week.
EMA/HMPC/228759/2016 Page 7/133
Posology
Duration of use
Use for more than 1-2

weeks requires medical
supervision
Sennae folium Herbal medicinal 1 tea bag (1 g of the WEU, 1996; CZ

product for short-term herbal substance)
use in cases of equivalent to 25–30 mg
occasional constipation of hydroxyanthracene
derivatives, calculated
as sennoside B, to be
taken once daily at
night. Normally it is
week.

supervision
Sennae folium Herbal medicinal 1 g of the herbal WEU, 1996; CZ

product for short-term substance equivalent to
use in cases of 25–30 mg of
occasional constipation hydroxyanthracene
taken once daily at
week

supervision
Herbal tea Herbal medicinal Herbal tea; adults and WEU, 1978; DE
product for short-term adolescents take ½ to
1.7 g Sennae folium
use in cases of 1 cup of tea daily
standardised to 30 mg
sennoside B 1-2 weeks
product for short-term adolescents take ½ to
0.8 g Sennae folium
use in cases of 1 cup of tea daily
EMA/HMPC/228759/2016 Page 8/133
Posology
Duration of use
product for short-term adolescents take 1 to 2
1.5 g Sennae folium
use in cases of cup of tea daily
Sennae folium Herbal medicinal Tea bags WEU, 2002; Standard

product for short-term marketing
Adults and children
use in cases of authorization; DE
from 10 years on drink
one cup of 150 ml
containing 0.5 g
Sennae fructus; 10-15
min preparation time

supervision
Calcium sennosides As a laxative for the Syrup Full MA; IE

equivalent to 7.5 mg relief of occasional or
7.5 mg/5 ml syrup is Not relevant with
per 5 ml total non-persistent
for oral administration. respect to products in
sennosides (calculated constipation.
the market, because
as sennoside B) Adults, including the
the products is not a
elderly and children
herbal medicinal
over 12: two 5 ml
product
spoonfuls.
Information in the
Not to be given to
assessment report is
children under 12 years
kept, because due to
except on medical
standardisation data
advice. Where
are supportive
administration to
children is necessary,
the recommended dose
is as follows
Children over 6 years:

one 5 ml spoonful
Children aged 2 to 6
years: half to one 5 ml
spoonful in 24 hours
Should be taken as a
single dose at bedtime
by adults and in the
EMA/HMPC/228759/2016 Page 9/133
Posology
Duration of use
morning by children
New users should start

with the lowest dose
and increase it, if
necessary, by one half
of the initial dose each
day
Once regularity has

been regained the
dosage should be
gradually reduced and
stopped
Sennae folium herbal Herbal medicinal Herbal tea WEU, since May 1998;
substance dried product for short-term SK
The maximum daily
leaflets use in cases of
dose of
hydroxyanthracene
glycosides is 30 mg.
Duration of use: 1-2

weeks
Sennae folium, herbal For short-term use in One sachet contains WEU, since 1999; LV
tea in teabags cases of occasional 0.9 g of Sennae folium,
constipation corresponding to 16.2
mg-30 mg
hydroanthracene
glycosides expressed as
sennoside B
Adolescents over 12
years of age, adults,
elderly: to be taken
once daily at night
Normally it is sufficient
to take this medicinal
product up to two to
three times a week
Contraindicated for use

in children under 12
years of age

EMA/HMPC/228759/2016 Page 10/133
Posology
Duration of use
supervision
Sennae folium, herbal For short-term use in One sachet contains WEU, since 1999; LV
tea in teabags cases of occasional 1.2 g of Sennae folium,
constipation corresponding up to 30
mg hydroanthracene
glycosides
Adolescents over 12
elderly: to be taken
once daily at night
three times a week

years of age

supervision
Sennae folii extractum For short-term use in Each tablet contains WEU, since 1999 and
cases of occasional extract corresponding 2003; LV
constipation to 13.5 mg of
sennosides calcium
Adolescents over 12
elderly: 1 tablet once
daily at night. If
necessary, dose can be
increased to 2 tablets
three times a week

years of age

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Posology
Duration of use
supervision
Senna pods
Standardised dry Constipation Coated tablet WEU, 1991; AT

aqueous extract (DER
Adults and adolescents
4-6:1) from Sennae
1 coated tablet daily
fructus angustoliae; 20
mg hydroxyanthracene
derivatives per coated
tablet
Standardised dry Constipation Film-coated tablet WEU, 1969; AT

aqueous extract (DER
3-5:1) from Sennae
2-4 film-coated tablets
fructus acutifoliae; 8.6
daily
derivatives per film-
coated tablet
Standardised dry Cleaning of bowels Oral solution WEU, 1971; AT

aqueous extract (3- before diagnostic
150 mg
5:1) from Sennae purposes or surgery
hydroxyanthracene
fructus acutifoliae
derivatives as single
dose
Sennae angustifoliae Herbal medicinal Herbal tea for oral use WEU, 1995; CZ
fructus product for short-term
1.1 g of the herbal
use in cases of
substance) one tea
spoon) equivalent to
Cleaning of bowel 15–30 mg of
before diagnostic hydroxyanthracene
endoscopic and derivatives, calculated
radiological as sennoside B, to be
examination taken once daily at
week.

supervision
Dry extract (DER 6- Short-term use incases Daily dose: 7.5 to 30 WEU, 1978; DE
12:1) Alexandrian of occasional mg hydroxyanthracene
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Posology
Duration of use
senna pods, extraction constipation derivatives

solvent ethanol 60%
V/V; standardised to
contain 7.5 to 15 mg
hydroxyanthracene
derivatives
Dry extract (DER 5.6- Short-term use incases Daily dose: 12.5 to 25 WEU, 1978; DE
6.9:1) Alexandrian of occasional mg hydroxyanthracene
senna pods, extraction constipation derivatives
V/V; standardised to
contain 12.5 mg
hydroxyanthracene
derivatives
1 bag contains 40 g Herbal medicinal Ethanolic extract; WEU, 1978; DE

Tinnevelly-senna pods product for short-term adults and adolescents
comminuted;16.0– use in cases of take 4 to 5 measuring
22.4 g standardised to occasional constipation spoons daily
561 mg sennoside B corresponding to
22.44-28.05 mg
sennoside B
1-2 weeks
250-318 mg Herbal medicinal Tablets; adults and WEU, 1978; DE

Tinnevelly-senna pods, product for short-term adolescents take 1 to 4
comminuted, use in cases of tablets corresponding
standardised to 7 mg occasional constipation to 7-28 mg sennoside B
sennoside B
Sennae fructus Herbal medicinal Drink one cup of 150 WEU, Standard
product for short-term ml containing 0.5 g Marketing
use in cases of Sennae fructus; 10-15 Authorisation 2002;
occasional constipation min preparation time. DE

supervision
Comminuted herbal Herbal medicinal Tablets MA 1997; HR

substance (Cassia product for short term
Posology: 1-3 tablets
angustifolia Vahl, use in constipation
daily when needed.
fructus) 280 mg
corresponding to 6 mg Not to be used for more
sennoside B than 1 week
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Posology
Duration of use
1 g tea contains: Herbal medicinal Herbal tea MA 1995; MA 1996;

Comminuted Cassia product for short tern DK
Posology: Adults: 2.5-5
angustifolia Vahl, use in constipation
ml (½-1 teaspoon)
fructus, corresponding
daily. Pour over with
to 22 mg
boiling water and wait
hydroxyanthracene
5-10 minutes
derivates, calculated
as sennoside B Not to be used for more
than 1 week
Same product in 2g
sachets
Dry extract from Short-term use in the Herbal tea WEU 2011; HR
Cassia senna L., case of occasional
650 mg herbal tea (1
fructus and Cassia constipation
teaspoon) contains
angustifolia Vahl,
200-333 mg extract,
fructus
corresponding to 20 mg
(DER 4.5-5.5:1), hydroxyanthracene
extraction solvent glycosides calculated as
water corresponds to sennoside B
20 mg
hydroxyanthracene
over 12 years of age:
glycosides calculated
½ to 1½ teaspoon;
as sennoside B
One week if symptoms
persist or worsen
during the use of the
medicinal product

supervision
Dry extract from Short-term use in the Coated tablets WEU, 2011; HR
Cassia angustifolia case of occasional
1 coated tablet
Vahl, fructus (DER 4- constipation
contains 150 to 220 mg
6:1), extraction
extract (as dry extract)
solvent water
from Cassia angustifolia
corresponds to 20 mg
Vahl, fructus (4-6:1),
hydroxyanthracene
glycosides calculated
hydroxyanthracene
as sennoside B
glycosides calculated as
sennoside B.

over 12 years of age: 1
EMA/HMPC/228759/2016 Page 14/133
Posology
Duration of use
tablet daily; one week

if symptoms persist or
worsen during the use
of the medicinal
product

supervision
Senna pods powdered As a laxative in the Tablet Full MA; 2003; CZ

treatment of
1 tablet contains 154 Adults only: 2-4 tablets
mg Cassia senna L. (C. in 24 hours, to be
acutifolia Delile) taken at night
(Senna pods,
Not to be given to
Alexandrian)/Cassia
children except on
angustifolia Vahl
medical advice
(Senna pods
Tinnevely),
standardised to
contain 7.5 mg total
sennosides per tablet,
calculated as
sennoside B
Combinations of senna leaves and senna pods
Fruit block; Herbal medicinal Fruit block: adults and WEU, 1978; DE
comminuted Senna product for short-term adolescents ½-1 fruit
leaves 0.43-0.64 g, use in cases of blocks
tinnevelly-senna pods occasional constipation
0.43-0.64 g;
(corresponding to 30
mg sennoside B)
Sennae folium and For short-term use in Each chewable tablet WEU, 1995; LV
Sennae fructus cases of occasional contains 0.71 g of
constipation Sennae folium and 0.3
g of Sennae fructus.
Each tablet contains
not more than 30 mg
hydroanthracene
sennoside B
Adults, elderly: 1 tablet

once daily at night
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Posology
Duration of use
Sennae folium and For short-term use in Each chewable tablet WEU, 1995; LV
Sennae fructus cases of occasional contains 0.71 g of
constipation Sennae folium and 0.3
g of Sennae fructus.
Each tablet contains
not more than 30 mg
hydroanthracene
sennoside B
Adults, elderly: 1 tablet

once daily at night.
Adolescents over 12
years of age ¼-½
tablets

years of age

supervision
10 g herbal tea contain Herbal medicinal Herbal tea; adults and WEU; 1978; DE
2.5 g senna leaves; 5- product for short-term adolescents 0.5 g–1 g
7.5 g Tinnevelly-senna use in cases of
½-1 measuring spoon
pods; Alexandrine occasional constipation
in 150 ml boiling water
senna pods 0-2.5 g
1 g granulate contains Herbal medicinal Granulate: adults and WEU; 1978; DE

senna leaves product for short-term adolescents take 1-2
comminuted 0.5779 g, use in cases of measuring spoon of the
Tinnevelly-senna pods occasional constipation granulate
comminuted 0.3853 g corresponding to
(corresponding to 26 0.575–1.150 g
mg sennoside B) granulate and to 15–30
mg Sennosid B)
This overview is not exhaustive. It is provided for information only and reflects the situation at the
time when it was established.
Information on relevant combination medicinal products marketed in the EU/EEA
Not applicable
Information on other products marketed in the EU/EEA (where relevant)
EMA/HMPC/228759/2016 Page 16/133
Not applicable
2.1.2. Information on products on the market outside the EU/EEA
Not applicable
2.2. Information on documented medicinal use and historical data from

literature
Senna has been used for medicinal purposes for centuries (Lemli 1995). It was introduced into
European medicine by the Arabs in the 9th or 10th century.
Tabernaemontanus, (1625) (Kräuterbuch von Jacobus Theodorus, 1625) mentions “Kassie” (Cassia
alata). Different parts and preparations of the plant were used: “CASSIA FISTULA” or “CASSIA
FISTULATIS”, MEDULLA CASSIAE, FLORES CASSIAE and CASSIA EXTRACTUM CUM FOLIIS SENNAE.
The last one was an electuary (a medicine composed of powders, or other ingredients, incorporated
with some conserve, honey, or syrup, a soft solid) which was prepared from MEDULLA CASSIAE and
different other herbs and senna leaves. This extract was used as a clysma. Tabernaemontanus also
mentioned the use as a purgative, which was administered in case of fever or heat. In the “American
Materia Medica, Therapeutics and Pharmacognosy” of Finley Ellingwood (Ellingwood, 1919) “Alexandria
Senna” is described as an efficient remedy, mild, kindly, certain and uniform in its action. It is a
constituent of the larger number of the proprietary laxative or cathartic compounds, syrups, cordials or
elixirs. It is used in all cases of temporary constipation, however induced.
Frerichs et al., (1927) also mentions the use of an electuary of senna as a laxative which was
sometimes used as a klysma. Combination preparations with senna are used for purification the blood,
to treat obesity and gallstones. “Sennatin”, an extract of senna leaves, was administered
subcutaneously or intramuscular to treat constipation.
Thoms (1927) describes the use of senna in teas for purification of blood and as a laxative. He also
mentioned “Sennatin”.
Madaus (1976) gave a review of the use of senna. Paracelsus already indicated the use as a purgative
(Madaus, 1976). Also Hecker in1814, Lonicerus in 1564, Bock in 1565, Matthiolus in 1626 and Clarus
in 1860 described the use as a laxative (Madaus, 1976). Matthiolus also cured lues venerea (syphilis)
with senna. Hoppe (1949) mentioned senna leaves as a laxative in cases of acute and chronic
constipation.
In Todd (1967) (Martindale) senna is described as a purgative for the treatment of constipation.
The Pharmacopoeia Austriaca, (1812) lists senna leaves as “infusum laxativum”.
In his “Manual of Materia Medica and Pharmacology” Culbreth, (1927) described the use of “Cassia
senna” as follows: “The Arabians used it in skin affections”; the herbal substance is “now employed for
habitual constipation, haemorrhoids, fissura ani, fevers”. But “its smell, taste, tendency to nauseate,
injurious effects in hemorrhoids, intestinal hemorrhage, and inflammation, all lessen its popularity.”
In Hungary, combinations with senna preparations are used traditionally as cholagoga. Two
prescriptions can be found in Hungarian Pharmacopoiea (in Edition VI., 1967) and some in the
Formulae Normales (the officinal compendium of prescriptions, Edition V., 1967) and there are some
“paramedicines” with this indication. But the pharmacological data available for senna do not support
such use; taking into consideration the benefit-risk ratio for senna, this use cannot be accepted.
EMA/HMPC/228759/2016 Page 17/133
In India, senna leaves are also used in loss of appetite, abdominal pain, liver disease, splenetic
extension, hepatitis, anaemia, leprosy, foul smelling breath, bronchitis and tumours (Kirtikar and Basu,
1975). In his “Indian materia medica” Nadkarni, (1976) described senna leaves and pods as
purgatives. Therapeutical doses stimulate intestinal peristalsis. Furthermore externally powdered
leaves mixed with vinegar and made into a plaster are applied locally in certain skin diseases. Senna
leaves combined with Henna are also used as a hair-dye to make the hair black.
As von Koenen described 1977, senna was used in South Africa for treatment of influenza and as
secretolytic ointment. In Central Africa, senna was used in digestive complaints and to treat wounds,
burns and furuncles.
The WHO monographs “Folium Sennae” and “Fructus Sennae (WHO, 1999i, 1999ii) mention the
following uses described in folk medicine, not supported by experimental or clinical data: as an
expectorant, a wound dressing, an antidysenteric, a carminative agent; and for the treatment of
gonorrhoea, skin diseases, dyspepsia, fever, and haemorrhoids.
Table 2 Overview of historical data
Herbal preparation Documented use / Pharmaceutical Reference

Traditional use form
Senna All diseases where an Medium daily dose: Senna (Kommission

easy defaecation is 20 mg bis 60 mg E monograph,
desirable: e.g. hydroxyanthracene 1984)
analfissures, derivatives
haemorrhoids, after
Comminuted herbal
rectoanal surgery.
substance, powder or
For bowel cleansing dry extracts for
before diagnostic infusion, decoction or
procedures or surgery; cold mazerates
Constipation Fluid and solid

pharmaceutical forms
only for oral
application
Sennae folium Constipation Comminuted herbal Sennae folium

substance, powder or
(Kommission E
dry extracts for
monograph, 1993)
infusion, decoction or
cold mazerates. Fluid
and solid
only for oral
application
20-30 mg
hydroxyanthracene
derivatives per day,
calculated as
sennoside B
EMA/HMPC/228759/2016 Page 18/133
The correct individual

dose is the lowest to
achieve a soft formed
stool
Sennae fructus Constipation Comminuted herbal Kommission E

substance, powder or Monograph, 1993)
dry extracts for
infusion, decoction or
cold mazerates. Fluid
and solid
only for oral
application
20-30 mg
hydroxyanthracene
derivativesper day,
calculated as
sennoside B
The correct individual

dose is the smallest
required to produce a
comfortable soft
formed motion
Sennae folium For short-term use in The correct individual ESCOP Monographs
cases of occasional dose is the smallest 3rd ed. November
constipation required to produce a 2003
comfortable soft
formed motion
Adults and children

from 10 years on:
preparations
equivalent to 15-30
mg
hydroxyanthracene
taken once daily at
night
Sennae fructus For short-term use in The correct individual ESCOP Monographs
acutifoliae cases of occasional dose is the smallest 3rd ed. November
comfortable soft
EMA/HMPC/228759/2016 Page 19/133
formed motion
Adults and children

from 10 years on:
preparations
equivalent to 15-30
mg
hydroxyanthracene
taken once daily at
night
Sennae fructus For short-term use in The correct individual ESCOP Monographs
angustifoliae cases of occasional dose is the smallest 3rd ed. November
comfortable soft
formed motion.
Adults and children

from 10 years on:
preparations
equivalent to 15-30
mg
hydroxyanthracene
taken once daily at
night
Folium Sennae Short-term use in The correct individual WHO monographs

occasional constipation dose is the smallest on selected
required to produce a medicinal plants.-
comfortable, soft- Vol. 1. 1999
formed motion.
Powder: 1–2 g of leaf
daily at bedtime.
Adults and children
over 10 years:
standardised daily
dose equivalent to
10–30mg sennosides
(calculated as
sennoside B) taken at
night
EMA/HMPC/228759/2016 Page 20/133
Fructus Sennae Short-term use in The correct individual WHO monographs

occasional constipation dose is the smallest on selected
required to produce a medicinal plants.-
comfortable, soft- Vol. 1. 1999
formed motion.
Powder: 1–2g of leaf
daily at bedtime.
Adults and children
over 10 years:
standardised daily
dose equivalent to
10–30mg sennosides
(calculated as
sennoside B) taken at
night
2.3. Overall conclusions on medicinal use
From the multitude of products authorised in the European Union the 10 years of well-established use
can be attributed to various herbal preparations of senna leaf and senna pods (see table 3).
Because of the standardisation and the known mode of action of anthraquinon glycosides, the HMPC
decided to define the herbal preparations in the monographs only by reference to the standardisation.
In the posology section 4.2, a range for standardisation is mentioned which is based on the posologies
from products on the market. Additionally, a reference to the calculation based on a photometric
method is made, because the methodology described in the respective monographs of the European
Pharmacopeia is under revision. During revision of the monographs on Senna alexandrina, fructus and
Senna alexandrina, folium, the HMPC also decided to change the range of posology from 15-30 mg to
10 to 30 mg hydroxyl anthracene derivatives. This is supported by products in the market and follows
the approach to minimise the amount used. The range is now also consistent with the posology defined
in the revised monograph on Aloe barbadensis Mill. and on Aloe (various species, mainly Aloe ferox
Mill. and its hybrids), folii succus siccatus.
Table 3: Overview of evidence on period of medicinal use
Herbal preparation Indication Posology, Strength Period of medicinal

Pharmaceutical form use
Sennae folium
Comminuted herbal Short-term use in Daily dose: 0.9-2 g of Marketing
substance; standardised in cases of herbal substance, authorisations in DE,
the finished medicinal occasional standardised on 15-30 CZ, LV (2005 and
products to contain 15-30 constipation mg hydroxyanthracene earlier)
mg hydroxyanthracene derivatives
derivatives, calculated as
sennoside B
Dry extract (DER 7-10:1) Short-term use in Daily dose: 14 or 28 Marketing authorisation
EMA/HMPC/228759/2016 Page 21/133
extraction solvent methanol cases of mg hydroxyanthracene in DE (1978)

60% V/V; standardised to occasional derivatives
contain 11.0-15.0% constipation
hydroxyanthracene
sennoside B
Dry extract (DER 4.3-5.9:1) Short-term use in Maximum daily dose, Marketing authorisation
extraction solvent methanol cases of once: 30 mg in DE (1978)
60% V/V; standardised to occasional hydroxyanthracene
contain 11.0-15.0% constipation derivatives
hydroxyanthracene
sennoside B
Dry extract (DER 84.4:1) Constipation Daily dose: Marketing

extraction solvent methanol corresponding to 12-24 authorisations in AT
75% V/V; standardised to mg hydroxyanthracene (2013 and 1985)
47.5-52.5% derivatives
hydroxananthracene
derivatives
Dry extract (DER 6-12:1) Symptomatic Daily dose: Marketing authorisation

treatment of corresponding to 20-30 in BE (2002)
Extraction solvent ethanol
constipation mg hydroxyanthracene
60% V/V
derivatives
Sennae fructus
Comminuted herbal Short-term use in Herbal tea preparation Marketing

substance cases of authorisations in CZ,
Daily dose: 0.5-1.1 g of
occasional DE, DK (2002 and
herbal substance,
constipation earlier)
standardised on 15-30
as sennoside B
Comminuted herbal
substance in solid
dosage forms: daily
dose: 6-30 mg
hydroxyanthracene
derivatives, once
Single dose: 250-320

mg herbal substance,
standardised to 6-7.5
EMA/HMPC/228759/2016 Page 22/133
derivatives
Dry extract (DER 4-6:1) Short-term use in Daily dose: 20 mg Marketing authorisation
extraction solvent water cases of hydroxyanthracene in HR (2011)
occasional derivatives
constipation
Dry extract (DER 3-6:1) Constipation Daily dose: 20 mg or Marketing authorisation

extraction solvent water 17.2 to 34.4 mg in AT (1991 and 1969)
hydroxyanthracene
derivatives
Dry extract (DER 3-5:1) Cleaning of bowels Single dose: 150 mg Marketing authorisation
extraction solvent water before diagnostic hydroxyanthracene in AT (1971)
purposes or derivatives
surgery
Dry extract (DER 6-12:1) Short-term use in Daily dose: 7.5 to 30 Marketing authorisation
extraction solvent ethanol cases of mg hydroxyanthracene in DE (1978)
contain 7.5 to 15 mg constipation
hydroxyanthracene
derivatives
Dry extract (DER 5.6-6.9:1) Short-term use in Daily dose: 12.5 to 25 Marketing authorisation
extraction solvent methanol cases of mg hydroxyanthracene in DE (1978)
contain 12.5 mg constipation
hydroxyanthracene
derivatives
3. Non-Clinical Data
3.1. Overview of available pharmacological data regarding the herbal

substance(s), herbal preparation(s) and relevant constituents thereof
3.1.1. Primary pharmacodynamics
Data on herbal preparations
Senna leaves belong to the stimulant laxatives. Pharmocodynamic data regarding different forms of
herbal preparations are not available.
Data derived from studies on Hydroxyanthracene Derivatives
Ishii et al. (1990) investigated the mechanism of action of aloe emodin-9-anthrone in causing a
significant increase in the water content of the rat large intestine. Aloe emodin-9-anthrone inhibited rat
colonic Na+/K+-adenosine triphosphatase in vitro, and increased the paracellular permeability across
the rat colonic mucosa in vivo. Therefore, it seemed that the increase in water content of the rat large
EMA/HMPC/228759/2016 Page 23/133
intestine produced by aloe emodin-9-anthrone was due to both, inhibition of absorption and
stimulation of secretion without stimulation of peristalsis. Since pretreatment with loperamide
completely prevented the increase of paracellular permeability induced by aloe emodin-9-anthrone, but
did not completely reduce the concomitant increase in residual fluid volume, other multiple
mechanisms of action might be involved in the increase of water content in the rat large intestine.
The effect of rhein and rhein anthrone on the transit and the transport of water and electrolytes in the
large intestine were investigated by van Hoestenberghe et al. (1992) in germ-free rats. After
intracaecal administration, neither of the two compounds was found to accelerate the transit of a
colour marker through the large intestine. Both compounds reduced the net absorption of sodium and
chloride in the colon and enhanced net potassium secretion. Net water absorption was decreased by
rhein and even reversed into net secretion by rhein anthrone. The secretagogue activity of the
compounds is not sufficient to induce laxation in germ-free rats. Furthermore rhein and rhein anthrone
had no laxative properties under these experimental conditions. No laxative effect was seen in germ-
free animals by Nijs et al. (1993) as well.
Hoenig et al. (1992), and Rauwald et al. (1992) studied the influence of 15 anthraquinones and 8
corresponding anthrones on the regulatory volume decrease which is affected in Ehrlichs ascites tumor
cells by activation of Cl- channels. They showed that the strongest inhibition of the Cl- channels’
activity was caused by aloe emodin-anthrone and aloe emodin. These anthraquinones reduce the Cl-
permeability of the cells, this influence being sometimes more pronounced than that of the Cl- channel
blocker 130B. In contrast to the investigations of Ishii et al. (1990), both substances showed no
pronounced inhibition activity of the Na+/K+-ATPase. Rhein, frangula-emodin and other anthraquinones
with an additional phenolic hydroxyl group showed inhibition.
Results of investigations of Capasso et al. (1983) in rat isolated colon suggest that the laxative
properties of aloin and 1.8-dioxyanthraquinone may depend, at least in part, on increased
prostaglandin synthesis by the intestinal tissue.
The effect of sodium rhein on contractile activity and fluid flow in the rat complete large intestine was
studied by Rumsey et al. (1993) in vitro. Contractile activity was recorded using serosal strain gauges
and volume transducers recorded distal fluid flow from the segment. Luminal sodium rhein (1 mM)
produced a protracted increase in caecal activity yet increased colonic contractility transiently. Fluid
flow from the preparation was increased and the number of propagated complexes was elevated after
the initial 10 min of exposure. The effect did not appear to be related directly to dose. Sodium rhein
(0.1 mM) did not significantly stimulate contractility and a higher dose (5 mM) only produced a
transient effect on propagated contractions. However, this dose had the effect of significantly reducing
activity when the rhein was replaced by normal buffer. The data suggest that the action of sodium
rhein is subtle; after an initial excitation, the glycoside shifts the pattern of motor activity in favour of
propulsion at the expense of segmentation. The large intestine is more able, therefore, to expel
luminal contents in a caudal direction following the addition of this anthraquinone laxative.
The quantity of the laxative effect is dependent on the orocaecal transit time and colonic metabolism of
sennosides (Frexinos et al., 1989), the dosage of sennosides, the amount and period of accompanying
fluid intake (Fioramonti et al., 1988, Okawa et al., 1990).
Rhein anthrone (12.48 mg/kg) produces watery and mucoid diarrhoea approximately 20 min after
intracaecal administration to rats. Pretreatment with the prostaglandin (PG) biosynthesis inhibitor
indomethacin (10 mg/kg, i.p.) only delayed and did not completely block the onset of the induced
diarrhoea. Rhein anthrone stimulated PGE2 release into the rat colonic lumen and the increased
release was depressed by indomethacin. Rhein anthrone also accelerated large intestinal transit and
EMA/HMPC/228759/2016 Page 24/133
this acceleration could be partly inhibited by indomethacin, which was probably responsible for the
delay in the onset of diarrhoea. Indomethacin prevented the enhanced water, K+ and mucus secretion
and the reduced Na+ absorption in the colon which were induced by rhein anthrone. The net water
secretion could not be reversed to net absorption and the mucus secretion was only slightly depressed
by indomethacin. Thus, the authors suggested that other mechanisms, together with the PG-
dependent mechanism, are involved in the purgative action of rhein anthrone in rats (Yagi et al.,
1991).
The involvement of Ca2+ in the mechanism of the purgative action of rhein anthrone in rats was
studied by Yamauchi et al., (1993). Among individual or combination pretreatments with calcium
channel blockers, calmodulin antagonists and prostaglandin biosynthesis inhibitors, the combination of
indomethacin and nifedipine completely blocked the diarrhoea induced by rhein anthrone and also
inhibited its effects on colonic fluid and electrolyte transport, and large intestinal motility. Calmodulin
antagonists were less active regarding suppression of the effects of rhein anthrone. The authors
concluded that, in addition to prostaglandins, diarrhoea induced by rhein anthrone must also involve
the calcium channel which can be blocked by nifedipine, but not verapamil.
After gastric administration of daily 100 mg sennosides/kg body weight, no morphological differences
could be found between the colon of treated rats and the controls by Rudolph and Mengs (1988). In
particular, no damage to the intramural nerve tissue could be seen under the electron microscope.
Ishii et al., (1994) measured the charcoal transport, as an indicator of the degree of peristalsis, and
water content in the large intestine after intracaecal administration of barbaloin simultaneously in the
same rat. Charcoal transport was significantly accelerated at both 3.5 and 6.5 hours after the
administration of barbaloin. At 6.5 hours, diarrhoea instead of normal faeces was observed. Moreover,
at 1 h before the acceleration of charcoal transport, a marked increase in water content of the large
intestine was observed. It appeared that the increase in water content of the large intestine induced by
barbaloin preceded the stimulation of peristalsis, attended by diarrhoea. The authors therefore
suggested that the increase in water content is a more important factor than the stimulation of
peristalsis in the diarrhoea induced by barbaloin.
Table 4: Overview of the main non-clinical data/conclusions
Herbal preparation Posology Experiment Reference Main non-clinical

tested al model conclusions
Hydroxyanthracene derivatives
Aloe emodin-9- 10-3 M, 2 ml In vivo/ Ishii et al. Increase in water

anthrone In vitro (1990) content of the rat
large intestine
Barbaloin, aloe- 10-3 M, 2 ml
produced by aloe
emodin and
10-3 M, 2 ml emodin-9-anthrone
sennoside A
was due to both
10-3 M, 2 ml
inhibition of
absorption and
stimulation of
secretion without
stimulation of
peristalsis
Rhein and rhein 3 mM In vivo van No laxative effect
EMA/HMPC/228759/2016 Page 25/133
anthrone 15-20 mg kg-1 germ-free Hoestenberg

Fisher rats he et al.
Intracaecal
(1992)
application
15 anthraquinones No information In vitro Hoenig et al. Strongest

and 8 corresponding (1992) inhibition of the Cl-
anthrones channels’ activity
was caused by aloe
emodin-anthrone
and aloe emodin
15 anthraquinones No information In vitro Rauwald et Strongest

and 8 corresponding al. (1992) inhibition of the Cl-
anthrones hannels’ activity
was caused by aloe
emodin-anthrone
and aloe emodin
Barbaloin 31.1 mg/10ml kg-1 In vivo Ishii et al. The increase in

(1994) water content is a
more important
factor than the
stimulation of
peristalsis in the
diarrhoea induced
by barbaloin
Na-rhein 1 mM (0.1-5 mM) In vitro Rumsey et Produced a

al. (1993) protracted increase
in caecal activity
yet increased
colonic contractility
transiently; expels
luminal contents in
a caudal direction
Rhein anthrone (12.48 mg/kg) In vivo Yagi et al. Indomethacin

(1991) prevented the
Intracaecal
enhanced water,
application
K+ and mucus
secretion and the
reduced Na+
absorption in the
colon which were
induced by rhein
anthrone. The net
water secretion
EMA/HMPC/228759/2016 Page 26/133
could not be
reversed to net
absorption and the
mucus secretion
was only slightly
depressed by
indomethacin
Rhein anthrone Rhein anthrone In In vivo Yamauchi et Among individual

2% sodium al. (1993) or combination
bicarbonate solution pretreatments with
calcium channel
12.48 mg/kg i.c.
blockers,
Indomethacin 10 calmodulin
mg/kg i.p. antagonists and
prostaglandin
Trifluoperazine
biosynthesis
10mg/kg oral
inhibitors, the
W-7 10 mg/kg oral combination of
indomethacin and
Dilthiazem 30mg/kg
nifedipine
i.p.
completely blocked
Nicardipine 15mg/kg the diarrhoea
i.p. induced by rhein
anthrone and also
Nifedipine 20mg/kg
inhibited its effects
i.p.
on colonic fluid and
Verapamil 20 mg/kg electrolyte
i.p. transport, and
large intestinal
motility
3.1.2. Secondary pharmacodynamics
In a study on protective effects senna leaves were extracted with five different solvents. (Lin et al.
2014). The five extracts were evaluated for the protective effects against •OH- induced DNA damage,
antioxidant abilities in vitro, and chemical contents using various methods. On this basis, the
correlation graphs between the pharmacological effects and chemical contents were plotted to obtain
the correlation coefficients (R values). Finally, in order to obtain biological evidence, ethyl acetate
extract of folium sennae was investigated for the protective effect against oxygen radical induced
mesenchymal stem cells damage using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl) assay. The
pharmacological assays indicated that five folium sennae extracts could effectively protect against
oxygen radical induced DNA damage. The correlation analysis suggested that the average R values of
total phenolics, total anthraquinones, aloe emodin, rhein, and emodin were respectively 0.843, 0.833,
EMA/HMPC/228759/2016 Page 27/133
0.753, 0.820, and 0.784, while those of total sugars and total saponins were respectively 0.103 and
0.0068. The mechanistic analysis revealed that five folium sennae extracts could also scavenge free
radicals, and reduce Cu2+ to Cu+. The MTT assay revealed that the viability of mesenchymal stem cells
which were treated with oxygen radicals, has been effectively protected by ethyl acetate extract of
folium sennae (3 and 30 μg/ml). On this basis, the authors concluded that: (i) Folium sennae exhibits
a protective effect against oxygen radicals induced damages to DNA and mesenchymal stem cells; (ii )
The effects may be attributed to phytophenols (especially aloe emodin, rhein, and emodin), not sugars
or saponins; (iii) They exert the protective action via hydrogen atom transfer and/or sequential
electron proton transfer mechanisms which make phenolic –OH moiety be oxidized to stable
semiquinone form; (iv) The stability of the semiquinone form may ultimately be responsible for the
protective or antioxidant effect of phytophenols.
Data on hydroxyanthracene derivatives
Rhein (4,5-dihydroxyanthraquinone-2-carboxylic acid), the primary anthraquinone in the roots of

Cassia alata L., is a naturally occurring quinone which exhibits a variety of biologic activities including
anti-proliferative activity. However, the effect of rhein on endothelial or cancer cells under hypoxic
conditions has never been delineated. Therefore, the aim a study by Fernand et al. (2011) was to
investigate whether rhein inhibits angiogenesis and the viability of hormone-dependent (MCF-7) or -
independent (MDA-MB-435s) breast cancer cells in vitro under normoxic or hypoxic conditions. Rhein
inhibited vascular endothelial growth factor-stimulated human umbilical vein endothelial cell tube
formation, proliferation and migration under normoxic and hypoxic conditions. In addition, rhein
inhibited in vitro angiogenesis by suppressing the activation of phosphatidylinositol 3-kinase,
phosphorylated-AKT (p-AKT) and phosphorylated extracellular signal-regulated kinase (p-ERK) but
showed no inhibitory effects on total AKT or ERK. Rhein dose-dependently inhibited the viability of
MCF-7 and MDA-MB-435s breast cancer cells under normoxic or hypoxic conditions, and inhibited cell
cycle in both cell lines. Furthermore, Western blotting demonstrated that rhein inhibited heat shock
protein 90alpha (Hsp90α) activity to induce degradation of Hsp90 client proteins including nuclear
factor-kappa B (NF-κB), cyclooxygenase 2, and human epdiermal growth factor receptor 2. Rhein also
inhibited the expression of hypoxia-inducible factor-1 alpha, vascular endothelial growth factor,
epidermal growth factor, and the phosphorylation of inhibitor of NF-κB (I-κB) under normoxic or
hypoxic conditions. Therefore, further studies including in vivo and pre-clinical experiments concerning
rhein as a promising anti-angiogenic compound for breast cancer cell viability and growth need to be
performed (Fernand et al., 2011).
3.1.3. Safety pharmacology
In theory, it is possible that reflex stimulation might occur, involving not only the colon but also uterine
muscles and then might lead to the development of hyperaemia in the pelvic region and to miscarriage
as a result of neuromuscular stimulation of uterine muscles (Blaschek et al., 2003).
Data on studies with the herbal substance
The toxic effects of diet containing 10% of C. senna fruits or 10% of N. oleander leaves or their 1:1
mixture (5%+5%) on male Wistar rats, treated for 6 weeks, were investigated. Diarrhea was a
prominent sign of C. senna toxicosis. In both groups (C. senna fruits vs. N. oleander leaves), there
were decreases in body weight gains, inefficiency of feed utilization, dullness and
enterohepatonephropathy. These findings accompanied by leukopenia and anemia were correlated with
alterations of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline
phosphatase (ALP) activities and concentrations of total protein, albumin, urea and other serum
EMA/HMPC/228759/2016 Page 28/133
constituents. In both phytotoxicities, the ability of the liver to excrete bilirubin remained unchanged
(Al-Yahya et al., 2002).
Data on studies with hydroxyanthracene derivatives
Rats were treated with sennosides (6x10, 6x40 or 2x30 mg/kg weekly) or with danthron (6x500 mg/kg
weekly) for 6 months. The laxative effect as measured by faecal wet weight during the first 10 hours
after treatment increased 3- to 4-fold by the higher sennoside doses (daily or intermittently) and 1- to
3-fold by danthron. The low sennoside dose had no measurable effect except on the 1st day (2 fold)
compared with the control group. Mean faecal water content increased from 53% (controls) to 66-79%
in rats treated with high sennoside doses and to 57 (1st day) -69% in danthron-treated rats. Serum
aldosterone levels and mucosal Na(+) -K(+) -ATPase activities in the small intestine and colon did not
change with treatment. There were no signs of habituation or secondary hyperaldosteronism due to
sennosides or danthron in spite of chronic diarrhoea over 6 months (Leng-Peschlow et al., 1993).
3.1.4. Pharmacodynamic interactions
For interactions see section 5.5.4.
3.1.5. Conclusions
In vitro data show a dose dependent absortion and secretion of dianthrones and their aglycones
(Waltenberger et al., 2008). Increase in water content of the rat large intestine produced by aloe
emodin-9-anthrone was due to both inhibition of absorption and stimulation of secretion without
stimulation of peristalsis (Ishii et al., 1990). In germ-free Fisher rats rhein and rheinanthrone induced
no laxative effect (van Hoestenberghe et al., 1992). The strongest inhibition of the Cl-channels’ activity
was caused by aloe emodin-anthrone and aloe emodin (Hoenig et al., 1992). Na-rhein induced a
transient increase of peristalsis (Rumsey et al., 1993). Among individual or combination pretreatments
with calcium channel blockers, calmodulin antagonists and prostaglandin biosynthesis inhibitors, the
combination of indomethacin and nifedipine completely blocked the diarrhoea induced by rhein
anthrone and also inhibited its effects on colonic fluid and electrolyte transport, and large intestinal
motility (Yamauchi et al., 1993). These data on hydroxyanthracenes support the efficacy of the
standardised senna extracts of the monograph under well established use.
Rhein-9-anthrone is the most important metabolite, which is produced by the bacteria of the large
intestine. The mode of action is based on two mechanisms. Firstly, colonic motility is increased leading
to a reduced transit time and reduced fluid absorption. Secondly, an influence on secretion processes
by two concomitant mechanisms, namely 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), results in enhanced concentrations of fluid and electrolytes in the lumen of the
colon.
These findings are based on investigations with different anthrones including also other anthranoid-
containing herbal substances, but the results of these investigations are not always consistent.
3.2. Overview of available pharmacokinetic data regarding the herbal

substance(s), herbal preparation(s) and relevant constituents thereof
Data on herbal preparations from animal studies
EMA/HMPC/228759/2016 Page 29/133
The kinetics of anthraquinones were investigated following oral administration of senna-containing
products to rats (Mengs et al., 2004; Mitchell et al., 2006). Concentrations of rhein and aloe emodin
were determined in the blood of rats at various time points on days 90 and 91 of a 13-week gavage
study (100 to 1,500 mg/kg) of powdered Tinnevelly senna fruit (Mengs et al., 2004). The
concentrations in plasma were proportional to dose from 100 to 750 mg/kg, and were generally higher
in females than in males. Chrysophanol was detected in some plasma samples. Blood was sampled at
6, 12, and 24 months in a 2-year oral carcinogenicity study in rats receiving powdered Tinnevelly
senna fruit (25 to 300 mg/kg) (Mitchell et al., 2006). In the study, emodin and chrysophanol were
generally not detected and aloe emodin was only detected in the plasma of the high-dose group.
Concentrations of rhein were higher in females at 6 and 12 months, but were similar to males at 24
months. In a radiolabeled study of aloe emodin in gavaged rats, the 14C was absorbed, distributed to
all assayed tissues, and 30% of the total dose was excreted in urine as rhein, an unidentified
metabolite, and their conjugates (Lang, 1993). The remainder of the dose was excreted in faeces. The
biotransformation of emodin and chrysophanol were investigated in induced liver microsomes from
male and female rats (Mueller et al., 1998). Emodin was metabolized to omega-hydroxyemodin and 2-
hydroxyemodin; whereas chrysophanol was metabolized to emodin (NTP, 2012).
Data on hydroxyanthracenes from animal studies
The glycosidic sennosides are not absorbed. They are hydrophilic and do not pass the gastrointestinal
tract membranes (Westendorf, 1993). Neither the gastric acid nor the α-glycosidase of the small
intestine is able to hydrolyse the β-O-glycosidic linkages of the sennosides. Only the β-glycosidase of
the bacteria of the large intestine is able to hydrolyse them to sennidins. These sennidins are further
cleaved to the active metabolite (rhein anthrone) by the bacteria (Blaschek et al., 2003). Aglycones
are absorbed in the upper gut.
Until now it is unclear how much of the rhein anthrone is absorbed. The absorbed rhein anthrone is
glucuronidised in the liver. One part of the glucuronides is excreted via the urine and cause the yellow
or redbrown discolouration of the urine. The other part is excreted via the bile (Lemli et al., 1980).
Animal experiments with radio-labeled rhein anthrone administered directly into the caecum of rats
demonstrated absorption <10% (De Witte and Lemli, 1988).
Excretion of sennosides and their known metabolites is mainly by faeces. According to different
analysing methods, sennosides are recovered from faeces at up to 92.8% in unbound or bound
polymerised forms (Hietala et al., 1988). In experimental animal studies, nearly 6% of the amount of
the oral administered anthranoids could be found unchanged in the urine and faeces (Lemli and
Lemmens, 1980, Lemli, 1988).
The in vitro microbial degradation and the urinary excretion and biliary secretion in rats of two
anthraquinone glycosides (sennosides A and B) and four aglycones (sennidins A and B, rhein, and
danthron) were studied using a high performance liquid chromatographic system with gradient elution
and amperometric detection. Microbial degradation of sennosides A and B occurred almost exclusively
in the presence of mice caecum inoculae and was associated with the release of sennidins A and B.
Rhein and danthron were indiscriminately metabolized by bacteria sampled from all regions of mice
intestine, whereas sennidins lacked stability in biological media. The fraction of the dose administered
orally to rats and recovered as aglycones or as glucuronides in bile and urine after 48 hours was five
times higher for rhein (15%) and danthron (13.4%) than for sennosides A (1.8%) and B (2.8%)
excreted or secreted as sennidins (Moreau et al., 1985).
The pharmacological activity of senna is associated with sennosides A and B, the most abundant
anthranoids and the precursors of the active metabolite, rhein anthrone (also known as rhein-9-
EMA/HMPC/228759/2016 Page 30/133
anthrone) (Breimer and Baars, 1976; Sasaki et al., 1979; Lemli and Lemmens 1980, Hietala et al.,
1988; de Witte, 1993; Franz, 1993). The in vivo fate of the sennosides and the other senna
anthranoids are described as follows. Sennosides are not readily absorbed from the mammalian gut;
therefore, the activity depends on formation of rhein anthrone following deconjugation and reduction
by microflora in the large intestine (Breimer and Baars 1976; Sasaki et al., 1979; Lemli and Lemmens
1980. Moreover, Lemli and Lemmens (1980) postulated that rhein anthrone arises through formation
of a free radical following reduction of sennidin in the gastrointestinal tract. The systemic bioavailability
of rhein anthrone is low, putatively due to limited absorption associated with binding to gut contents
and rapid oxidation to rhein and sennidin once it is absorbed (Lemli and Lemmens 1980; Grimminger
and Leng-Peschlow 1988; de Witte, 1993). It was shown by Lemli and Lemmens (1980) that recovered
less than 4% of an oral dose. Small amounts of free anthraquinones and their glycosides are present in
senna (Franz, 1993; Newall et al., 1996), including rhein. Absorption of rhein from the rat gut appears
to be higher than absorption of rhein anthrone (de Witte and Lemli 1988). The cumulative urinary
14C-labeled
excretion of a single dose of rhein or 14C-labeled rhein anthrone over 5 days was 37.1%
and 2.8%, respectively. Rhein was primarily excreted as glucuronide and/or sulfate conjugates. Most of
the rhein anthrone-derived 14C excreted in urine was recovered as rhein following oxidative hydrolysis
and extraction of the urine. In a separate study, rhein-derived 14C was highest in the tissues of the
gastrointestinal tract in gavaged rats (Lang 1993). Other tissues contained low levels of radioactivity 7
days following dosing, probably due to protein binding in the blood. The total absorbed dose was
estimated to be 50% and was excreted in urine, primarily as conjugates. In a study conducted by
Dahms et al. (1997), specific metabolites, mostly glucuronide and sulfate conjugates, were identified in
other at 10 to 11 hours. The authors postulated that the first peak arose from the presence of free or
glycosylated rhein in the products and the second peak represented rhein derived from sennosides. In
addition to work in animals, Dahms et al. (1997) investigated the metabolism of rhein in human
volunteers receiving an oral dose of 14C-labeled diacetylrhein. Diacetylrhein was converted to rhein by
gut microflora. Some rhein-derived glucuronide and sulfate conjugates excreted in the urine of humans
were common to the urine of rats, rabbits, and dogs receiving oral doses of 14C rhein. However,
potentially reactive metabolites (i.e., quinoids and diglucuronides) observed in some animals were not
present in human urine, and the radioactivity in human serum was highly extractable over time
indicating little potential for protein binding (NTP 2012).
Intracaecal administration of an equimolar mixture of aloe emodin anthrone and rhein anthrone
produced a synergistic laxative effect in female albino mice (Yagi et al., 1991). A laxative effect is
driven by increasing peristalsis and reduced absorption of water and electrolytes (Leng-Peschlow,
1993). In female Wistar rats, oral administration of 50 mg/kg sennosides reduced large intestinal
transit time. Intracecal administration of equimolar doses of sennosides A+B, sennidins A+B, and
rhein-9-anthrone produced similar responses in reduced large intestine transit time and increased soft
faeces (Leng-Peschlow et al. 1993). Application of rhein anthrone on mucosa of isolated guinea pig
ileum dose-dependently increased parameters of peristaltic reflex (longitudinal muscle tension,
intraluminal pressure, and volume displacement) (Nijs et al., 1993). In isolated large intestine from
male Wistar rats, application of rhein (1 mM) in the lumen increased contractility in the colon, the
number of migrating contractions, and fluid flow (Rumsey et al., 1993) (NTP, 2012).
Oral administration of sennosides in rats in vivo, as well as application of rhein on the mucosal side of
isolated rat colon in vitro, decreased absorption of water and sodium; enhanced secretion of water,
sodium, and potassium; and reduced Na+, K+-ATPase activity (Leng-Peschlow et al., 1993). In
addition, in humans, perfusion with rhein reversed absorption of water and sodium into secretion in the
jejunum and colon, increased chloride secretion in the jejunum, reduced chloride absorption in the
colon, and enhanced potassium secretion in the jejunum and colon (Ewe, 1993) (NTP, 2012).
EMA/HMPC/228759/2016 Page 31/133
Detailed information concerning the metabolism and pharmacokinetic characteristics of anthranoid
derivatives had been available only in a few cases. After oral administration, sennoside is degraded
only in the lower parts of the gastrointestinal tract, releasing its active metabolite rhein anthrone.
Nowadays, this process is understood at the molecular level. A study with 14C-labelled rhein anthrone
administered intracecally to rats, revealed that the compound is scarcely absorbed. Since on the
contrary its anthraquinone equivalent is absorbed to a much larger extent, it is inferred that
dianthrone- or anthrone-glycosides exhibit a lower systemic availability than anthraquinone O-
glycosides (de Witte 1993).
Because of previously observed species differences in rhein tolerability, with rabbits being very
susceptible to kidney disturbances, in vivo and in vitro biotransformation studies were performed to
find out whether the differences in the undesired effects of rhein are associated with qualitative,
species-dependent differences in its metabolism. First hints on species-dependent biotransformation
profiles were obtained from in vivo experiments with 14C-labeled rhein in rat, rabbit, dog, and man.
TLC-analysis of urine samples obtained after oral administration of 14C-rhein to rabbits revealed an
additional, hydrophilic metabolite fraction in rabbit urine as compared with dog and human urine, all of
which contain phenolic monoglucuronide and monosulfate as major metabolites. An investigation of
urine samples (obtained from dogs, rabbits, rats, and human volunteers after oral application of
unlabeled rhein) was conducted by means of mass spectrometric tandem techniques including on-line
HPLC-MS/MS. In vitro experiments with subcellular liver fractions of rats and rabbits revealed the
presence of three monohydroxylated metabolites of rhein, their quinoid oxidation products, and a
bishydroxylated derivative of rhein. The hydroxylated phase I metabolites were detected as glucuro-
nides in urine samples of all investigated species, whereas the quinoid product was present only in
rabbit urine. Moreover, two regioisomeric phenolic glucuronides and sulfates or glucosides of rhein
were found as major phase II metabolites in urine of all species. Furthermore, acyl glucuronides of
rhein and monohydroxylated rhein and their respective isomeric acyl migration products were
identified in human urine. In rabbit urine different bisglucuronides (bisphenolic glucuronide, mixed
ether/ ester glucuronides) were identified, whereas in rats only the bisether/ether glucuronide was
present. In addition, the investigations of dog and human urine showed the formation of two
regioisomeric phenolic glucosides. With respect to a potential reactivity with endogenous
macromolecules the quinoid metabolites as well as the bisester/ether glucuronides appear most
relevant (Dahms et al., 1997).
In experiments with rats, chrysophanol showed a cytochrome P450-dependent conversion to aloe

emodin. In turn, aloe emodin can be metabolized to rhein in the liver (Mueller et al., 1998; Lang,
1993).
Animal experiments demonstrated that placental passage of rhein in rats was small. Senna leaves act
within 8 to 12 hours due to the time taken for transport to the colon and metabolisation into the active
compound.
In order to measure the serum concentrations of senna anthranoids (sennosides, aloe emodin, and
rhein), Sprague-Dawley rats were orally administered with single dose and multiple doses of Folium
Sennae. The concentrations of anthranoids in serum were determined by HPLC method before and
after hydrolysis with sulfatase and β-glucuronidase. The results showed that in the serum, aloe emodin
glucuronides and rhein glucuronides were the major metabolites. Traces of rhein free form were
present transiently during the early phase, whereas the free form of aloe emodin was not detected.
The modulation effect of Folium Sennae on P-glycoprotein by using the LS 180 cell model which
showed that it significantly inhibited P-glycoprotein by 16-46% was also evaluated. Peng et al.
concluded that senna anthranoids were rapidly and extensively metabolized to rhein glucuronides and
EMA/HMPC/228759/2016 Page 32/133
aloe emodin glucuronides in rats. Folium Sennae ingestion inhibited the efflux function of P-
glycoprotein in the intestine (Peng et al., 2014).
Data on herbal preparations from human studies
Faber et al. (1988) investigated the excretion of rhein in 100 breast milk samples of 20 post-partum
women after intake of a “standardised senna laxative”, which also contains Plantago ovata seeds/husks
as bulk substances. After daily doses of 5 g of the senna laxative containing 15 mg sennosides for 3
days, the rhein concentration in milk samples from every lactation during 24 hours post-dose varied
between 0 and 27 ng/ml with values below 10 ng/ml in 94%. Based on median values, 0.007% of the
sennoside intake (calculated as rhein) was excreted in breast milk. None of the breast-fed infants had
an abnormal stool consistency. Assuming theoretically a complete metabolism of sennosides to rhein in
the mother, the amount of rhein delivered to the infant (ng/kg b.w.) is by the factor 10-3 below the
rhein intake of the mother.
Data on hydroxyanthracenes from in vitro studies
Laxative effects of senna preparations are mainly mediated by rheinanthrone, a metabolite formed in
the intestinal flora from dianthrones. Nevertheless, it was not clear whether dianthrones are
bioavailable at all and contribute to the overall effects of this important medicinal plant. Using the
Caco-2 human colonic cell line as an in vitro model of the human intestinal mucosal barrier, the
bioavailability of dianthrones was studied by Waltenberger et al. (2008) in apical to basolateral
(absorptive) and basolateral to apical (secretive) direction. Permeability coefficients (P(c)) and %
transport were calculated based on quantitations by HPLC. From the data obtained it was concluded
that sennosides A and B, as well as their aglycones sennidine A and B are transported through the
Caco-2 monolayers in a concentration-dependent manner and their transport was linear with time. The
absorption in apical to basolateral direction was poor and P(c) values were comparable to mannitol.
The transport was higher in the secretory direction, indicating a significant efflux (e.g. by efflux
pumps) of the (poorly) absorbed compounds in the intestinal lumen again. The laxative effects of
senna are explainable mainly by metabolites and not by the natively present dianthrones.
3.3. Overview of available toxicological data regarding the herbal

substance(s)/herbal preparation(s) and constituents thereof
3.3.1. Single dose toxicity
In mice, the estimated LD50 of senna extracts (calcium sennosides A+B, 20%) administered by gavage
was higher than 2.5 g/kg (Marvola et al., 1981) For sennosides administered by gavage the estimated
LD50 was higher than 5 g/kg for mice and was also higher than 3.5g/kg for rats (Marvola et al., 1981;
Mengs, 1988).
Hietala et al. investigated 1987 the laxative effect and acute toxicity of certain fractions of senna
extracts in mice. The same tests were also carried out with several pure anthraquinone derivatives
common in senna pods. The results showed that the laxative and toxic components of senna pods and
senna extracts can be separated. The most potent laxative components, sennosides A+B and fraction
V (relative potencies 1 and 0.9 respectively), have the lowest toxicity (relative intravenous toxicities 1
and less than 1). Fractions with very low laxative activity (rhein-8-glucoside and fraction IV, relative
potencies 0.56 and 0.05) have the highest acute toxicity (relative toxicities 10 and 32 respectively).
EMA/HMPC/228759/2016 Page 33/133
3.3.2. Repeat dose toxicity
Data on the herbal substance
Male Wistar rats fed a diet containing 10% senna (pods, powdered) for 3 or 6 weeks exhibited
diarrhea, decreased food intake, and decreased body weight gain compared to controls. The result
showed an increased serum index of liver toxicity (alanine aminotransferase and aspartate
aminotransferase) and increased urea in serum along with slight degenerative changes in the liver,
kidney, and intestines but decreased calcium levels in serum and decreased white blood cell counts
compared to controls (Al-Yahya et al., 2002).
Oral administration of senna (750 mg/kg or higher; powdered Tinnevelly senna pods diluted with 0.1%
carboxymethylcellulose) to Sprague-Dawley rats for 13 weeks increased soft faeces and water
consumption in males and females and reduced body weight gain in males (Mengs et al. 2004).
Administration of up to 1500 mg/kg senna for 13 weeks decreased sodium in urine and increased
kidney weights in 1500 mg/kg male and 750 and 1500 mg/kg female Sprague-Dawley rats compared
to controls (Mengs et al., 2004). Minimal to slight hyperplastic changes in the mucosa of the large
intestine in rats receiving more than 100 mg/kg of senna and minimal to slight hyperplastic epithelium
of the forestomach in rats receiving 1500 mg/kg were observed. These hyperplastic changes were
reversible. Hyperplastic changes were not observed in animals 8 weeks after the 13 weeks of senna
administration ended.
Groups of five male and five female mice (C57BL/6NTAC mice) were exposed to 0, 625, 1250, 2500,
5000, or 10000 ppm senna (equivalent to average daily doses of approximately 115, 245, 490, 975, or
2075 mg senna/kg body weight to males and 160, 310, 625, 1190, or 2570 mg/kg to females) in feed
for 5 weeks. All mice survived to the end of the study. Mean body weights of exposed groups were
similar to those of the controls. No differences in feed consumption were noted between exposed and
control groups. Significantly increased incidences of epithelial hyperplasia of the cecum occurred in
males exposed to 10000 ppm and females exposed to 5000 or 10000 ppm; significantly increased
incidences of epi-thelial hyperplasia of the colon occurred in males and females exposed to 5000 or
10000 ppm (NTP, 2012).
Groups of 25 male and 25 female mice (heterozygous F1 P53+/− mice) were exposed to 0, 100, 300,
1000, 3000, or 10000 ppm senna (equivalent to average daily doses of approximately 12, 36, 120,
365, or 1260 mg/kg to males and 14, 42, 140, 435, or 1520 mg/kg to females) in feed for 40 weeks.
Mean body weights of exposed male and female mice were within 10% of those of the controls
throughout the study. Feed consumption by exposed mice was generally similar to that by the controls.
Significant increases in the incidences of epithelial hyperplasia of the colon and cecum occurred in
10000 ppm males and females, and the incidence of epithelial hyperplasia of the colon was
significantly increased in 3000 ppm females (NTP, 2012).
Several studies in the literature have examined the relationship between the use of senna and damage
in the enteric nervous system of the colon. For example, a study by Smith observed 1968 damage to
intestinal nerves of mice given senna syrup. However, other rodent studies failed to show damage in
the enteric nervous system of the colon after ingestion of senna or sennosides (Dufour and Gendre,
1984; Rudolph and Mengs, 1988; Mengs et al., 2004; Mitchell et al., 2006; NTP, 2012).
Data on other Senna species
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Silva et al. (2011) performed a pre-clinical safety evaluation of hydroalcoholic extract of Cassia
occidentalis stem and leaf in male and female Wistar rats. In acute toxicity tests, four groups of rats
(n=5/group/sex) were orally treated with doses of 0.625, 1.25, 2.5 and 5.0 g/kg and general behavior,
adverse effects and mortality were recorded for up to 14 days. In subacute toxicity assays, animals
received Cassia occidentalis by gavage at the doses of 0.10, 0.50 or 2.5 g/kg per day
(n=10/group/sex) for 30 days and biochemical, hematological and morphological parameters were
determined. Cassia occidentalis did not produce any hazardous symptoms or death in the acute toxicity
test, showing a LD50 higher than 5 g/kg. Subacute treatment with Cassia occidentalis failed to change
body weight gain, food and water consumption and hematological and biochemical profiles. In addition,
no changes in macroscopical and microscopical aspect of organs were observed in the animals. The
results showed that acute or subacute administration of Cassia occidentalis is not toxic in male and
female Wistar rats, suggesting a safe use by humans.
In male and female Wistar rats, administration of 25 mg/kg sennosides produced a laxative effect and
administration of 100 mg/kg for 6 months induced diarrhea and decreased body weight gain by
approximately 50% compared to controls. Single administration of sennosides (2 to 7.5 g/kg) to male
and female Wistar rats produced diarrhea, sedation, hunched posture, piloerection, and death (Mengs,
1988).
Male Sprague-Dawley rats fed a diet containing 0.2% sennosides for 56 days had diarrhea, reduced
body weight gain, and decreased survival compared to controls (Mereto et al., 1996). In NMRI mice,
oral administration of 9.35 mg/kg of sennosides induced a laxative effect and 2.5 g/kg of sennosides
induced diarrhea (Dufour and Gendre 1984; Mengs 1988). A mild laxative effect was induced in male
NMRI mice fed a diet containing 0.03% sennosides (86% sennosides) for 20 weeks (Siegers et al.,
1993a). Mild kidney effects of sennosides have been observed.
In male and female Wistar rats treated with 2 to 20 mg/kg sennosides for 4 weeks, no changes in
hematological, biochemical, or urinary parameters were observed (Mengs, 1988). However, in 20
mg/kg rats, mean kidney weights were higher than that of the control group and small sudanophilic
globules within the convoluted tubules of the kidney were observed. In male Wistar rats administered
25 or 100 mg/kg sennosides for 6 months, no hematological or urinary changes were observed, but
increased kidney weights as well as dose-related basophilia of convoluted renal tubules were observed.
In male F344 rats fed sennoside A (0.006% to 0.05%) for 7 days, cell proliferation in the colorectum
was increased and inflammatory changes in the large intestine were observed (Toyoda et al., 1994).
However, in female Wistar rats, administration of 30 mg/kg sennosides for 12 weeks did not affect cell
proliferation in the large intestine (Geboes et al., 1993). Administration of 50 mg/kg sennosides did
not affect lactic acid dehydrogenase release into the colon lumen of female Wistar rats (Leng-Peschlow
1993). In male Wistar rats, administration of sennosides (10 or 40 mg/kg) for 23 weeks did not affect
the duration or frequency of the long-spike burst in the large intestine (Fioramonti et al., 1993; NTP,
2012).
Emodin
In 2001 the National Toxicology Program (NTP) of the U.S. Department of Health and Human Services
published a technical report on toxicology and carcinogenesis studies of emodin:
16-day study in F344/N rats
Groups of 5 male and 5 female rats were fed diets containing 0, 600, 2000, 5500, 17000, or 50000
ppm emodin. This corresponds in males to average daily doses of approximately 50, 170, 480, 1400,
EMA/HMPC/228759/2016 Page 35/133
or 3700 mg emodin/kg bw and in females to 50, 160, 460, 1250, or 2000 mg/kg bw. Three female rats
died before the end of the study. Mean body weights of males and females exposed to 5500 ppm or
higher were significantly less than those of the controls. Feed consumption by males and females
receiving 17000 or 50000 ppm was decreased throughout the study. Macroscopic lesions were present
in the kidney of rats exposed to 17000 or 50000 ppm (NTP, 2001).
16-day study in B6C3F1 mice
The size of the groups and the administered concentrations were the same as described above. The
concentrations correspond in males to average daily doses of approximately 120, 400, 1200 or 3800
mg/kg bw and in females to 140, 530, 1600 or 5000 mg/kg bw. 50000 ppm equivalents were not
calculated due to high mortality. All mice exposed to 50000 ppm died before the end of the study. Mice
in the 17000 ppm groups lost weight during the study. Feed consumption by 5500 ppm females was
higher than that by the controls. Macroscopic lesions were present in the gallbladder and kidney of
mice exposed to 17000 ppm (NTP, 2001).
14-week study in rats
Groups of 10 male and 10 female rats were fed diets with 0, 312.5, 625, 1250, 2500 or 5000 ppm
emodin. This corresponds to average daily doses of approximately 20, 40, 80, 170, or 300 mg/kg bw
in males and females. Among others, relative kidney weights of rats exposed to 1250 ppm or higher
and relative lung weights of rats exposed to 625 ppm or higher were significantly increased compared
to the control groups. Relative liver weights were increased in females exposed to 625 ppm or higher.
The estrous cycle length was significantly increased in females exposed to 1250 or 5000 ppm. All male
rats exposed to 1250 ppm or higher and all exposed female rats had pigment in the renal tubules; and
the severity of pigmentation generally increased with increasing exposure concentration. The
incidences of hyaline droplets in the cortical epithelial cytoplasm were increased in all groups of
exposed males and in females exposed to 312.5, 625, or 1250 ppm (NTP, 2001).
14-week study in mice
The size of the groups and the administered concentrations were the same as described above. This
corresponds to average daily doses of approximately 50, 100, 190, 400, or 800 mg/kg to males and
60, 130, 240, 500, or 1100 mg/kg to females. Relative kidney weights of male mice exposed to 1250
ppm or higher, relative lung weights of males exposed to 625 ppm or higher, and relative liver weights
of female mice exposed to 625 ppm or higher were increased. The incidences and severities of
nephropathy were increased in males and females exposed to 1,250 ppm or higher. The incidences of
renal tubule pigmentation were significantly increased in males exposed to 625 ppm or higher and in
females exposed to 1250 ppm or higher (NTP, 2001).
3.3.3. Genotoxicity
In a chromosome aberration assay in bone marrow cells of the rat, micronucleus test in rats, mouse
xpot test no cytotoxic, toxic, embryotoxic or genotoxic effect could be found (Kommission E
monograph of Sennae folium, 1993). Therefore use during pregnancy can not be recommended for
such a specified extract, because of the experimental data concerning a genotoxic risk of several
anthranoids.
Sandnes et al. (1992) investigated the mutagenicity of senna glycosides and extracts of Sennae folium
and Sennae fructus in the Salmonella typhimurium reversion assay. Senna glycosides were inactive in
all strains, except for a slight, but significant increase in mutant frequency in TA102 in the absence and
EMA/HMPC/228759/2016 Page 36/133
presence of liver microsomes. Extracts of Sennae fructus and sennae folium demonstrated weak
activity in TA97a, TA100 and TA102 in the presence of liver microsomes, and in TA97a and TA102 in
the absence of liver microsomes. A strong increase in mutant frequency (3- to 5-fold above
background frequency) was observed with all extracts in TA98 in the presence of liver microsomes.
This activity increased further following enzymatic hydrolysis with hesperidinase of extracts of Sennae
fructus from one source, and could be correlated to the release of the flavonol aglycones kaempferol
and quercetin.
Genotoxicity tests were performed by several laboratories with Sennae fructus, senna extract,
sennosides, rhein and aloe emodin. Sennae fructus, the sennosides and rhein did not increase
mutation frequencies in the following test systems: bacterial systems (Salmonella reverse mutation
test and/or Escherichia coli forward mutation test); mammalian cell cultures [hypoxanthine guanine
phosphoribosyl transferase (HGPRT) test; mouse lymphoma test; chromosome aberration test with
Chinese hamster ovary cells]; bone marrow (micronucleus test; chromosome aberration test);
melanoblast cells (mouse spot test) of rodents. With aloe emodin mutagenic effects were observed
only in vitro in the chromosome aberration test with CHO cells and in the Salmonella reverse mutation
test (frameshift mutations in strains TA 1537, TA 1538 and TA 98). In the in vitro gene mutation test
with V79 cells (HGPRT test) no mutagenic potential of aloe emodin was observed. In in vivo studies
(micronucleus test with bone marrow cells of NMRI mice, chromosome aberration test with bone
marrow cells of Wistar rats, mouse spot test (crossing DBA/2J x NMRI) no indication for a mutagenic
activity of aloe emodin was found. The relevance of the absence of a mutagenic potential in in vivo test
systems was strengthened by the fact that aloe emodin could be found in the blood serum after oral
administration. Additional information on the interaction of aloe emodin with DNA was obtained from
an ex vivo unscheduled DNA synthesis test performed with hepatocytes of male Wistar rats: aloe
emodin did not induce unscheduled DNA synthesis as expression of DNA damage (Heidemann et al.,
1993).
Four different samples of senna, including three samples of the same lot (0.7% sennoside A, 1.3%
sennoside B, 0.06% sennidin A, and 0.03% sennidin B) were tested for mutagenicity in bacterial test
systems. In two samples, no evidence of mutagenicity was seen in several strains of S. typhimurium
and E. coli, with or without exogenous metabolic activation. In the other two samples, mutagenic
activity was seen in S. typhimurium strains TA98 and TA100, with variable requirements for exogenous
metabolic activation. In vivo, no increases in the frequencies of micronucleated erythrocytes were seen
in male mice exposed for 40 weeks to senna via dosed feed. No significant changes in the percentage
of reticulocytes among erythrocytes were observed in male mice, suggesting that exposure to senna
did not induce bone marrow toxicity (NTP, 2012).
Toxicological data indicate that two hydroxyanthraquinones, emodin and aloe emodin, present as
minors component in senna, might represent a genotoxic or carcinogenic risk (Mori et al., 1990;
Siegers et al., 1992; Brusick and Mengs, 1997). While most studies gave negative responses, results
from some studies suggest a genotoxic activity by both (Wölfle et al., 1990; Westendorf et al., 1990;
Westendorf 1993). These were Ames tests showing an interaction with Salmonella DNA resulting in the
production of frameshift mutations (Westendorf et al., 1990; Sandnes et al., 1992; Heidemann et al.,
1993). Other sennosides and rhein were mostly negative in the respective tests. In three in vivo
studies the crude senna herbal substance at a concentration of 1 or 1.5 g/kg body weight showed no
evidence of any genetic effects (Heidemann et al., 1993). In vitro assays overestimate the potential
hazard from exposure and must be reevaluated by in vivo experiments.
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Westendorf et al. (1990) reported that in the Ames test aloe emodin was mutagenic in S. typhimurium
strain TA1537 and furthermore active against TA98, TA1538 and TA97 (all frameshift mutant sites).
The activity was independent of metabolic activations; in fact, the addition of the S9 mix tended to
suppress the mutagenicity.
In the Mammalian Cell Mutation Test, Westendorf et al. (1990) reported that aloe emodin was
mutagenic to V79 cells. However, other scientists question this conclusion. The highest concentration
employed was 30 µg/ml and did not show much, if any toxicity. This indicates the possibility of a
problem, since mutagenic effects in this assay are typically associated with toxicity. The apparent
positive response was based on a very low spontaneous mutant frequency. Numerous laboratories
have recognised that the spontaneous background for HGPRT-mutants (hypoxanthine-guanine
phosphoribosyl transferase) is quite variable and increase of at least 3-5 fold are required in duplicate
tests to confirm an effect.
In the in vitro unscheduled DNA synthesis (UDS) assay, also conducted by Westendorf et al. (1990),
aloe emodin was associated with a significant increase in net grains/nucleus. Two trials were reported.
The concentrations range in both covered 6.3 µg/ml to 100 µg/ml. At a concentration of 25 µg/ml, the
net grains/nucleus reached the criteria to call the response positive.
The three in vivo studies by Heidemann et al. (1993) which showed no evidence of any genetic effects,
were the Chromosome Aberration Test, the Mouse Spot Test, and the in vivo/in vitro UDS test in rat
hepatocytes:
Chromosome Aberration Test (Heidemann et al., 1993): Each of NMRI mice or Wistar rats,
conventionally housed, received aloe emodin orally via stomach tube. They were suspended in either
0.3–0.5% tragacanthe in aqua destillata or aqua destillata. The volume administered was 15 ml/kg.
2.5 hours prior to sacrifice the animals were injected intraperitoneally with the spindle inhibitor
colcemid (2 mg/kg) to arrest cells in metaphase. The preparation intervals were 6, 24 and 48 hours
after treatment. After flushing out of the bone marrow from the femora with hypotonic potassium
chloride solution the cells were fixed, spread by flame drying and stained with Giemsa solution. The
mitotic index from 1,000 cells was determined in each experimental group, and scoring of
chromosomal aberrations was done in 50 metaphases per animal on coded slides of each 5 males and
females per group. A test substance was classified positive if it induced either a dose-related increase
in the number of structural chromosomal aberrations or a statistically significant (Mann-Whitney test)
positive response for at least one of the test points.
Mouse Spot Test (Heidemann et al., 1993): Housing of the animals and treatment with aloe emodin
were as described above. In the spot test embryos were exposed to the test substances at an
appropriate stage of development, mostly day 9, and allowed to grow. The target cells in the
developing embryos were melanoblasts, and target genes were those which control the pigmentation
of the coat hairs. The embryos were heterozygous for three coat colour genes. A mutation in or loss of
the dominant allele of such genes resulted in the expression of the recessive genotype forming a spot
of altered colour in the black coat of the F1 mouse. The F1 offspring were examined for coat colour
spots 3 weeks after birth. Brownish or greyish pigmented spots and non-midventral white spots were
regarded to have genetic relevance. A test substance was classified as positive if it induced either a
dose-related increase in the frequency of genetically relevant spots or a statistically significant (exact
Fisher Yates test) positive response for at least one of the test points.
In vivo/in vitro UDS test in rat hepatocytes (Heidemann et al., 1993): Housing of the animals and
treatment with the test substances were as described above. After a treatment period of 4 and 16 h,
the animals were anaesthetised and sacrificed during liver perfusion. Primary hepatocyte cultures were
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set up and exposed for 4 h to 3H-thymidine, which is incorporatedinto the DNA if UDS occurs. The
uptake of 3H-thymidine by the hepatocytes was determined by autoradiography. For each test group
hepatocytes from 3 animals were assessed for the occurrence of UDS. The number of silver grains
above the nuclear area was counted using Artek 880 or 982 counter. In addition, the number of grains
of one nuclear-sized cytoplasmic area adjacent to the nucleus was counted. At least two slides per
animal and 50 cells per slide were evaluated. A test substance was classified as positive if it induced
either a dose-related increase in 3H-thymidine incorporation expressed as grains per nuclear area
(=nucleus) or a statistically significant (Mann-Whitney test) positive response for at least one of the
test points.
In the following study, Aviello et al. (2010) evaluated the cytotoxicity of rhein, the active metabolite of
senna, on human colon adenocarcinoma cells (Caco-2) and its effect on cell proliferation. Cytotoxicity
studies were performed using 3-(4.5-dimethylthiazol-2-yl)-2.5-diphenyltetrazolium bromide (MTT),
neutral red (NR) and trans-epithelial electrical resistance (TEER) assays whereas (3)H-thymidine
incorporation and Western blot analysis were used to evaluate the effect of rhein on cell proliferation.
Moreover, for genoprotection studies the Comet assay and oxidative biomarkers measurement
(malondialdehyde and reactive oxygen species) were used. Rhein (0.1-10 µg/ml) had no significant
cytotoxic effect on proliferating and differentiated Caco-2 cells. Rhein (0.1 and 1 µg/ml) significantly
reduced cell proliferation as well as mitogen-activated protein (MAP) kinase activation. By contrast, at
high concentration (10 µg/ml), rhein significantly increased cell proliferation and extracellular-signal-
related kinase (ERK) phosphorylation. Moreover, rhein (0.1-10 microg/ml): (i) did not adversely affect
the integrity of tight junctions and hence epithelial barrier function; (ii) did not induce DNA damage,
rather it was able to reduce H(2)O(2)-induced DNA damage and (iii) significantly inhibited the increase
in malondialdehyde and reactive oxygen species (ROS) levels induced by H(2)O(2)/Fe(2+). Rhein was
devoid of cytotoxic and genotoxic effects in colon adenocarcinoma cells. Moreover, at concentrations
present in the colon after a human therapeutic dosage of senna, rhein inhibited cell proliferation via a
mechanism that seems to involve directly the MAP kinase pathway. Finally, rhein prevents the DNA
damage probably via an anti-oxidant mechanism.
Emodin was mutagenic in Salmonella typhimurium strain TA100 in the presence of S9 activation; no
mutagenicity was detected in strain TA98, with or without S9. Chromosomal aberrations were induced
in cultured Chinese hamster ovary cells treated with emodin, with and without S9. Three separate in
vivo micronucleus tests were performed with emodin. A male rate bone marrow micronucleus test,
with emodin administerd by 3 intraperitoneal injections, gave negative results. Results of acute-
exposure (intraperitoneal injection) micronucleus tests in bone marrow and peripheral blood
erythrocytes of male and female mice were negative. In a peripheral blood micronucleus test on mice
from the 14-week study, negative results were seen in male mice, but a weakly positive response was
observed in similarly exposed females. The studies give no evidence of carcinogenic activity of emodin
in male rats and female mice, and equivocal evidence in female rats and male mice. In view of
conflicting results on genotoxicity, it was noted the first pass effect and need for metabolic activation
suggesting a metabolite as the genotoxic form. The metabolite 2-hydroxyemodin acts as the genotoxin
(Masuda et al., 1985).
The NTP (2012) tested rhein for mutagenicity in S. typhimurium strains TA98 and TA100. Dose-related
increases in mutant colonies were seen with both strains in the presence of rat or hamster liver S9.
Rhein showed effects at lower concentrations than were required for the positive responses seen with
senna samples. Another component of senna, chrysophanic acid, was tested for mutagenicity in TA98,
TA100, and TA1535. Weak and inconsistent responses were seen in TA100 with rat and hamster liver
S9. Sennosides A and B were also tested for mutagenicity in bacterial test systems; neither compound
was mutagenic, with or without S9 metabolic activation.
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3.3.4. Carcinogenicity
Mascolo et al. (1999) investigated the influence of senna extract on the growth and initiation of
malignant tumours in rat colon. In the dose of 10 mg of extract/kg, which just produced a slight
laxative effect, no carcinogenic or tumourigenic effects were observed. Only the second dose level of
100 mg/kg given for 13–28 weeks together with azoxymethane produced a higher rate of tumours
compared to the control group (only given azoxymethane). The authors concluded that, under
therapeutic dosage, senna extracts have no carcinogenic effects at all. The dose of 100 mg/kg led to
permanent diarrhoea in the animals for 3 months and was thus clearly too high and of no therapeutic
relevance.
Mengs et al. conducted 2004 a toxicity study on senna in male and female rats. The administered
senna preparation were powdered Tinnevelly senna pods containing 1.829% of sennosides A-D,
1.596% of potential rhein, 0.111% of potential aloe emodin, 0.014% of total emodin, and 0.004% of
total chrysophanol (sum of potential hydroxyanthraquinones 1.725%). Senna was administered by
gavage to Sprague Dawley rats once daily at dose levels of 0, 100, 300, 750 or 1,500 mg/kg for up to
13 consecutive weeks followed by an 8-week recovery period for selected animals. There was a dose-
dependent laxative effect at 300 mg/kg per day and above. Animals receiving 750 or 1,500 mg/kg per
day had significantly reduced body weight gain (males only) and, related to the laxative properties of
senna, increased water consumption and notable electrolyte changes in blood and urine. At both the
terminal and recovery phase necropsy, an increase in absolute and relative kidney weights was seen
for male and female animals receiving 750 and/or 1,500 mg/kg per day. A dark discolouration of the
kidneys was observed at necropsy along with histopathological changes (slight to moderate tubular
basophilia and pigment deposits) at 300 mg/kg and above. Although the pigmentation decreased
towards the end of the recovery period, it still remained to a lesser degree. However, there were no
indications in laboratory parameters of any renal dysfunction. In addition, for all treated groups,
minimal to slight hyperplasia was recorded in the forestomach and large intestine, which was
reversible within the 8-week recovery period. The histological changes were considered a physiological
adaptation to the laxative substance. Under the conditions of the study, there were no alteration seen
in the colonic nervous plexus. Even in the highest dose group, there was no indication of any pigment
deposits in the mucous membranes of the large intestine. The authors concluded that senna did not
cause any notable target organ toxicity up to the highest dose tested. A no-observable-effect-level
(NOEL) could not be obtained, but the changes seen were considered to represent a physiological
adaptation to treatment and not a true toxic response.
To determine the potential toxic effects of senna, a 40-week toxicology and carcinogenesis study in the
C3B6.129F1-Trp53 (tm1Brd) N12 haploinsufficient (p53 (+/-)) mouse were conducted within the NTP
programme (Surh et al. 2013; see also NTP, 2012). Groups of 25 male and 25 female mice were
exposed to 0, 100, 300, 1,000, 3,000, or 10,000 ppm senna (equivalent to average daily doses of
approximately 12, 36, 120, 365, or 1,260 mg/kg to males and 14, 42, 140, 435, or 1,520 mg/kg to
females) in feed for 40 weeks. Mean body weights of exposed male and female mice were within 10%
of those of the controls throughout the study. Feed consumption by exposed mice was generally
similar to that by the controls. Significant increases in the incidences of epithelial hyperplasia of the
colon and cecum occurred in 10,000 ppm males and females, and the incidence of epithelial
hyperplasia of the colon was significantly increased in 3,000 ppm females.
To evaluate the carcinogenic potential of anthraquinones, the effect of long-term senna pod extract
treatment on either healthy rats or rats treated with an initiating tumor agent (azoxymethane) has
been studied. Senna pod extract (30 and 60 mg/kg), administered for 110 weeks, did not induce the
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development of aberrant crypt foci and tumors in healthy rats. The development of aberrant crypt foci
and tumors in rats treated with azoxymethane were significantly reduced by senna pod extract (30 and
60 mg/kg) (Borelli et al., 2005)
In vivo/in vitro UDS test in rat hepatocytes: A carcinogenicity study was performed by Lyden-
Sokolowski et al. (1993). Rats received for 2 years a purified senna extract, that contained
approximately 40.8% anthranoids, of which 35.7% were total sennosides, corresponding to
approximately 25.2% calculated potential total rhein, 2.3% potential aloe emodin and 0.007%
potential emodin. Besides the control group, 3 dosages groups (5, 15 and 25 mg/kg) were tested,
which showed clinical signs of chronic electrolyte loss, mostly in the high-dosage 25 mg/kg group. No
treatment-related increase in tumours of the gastro-intestinal tract, liver or kidneys could be found.
The highest dose level was approximately 20-25 times the recommended clinical dose.
Mereto et al. (1996) found that senna glycosides acted as weak promoters of rat colon carcinogenesis.
The doses used were considerably above those taken by humans and which are usually used in
therapy.
Induction of cell proliferation by laxatives and related compounds in rat intestines was analysed by
BrdU-labelling and compared with histopathological changes in the mucosa and findings for faeces by
Toyoda et al. (1994). Male F344 rats were fed a diet containing danthron, sennosid A, bisacodyl, 1-
hydroxyanthraquinone, magnesium sulfate, dextran sulfate sodium, pectin, carboxymethylcellulose
sodium (CMC-Na) or sodium chloride (NaCl) for 7 days. The stimulant laxatives, danthron, sennosid A
and bisacodyl significantly induced cell proliferation in almost the entire intestinal epithelia in a clear
dose-dependent manner. DSS also induced cell proliferation in some portions at high doses. Increase
in BrdU-labelling indices was correlated well with the severity of inflammatory changes in the intestinal
mucosa as well as with purging effects of stimulant laxatives and dextran sulfate sodium. In contrast,
the bulk-forming laxative CMC-Na did not consistently enhance cell proliferation nor cause apparent
cytotoxicity in the intestine despite exerting remarkable purging effects. 1-hydroxyanthraquinone and
magnesium sulfate slightly induced cell proliferation in the cecum and the colorectum, although there
was little or no intestinal cytotoxicity. Pectin and NaCl did not influence cell kinetics of the epithelia,
nor cause any inflammatory changes in the mucosa. The results thus indicate that diarrhea caused by
laxatives is not necessarily correlated with induction of cell proliferation, as in the intestinal mucosa,
and that inflammatory changes followed by regenerative process could be responsible for enhancing
cell kinetics.
The carcinogenic activities of anthraquinone and six derivatives were compared and contrasted.
Studies included representatives of amino, alkyl, nitro, hydroxy, or halogen-containing anthraquinones,
with the purpose of uncovering general structure-activity relationships. Anthraquinone, 2-
aminoanthraquinone, 1-amino-2-methylanthraquinone, 2-methyl-1-nitroanthraquinone,1-amino-2,4-
dibromoanthraquinone, 1,4,5,8-tetraaminoanthraquinone, and 1,3,8-trihydroxy-6-
methylanthraquinone (of varying purities) were administered via feed to Fischer 344/N rats and
B6C3F, mice. In rats, anthraquinone induced tumors in the liver, kidney, and urinary bladder. A 2-
amino substitution narrowed the carcinogenicity to the liver, while multiple amino substitutions led to a
carcinogenic response in the urinary bladder alone. A methyl substitution ortho to a 1-aminogroup
preserved the hepatic and renal neoplasms seen with the parent anthraquinone, but did not induce
urinary bladder tumors; amino or bromo substitutions para to a 1-amino group were related to urinary
bladder neoplasms. The intestine may have been a target organ for bromine-substituted
anthraquinones. The presence of a nitro group altered the targets of carcinogenicity, and skin tumors
may have been associated with this particular functional group in both, rats and mice. Overall for mice,
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the findings were somewhat different and limited by the small number of common target organs. The
parent anthraquinone was clearly carcinogenic only to the liver. There were no other effects of single
amino substitutions, in the presence or absence of an additional methyl group, on the carcinogenicity
or the site of carcinogenesis of anthraquinone in mice. Multiple amino substitutions diminished, while
bromine substitutions enhanced the carcinogenicity induced by anthraquinone and extended the target
organs to include forestomach and lung (Doi et al., 2005).
In 2001, the National Toxicology Program (NTP) of the U.S. Department of Health and Human Services
published a technical report on toxicology and carcinogenesis studies of emodin:
Two-year (105 weeks) study in rats: Groups of 65 male and 65 female rats were fed diets containing
0, 280, 830, or 2,500 ppm emodin (equivalent to average daily doses of approximately 110, 320, or
1,000 mg/kg to males and 120, 370, or 1,100 mg/kg to females). Three Zymbal’s gland carcinomas
were observed in female rats exposed to 2,500 ppm. This incidence exceeded the range observed for
current historical controls and was considered an equivocal finding. At the 6- and 12-month interim
evaluations and at 2 years, emodin-related increases in the incidences of renal tubule hyaline droplets
occurred in all exposed groups. The incidences of renal tubule pigmentation were significantly
increased in all exposed groups of males at 2 years. There were negative trends in the incidences of
mononuclear cell leukaemia in male and female rats, and the incidences in the 2,500 ppm groups were
significantly decreased. In females exposed to 2,500 ppm, the incidence was below the historical
control range; the incidence in males exposed to 2,500 ppm was at the lower end of the historical
control range.
2-year (105 weeks) study in mice: Groups of 60 male mice were fed diets containing 0, 160, 312, or
625 ppm emodin (equivalent to average daily doses of approximately 15, 35, or 70 mg/kg). Groups of
60 female mice were fed diets containing 0, 312, 625, or 1,250 ppm emodin (equivalent to average
daily doses of approximately 30, 60, or 120 mg/kg). Low incidences of renal tubule adenoma and
carcinoma occurred in exposed male mice; these incidences included one carcinoma each in the 312
and 625 ppm groups. Renal tubule neoplasms are rare in male mice, and their presence in these
groups suggested a possible association with emodin exposure. At the 12-month interim evaluation,
the severity of nephropathy was slightly increased in males exposed to 625 ppm. Also at 12 months,
the severity of nephropathy increased from minimal in the lower exposure groups to mild in females
exposed to 1,250 ppm; the incidence in this group was significantly increased compared to the control
group. At 2 years, the severities of nephropathy were slightly increased in males exposed to 625 ppm
and females exposed to 1,250 ppm. The incidences of nephropathy were significantly increased in all
exposed groups of females. At the 12-month interim evaluation, the incidences of renal tubule
pigmentation were significantly increased in all exposed groups of males and in females exposed to
625 or 1,250 ppm. The severities increased while increasing exposure concentration. At 2-years, the
incidences of renal tubule pigmentation were significantly increased in all exposed groups; severities
also raised up accordingly, with increasing exposure concentration.
3.3.5. Reproductive and developmental toxicity
Garcia-Villar evaluated in 1988 the effects of sennosides on uterine motility in the pregnant ewe.
Repeated intracolonic administration of laxative doses of sennosides A+B (60 mg/kg) between the
70th and 120th day of the pregnancy had no effect on cervical motility but significantly reduced uterine
motility in some ewes. Pregnancy maintenance was normal (Blaschek et al., 2003).
3.3.6. Local tolerance
There are no studies available regarding local tolerance.
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3.3.7. Other special studies
Interactions between widely used anthranoid laxatives and other simultaneously administered drugs
were studied by Laitinen et al 2007. The influence of rhein, danthron, sennidins A/B, sennosides A/B,
and senna leaf infusion on the permeability of furosemide, ketoprofen, paracetamol, propranolol,
verapamil, digoxin, and Rhodamine 123, respectively, across Caco-2 monolayers was investigated. The
effects on monolayer integrity ([(14)C]mannitol permeability, trans-epithelial electrical resistance)
were also determined. The in vitro absorption of highly permeable drugs was not strongly affected
during co-administration of the laxatives. Furosemide permeability was enhanced by rhein and
danthron (3.6 and 3.0-fold), which may partly be due to opening of the paracellular spaces and/or
effects on active efflux. However, the secretory permeability of digoxin and Rho 123 was not strongly
affected by rhein and danthron, suggesting that inhibition of MDR1 was not responsible for the
increased permeation of furosemide. The absorptive permeability of digoxin was decreased by rhein
and danthron, offering evidence for effects on apical membranes. According to the authors, the effects
on monolayer integrity were detectable, but reversible. According to presented experiments, daily use
of laxatives with well-absorbing drugs would seem unlikely to affect drug permeability, but the effects
on the absorption of poorly permeable drugs cannot be excluded.
3.3.8. Conclusions
Genotoxicity tests were performed by several laboratories with the herbal substances of Sennae
fructus, senna extract, as well as to several sennosides, rhein and aloe emodin. The herbal substance
Sennae fructus, the sennosides and rhein did not increase mutation frequencies in the following test
systems: bacterial systems (Salmonella reverse mutation test and/or Escherichia coli forward mutation
test); mammalian cell cultures [hypoxanthine guanine phosphoribosyl transferase (HGPRT) test;
mouse lymphoma test; chromosome aberration test with Chinese hamster ovary cells]; bone marrow
(micronucleus test; chromosome aberration test); melanoblast cells (mouse spot test) of rodents. In in
vivo studies [micronucleus test with bone marrow cells of NMRI mice, chromosome aberration test with
bone marrow cells of Wistar rats, mouse spot test (crossing DBA/2J x NMRI)] no indication for a
mutagenic activity of aloe emodin was found.
The review of Morales et al. (2009) summarises that there is no convincing evidence that the chronic
use of senna has, as a consequence, a structural and/or functional alteration of the enteric nerves or
the smooth intestinal muscle. There is also no relation between long-term administration of a senna
extract and the appearance of gastrointestinal tumors or any other type in rats. Furthermore, senna is
not carcinogenic in rats even after a two-year daily dose of up to 300 mg/kg per day. It is concluded
that the current evidence does not show a genotoxic risk for patients who take laxatives containing
senna extracts or sennosides.
Overall, available data are insufficient and the results of available investigations are not consistent.
However, there is a concern with regards to the genotoxic and carcinogenic potential of
anthraquinones and their derivatives. This concern must be taken into account as long as no conclusive
data are generated. Therefore, use during pregnancy and lactation is contraindicated, although no
irreversible changes or risks have been observed regarding reproduction toxicity in vivo when using the
normal recommended doses. Other treatments like behavioural modification, dietary changes and use
of bulk forming agents should be the first actions taken during pregnancy and lactation to treat
constipation. Secondly, it is regarded appropriate to restrict the duration of use to a maximum of one
week.
Use during lactation is contraindicated as there are insufficient data on the excretion of metabolites in
breast milk. Investigations with a “standardised senna laxative”, which also contains Plantago ovata
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seeds/husks as bulk substances, showed that small amounts of active metabolites (rhein) are excreted
in breast milk. No laxative effect in breast fed babies has been reported (Faber and Strenge-Hesse,
1988). Aloe emodin is quickly oxidised to rhein an unknown metabolite or conjugated. Data on
excretion of anthraquinones or derivatives via milk in any species are lacking.
The EFSA Panel on Food Additives and Nutrient Sources added to Food delivered a scientific opinion on
the safety of hydroxyanthracene derivatives (EFSA, 2018). The conclusions were in line with the
assessment of the HMPC.
The HMPC decided to to condense information given in section 5.3 of the monographs as far as
possible. A short summary of the 90-day study in rats is presented as well as a remark on the different
data on genotoxicity and carcinogenicity.
3.4. Overall conclusions on non-clinical data
Preclinical data show the laxative pharmacodynamic effects of preparations containing senna leaves
and pods.
The use during pregnancy is contraindicated in the monograph because there is a concern on the
genotoxic and carcinogenic potential of several anthranoids, e.g. emodin and aloe emodin (see also
section 3.3.8).
4. Clinical Data
4.1. Clinical pharmacology
Constipation is said to be present when passed stools are of hard consistency and when evacuation of
faeces is too difficult, too infrequent and irregular. The physiological range for frequency of bowel
movements is wide, extending from three times daily to once every 2 to 3 days. In the pathogenesis of
constipation the colon plays a key role because this is where the content of the gut remains for 24–
48 h. During this period the liquid contents from the small intestine are converted into faeces by
absorption of water and electrolytes in response to the action of bacteria. These functions are
dependent on the interplay of peristaltic processes, which mix the contents and the normal
coordination of the anorectal muscles during defaecation. A disturbance involving any of these
individual areas may lead to constipation. In this context, functional disturbances are far more
common than those of an organic origin. In addition, assessment is problematic because the symptoms
are perceived differently by the individuals affected (Ewe 1994, Gabler 1994), due to different concepts
of what normal bowel habits are.
4.1.1. Overview of pharmacodynamic data regarding the herbal

substance(s)/preparation(s) including data on relevant constituents
Ewe et al. (1993) measured gastric emptying, small and large intestinal transit in 24 healthy
volunteers using a metal detector method. Twelve persons taking a normal diet received loperamide in
a dose sufficient to double the individual transit time. All subjects measured gastrointestinal transit
time under normal conditions (A) and with a product containing purified sennosides 20 mg (B), a fibre
product containing 20 g Plantago ovata seeds/husks (C), or a combination of 5.4 g Plantago ovata
seeds/husks+1.2 g senna pod with a sennoside content of 30 mg (D). Colonic transit was reduced by
(B) and (D) from 39±4 h to 17±3 h (p<0.005). (C) did not influence colonic transit (39±3 h).
Loperamide prolonged colonic transit from 27±0.7 h to 72±12 h. This effect was abolished by (B)
(30±5 h) and (D) (27±1 h) (p<0.005), but not by (C) (64±13 h). The same effects were seen when
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right and left colonic transit were analysed separately. Neither gastric emptying nor small intestinal
transit was affected by either substance. All three investigated medicinal products increased stool
weight significantly (p<0.05). When stool frequency and consistency were compared, the effects were
less clear. (D) caused the greatest, (C) the least changes of these parameters. Oroanal transit times
measured by the metal detector and by the Hinton method using 20 radiopaque markers were similar
(43±6 h and 47±6 h, respectively).
Buhmann et al. (2005a) enrolled 15 healthy individuals (8 males, 7 females, 20 to 45 years old)
with no history or present symptoms of bowel disorders in a functional cine-MRI examination at 6 am.
after a starving phase for at least eight hours before and after oral administration of senna leaves tea.
Two consecutive sets of repeated measurements of the entire abdomen were performed using a 1.5T
MRI system with coronal T2-weighted HASTE sequences anatomically adjusted to the course of the
large bowel. A navigator technique was used for respiratory gating at the level of the right dorsal
diaphragm. The changes in diameter (given in cm) were measured at 5 different locations of the
ascending (AC), transverse (TC) and descending colon (DC), and assessed as parameters for the bowel
motility. The mean values as a statistical measure for large bowel relaxation were determined. Before
ingestion of senna tea, the mean diameter measured 3.41 cm (AC), 3 cm (TC) and 2.67 cm (DC). After
the ingestion of senna tea, the mean diameter increased to 3.69 cm (AC), to 3.4 cm (TC) and to 2.9
cm (DC). A statistically significant difference was demonstrated with the Wilcoxon test (level of
confidence 0.05). For the determination of dynamic increase, the changes of the statistical scatter
amplitude to the mean value were expressed as percentage before and after the ingestion of senna
tea. Thereby, an increase in variation and dynamic range was detected for the AC (112.9%) and DC
(100%), but a decrease in the dynamics for the TC (69%). This study investigated a non-invasive
method for the assessment of bowel motility for the first time. The results have therefore to be
regarded with caution. Further studies have to determine whether the results of this technique are
clinically relevant.
Buhmann et al. (2005b) sought to assess large bowel motility, induced by 2 prokinetic agents:
senna leaves tea and erythromycin, using functional cine magnetic resonance imaging (MRI). Twelve
volunteers underwent functional cine MRI before and after the administration of senna tea or
erythromycin. The protocol consisted of 2 sets of repeated measurements using coronal T2-weighted
HASTE sequences, adjusted to the course of the colon. For the assessment of large bowel motility, the
changes of the luminal diameter were measured at 5 defined locations in the ascending, transverse,
and descending colon. In all examined volunteers after senna tea, the mean number of significant
changes in the ascending colon was 8.6 and after erythromycin, 7.2. In the transverse colon, 9.6
diameters changed significantly for senna tea and 7.2 for erythromycin. In the descending colon, 6.6
diameters changed after senna tea and 7.2 after erythromycin. Senna tea and erythromycin proved to
induce large bowel motility; senna tea was more effective. Functional cine MRI is a reliable,
noninvasive method for the assessment of colonic motility.
In a pharmacological study the jejunum and the colon of humans were perfused with 15 mg and 20 mg
rhein, respectively, via tube. The fluid absorption was turned into a fluid secretion. The net transport of
sodium changed and there was a loss of potassium (Symposium Anthrachinon-Laxantien, 1985).
4.1.2. Overview of pharmacokinetic data regarding the herbal

substance(s)/preparation(s) including data on relevant constituents
Kobashi et al. (1980) demonstrated that sennosides could be converted to rhein anthrone by specific
cultured bacteria strains from the human intestine. Further, Hattori et al., 1993, demonstrated
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cleavage of the O-glucosyl bond of sennoside B, reduction of sennidin B, and accumulation of rhein
anthrone in a coculture of two bacteria strains isolated from human faeces (NTP, 2012).
Concentrations of rhein and aloe emodin were determined over time in plasma of human volunteers
receiving four daily therapeutic doses of either of two senna-containing laxatives (Krumbiegel and
Schulz, 1993). No aloe emodin was detected in any samples. Two peak concentrations of rhein were
observed in plasma following each dose, one at 3 to 5 hours and the anthrone has a weaker laxative
effect than rhein anthrone. In humans, intraluminal introduction of senna, which was preincubated
with faeces or Escherichia coli, produced peristalsis within 1 hour. Intraluminal application of rhein
anthrone also produced peristalsis within 1 hour (Hardcastle and Wilkins, 1970; NTP, 2012).
Therapeutic doses of two laxatives were repeatedly administered to 10 healthy volunteers in a two-way
change-over design (Krumbiegel and Schulz, 1993). One laxative contained purified sennosides 20 mg,
and the other was a combination of Plantago ovata seeds/husks and senna pod. Blood samples were
collected up to 96 h after the first dose, and plasma levels of total aloe emodin and rhein were
determined simultaneously with a sensitive (lower limit of quantification: 0.5 ng aloe emodin and 2.5
ng rhein per millilitre plasma) and specific fluorometric HPLC method. Aloe emodin was not detectable
in any plasma sample of any subject. Rhein concentration time courses showed highest levels of 150–
160 ng/ml, mean 81.8 ng/ml (combination) and 49.6 ng/ml (purified sennosides), and peak maxima at
3–5 hours and 10–11 hours after dosing probably according to absorption of free rhein and rhein
released from prodrugs (e.g. sennosides) by bacterial metabolism, respectively.
Hattori et al. (1988) reported that during the course of studies on the metabolism of sennosides by
human intestinal bacteria, an enzyme which takes part in the reduction of sennosides and sennidins
could be originally isolated from Peptostreptococcus intermedius. This enzyme catalysed the electron
transfer from NADH (nicotinamide adenine dinucleotide) to FAD (flavin adenine dinucleotide), FMN
(riboflavine 5’phosphate) or benzyl viologen, which reduced non-enzymatically sennosides and
sennidins to 8-glycosyl-rhein anthrone and rhein anthrone, respectively.
A gas chromatography-mass spectrometry (GC-MS)-based screening procedure was developed for the
detection of stimulant laxatives and/or their metabolites in human urine after enzymatic cleavage of
conjugates followed by extractive methylation. The part of the phase-transfer catalyst remaining in the
organic phase was removed by solid-phase extraction on a diol phase. The compounds were separated
by capillary GC and identified by computerized MS in the full scan mode. By use of mass
chromatography with the ions m/z 305, 290, 335, 320, 365, 350, 311, 326, 271, and 346, the possible
presence of stimulant laxatives and/or their metabolites could be indicated. The identity of positive
signals in such mass chromatograms was confirmed by comparison of the peaks underlying full mass
spectra with the reference spectra. This method allowed the detection of the diphenol laxatives
bisacodyl, picosulfate, and phenolphthalein and of the anthraquinone laxatives contained in plant
extracts and/or their metabolites in human urine samples. The overall recoveries of the stimulant
laxatives and/or their metabolites ranged between 33% and 89% with a coefficient of variation of less
than 15%, and the limits of detection ranged between 10 and 25 ng/ml (S/N 3) in the full scan mode.
After ingestion of the lowest therapeutic dose of a senna extract, the main metabolite of sennosides,
rhein, was detectable in urine samples for 24 hours (Beyer et al., 2005).
Diacerhein is a drug for the treatment of patients with osteoarthritis. This drug is administered orally
as 50 mg twice daily. Diacerein is entirely converted into rhein before reaching the systemic
circulation. Rhein itself is either eliminated by the renal route (20%) or conjugated in the liver to rhein
glucuronide (60%) and rhein sulfate (20%); these metabolites are mainly eliminated by the kidney.
The pharmacokinetics characteristics of diacerein are about the same in young healthy volunteers and
elderly people with normal renal function, both after a single dose (50 mg) or repeated doses (25 to
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75 mg twice daily). Rhein’s kinetics after single oral doses of diacerein are linear in the range 50 to
200 mg. However, rhein’s kinetics are time-dependent, since the nonrenal clearance decreases with
repeated doses. This results in a moderate increase in maximum plasma concentration, area under the
plasma concentration-time curve and elimination half-life. Nevertheless, the steady-state is reached by
the third administration and the mean elimination half-life is then around 7 to 8 hours. Taking
diacerein with a standard meal delays systemic absorption, but is associated with a 25% increase in
the amount absorbed. Mild-to-severe (Child Pugh's grade B to C) liver cirrhosis does not change the
kinetics of diacerein, whereas mild-to-severe renal insufficiency (creatinine clearance <2.4 per hour) is
followed by accumulation of rhein which justifies a 50% reduction of the standard daily dosage. Rhein
is highly bound to plasma proteins (about 99%), but this binding is not saturable so that no drug
interactions are likely to occur, in contrast to those widely reported with nonsteroidal anti-
inflammatory drugs. Except for moderate and transient digestive disturbances (soft stools, diarrhoea),
diacerein is well tolerated and seems responsible neither for gastrointestinal bleeding nor for renal,
liver or haematological toxicity (Nicolas et al., 1998).
4.2. Clinical efficacy
4.2.1. Dose response studies
There are no dose-finding studies available.
An overview on documented medicinal use and historical data from literature is given in section 2.2.
In literature it is reported that it is normally sufficient to take an anthranoid-containing laxative up to

two to three times a week (Hitzenberger et al., 1999).
4.2.2. Clinical studies (case studies and clinical trials)
The efficacy of senna preparations has been evaluated in clinical trials in the treatment of constipation,
in irritable bower syndrome, for bowel cleansing before radiological investigations or colonoscopy, in
chemotherapy induced constipation, in postoperative constipation, in opioid-induced constipation after
orthopaedic surgery and in opioid-induced constipation in palliative care. In some of the studies,
combinations of senna with fibre were investigated. For bowel cleansing high doses of a senna
preparation were tested.
4.2.2.1. Constipation
Pers et al. (1983) treated 20 elderly in-patients (above 60 years old) suffering from severe
constipation, once daily for 2 weeks with combination (A) (“2.6 g Semen plantaginis ovatae, 0.11 g
Ispaghula husk and 0.62 g Sennae fructus angustifolie equivalent to 15 mg glycoside A+B per sachet
of 5 g”) or combination (B) (“3.3 g Testa ispaghula ‘Tika’ and 25 mg glycoside sennae A+B per
sachet”). The patients were allocated randomly into the two treatment groups, one starting with (A),
the other with (B). The investigation comprised three periods. The first one was the week prior to the
treatment with either of the two preparations. During that week the patients received the medication
routinely used at the department. The second period comprised 2 weeks treatment with one or the
other of the 2 preparations. During the third period, of another 2 weeks, the preparations were
changed. The periods were strictly consecutive. The dosage was one sachet in the evening. Nineteen
patients completed the trial. In one patient diarrhoea from sources obviously not related to the
medication occurred and this patient was classified as a drop-out. The defaecation frequency was
higher during the (B) treatment than during the (A) one. This was expected as the given dose of (B)
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contained 10 mg glycosides more than that of (A). Precise data are not given in the publication. Large
differences were seen both between individuals and for the same individual during treatment. Enemas
were given to a few patients during the first period as well as during the second and third period.
There were no differences between the two treatments. Concerning ease of administration, ease of
swallowing and taste, there were also no differences. No-side effects were seen. The authors concluded
that both preparations worked well, even if they have differences in senna glycoside content in the
given dosage.
Marlett et al. (1987) conducted a study involving 42 adults with chronic constipation who remained
constipated after a week of single-blind placebo treatment. Qualifying patients were than randomised
to receive ispaghula husk (7.2 g per day) or psyllium plus senna (6.5 g+1.5 g per day) for 1 week. The
ingested amount of sennosides is not mentioned in the publication. Because the psyllium and senna
preparation is a granular formulation ingested with a cold liquid, and the ispaghula husk product is a
powder that must be mixed with a liquid before ingestion, no attempt was made to blind the identity of
the treatment. Both preparations significantly increased stool frequency (p<0.001). In the ispaghula
husk group stool frequency increased from 2.3±0.1 during placebo to 3.6±0.3 stools per week during
laxative ingestion and in the combination group from 2.0 to 6.8 stools per week. Both treatments also
significantly increased mean wet and dry stool weights, although the added effect of senna was clearly
evident. Ispaghula husk treatment increased the mean wet stool weight from 254.2 g to 444.8 g per 7
days and the mean dry stool weight from 75.4 g to 126.5 g per 7 days. The combination treatment
increased the mean wet stool weight from 277.7 g to 982.1 g per 7 days and the mean dry stool
weight from 79.9 g to 190.8 g per 7 days. Overall relief of constipation was reported by 90% of
patients on the combination therapy and by 85% of patients on ispaghula husk alone. Interestingly,
the objective improvement in stool frequency in both groups did not attain the high level of subjective
improvement; 63% of the combination group and 48% of the ispaghula husk group had more than
three bowel movements during the week of treatment. Reports of gastrointestinal side effects (pain
and cramping) were predominant in the combination group (32% versus 14% for ispaghula husk
alone). Three of the 22 patients treated with ispaghula husk reported side effects of cramping and gas.
Seven of the 22 patients treated with the combination experienced 11 episodes of side effects, which
included mainly cramps, uncomfortable diarrhoea, as well as bloating, gas, and nausea. After
completion of the protocol and evaluation of the data, two distinct responses to the combination
therapy were evident. These two groups were designated as normal responders and high responders.
The subpopulation of high responders was responsible for most of the increases in stool frequency and
wet weight and all of the effect on dry stool weight. All seven high responders classified their bowel
movements as too frequent. Despite significant positive results from the objective faecal parameters,
including an increase to more than 3 bowel movements per week after treatment, and despite the fact
that 85% of patients reported relief of constipation, the authors concluded that a dose higher than 7 g
psyllium per day or a period of treatment longer than 7 days might be necessary to produce an effect
in a chronically constipated population. The single daily dose of “senna plus psyllium” had two distinct
effects; approximately one-third of the subjects had a marked response, which included
gastrointestinal side effects, while two-thirds had a mild response not significantly different from those
given by ispaghula husk alone. The authors suggested that doses of psyllium+senna be individualised,
given the higher incidence of undesirable side effects with combination therapy.
Passmore et al. (1993a, 1993b) compared the efficacy of a senna-fibre combination, a ispaghula-
senna combination ( ispaghula 54.2%, senna 12.4% (m/m)) and lactulose in 77 elderly patients
(average age: 82.9 years) with a history of chronic constipation in long-term hospital or nursing home
care in a randomised, double-blind, crossover study. The patients received active senna-fibre
combination 10 ml daily with lactulose placebo 15 ml twice daily, or active lactulose 15 ml twice daily
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with senna-fibre placebo 10 ml daily for two 14 day periods. Doses could be increased or decreased
according to response. The maximum daily dose for active or placebo senna-fibre was 20 ml (10 ml
twice daily) and for lactulose or lactulose placebo 60 ml. Before entry into the first phase, and between
treatments, subjects had a three to five day period free of laxatives. The number of stools and their
consistency and ease of evacuation, together with any other symptoms or adverse effects were noted
daily. Mean daily bowel frequency was higher with the senna-fibre combination (0.8, 95% confidence
interval 0.7 to 0.9) than with lactulose (0.6 (0.5 to 0.7); t=3.51, p<0.001). Scores for stool
consistency and ease of evacuation were significantly higher for the senna-fibre combination than for
lactulose (p<0.005, p=0.02 respectively). The recommended dose was exceeded more frequently with
lactulose than the senna-fibre combination. Compared with the recommended daily dose, this equates
to a dose per stool of 1.52 for lactulose and 0.97 for the senna-fibre combination. Twenty one patients
had adverse effects with lactulose: 7 cramps, 7 urgency, 8 wind or flatulence, 3 bloating, 1 headache,
4 anorexia. Twenty four patients had adverse effects with the combination: 7 cramps, 13 urgency, 10
wind or flatulence, 2 nausea, 3 bloating, 1 anorexia. There was no difference between treatments
when adverse effects were analysed, individually or overall. The authors concluded that both
treatments were effective and well tolerated for chronic constipation in long stay elderly patients. The
senna-fibre combination was significantly more effective than lactulose at a lower cost.
Kinnunen et al. (1993) compared the efficacy of a senna-fibre combination and lactulose in 30 long
stay elderly patients aged 65–94 years (mean 81.8 years) in the treatment of chronic constipation. The
trial was an open, randomised and controlled crossover study. A week’s run-in without laxatives was
followed by a 5-week period (I) of a daily dose of 14.8 mg (20 ml) senna-fibre combination or 20.1 g
(30 ml) lactulose. The senna-fibre combination contained Plantago ovata seed 521.6 mg (bulk
forming), Fructus cassiae angustifoliae 138 mg (stimulant) and atsulen 70 g (anti-inflammatory).
Period I ended with a week’s wash-out, which was followed by another 5-week period with crossed
medicines (period II). If over 4 days had elapsed since the last defaecation, 10 mg bisacodyl was given
per rectum. The bowel frequency, bisacodyl use and stool consistency, were recorded. In period I, 21
patients received senna-fibre combination and 9 patients lactulose; in period II, 7 patients received
senna-fibre combination and 18 patients lactulose. Bowel frequency/week was significantly higher on
senna-fibre combination treatment during both periods, mean (SD) in period I: 4.5 (2.3); period II:
4.5 (2.4), compared to lactulose. Bowel frequency on lactulose treatment was in period I 2.2 (0.9)
(p=0.0006) and in period II 1.9 (0.9) (p=0.027). There was a tendency for the number of bisacodyl
doses to be higher when lactulose was used. During both periods bulk plus senna tended to produce
more frequently hard, normal or watery stools but the differences did not reach any statistical
significance. The frequency of loose stools was higher (p<0.05) during the bulk plus senna period. No
complications or such changes in laboratory parameters which could be indicated as medicinal product
related could be found. The authors concluded that bulk laxatives plus senna was more efficient than
lactulose.
A systematic review of the efficacy and safety of traditional medical therapies for chronic constipation
was undertaken, making evidence-based recommendations. Ramkumar and Rao (2005) searched
the English literature for drug trials evaluating treatment of constipation by using MEDLINE and
PUBMED databases from 1966 to 2003. Only studies that were randomised, conducted on adult
subjects, and published as full manuscripts were included. Studies were assigned a quality score based
on published methodology. Standard forms were used to abstract data regarding study design,
duration, outcome measures, and adverse events. By using the cumulative evidence of published data
for each agent, recommendations were made regarding their use following the United States
Preventive Services Task Force guidelines. Good evidence (Grade A) was found to support the use of
polyethylene glycol (PEG) and tegaserod. Moderate evidence (Grade B) was found to support the use
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of psyllium, and lactulose. There was a paucity of quality data regarding many commonly used agents
including milk of magnesia, senna, bisacodyl, and stool softeners. There is good evidence to support
the use of PEG, tegaserod, lactulose, and psyllium. Surprisingly, there is a paucity of trials for many
commonly used agents. These aspects should be considered when designing trials comparing new
agents with traditional therapies because their use may not be well validated.
4.2.2.2. Irritable Bowel Syndrome
Hübner and Moser (2002) enrolled 284 patients between 19 and 70 years suffering from irritable
bowel syndrome (IBS) in a 12-week double blind, controlled, randomised, multicentre and prospective
clinical trial to compare the efficacy as well as the tolerance of tablets (containing as active ingredients
“180 mg Carbo ligni”, i.e. vegetable, non-activated charcoal, “105 mg Fol. Sennae, 25 mg rhubarb
extract”) (CL+) to Carbo ligni (CL) containing tablets. Men and women who met the Rome criteria for
IBS (all forms) for at least 3 months were eligible. 145 patients received CL+ and 139 patients Carbo
ligni. During the first 4 weeks, the physician was allowed to adapt the dosage to a patient’s individual
needs, from one to eight tablets per day. No dosage changes were allowed after the fourth week. The
number of tablets prescribed daily (1-3, 4-6, or >6) was similar between groups, although a tendency
to use fewer tablets was evident in the charcoal group. After the 12-week treatment period, 262
patients were available for intention-to-treat (ITT) analysis and 144 for per-protocol (PP) analysis
whereby changes of the disease were evaluated with scores based on the Francis IBS system (Francis
et al., 1997) modified with an open upper boundary (a patient-administered questionnaire that uses a
visual analogue scale (VAS) (0%-100%) to score the severity of pain, distension, bowel dysfunction,
and quality of life/global well-being) as the primary efficacy parameter. Scores on the VAS for overall
well-being decreased in the PP population from 48 with CL+and 46 with CL before treatment (ITT, 47
and 47) to 18 and 20 after 12-week treatment (ITT, 19 and 22). This translates to an amelioration of
symptoms in the PP population by 62.5% with CL+ and 56.5% with CL; respective values in the ITT
population were 59.6% and 53.2%. The relative gain in efficacy with CL+ compared with its basic
component (charcoal) was therefore only about 8% to 9% without statistical significance. Differences
in the Francis score became more prominent in some subgroups selected for exploratory analysis. The
patients, who described “often normal stools” at baseline achieved significantly higher overall well-
being after treatment with CL+ (p=0.038, Wilcoxon test, PP population). Similar improvement in the
subgroup admitting to “movements often hard” was more pronounced with CL+ than with CL (not
statistically significant). Both treatments were well tolerated, adverse events occurred with similar
frequency in both groups (22% of patients treated with CL+ vs. 17% treated with CL). In most cases,
it was not possible to distinguish the event from symptoms of IBS. The ingested dose of
hydroxyanthracene derivatives is not mentioned in the publication. The package leaflet obtained from
the chemical-pharmaceutical factory F. Trenka, Vienna, Austria, indicates an amount of 2.65–3.95 mg
anthraquinone per tablet. This study cannot prove the efficacy of senna leaves in irritable bowel
syndrome. The study treatment was a combination product and the differences between the groups
concerning the primary efficacy parameter were not statistically significant. Based on the results of this
study, it is not possible to recommend the specific indication “irritable bowel syndrome”.
4.2.2.3. Bowel cleansing
Colonoscopy plays an important role in the diagnosis and treatment of gastrointestinal illness in both
Western countries and Japan. However, preparative bowel cleansing for colonoscopy is frequently
troublesome for elderly and/or constipated patients, since they must drink larger volumes of lavage
solution for adequate cleansing.
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Adequate bowel cleansing before a colonoscopic procedure is necessary in order not to miss small
colonic lesions, leading to a proper diagnosis (Froehlich et al., 2005). Sodium phosphate (NaP)-based
precolonoscopic preparation regimes were determined to have at least similar effectiveness in bowel
cleansing as polyethylene glycol electrolyte lavage (PEG-EL)-based regimes, and they also have better
patient tolerance than that observed with PEG-EL (Thomson et al., 1996). PEG-EL has minimum side
effects, while, in contrast, NaP-based regimes can be dangerous for patients with chronic systemic
illness (Liebermann et al., 1996). On the other hand, inadequate bowel cleansing of patients is not
infrequent under PEG-based regimes, probably because of its huge volume and unpleasant taste. For
this reason, reducing the amount of PEG-EL, splitting the whole dose, and adding medications (such as
prokinetics or laxatives) have been investigated by researchers in recent years.
Several studies were conducted with a product containing 1.26-1.85 g dry extract from Sennae fructus
acutifoliae corresponding to 150 mg hydroxyanthracene glycosides, calculated as sennoside B; DER 3-
5:1,extraction solvent water, per single dose.
In the sixties, seventies and eighties, several studies were conducted with senna containing products
alone or in comparison with other cleansing methods. From the eighties onwards, studies compared
those products with the newly developed electrolyte solutions. The more recent studies are presented.
First clinical trials using standardised herbal medicinal products (150 mg hydroxyanthracene glycoside
per day) for bowel cleansing without additional enema are presented.
Attempts have been made to further improve the widely performed colonoscopy preparation with
lavage. In a prospective study, 120 outpatients and inpatients scheduled for total colonoscopy were
randomised to two preparatory regimens. The day before endoscopy either extractum sennae (N=60)
or a placebo solution (N=60) was given. Just before examination all patients underwent whole gut
irrigation with a polyethylene glycol electrolyte lavage solution (PEG-ELS). Adequacy of preparation,
patient tolerance, and the necessary amount of PEG-ELS were assessed. Physician assessment of colon
cleansing showed superiority in the group with additional laxative. The colon was free of solid debris in
66.7% of patients after PEG-ELS and in 90% after senna/PEG-ELS administration (p less than 0.01).
Patient tolerance was similar in both groups with 86.7% vs. 83.3% of subjects rating the preparation
as tolerable. Severe adverse events were not observed. In the senna/PEG-ELS group, significantly less
(p less than 0.05) lavage fluid was needed. Ziegenhagen et al. (1991) conclude that the
combination of senna and PEG-ELS is more effective than PEG-ELS in cleansing the colon for
colonoscopy.
Frigerio et al. (1996) compared two doses of senna (product containing 1.26-1.85 g dry extract
Sennae fructus acutifoliae corresponding to 150 mg hydroxyanthra-cene glycosides, calculated as
sennoside B; DER 3-5:1, extraction solvent water , per single dose) for colon cleansing. 473 patients
(225 males and 248 females with a mean age of 59.7 years, range 14–96 years) referred for
colonoscopy participated in the randomised, single-blind study. 250 patients (group A) received a dose
of the solution equivalent to 150 mg sennosides in a single administration the evening before the
examination. 223 patients (group B) received two doses, one at mid-day and one on the evening prior
to the examination, equivalent to 300 mg sennosides. All patients were advised to consume liquids
orally according to need, and no enema was given. At the end of the colonoscopy the following scores
were attributed: 0=perfect examination, possible to observe the entire colon mucosa; 1=acceptable
examination, capable of responding to the diagnostic problem but with insufficient observation of some
areas; 2=examination impossible, requiring repetition. Colonoscopy was impossible (and had to be
repeated) in 44 patients (M/F=22/22), 38 of these (15.2%) belonged to group A (150 mg) and 6
(2.7%) belonged to group B. The observed difference was highly significant (p=0.000006). The
examination was acceptable in 148 patients (M/F=79/69), 85 (34.0%) belonging to group A and 63
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(28.3%) to group B (p=0.02). A perfect examination could be carried out in 281 patients, 127 patients
(51%) belonging to group A and 154 patients (69%) belonging to group B. 48 patients (M/F=22/26),
23 (9.2%) belonging to group A and 25 (11.2%) to group B (p=0.568 NS) complained of side effects:
group A: abdominal pain 19, nausea 2, fainting 3; group B: abdominal pain 17, nausea 5, fainting 1,
headache 1. The authors concluded that 300 mg of senna was more efficacious than 150 mg and that
both doses were well tolerated.
Schanz et al. (2008) compared different bowel cleansing modalities referring to tolerability (primary
aim), cleanliness and acceptance (secondary aims). 355 consecutive out-patients between 18 and 75
years undergoing colonoscopy were randomised to 3 groups (A, B, C). Group A received a sodium
phosphate solution. Group B received a sodium phosphate solution and a senna preparation (1.26-1.85
g dry extract Sennae fructus acutifoliae corresponding to 150 mg hydroxyanthracene glycosides,
calculated as sennoside B; DER 3-5:1, extraction solvent water, calculated as sennoside B, per single
dose). Group C received PEG-ELS and the same senna preparation. Gastroenterologists performing
colonoscopy were blinded to the type of preparation. All patients documented tolerance and adverse
events. Vital signs, premedication, completeness, discomfort and complications during the procedure
were recorded. A quality score (0–4) of cleanliness was generated: 0=excellent to 4=repeated
examination necessary. The 3 groups (A=128, B=133, C=94) were similar with regard to age, sex,
Body Mass Index (BMI), indication for colonoscopy and comorbidity. Drinking volumes (l)
(A=4.33+1.2, B=4.56+1.18, C=4.93+1.71) were different (p=0.005). Discomfort from ingested fluid
as recorded in A=39.8% (vs. C: p=0.015), B=46.6% (vs. C: p=0.147) and C=54.6%. No differences
in adverse events and the cleanliness effects occurred in the three groups (p=0.113). Tolerability in
group A was bad in 6.4%, moderate in 21.6% and good in 72%, in group B 7.5%, 20.3% and 72.2%,
respectively, in group C 5.4%, 10.9% and 83.7%, respectively. The cleanliness quality scores 0–2
were calculated in A: 77.7%, B: 86.7% and C: 85.2%. Acceptance between the 3 groups was not
different: refusal for repeated equal preparation procedure reported in A: 14.8%, B: 18.5% and C:
17% (p=0.737). Alternative bowel preparation would prefer in A: 30.2%, B: 30%, C: 37.2% (n.s.).
These data do not demonstrate significant differences in tolerability, preparation quality and
acceptance between the 3 types of bowel preparation for colonoscopy. Cleansing with the sodium
phosphate solution was not superior to PEG-ELS.
According to Kositchaiwat et al. (2006), 134 patients, who needed elective colonoscopy, were
randomly allocated to take 180 mg senna tablets (24 tablets of 7.5 mg sennosides per tablet) or 95 ml
sodium phosphate solution on the day before colonoscopy. The efficacies of both laxatives were
compared using the mean difference of colon-cleanliness score of the rectum, sigmoid segments,
descending colon, transverse colon and cecum. The scores were rated by two observers who were
blinded to the laxatives administered. The higher score means that the colon is cleaner. The efficacy of
both laxatives was equivalent if the 95% confidence interval of the mean difference of the score of
colon lie within -1 to +1. On intention-to-treat analysis, the mean cleanliness scores in the four
segments of colon except the cecum were higher in the sodium phosphate group than those in senna
group (7.9±1.7 vs. 8.3±1.5, 8.0±1.8 vs. 8.5±1.4, 7.9±2.0 vs. 8.5±1.3, 7.9±2.0 vs. 8.2±1.4 and
7.2±1.7 vs. 6.9±1.4, respectively). The 95% confidence intervals (95% CI) of mean difference in each
segment of colon were not found to lie within 1 point which indicated that their efficacies were not
equivalent. The taste of senna was better than sodium phosphate solution. Also, senna had fewer side
effects. It was concluded that the efficacy of senna is not equivalent to sodium phosphate solution in
bowel preparation for colonoscopy, but senna may be considered an alternative laxative.
Valverde et al. (1999) included 523 patients with colonic or rectal carcinoma or sigmoid diverticular
disease, undergoing elective colonic or rectal resection followed by immediate anastomosis in a
prospective, randomised, observer-blind, parallel, multicentre study. 262 patients received senna
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(sennosides corresponding to 120 mg or 240 mg in obese patients) in the evening before surgery. 261
patients received polyethylene glycol (PEG) (2 packages diluted in 2–3 l of water) in the evening
before surgery. All patients received 5% povidone iodine antiseptic enemas (2 l) the evening and the
morning before surgery. Criteria of evaluation were the surgeons’ assessment of bowel cleanliness by a
3-stage score according to Hollender et al. (0=no faecal matter, +=small amount of faecal matter,
++=faecal matter bothersome to the surgery). Other criteria were consistency of faecal matter, rate
and magnitude of intraoperative faecal soiling, rate of abdominal infective complications and patient
tolerance. Colonic cleanliness was better (p=0.006), faecal matter in the colonic lumen was less fluid
(p=0.001), and the risk for moderate or large intraoperative faecal soiling was lower (p=0.11) with
senna. Overall, clinical tolerance did not differ significantly between groups, but 20 patients receiving
PEG (vs 16 with senna) had to interrupt their preparation. Adverse reactions with senna were reported
as follows: discomfort 55 patients (21%), vomiting 12 (4.6%), abdominal pain 35 (13.4%), distension
8 (3%), malaise 23 (8.8%). In the other group the following adverse reactions were reported:
discomfort 55 patients (21.1%), vomiting 7 (2.7%), abdominal pain 30 (11.5%), distension 15
(5.7%), malaise 15 (5.7%). Senna was better tolerated (p=0.03) in the presence of stenosis. There
was no statistically significant difference found in the number of patients with postoperative infective
complications (14.7% vs. 17.7%) or anastomotic leakage (5.3% vs. 5.7%) with senna and PEG,
respectively. The authors concluded that mechanical preparation before colonic or rectal resection with
senna is better and easier than with PEG. An analysis of the subgroups receiving either 120 mg or 240
mg sennosides is not given. All patients additionally received two enemas.
Additional data are presented from clinical trials using standardised herbal medicinal products for
bowel cleansing with an additional enema:
In a prospective randomised clinical trial, three colon cleansing methods for colonoscopy were
compared by Hanggartner et al. (1989) with regard to a) side effects, b) patient acceptance, c)
residual liquid and stool during colonoscopy, and d) quality of the examination. The patients were
randomly assigned to one of the following three groups for colon preparation: Group 1 (n=100) 4 l of
PEG-ELS (polyethylene glycol 3350 and electrolytes for oral solution) , group 2 (n=102) 2 l of PEG-ELS
combined with a Cascara-preparation, and group 3 (n=98), senna preparation (1,26-1,85 g dry extract
Sennae fructus acutifoliae corresponding to 150 mg hydroxyanthra-cene glycosides, calculated as
sennoside B; DER 3-5:1,extraction solvent water) combined with an enema. Group 3 caused
significantly more abdominal cramps than 4 l of PEG-ELS (group 1) or 2 l of PEG-ELS with a Cascara-
preparation (group 2) (p less than 0.001). Vomiting was most frequent in group 1 (p less than 0.05 vs.
group 3). The patients therefore preferred senna preparation to 4 l of Golytely (p less than 0.01). The
cleanest colon was obtained with 4 l of PEG-ELS, while 2 l of PEG-ELS with Cascara-preparation was
least efficacious. The quality of the examination was equal in groups 1 and 3, and clearly better than in
group 2 (p less than 0.01). The authors concluded that while 4 l of PEG-ELS and senna preparation
plus enema have equivalent cleansing efficacy for colonoscopy, patients judged the senna preparation
to be less unpleasant.
Krakamp et al. (1996) tested three different colonoscopy preparation methods in 150 out-patients,
who received colonoscopies, 50 in each group, in a randomised simple-blind study. The original PEG-
ELS -recepture (polyethylene glycol 3350 and electrolytes for oral solution) with 3 l of liquid between 5
and 8 am. on the day of colonoscopy (group 1) was tested against PEG-ELS, which was dissolved in
four litres of liquid and administered between 3 and 7 pm. on the day before colonoscopy (group 2).
Both receptures had the same isotonic salt solutions. The third group was a method with a laxative (a
senna fruit dry extract preparation corresponding to 150 mg hydroxyanthracene glycosides, calculated
as sennoside B, per single dose) administered at 1 pm. on the day before colonoscopy including eating
restriction lasting three days (for 3 days diet easy to digest, the day before colonoscopy clear liquid
EMA/HMPC/228759/2016 Page 53/133
diet) and an enema one hour before colonoscopy. The mean age was 57±19 years in group 1, 55±15
years in group 2 and 57±17 years in group 3. The judgement criteria were the cleanliness of the bowel
by a 4-stage score (‘excellent’ to ‘colonoscopy not possible’), the formation of foam by a 4-stage score
(‘no foam’ to ’examination strongly restricted’) and the subjective sensitivity of the patient during the
preparation phase. The preparation with the three bags containing 3 l of PEG-ELS according to the
original recepture proved to be the least troublesome for the patients and was the most efficient
method when it came to cleanliness and the formation of foam. The costs of this preparation method
were lower than those of the other methods.
Bokemeyer (2000) compared in an open prospective study different colonoscopy preparations in

more than 300 outpatient colonoscopies. Endoscopists assessed the bowel cleanliness by a score 1
(best)–6 (worse). Patients assessed the tolerance and acceptance by a score 1 (best)–6 (worse).
Following colonoscopy preparation with PEG-ELS (2 l on the day before colonoscopy and 2 l on the day
of colonoscopy p.o.), PEG-ELS-RSS (3 l on the day of colonoscopy p.o.) and sodium phosphate
solution(45 ml on the day before and 45 ml on the day of colonoscopy p.o.) mainly good or excellent
cleansing results were found: score for PEG-ELS 2.1, for PEG-ELS -RSS 2.1 and for sodium phosphate
solution 1.9. Colonoscopy preparation with a smaller volume of PEG-lavage solution in combination
with a laxative (1.26-1.85 g dry extract Sennae fructus acutifoliae corresponding to 150 mg
hydroxyanthra-cene glycosides, calculated as sennoside B; DER 3-5:1, extraction solvent water, per
single dose, and an enema and 2 l PEG-ELS on the day before colonoscopy p.o. and an enema in the
morning before colonoscopy) produced significantly worse results: score 3.0. The questioning of the
patients before and after endoscopy demonstrated the sufficient tolerance of colonoscopy preparation
and colonoscopy overall. Problems resulted from a relative large volume of remaining fluid in the bowel
especially after 1-day preparation with PEG-lavage solutions. By using an additional dose of cisaprid
the remaining fluid could be reduced and the cleansing result was better. In patients prepared with
sodium phosphate solution, disturbing bubbles were found more often and in most cases significant
changes were observed in serum electrolyte levels (97.6%).
Clinical studies using calcium sennosides in a daily dose of 120 mg–300 mg HAD for bowel
cleansing (presented as supportive data)
Arezzo (2000) compared in a randomised observer-blind, parallel study the effectiveness and
tolerance of different bowel preparations. 300 patients were randomised into three groups, to be
administered either a senna compound (group 1; 12 tablets each containing 12 mg sennosides A+B at
10 am. and magnesium sulfate 15 g at 5 pm. on the day before colonoscopy p.o.), a PEG lavage
(group 2; 4 l at 4 pm. on the day before colonoscopy p.o.), or an oral sodium phosphate solution
(group 3; 40 ml at 6 pm. on the day before and 40 ml at 6 am. on the day of colonoscopy). After each
colonoscopy, the endoscopist blindly scored cleansing for each bowel segment (‘good’, ‘medium’,
‘scarce’) and defined the quality of the examination as ‘optimal’, ‘acceptable’ or ‘to be repeated’. Bowel
cleanliness was scored as ‘good’ in 38 (group 1), 50 (2), 68 (3) patients. Bowel cleanliness was scored
as ‘good’ or ‘medium’ in 73 (group 1), 77 (2) and 95 (3) patients. Bowel cleanliness was scored as
‘scarce’ in 27 (group 1), 23 (2) and 5 (3) patients. Significant more patients in group 3 (68%)
achieved a good cleansing compared with group 2 (50%) (p<0.0001) and group 1 (38%) (p<0.005).
Significant more patients in group 3 achieved a ‘good’ or ‘medium’ cleansing compared with group 2
and group 1. 63% of constipated patients obtained a good preparation in group 3, which was
significantly higher than in group 1 (28%, p<0.05) and than in group 2 (42%, p<0.02). Feasibility of
the examination was considered ‘optimal’ significantly more in group 3 (80 patients) than in group 2
(62 patients, p<0.005)) and in group 1 (59 patients, p<0.005). There was, however, no difference
between the groups when ‘optimal’ and ‘acceptable’ examinations were considered together (96
patients group 1, 96 patients group 2 and 100 patients group 3). There was no statistically significant
EMA/HMPC/228759/2016 Page 54/133
difference between the three groups with regard to patient tolerance. Eighty seven patients (group 1),
85 patients (2) and 93 patients (3) rated the preparation as ‘good’ (no symptoms), 10 patients (group
1), 10 patients (2) and 5 patients (3) as ‘medium’ (nausea, mild abdominal pain) and 3 patients
(group 1), 5 patients (2) and 2 patients (3) as ‘scarce’ (vomiting, severe abdominal pain, severe
diarrhoea). The author concluded that the sodium phosphate solution should be the standard
preparation for elective colonoscopy.
Tasci et al. (2003) conducted a prospective randomised trial to assess the cleansing ability and
tolerance of bowel preparations for colonoscopy in a group of 953 patients. Of the 1021 patients
enrolled, 68 were excluded from analysis because of intolerance to the solutions or medicinal products,
improper use of the regimen, electrolyte imbalance, and cardiac disorders or vomiting. The bowel
cleansing methods were: i) sennoside calcium (300 ml of a 1 mg/ml solution given 2 days prior to
colonoscopy), ii) PEG lavage (3 l given 1 day prior to colonoscopy), iii) oral sodium phosphate solution
in one 90 ml-dose 1 day prior to colonoscopy, iv) oral sodium phosphate solution in 2 doses (90 ml 1
day prior to colonoscopy+45 ml 5 hours prior to colonoscopy), v) oral sodium phosphate solution in 2
doses (45 ml+90 ml), vi) oral sodium phosphate solution in 2 doses (45 ml+90 ml) plus 10 mg
cisapride, and vii) oral sodium phosphate solution in 2 doses (45 ml+90 ml) plus 10 ml domperidone.
All patients were recommended to take clear liquid diet one day before starting the bowel cleansing
regimen. Sodium phosphate enema was applied to the patients on the morning of colonoscopy. The
efficiency of the different procedures was evaluated according to a 5-point scale. The cisapride-
containing procedure was abandoned partially through the study because of its adverse effects.
Overall, bowel cleansing was effective in 890 (93%) patients. Procedures using sodium phosphate
solution and either cisapride or domperidone were effective in all patients, while the other 5 protocols
led to insufficient bowel preparation in some patients (p<0.05). Among these first 5 protocols, those
using 2 doses of sodium phosphate solution were superior to the single treatments of the first 3 groups
(p<0.05). Tolerance to sennoside calcium and PEG lavage in comparison to other groups was
significantly worse (p<0.05). Of the patients who received sodium phosphate-based treatments, 72%-
78% stated that they would undergo the procedure again if necessary, while only 21% of patients in
the sennoside calcium group and 11% in the PEG group were willing to do so (p<0.05). The authors
concluded that 2 doses of the sodium phosphate solution (45 ml+90 ml) plus domperidone for colon
cleansing is a safe, effective, rapid, inexpensive and well tolerated procedure.
Radaelli et al. (2005) in a trial compared the efficacy and patient acceptance of an oral high dose of
senna to conventional polyethylene glycol-electrolyte lavage solution (PEG-ELS) in adults undergoing
elective colonoscopy. Consecutive outpatients referred for elective colonoscopy were prospectively
randomly assigned to receive, the day before the procedure, either 24 tablets of senna (12 mg extract
of sennoside A and B), divided into two doses at 1 pm. and 9 pm. (senna group, n=191), or standard 4
l PEG-ELS (PEG-ELS group, n=92). The overall quality of colon cleansing (primary outcome measure)
and cleansing in the right colon were evaluated using the Aronchick scoring scale (1=excellent to
4=inadequate; Aronchick et al., 2000) by the investigator/endoscopist who was blinded to the
treatment assignment. Patient acceptance and the safety of the preparation were assessed by a nurse,
using a structured questionnaire covering compliance with the dosing, overall tolerance of the
preparation (1=none or mild discomfort to 4=severely distressing), and adverse events. The quality of
colon cleansing, overall tolerance of the preparation, and compliance were significantly better with
senna; overall cleansing was excellent or good in 90.6% of patients in the senna group and in 79.7%
in the PEG-ELS group (p=0.003). The percentage of procedures rescheduled because of insufficient
colon cleansing was 7.3% in the PEG-ELS group and 2.6% in the senna group (p=0.035). Multivariate
logistic regression modeling showed the PEG-ELS preparation as negative independent predictor of
unsuccessful bowel cleansing. The incidence of adverse reactions was similar in the two groups;
EMA/HMPC/228759/2016 Page 55/133
patients who received senna experienced significantly less nausea and vomiting, but more abdominal
pain. An oral high dose of senna is a valid alternative to standard PEG-ELS for outpatient colonoscopy
preparation.
Patients' compliance with and tolerance of large-volume polyethylene glycol electrolyte solution (PEG-
ELS) have prompted continuous investigation with alternative forms of cleansing. High-dose senna is
superior to PEG-ELS for the quality of bowel cleansing, patient compliance, and tolerance, but its
acceptance may be influenced by the incidence of abdominal pain. Amato et al. (2010) have
proposed that potentially a combination of half doses of PEG-ELS and senna could minimie the
incidence of abdominal pain without affecting the quality of bowel preparation. This randomised;
investigator-blinded trial has been conducted on consecutive outpatients scheduled for elective
colonoscopy at a single community-based hospital. Patients were randomly assigned to receive either
12 tablets of 12 mg senna and 2 l of PEG-ELS (half-dose group, HDG) or 24 tablets of senna divided in
two doses (senna group, SG) the day before colonoscopy. The main outcome measures were the
quality of colon cleansing (Aronchick scoring scale; Aronchick et al., 2000)) and the incidence of
preparation-related abdominal pain. Secondary outcome measures were patients' compliance with the
cleansing regimen, overall tolerability, prevalence of predefined side effects, and quality of right colon
cleansing. A total of 296 patients were enrolled (HDG=151 and SG=145). Overall cleansing was
excellent to good in 90.1 and 88.3% patients in HDG and SG, respectively (P=0.62). Preparation-
related moderate-to-severe abdominal pain was reported by 6% patients in HDG and 15.2% in SG
(P=0.009). No significant differences were observed for secondary outcomes. The author concluded
that the regimen combining half doses of PEG-ELS and senna provides high-quality bowel preparation
and acceptable patient tolerance, with less abdominal pain compared to high-dose senna.
High-quality video colonoscopy requires adequate preparation of the bowel to ensure both adequate
procedure completion rates and polyp detection rates. A prospective audit of the efficacy, safety, and
acceptability of low-volume polyethylene glycol (PEG) (2 l) versus standard volume PEG (4 l) versus
magnesium citrate plus stimulant laxative as bowel preparation for colonoscopy was published by
Kelly et al. (2012). A total of 258 (female: 138; 53.5%) patients were recruited, 91 in the PEG 4 l
group (female: 45, 49.5%), 86 patients in the PEG 2 l group (female: 45; 52.3%), and 81 in the
Senna/magnesium citrate group (female: 44; 54.3%). Significantly more patients were unable to take
the prescribed dose of PEG 4 l when compared with the other 2 regimes (19.6%; P<0.0001 vs.
polyethylene glycol 2 l; P<0.0001 vs. Senna/magnesium citrate). A total of 45.65% of patients
reported PEG 4 l as tasting unpleasant. This was significantly more than both PEG 2 l (10.47%;
P=0.008) and Senna/magnesium citrate (9.88%; P<0.0001). The overall cleansing efficacy across the
3 groups (those with grades A or B) was 73.9%, 74.5%, and 86.5% for PEG 4 l, PEG 2 l, and
Senna/magnesium citrate, respectively. In this series Senna/magnesium citrate proved significantly
better at bowel cleansing than PEG 4 l (P<0.05) and it showed a trend toward better cleansing when
compared with PEG 2 l (P=0.08). In summary, low-volume PEG and Senna/magnesium citrate
combination were better tolerated than large volume PEG with Senna/magnesium citrate providing
superior mucosal cleansing.
The patients were prospectively randomised to 2 arms of sodium phosphate versus sennoside A+B
calcium preparation (medicinal product not mentioned) for the investigation of Manukyan et al.
(2011). Laboratory assessment, body weight, height, and vital signs were obtained at baseline and
before colonoscopy. A self-administered questionnaire was completed by the patients. The time taken
to complete the colonoscopy and the segment of the colon examined were recorded. The patients in
the sennoside A+B calcium group were more comfortable with the taste of the solution. Patients using
sodium phosphate faced more nausea and significantly lower Ca levels and P values. The pulse rate
was significantly higher in this group. Patients in the sennoside group had better grades of bowel
EMA/HMPC/228759/2016 Page 56/133
cleansing in sigmoid and descending segments of the colon. Sennoside A+B calcium is more effective
in some of the colonic segmental cleansing, causes fewer changes on serum electrolyte levels, and is
better tolerated. Split-dosing regime for morning and afternoon lists may have confounded results.
Inadequate bowel cleaning leads to a suboptimal colonoscopic examination. Gum chewing has been
reported to have a favorable effect on postoperative bowel functions. Ergül et al. (2014) conducted a
study to establish if gum chewing added to high-dose senna before colonoscopy promotes bowel
cleaning. In this randomised controlled study, consecutive outpatients scheduled for elective
colonoscopy were randomised into two groups. Group 1 patients (n=65) used senna solution 150 ml
(300 mg senna) the night before colonoscopy. The patients also used sennoside tablet 80 mg daily for
3 days before the colonoscopy. Patients in group 2 (n=64) were additionally advised to chew sugarless
gum half an hour three-times daily after meals for these 3 days. The overall quality of colonoscopy
cleaning was evaluated using the Aronchick scale by a single endoscopist who was blinded to the
intervention (Aronchick et al. 2000). Difficulty of procedure, patients' tolerance, and adverse events
were also evaluated. A total of 129 patients were enrolled in the study. Superior cleaning was found in
the gum chewing group when compared with the other group particularly in the cecum and ascending
colon. Cecal intubation time was significantly shorter in the gum-chewing group (8.6±5.1 and 7.1±2.8
min, P=0.03). Adverse events were more common in group 1 compared to the gum-chewing group.
The authors concluded that gum chewing enhances colonoscopy bowel preparation quality.
Even though polyethylene glycol-electrolyte lavage solution (PEG-ELS)-based regimes have become
the gold standard in recent years, to finish drinking 4 l of PEG-ELS solution can be difficult. The quality
of sennoside-based bowel-cleansing regimes used in Turkey has been known for some time. Therefore,
Altinbaş et al. (2015) aimed to investigate the efficacy of both bowel-cleansing regimes. Patients
over 18 years old undergoing elective colonoscopic procedures between January and March 2011 were
included in the study. The patients were divided into 2 groups; in Group 1, 91 patients were given
sennoside a+b calcium 500 mg/250 ml, and in Group 2, 94 patients were given 4 l of PEG-ELS. The
mean age of the patients and the male distribution were similar in the 2 groups. Both inadequate
bowel cleansing and the best cleansed bowels were seen in Group 1. The number of inadequate
colonoscopies declined when using a whole bowel-cleansing regime from 24.5% to 19.3% in Group 2,
but it did not decline in Group 1. The best bowel cleansing can be achieved with sennoside-based
regimes, whereas a higher proportion of adequate results via colonoscopy were reached with the PEG-
ELS-based regimes.
Taylor et al. (2008) set out to establish the optimum barium-based reduced-laxative tagging
regimen prior to CT colonography (CTC). Ninenty five subjects underwent reduced-laxative (13 g
senna/18 g magnesium citrate) CTC prior to same-day colonoscopy and were randomised to one of
four tagging regimens using 20 ml 40% w/v barium sulphate. Regimen A: four doses, B: three doses,
C: three doses plus 220 ml 2.1% barium sulphate, or D: three doses plus 15 ml diatriazoate
megluamine. Patient experience was assessed immediately after CTC and 1 week later. Two
radiologists graded residual stool (1: none/scattered to 4: >50% circumference) and tagging efficacy
for stool (1: untagged to 5: 100% tagged) and fluid (1: untagged, 2: layered, 3: tagged), noting the
Hounsfiled units (HU) of tagged fluid. Preparation was good (76-94% segments graded 1), although
best for regimen D (P=0.02). Across all regimens, stool tagging quality was high (mean 3.7-4.5) and
not significantly different among regimens. The HU of layered tagged fluid was higher for regimens C/D
than A/B (P=0.002). Detection of cancer (n=2), polyps >or =6 mM (n=21), and <or =5 mM (n=72)
was 100, 81 and 32% respectively, with only four false positives >or =6 mm. Reduced preparation
was tolerated better than full endoscopic preparation by 61%. Reduced-laxative CTC with three doses
of 20 ml 40% barium sulphate is as effective as more complex regimens, retaining adequate diagnostic
accuracy.
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The effectiveness of polyethylene glycol solutions (PEG) for colon cleansing is often limited by the
inability of patients to drink adequate portions of the 4 l solution. The aim of the study of Hookey et
al. (2006) was to determine whether a reduced volume of PEG combined with stimulant laxatives
would be better tolerated and as or more effective than the standard dose. Patients undergoing
outpatient colonoscopy were randomly assigned to receive either low-volume PEG plus sennosides
(120 mg oral sennosides syrup followed by 2 l PEG) or the standard volume preparation (4 l PEG). The
subjects rated the tolerability of the preparations and their symptoms. Colonoscopists were blind to the
colonic cleansing preparation and graded the cleansing efficacy using the Ottawa scale (Rostom and
Jolicoeur 2004). The low-volume PEG plus sennosides preparation was significantly better tolerated
than the standard large volume PEG (P<0.001) but was less efficacious (P=0.03). Thirty-eight per cent
of patients in the large volume PEG group were unable to finish the preparation, compared with only
6% in the reduced volume group. There were no adverse events reported. Although the low-volume
PEG plus sennosides preparation was better tolerated, it was not as effective as standard large-volume
PEG. However, in view of the significant difference in tolerance, further research investigating possible
improvements in the reduced-volume regimen seems warranted.
Senna has also been investigated in combination with low-volume PEG solutions in three trials (Lemli
et al., 1983, Iida et al., 1992, Ziegenhagen et al., 1991). Although Iida et al. (1992) reported
increased efficacy with 2 l of PEG combined with sennosides (36 mg), this trial was nonrandomised,
used a historical control group, and data collection from both patients and endoscopists was
incomplete. Another approach was reported by Ziegenhagen et al. (1991), in which PEG was
administered by mouth or nasogastric tube the morning of colonoscopy until rectal effluent was clear.
The addition of senna the night before significantly reduced the amount of PEG required for an
adequate preparation. Recently, 2 l of PEG and 120 mg of sennosides syrup were compared with 4 l of
PEG, and results showed that although the lower volume preparation was better tolerated, it was less
efficacious (Lemli et al., 1983). In the present review, the sennosides were given just before the
ingestion of PEG and altering the timing of the sennosides from 30 min to 60 min before the PEG may
be more beneficial.
Iida et al. (1992) reported increased efficacy with 2 l of PEG combined with sennosides (36 mg). This
trial was non-randomised, used a historical control group, and data collection from both patients and
endoscopists was only partially complete. Senna has also been investigated in combination with low-
volume PEG solutions in different trials. Another approach was reported by Ziegenhagen et al. (1991),
in which PEG was administered orally or by nasogastric tube the morning of colonoscopy until rectal
effluent was clear. The addition of senna the night before significantly reduced the amount of PEG
required for an adequate preparation. In another study, 2 l of PEG and 120 mg of sennosides syrup
were compared with 4 l of PEG, and results showed that the lower volume preparation was better
tolerated, though it was less efficacious (Hookey et al., 2006). In the review of Hookey et al. (2007),
the sennosides were given just before the ingestion of PEG and altering the timing of intake of
sennosides from 30 min to 60 min before the PEG may be more beneficial.
PEG-ELS, which is the goldstandard agent for precolonoscopic bowel preparation, has an important
problem to be overcome: its large volume. In accordance with the literature, only 70% of patients
were able to finish the whole PEG-EL solution before the colonoscopic procedure. For this reason,
investigators have worked on therapeutic options to reduce the PEG-EL solution volume in recent years
(Altinbas et al., 2015).
Clinical trials using senna and sennoside preparations below 80 mg HAD per day are
described below:
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In an uncontrolled study Iida et al. (1992) investigated a colon cleansing preparation regimen in
which examinees had to drink 2 l of PEG-ELS on the day of examination by taking 36 mg of sennosides
(no further information of the formulation) orally in the evening before colonoscopy. Bowel preparation
was carried out in 297 examinees (219 male and 78 female; mean age 57 years). No special diet was
recommended. 97% of the patients were able to drink the total dose of 2 l PEG-ELS. Bowel cleanliness
was assessed as ‘excellent’ or ‘good’ in 90% to 97% of the patients at all sites in the colon and rectum.
There was a tendency for better irrigation to be achieved in the proximal colon compared with the
distal colon. With regards to foam and peristalsis, there were no problems in 85% respectively 92% of
the patients. No severe adverse reactions were noted. During the drinking of PEG-ELS, 1% of patients
complained of abdominal pain, 10% of chills or nausea and 24% of abdominal fullness. 54% of
patients had no adverse reactions.
Chilton et al. (2000) compared in a randomised, observer-blind, parallel study a novel low-dose,
low-volume triple regimen with sodium phosphate solution. A blinded, experienced colonoscopist
examined 132 consecutive patients randomly allocated to receive i) either a triple regimen consisting
of 75 mg sennoside A+B at 10 am.+sodium picosulphate 10 mg at 2 pm.+PEG-ELS 1 l at 6 pm. on the
day before colonoscopy when colonoscopy took place before 12 am. or 75 mg sennosides A+B at 2
pm.+sodium picosulphate 10 mg at 6 pm.+PEG-ELS 1 l at 7 am. on the day of colonoscopy when
colonoscopy took place after 12 am. (n=81), ii) or sodium phosphate solution 45 ml at 8 am. and 45
ml at 8 pm. on the day before colonoscopy when colonoscopy took place before 12 am. or sodium
phosphate solution 45 ml at 8 pm. and at 8 am. in the morning of the colonoscopy when colonoscopy
took place after 12 am. (n=51). Endoscopists assessed bowel cleanliness by a 4-stage score (excellent,
good, intermediate, poor). Further on time taken to reach the caecum and completeness of
examination were assessed. In the triple regimen group, 73% of the patients were scored ‘excellent’ or
‘good’ compared with 57% in the other group (p=0.037 Mann-Whitney U-test). Examination of the
caecum was achieved in 95% of patients of the triple regimen group and in 89% of the other group.
Among those examined as far as the caecum, the time to reach the caecum was 11 minutes (range 5–
50 min) in the triple regimen group compared with 16 minutes (range 5–65 min) in the other group
(p=0.08, Mann-Whitney U-test). Patient tolerability was not assessed in this study. The authors
concluded that this novel triple regimen produces a cleaner colon than Phospho-soda, is associated
with a trend towards a quicker and more efficient colonic examination, and is also 30% cheaper per
patient.
Four liters or more of orally taken polyethylene glycol solution (PEG) has proved to be an effective
large-bowel cleansing method prior to colonoscopy. The problem has been the large volume of fluid
and its taste, which is unacceptable to some examinees. Haapamäki et al. (2011) aimed to
investigate the effectiveness of 2 l PEG combined with senna compared with 4 l PEG for bowel
preparation. The design was a single-center, prospective, randomised, investigator-blinded study with
parallel assignment, in the setting of the Endoscopy Unit of Umeå University Hospital. Outpatients
(n=490) scheduled for colonoscopy were enrolled. The standard-volume arm received 4 l PEG, and the
low-volume arm received 36 mg senna glycosides in tablets and 2 l PEG. The cleansing result (primary
endpoint) was assessed by the endoscopist using the Ottawa score. The patients rated the subjective
grade of ease of taking the bowel preparation. Analysis was on an intention-to-treat basis. There were
significantly more cases with poor or inadequate bowel cleansing after the low-volume alternative with
senna and 2 l PEG (22/203) compared with after 4 l PEG (8/196, p=0.027). The low-volume
alternative was better tolerated by the examinees: 119/231 rated the treatment as easy to take
compared with 88/238 in the 4 l PEG arm (p=0.001). Four l PEG treatment is better than 36 mg senna
and 2 l PEG as routine colonic cleansing before colonoscopy because of fewer failures.
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Capsule endoscopy (CE) is limited by incomplete small-bowel transit and poor view quality in the distal
bowel. Currently, there is no consensus regarding the use of bowel purgatives or prokinetics in CE. To
evaluate the usefulness of bowel purgatives and prokinetics in small-bowel CE. The cited study is a
prospective single-blind randomised controlled study by Postgate et al. (2009). A total of 150
patients were prospectively recruited. Patients were randomised to 1 of 4 preparations: "standard"
(fluid restriction then nothing by mouth 12 hours before the procedure, water and simethicone at
capsule ingestion [S]); "standard"+10 mg oral metoclopramide before the procedure (M); magnesium
citrate+senna bowel-purgative regimen the evening before CE (CS); magnesium citrate+senna+10 mg
metoclopramide before the procedure (CSM). The primary outcome measures were gastric transit time
(GTT) and small-bowel transit time (SBTT), completion rates (CR), view quality, and patient
acceptability. Secondary outcome measures: positive findings, diagnostic yield. No significant
difference was noted among groups for GTT (median [minutes] M, CS, and CSM vs S: 17.3, 24.7, and
15.1 minutes vs 16.8 minutes, respectively; P=0.62, 0.18, and 0.30, respectively), SBTT (median
[minutes] M, CS, and CSM vs S: 260, 241, and 201 vs. 278, respectively; P=0.91, 0.81, and 0.32,
respectively), or CRs (85%, 85%, and 88% vs 89% for M, CS, and CSM vs. S, respectively; P=0.74,
0.74, and 1.00, respectively). There was no significant difference in view quality among groups (of 44:
38, 37, and 40 vs. 37 for M, CS, and CSM, vs S, respectively; P=0.18, 0.62, and 0.12, respectively).
The diagnostic yield was similar among the groups. CS and CSM regimens were significantly less
convenient (P<.001), and CS was significantly less comfortable (P=.001) than the standard
preparation. The authors concluded that bowel purgatives and prokinetics did not improve CRs or view
quality at CE, and that bowel purgatives reduce patient acceptability.
Assessor’s comment:
No specific posology for senna; two “packets of senna”.
As with colonoscopy, adequate bowel cleansing is essential prior to colon capsule endoscopy (CCE).
Because CCE requires that the capsule traverse the entire gastrointestinal tract during the
examination, laxative 'boosters' are used. The objective of a prospective, single-center, single-arm
study by Kashyap et al. (2015) was to evaluate the safety of a bowel preparation consisting of
polyethylene glycol (PEG) plus an oral sulfate solution. Subjects were healthy volunteers aged 50-75
years old with normal baseline serum chemistry. The bowel preparation consisted of 4 senna tablets, 4
l of PEG (split dose), 10 mg metoclopramide, 2 oral sulfate solution boosters (6 oz. and 3 oz.), and 10
mg bisacodyl. Serum chemistry was performed at baseline, following PEG intake, 24 hours after
bisacodyl administration, and at 7 days post procedure (in subjects with abnormal 24-hour results).
The primary endpoints were the percentage of subjects with a clinically significant change in serum
chemistry at the last test and the adverse event (AE) rate. A total of 25 subjects were enrolled. The
serum chemistry was normal in all subjects at the final evaluation. One subject showed a slight
elevation in creatinine (1.08 mg/dl 7 days post procedure from 0.84 mg/dl at baseline), deemed not
clinically significant. Another subject had a transient elevation in serum creatinine (from 1.01 mg/dl at
baseline to 1.45 mg/dl at 24 hours after the bowel preparation); values returned to near baseline at 7
days post procedure (1.06 mg/dl). There were no serious adverse events (AEs), three moderate AEs
related to the bowel preparation (nausea, headache, elevated creatinine) and two mild unrelated AEs
(chills, abdominal cramping). The authors concluded that a bowel cleansing regimen of PEG plus an
oral sulfate solution can be used in healthy volunteers.
The aim of a study by Poyrazoglu and Yalniz (2015) was to compare the efficacy, adequacy, side
effects, and patient compliance of sodium phosphorus (NaP) and senna solutions when preparing the
colon before colonoscopy. A total of 137 consecutive patients who were considered for colonoscopy
evaluation had randomly received one of two premeditated regimens: 90 ml of oral NaP (NaP group) or
500 ml of 1,000 mg of sennosides A and B calcium+66.6 g of sorbitol (senna group). Patients'
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compliance with the bowel-cleansing method was determined using a questionnaire prior to the
colonoscopic examination. On the other hand, the adequacy of the bowel-cleansing method was
evaluated by the colonoscopist who was blind to the bowel-cleansing regimen used prior to the
examination of the colon from the rectum to the cecum. Nausea and vomiting complaints were seen
more frequently in the NaP group than in the senna group (47 vs. 28 and 31 vs. 10; P<0.05 and
P<0.01, respectively). The response to the question of whether the patients would like to use the same
regimen again or not was similar in both groups. The acceptable bowel-cleansing rate was also
comparable across both groups. Nevertheless, the number of patients that experienced excellent bowel
cleansing in terms of general appraisal of the colonoscopic evaluation was significantly higher in the
NaP group than in the senna group (46 vs. 25; P<0.001). Although bowel cleansing was better in the
NaP group, both cleansing regimens were comparable regarding the admissibility of the preparations
for the procedure. The authors concluded that the senna regimen is, however, superior to the NaP
regimen in terms of application compliance and its side effects, and it may be an effective alternative
for cleansing the bowel prior to colonoscopic examination.
To prospectively investigate the effectiveness and patient's tolerance Vradelis et al. (2009)
investigated two low-cost bowel cleansing preparation protocols based on magnesium citrate only or
the combination of magnesium citrate (1 sachet contains 11.6 g magnesium carbonate and 17.8 g
anhydrous citric acid) and senna (1 sachet; no further information). A total of 342 patients who were
referred for colonoscopy underwent a colon cleansing protocol with magnesium citrate alone (n=160)
or magnesium citrate and senna granules (n=182). The colonoscopist rated the overall efficacy of
colon cleansing using an established score on a 4-point scale. Patients were questioned before
undergoing colonoscopy for side effects and symptoms during bowel preparation. The percentage of
procedures rescheduled because of insufficient colon cleansing was 7% in the magnesium citrate group
and 4% in the magnesium citrate/senna group (P=0.44). Adequate visualization of the colonic mucosa
was rated superior under the citramag/senna regimen (P=0.004). Both regimens were well tolerated,
and did not significantly differ in the occurrence of nausea, bloating or headache. However, abdominal
cramps were observed more often under the senna protocol (29.2%) compared to the magnesium
citrate only protocol (9.9%, P<0.0003). It was concluded that the addition of senna to the bowel
preparation protocol with magnesium citrate significantly improves the cleansing outcome.
Conclusions on herbal preparations of senna pods for bowel cleansing
In the European Union, there exist medicinal products with senna pod herbal preparations as active
substance with an indication in the therapeutic area of bowel cleansing before diagnostic investigations
or surgery.
The safety and efficacy of senna pods in this indication has as well been investigated in more than 20
clinical trials. A series of clinical trials with an extract of senna pods (e.g. Ziegenhagen et al., 1991;
Frigerio et al., 1996; Schanz et al., 2008; Kosichaiwat et al., 2006; Valverde et al., 1999) proved
effectiveness for bowel cleansing. Some of these trials compared efficacy with treatment with sodium
phosphate solution and it was concluded that treatment with senna extract was not absolutely
equivalent to the treatment with sodium phosphate.
However, especially the clinical studies by Ziegenhagen et al. (1991, senna/PEG-ELS-group with
significantly less lavage fluid needed in comparison to PEG-ELS-placebo group), Valverde et al. (1999,
better cleansing for senna group compared to PEG-group) and Krakamp et al. (1996, 90% of senna
group adequately prepared in comparison with different PEGpreparations) clearly support well-
established use. The results of further clinical trials with isolated sennosides are additionally
contributing to the evidence. When higher dosages of senna pod preparations (equivalent to about
300 mg sennosides) were compared with lower dosages (equivalent to about 150 mg sennosides),
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higher dosages were slightly more effective, but revealed more adverse effects (e.g. Amato et al.,
2010).
The HMPC concluded that the requirements for well-established use with the indication “Herbal
medicinal product for bowel cleansing prior to clinical procedures requiring bowel preparations” are
fulfilled. A dosage equivalent to 150 mg sennosides is considered sufficient. It is up to the health care
professional to integrate the use of senna pod preparations into an adequate preparatory scheme such
as for instance described by Krakamp et al., 1996: “The preparation starts with a three days diet of
clear fluids, the herbal preparation is to be applied between 2 pm. and 4 pm. of the day before the
examination followed by a glass of water and drinking of 2 l of clear fluids until bedtime. No solid food
intake until examination.”. When deciding about appropriateness of application of senna pod
preparations, in this indication, it must be considered that standard therapies with sodium phosphate
or PEG-solutions was slightly more effective, but senna preparations were better tolerated (Amato et
al. 2010; Manukyan et al., 2011; Hookey et al., 2006). For senna preparations less vomiting but more
frequent spasms have been observed. Application of senna pod preparations may be a reasonable and
effective therapeutic option for patient groups with limitations in intake of high volumes of fluids.
4.2.2.4. Postoperative constipation
Patel et al. (2010) the objective of the study was to compare time to first bowel movement (BM)
after surgery in subjects randomised to placebo or senna with docusate. Ninety-six subjects completed
a baseline 7-day bowel diary before and after surgery. After pelvic reconstructive surgery, the subjects
were randomised to either placebo (n=45) or senna (8.6 mg) with docusate (50 mg) (n=48). Time to
first BM and postoperative use of magnesium citrate were compared. There was a significant difference
in the time to first BM in those receiving senna with docusate vs placebo (3.00±1.50 vs 4.05±1.50
days; P<0.002). More subjects in the placebo group needed to use magnesium citrate to initiate a
bowel movement (43.6% vs. 7.0%; P<0.001). As the outcome was reported that the use of senna
with docusate decreases time to first BM in those undergoing pelvic reconstructive surgery compared
with placebo. Furthermore subjects using senna with docusate were also significantly less likely to use
magnesium citrate.
4.2.2.5. Postoperative opiod-induced constipation
Marciniak et al. (2014) investigated the efficacy of lubiprostone compared to senna on bowel
symptoms and constipation in post-operative orthopedic patients treated with opioids. In this double
blind, randomised, active comparator trial, adults who required opioids for analgesia following
orthopedic procedures and who were admitted in inpatient rehabilitation were randomised following
baseline assessments to lubiprostone , orally twice a day or Senna (generic; no further information)
two capsules administered daily for six days. Subjects were assessed using the patient assessment of
constipation (PAC)-symptoms (PAC-SYM) and the PAC-quality of life (PAC-QOL) scales measured at
baseline and day 7; Subjects were assessed daily for secondary measures including the Bristol stool
scale bowel consistency, specific bowel symptom score (Nausea, cramping, straining, completeness,
abdominal pain, time per lavatory attempt, assistance needed), adverse events and rescue
medications required. Function was measured using the functional independence measure (FIM) at
admission and discharge. Length of stay (LOS) and missed treatments due to gastrointestinal
symptoms were also assessed. Sixty four adults were enrolled; 56 participants (28 in each group) had
baseline and follow up measures and were included in the intention to treat (ITT) analyses. Forty three
participants completed the study, 21 in the active lubiprostone and 22 in the active senna group. The
mean age of the participants was 71.5 years (SD=11.4 years, range: 28-96 years). In the ITT
analyses, participants showed significant improvement in bowel symptoms as measured by the PAC-
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SYM (mean±SD, -0.28±0.60, range: -1-2.33) and PAC-QOL (mean±SD, 0.33±0.81, range: -1.5-2.0)
over time, but there were no significant differences between the lubiprostone and senna groups in
mean change in the PAC-SYM (-0.20±0.60 vs. -0.36±0.61, P=0.61 respectively) or the PAC-QOL
(0.29±0.76 vs. 0.37±0.87, P=0.61 respectively). The mean change in each bowel symptom also did
not significantly differ between treatment groups on ITT analyses, except for completeness of bowel
movement, with the senna group showing higher negative mean change in bowel movement
completeness (-0.56±1.01 vs.-2.00±1.41, P=0.03) and for reduction of abdominal pain, favoring
senna (-0.14±0.73 vs. -0.73±1.08, P=0.04). Fifteen (75%) participants in the lubiprostone and in the
senna group requested rescue treatments. Participants made significant functional improvement from
admission to discharge over a median LOS of 12 d, with a mean FIM change of 29.13±13.58 and no
significant between group differences (27.0±9.2 vs. 31.5±16.6, P=0.27). The authors concluded, both
lubiprostone and senna improved constipation-related symptoms and QOL in opioid-induced
constipation, with no significant between-group differences.
4.2.2.6. Chemotherapy-induced constipation
In the study by Tao et al. (2012) 82 patients suffering from constipation after chemotherapy were
assigned to Group AB and Group BA. Group AB referred to patients who first took senna extract
(extraction solvent: no information available) in the 1st chemotherapeutic course and the crude fiber
diet in the 2nd chemotherapeutic course. But the sequence was just the opposite in Group BA. The
effective rates of relieving chemotherapy-induced constipation by senna extract and by the crude fiber
diet were observed. The differences of the digestive tract reaction and the hematotoxicity reaction
were compared. The conditions of patients' abdominal pain and stool properties were observed after
they took senna extract.The effective rate of constipation by taking senna extract was 92.68% and
that by the crude fiber diet was 10.93%, with statistical difference shown (P<0.01). There was no
statistic difference in adverse reaction rate such as decreased neutrophils over degree II, decreased
hemoglobin, decreased platelet, nausea, vomit, etc. (P>0.05). The occurrence rate of abdominal pain
over degree II after taking senna was 8.54%. In the distribution of stool properties, the rate of loose
stool was 35.53%.
4.2.2.7. Constipation in people receiving palliative care
Constipation is a frequent cause of distress in advanced cancer. Ramesh et al. (1998) conducted in a
palliative care unit a controlled trial comparing a liquid Ayurvedic (herbal) preparation with a
conventional laxative tablet (purified senna extract 60 mg containing 12 mg senna glucocides as
calcium salts) in the management of opioid-induced constipation in 50 patients with advanced cancer.
Laxative tablets were given in increasing amounts (2 tablets at night; 4 tablets at night; 2 tablets in
the morning+4 tablets at night every 2 days; n=25); the liquid Ayurvedic preparation in 2.5 ml; 5 ml;
10 ml. Although there was no statistically significant difference in the apparent degree of laxative
action between the two, the authors concluded that the small volume of the drug required for effective
laxative action, the tolerable taste, the once-daily dose, the acceptable side effect profile, and the low
cost make the Ayurvedic liquid a good choice for prophylaxis in opioid-induced constipation.
Agra et al. (1998) enrolled 91 terminal cancer patients treated with opioids in a randomised, open,
parallel group trial to determine treatment and cost efficiency for senna derivatives and lactulose and
to determine their efficacy at different opioid doses. Constipation is a frequent condition in terminal
cancer patients, approximately 80% of whom need laxatives to counteract it. The period of the study
was 7 days to assess laxative efficacy on defaecation days and laxative efficacy at variable opioid
dosage and 27 days to assess the mean morphine dose at which a laxative was necessary. Both
laxative and opioid treatments were initiated simultaneously. Laxative dosage increases were
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determined as a function of the patient’s intestinal rhythm, irrespective of opioid dose variation. Initial
daily intake in two doses was 0.4 ml (12 mg) for senna (no other information of the formulation are
given) and 15 ml (10 g) for lactulose, with increments of 0.4 ml and 15 ml, respectively, every 3 days,
according to clinical response. Maximum doses were 1.6 ml (48 mg) for senna and 60 ml (40 g) for
lactulose. When a patient reached the ceiling of his respective laxative and had a defaecation-free
period of 3 days, he was maintained on that dose and, in the absence of side effects, he was also given
the initial dose of the other laxative, which could then be increased at 3-day intervals until reaching
the experimental maximum. Forty three patients were assigned to senna and 48 to lactulose. Sixteen
patients dropped out during the first 4 days. By the end of the 27 days, 37 patients were lost: 21 in
the senna group and 16 in the lactulose group. Three developed vomiting, five refused to continue in
the protocol, 17 died, and 12 were hospitalised. No significant differences were found regarding the
number of defaecation-free 72-hour periods, mean number of defaecation days, or the general state of
health between the experimental groups. There were no differences in the respective defaecation-free
72-hour intervals as a function of opioid. The number of defaecation days was similar in both groups
(senna: mean 8.9 days; SD 6.6 days; lactulose: mean 10.6 days, SD 7.3 days). 37.5% of patients
tracked until the end of the study period required both laxatives. During the first 7 days, 6 patients (3
treated with senna and 3 treated with lactulose) presented adverse effects (diarrhoea, vomiting, and
cramps) easy to manage with conventional therapy. Fifteen patients, 8 with senna and 7 with
lactulose, required laxatives from days 12–27 of the study. The mean morphine dose at which
laxatives proved necessary was 84.1 mg (SD 72.3 mg).
To evaluate the evidence for clinically established pharmacological therapies for constipation in
palliative care, a systematic literature review was performed by Bader et al. (2012) in different
databases (Cochrane Library, Embase, PubMed, Ovid MEDLINE, CINAHL), textbooks, and publications.
Whereas 130 randomised controlled trials were found with patients outside of palliative care settings,
only 10 controlled studies with patients in end-of-life situations were identified: three RCTs with
methylnaltrexone and one with the combination of oxycodone and naloxone showed the effect and
safety of opiate antagonists for patients who are not at risk of gastrointestinal perforation. There have
been no studies which test methylnaltrexone against the optimization of therapy with conventional
laxatives. Six other controlled studies of limited quality in design and execution and with only few
participants tested naloxone, senna, lactulose, co-danthramer, an Ayurvedic preparation, magnesium
hydroxide, fluid paraffin, sodium picosulfate and docusate without finding statistically significant
differences in efficacy or side effects. Most patients in these studies had cancer. Only case studies with
few patients in palliative care were found for meglumine, neostigmine, and other substances
mentioned above. The authors concluded that evidence on medical treatment of constipation in
palliative care is sparse and guidelines have to refer to evidence from outside the palliative care setting
and to expert opinions. Results from studies with other patient groups can only be transferred with
limitations to very ill patients at the end of life who might have a higher risk for potential side effects
such as gastrointestinal perforation in case of abdominal tumor manifestation. Therefore further
studies are required to evaluate the medical treatment of multiple reasons for constipation in these
patients. These studies should focus on feasibility, clinical relevance and quality of life.
Constipation is reported in 52% of people with advanced malignancy. This figure rises to 87% in
people who are terminally ill and taking opioids. Constipation may be the most common adverse effect
of opioids. There is no reason to believe that people with chronic non-malignant disease who take
opioids will be any less troubled by this adverse effect. Ahmedzai and Boland (2010) conducted a
systematic review and aimed to answer the following clinical questions: What are the effects of oral
laxatives, rectally applied medications, and opioid antagonists for constipation in people prescribed
opioids? They searched: Medline, Embase, The Cochrane Library, and other important databases up to
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August 2009. They included harms alerts from relevant organisations such as the US Food and Drug
Administration and the UK Medicines and Healthcare products Regulatory Agency. The authors found
23 systematic reviews, RCTs, or observational studies that met the inclusion criteria. They performed a
GRADE evaluation of the quality of evidence for interventions. In this systematic review information
relating to the effectiveness and safety of the following interventions were presented: arachis oil
enemas, bisacodyl, co-danthrusate/co-danthramer, docusate, glycerol suppositories, ispaghula husk,
lactulose, liquid paraffin, macrogols plus electrolyte solutions, magnesium salts, methylcellulose, opioid
antagonists, phosphate enemas, senna, sodium citrate micro-enema, and sodium picosulfate. The RCT
they found suggested that the outcomes after senna are similar to those of lactulose. The agent of
choice therefore depends on patient preference and local cost. Despite the lack of strong RCT evidence,
senna is used commonly in the UK in people taking opioids. Senna is recommended in the UK over
lactulose as it is similar in terms of benefits and adverse effects but is less expensive. Further RCTs are
needed. Oral laxatives and rectal suppositories can only palliate the symptoms of opioid-induced
constipation and do not relieve other aspects of opioid-induced bowel dysfunction such as delayed
gastric emptying and abdominal cramps.
A second update of a Cochrane review on the effectiveness of laxatives for the management of
constipation in people receiving palliative care was published in 2015. Previous versions were published
in 2006 and 2010. In these earlier versions, the authors drew no conclusions on individual
effectiveness of different laxatives because of the limited number of evaluations. This is despite
constipation being common in palliative care, generating considerable suffering due to the unpleasant
physical symptoms and the availability of a wide range of laxatives with known differences in effect in
other populations. To determine the effectiveness and differential efficacy of laxatives used to manage
constipation in people receiving palliative care. The Cochrane Central Register of Controlled Trials
(CENTRAL; The Cochrane Library), MEDLINE, EMBASE, CINAHL and Web of Science (SCI & CPCI-S) for
trials to September 2014 were searched. Randomised controlled trials (RCTs) evaluating laxatives for
constipation in people receiving palliative care were included. Two authors assessed trial quality and
extracted data. The appropriateness of combining data from the studies depended upon clinical and
outcome measure homogeneity. Five studies involving the laxatives lactulose, senna, co-danthramer,
misrakasneham (an Ayurvedic preparation), docusate and magnesium hydroxide with liquid paraffin
were identified. Overall, the study findings were at an unclear risk of bias. As all five studies compared
different laxatives or combinations of laxatives, it was not possible to perform a meta-analysis. There
was no evidence on whether individual laxatives were more effective than others or caused fewer
adverse effects. This second update found that laxatives were of similar effectiveness but the evidence
remains limited due to insufficient data from a few small RCTs. None of the studies evaluated
polyethylene glycol or any intervention given rectally. The authors concluded that there is a need for
more trials to evaluate the effectiveness of laxatives in palliative care populations. Extrapolating
findings on the effectiveness of laxatives evaluated in other populations should proceed with caution.
This is because of the differences inherent in people receiving palliative care that may impact, in a
likely negative way, on the effect of a laxative (Candy et al., 2015).
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Table 5: Clinical studies on humans in constipation
References Design Test Product(s): Number Type of Outcomes Statistical Relevance

of analysis
subjects
subjects
Pers et al. Prospective A: 2.6 g Semen plantaginis 20; 1 Severe No difference between the No Limited
(1983) randomised ovata, 0.11 g Ispaghula husk dropout constipation preparation information relevance
and 0.62 g Sennae fructus available for
angustifolie equivalent to 15 Diarrhoea assessment
mg glycoside A+B per sachet of unknown (combina-
of 5 g origin tion of
laxatives)
B: 3.3 g testa ispaghula and
25 mg glycoside sennae A+B
per sachet
1 week prior
2 weeks Prep A
2 weeks Prep B
Marlett et al. Controlled, Ispaghula husk (7.2 g per 42 adults No No relevant outcome No Limited
(1987) randomised, day), n=20 information information relevance
single-blind available available for
Psyllium plus senna (6.5 assessment
g+1.5 g per day) for 1 week (combina-
n=22 tion of
laxatives)
Passmore et Randomised, Ispaghula 54.2%, senna 77 elderly History of Mean daily bowel frequency No Limited
al. (1993a, double-blind, 12.4% (m/m) and lactulose patients chronic was higher with the senna- information relevance
1993b) crossover senna-fibre combination 10 (average constipation fibre combination (0.8, 95% available for
study ml daily with lactulose-active age: 82.9 confidence interval 0.7 to assessment
senna-fibre combination 10 years) 0.9) than with lactulose (0.6 (combina-
ml daily with lactulose (0.5 to 0.7); t=3.51, tion of
placebo 15 ml twice daily p<0.001). The senna-fibre laxatives)
combination was
Active lactulose 15 ml twice significantly more effective
daily with senna-fibre placebo than lactulose at a lower
10 ml daily for two 14 day
Assessment report on Senna alexandrina Mill., (Cassia senna L.; Cassia angustifolia Vahl), folium and fructus
EMA/HMPC/228759/2016 Page 66/133
References Design Test Product(s): Number Type of Outcomes Statistical Relevance
of analysis
subjects
subjects
periods cost
Maximum daily dose for
active or placebo senna-fibre
was 20 ml (10 ml twice daily)
and for lactulose or lactulose
placebo 60 ml
Kinnunen et Open, A: Plantago ovata seed 521.6 30 long- Chronic Bowel frequency per week No Limited
al., 1993 randomised mg (bulk forming), Fructus stay elderly constipation significantly higher on A information relevance
and cassiae angustifoliae 138 mg patients treatment during both available for
controlled (stimulant) aged 65– periods; compared to B assessment
crossover 94 years mean (SD): (combina-
study B: 30 ml lactulose (mean tion of
81.8) (A) In period I: 4.5 (2.3) laxatives)
In period I,
21 patients (A) In period II: 4.5 (2.4),
received A (B) In period I 2.2 (0.9)
and 9 (p=0.0006)
patients B;
in period II, (B) In period II 1.9 (0.9)
7 patients (p=0.027)
received A
and 18
patients B
Table 6: Clinical study in irritable bowel syndrome
Reference Study Test Product(s): Number Type of Outcomes Statistical Clinical

Design of subjects analysis relevance
subjects
Hübner and 12-week Tablets CL+(containing as 284 Irritable Amelioration of symptoms in Limited
Moser double blind, active ingredients “180 mg patients bowel PP population by 62.5% relevance for
controlled, Carbo ligni”, i.e. vegetable, between 19 syndrome with CL+ and 56.5% with Two-sided assessment
EMA/HMPC/228759/2016 Page 67/133
subjects
(2002) randomised, non-activated charcoal, “105 and 70 (IBS) CL; respective values in the Mann-Whitney (combination
multicentre mg Fol. Sennae, 25 mg years ITT population were 59.6% U test; of laxatives),
and rhubarb extract” 2.65–3.95 Rome and 53.2%; relative gain in alpha=.05, no statistical
prospective mg anthraquinone per tablet) ITT- criteria for efficacy with CL+ compared beta=.10 significance
clinical trial (n=145) compared to Carbo analysis= IBS with its basic component CL
to compare ligni (CL) containing tablets 262 was about 8% to 9%
the efficacy (n=139). Adaptation from one PP- without
as well as to eight tablets per day analysis=
the tolerance 144
Table 7: Clinical studies for bowel cleansing (grouped according to active substance dosage of hydroxyanthracene derivatives (HAD))

subjects
150 mg–300 mg HAD without enema
Ziegenhagen Prospective The day before endoscopy: 120 Referred Bowel cleanliness p=0,05; CI Study
et al. (1991) randomised 1.26-1.85 g dry extract of outpatients for colono- 95% contributes to
investigator- Sennae fructus acutifoliae scopy colon was free of solid debris evidence for
blind corresponding to 150 mg all patients placebo/PEG-ELS: 66.7% of well-
hydroxyanthra-cene underwent patients established
glycosides, calculated as whole gut use
irrigation senna/PEG-ELS: 90% of
sennoside B; DER 3-5:1, patients (p less than 0.01)
extraction solvent water, with 2 l
n=60 placebo solution, n=60 PEG-ELS
Frigerio et Randomised, A: 1 dose of senna 1.26-1.85 473 Referred 300 mg of senna was more ef Study
al. (1996) single-blind g dry extract of Sennae patients for colono- contributes to
fructus acutifoliae (225 males scopy perfect examination: in 281 statistical evidence for
corresponding to 150 mg and 248 patients; of these model of well-
hydroxyanthra-cene females 127 patients (51%)=group A logistic established
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subjects
glycosides, calculated as with a 154 patients (69%)=group B multiple use

sennoside B; DER 3-5:1, mean age regression
extraction solvent water) for of 59.7 acceptable examination: in with perfect or
colon cleansing (n=250). years, 148 patients; of these acceptable
range 14– 85 patients (34%)=group A versus
B: 2 doses, one at mid-day 96 years) 63 patients (28.3%)=group B impossible re-
and one on the evening prior plies
to the examination, Liquids Colonoscopy impossible (and
had to be repeated): in 44 (dichotomous)
equivalent to 300 mg senna orally or perfect
(n=223) according patients; of these
38 patients (15.2%)=group A versus
to need, no acceptable
enema 6 patients (2.7%)=group B
versus
impossible
replies
(trichotomous
) and Harrell
C-index
Schanz et al. Randomised, A: sodium phosphate solution 355 conse- Referred Quality score (0–4) of No Supportive
(2008) multicenter, n=128 cutive out- for cleanliness was generated: information evidence for
observer- patients colonoscop 0=excellent to 4=repeated available well-
blinded B: sodium phosphate solution (18 and 75 y examination necessary established
and sennosides 1.26-1.85 g years) use
dry extract of Sennae fructus No differences in adverse
acutifoliae corresponding to Drinking events and the cleanliness
150 mg hydroxyanthra-cene volumes effects occurred in the three
glycosides, calculated as (L) groups (p=0.113)
sennoside B; DER 3- (A=4.33+
5:1,extraction solvent water, 1.2,
n=133 B=4.56+
1.18,
C: PEG-ELS and sennosides, C=4.93+
n=94 1.71) were
different
(p=0.005)
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subjects
Kositchaiwat Prospective 180 mg senna tablets (24 134 Referred The efficacy of both laxatives ITT; CI 95% Limited
et al. (2006) randomised tablets of 7.5 mg /tab), n=67 for elective were equivalent relevance for
colono- monograph
single 95 ml sodium phosphate scopy
blinded solution on the day before
colonoscopy, n=67
Valverde et Prospective, Dry extract of Sennae fructus 523 Colonic or 3-stage score according to χ2 test for Contribution
al. (1999) randomised, acutifoliae standardised to patients in rectal Hollender et al. (0=no faecal categorical to evidence
observer- 2 strata, ie, carcinoma matter, +=small amount of values and the for well-
blind, 120 mg sennosides A and B; those with or sigmoid faecal matter, ++=faecal Student t test established
parallel, evening before surgery, carcinoma diverticular matter bothersome to the for continuous use
multicentre n=262 and those disease surgery) variables
study Polyethylene glycol (PEG) 2 with undergoing
sigmoid elective Other criteria: Consistency of
packages a 59 g diluted in 2– faecal matter, rate and
3 l of water, n=261 diverticular colonic or
disease rectal magnitude of intraoperative
resection faecal soiling, rate of
5% followed by abdominal infective
povidone immediate complications and patient
iodine anastomo- tolerance.
antiseptic sis
enemas (2 Adverse reactions with senna:
l) the discomfort 55 patients (21%),
evening vomiting 12 (4.6%),
and the abdominal pain 35 (13.4%),
morning distension 8 (3%), malaise 23
before (8.8%). Adverse reactions
surgery with PEG: discomfort 55
patients (21.1%), vomiting 7
(2.7%), abdominal pain 30
(11.5%), distension 15
(5.7%), malaise 15 (5.7%).
Senna was better tolerated
(p=0.03) in the presence of
stenosis.
EMA/HMPC/228759/2016 Page 70/133
subjects
Colonic cleanliness was better

(p=0.006), faecal matter in
the colonic lumen was less
fluid (p=0.001), and the risk
for moderate or large
intraoperative faecal soiling
was lower (p=0.11) with
senna
There was no statistically
significant difference in the
number of patients with
postoperative infective
complications (14.7% vs.
17.7%) or anastomotic
leakage (5.3% vs. 5.7%) with
senna or PEG
150 mg HAD with an enema
Hangartner Prospective 4 l of PEG-ELS; n=100 300 Referred 4 l of PEG-ELS and Senna Descriptive Supportive
et al. (1989) randomised patients for extract plus enema have evidence for
2 l of PEG-ELS combined with colonoscop equivalent cleansing efficacy well-
a Cascara-preparation, n=102 Exclusion y for colonoscopy, patients established
of prior judged senna extract to be use
(1.26–1.85 g dry extract of colonic
Sennae fructus acutifoliae less unpleasant
surgery
hydroxyanthra-cene
glycosides, calculated as
sennoside B; DER 3-5:1,
extraction solvent water) for
colon cleansing) combined
with an enema, n=98
Krakamp et Prospective PEG-ELS-recepture 3 l; 3 150 out- Referred (1) Cleansing effect by a 4- Descriptive Contributes to
randomised for stage score (‘1 excellent’ dry evidence for
EMA/HMPC/228759/2016 Page 71/133
subjects
al. (1996) simple-blind hours, n=48 patients colonoscop colon or oclourless fluid; 2 well-
study y fluid residue in faeces like established
PEG-ELS, 4 l; 4 hours, n=48 57±19 colour; 3 sufficient inimal use.
years in solid faecal residue,
1.26–1.85 g dry extract of group 1,
Sennae fructus acutifoliae ‘colonoscopy not possible’)
55±15
corresponding to 150 mg years in (2) the formation of foam by
hydroxyanthra-cene group 2 a 4-stage score (‘no foam’ to
glycosides, calculated as and 57±17 ’examination strongly
sennoside B; DER 3-5:1, years in restricted’)
extraction solvent water, group 3;
n=50 three days 90% of the senna group was
eating adequately prepared,
restrictions 3 l of PEG-ELS the most
1 day clear efficient method when it came
fluids 1 to cleanliness and the
enema 1 formation of foam
hour before
procedure
Bokemeyer Open PEG-ELS ( 2 l on the day 165 Referred Endocopist: assessment of No Supportive
et al. 2000 prospective before colonoscopy and 2 l on outpatients for colono- bowel cleanliness by score: 1 information evidence for
study the day of colonoscopy p.o., scopy (best)–6 (worse) available well-
n=41 established
Patients: assessment of use
PEG-ELS-RSS ( 3 l on the day tolerance and acceptance by
of colonoscopy p.o.), n=40 score: 1 (best)–6 (worse)
sodium phosphate solution 45 mainly good or excellent
ml on the day before and 45 cleansing results:
ml on the day of colonoscopy PEG-ELS=2.1
p.o.), n=44 PEG-ELS–RSS= 2.1
sodium phosphate
1.26-1.85 g dry extract solution=1.9
Sennae fructus acutifoliae
corresponding to 150 mg questioning of the patients
EMA/HMPC/228759/2016 Page 72/133
subjects
hydroxyanthra-cene demonstrated sufficient

glycosides, calculated as tolerance of colonoscopy
sennoside B; DER 3-5:1, preparation and colonoscopy
extraction solvent water, per overall
single dose, and an enema
and 2 l PEG-ELS on the day
before colonoscopy p.o. and
an enema in the morning
before colonoscopy), n=40
Calcium sennosides (120-300 mg HAD)
Arezzo Randomised Group 1: 12 tablets, each 300 Referred Endocopist: blindly scored X2 test to Limited
(2000) observer- containing 12 mg calciumsalts patients; for colono- cleansing for each bowel assess support of
blind, of sennosides A+B (from a avoidance scopy segment (‘good’, ‘medium’, differences in well-
parallel standardised extract of senna of food ‘scarce’) and defined the proportions; established
leaves extraction solvent: with seeds quality of the examination as Fisher use
to compare methanol 66% V/V) at 10 am. for five ‘optimal’, ‘acceptable’ or ‘to correction
effectiveness and magnesium sulfate 15 g days be repeated’ used when
and at 5 pm. on the day before before groups con-
tolerance of colonoscopy p.o.+2 l water, colonoscop Bowel cleanliness was scored sidered were
different n=100 y; on the as ‘good’ in 38 (group 1), 50 particularly
bowel day before (2), 68 (3) patients small
preparations Group 2: PEG lavage (4 l at 4 colonoscop
pm. on the day before Significant more patients in
y, patients group 3 (68%) achieved a
colonoscopy p.o.), n=100 were asked good cleansing compared with
Group 3: an oral sodium to avoid group 2 (50%) (p<0.0001)
phosphate solution (40 ml at solid food and group 1 (38%)
6 pm. on the day before and after noon (p<0.005). Feasibility of the
40 ml at 6 am. on the day of examination was considered
colonoscopy), n=100 ‘optimal’ significantly more in
group 3 (80 patients) than in
group 2 (62 patients,
p<0.005)) and in group 1 (59
patients, p<0.005). the
EMA/HMPC/228759/2016 Page 73/133
subjects
sodium phosphate solution

should be the standard
preparation for elective
colonoscopy
Tasci et al. Prospective Sennoside calcium (300 ml of 953 Efficiency Bowel cleansing was effective Differences Limited
(2003) randomised a 1 mg/ml solution given 2 of the in 890 (93%) patients per ANOVA t- support of
trial days prior to colonoscopy), 1021 different test; CI 95% well-
n=150 patients procedures Tolerance to sennoside established
enrolled, was calcium and PEG lavage in use
PEG lavage (3 l given 1 day 68 were evaluated comparison to other groups
prior to colonoscopy), n= 145 excluded according was significantly worse
from to a 5- (p<0.05)
Oral sodium phosphate analysis
solution in one 90 ml-dose 1 point scale Of the patients who received
(intoleranc
day prior to colonoscopy, e to sodium phosphate-based
n=141 solutions or treatments, 72%-78% stated
medicinal that they would undergo the
Oral sodium phosphate procedure again if necessary,
solution in 2 doses (90 ml 1 products,
improper while only 21% of patients in
day prior to colonoscopy+45 the sennoside calcium group
ml 5 hours prior to use of the
regimen, and 11% in the PEG group
colonoscopy), n=136 were so willing (p<0.05)
electrolyte
Oral sodium phosphate imbalance,
solution in 2 doses (45 ml+90 cardiac
ml), n=147 disorders
or
Oral sodium phosphate
vomiting)
solution in 2 doses (45 ml+90
ml) plus 10 mg cisapride, Clear liquid
n=82 diet one
day before
Oral sodium phosphate
starting the
solution in 2 doses (45 ml+90
bowel
ml) plus 10 ml domperidone;
cleansing
n=152
EMA/HMPC/228759/2016 Page 74/133
subjects
regimen
Sodium
phosphate
enema was
applied to
the
patients in
the
morning of
colono-
scopy
Radaelli et Prospective Oral high dose of senna 24 283, low- Referred Aronchick scoring scale Multivariate Supportive
al. (2005) randomised tablets (tablet, each fiber diet for elective (1=excellent to logistic evidence for
single blind containing 12 mg calcium and colonoscop 4=inadequate) regression well-
salts of sennosides from a encouraged y modeling established
standardised extract of senna to increase The quality of colon cleansing, use
leaves, extraction solvent: water overall tolerance of the
methanol 66% (V/V)) intake (at preparation, and compliance
contains 12 mg of least 1.5 l) were significantly better with
concentrated extract of on the senna; overall cleansing was
sennoside A and B as calcium fourth excellent or good in 90.6% of
salts divided into two doses at through patients in the senna group
1 pm. and 9 pm.+2 l clear second and in 79.7% in the PEG-ES
liquid (n=191), pre- group (p=0.003)
procedural
Conventional polyethylene days. On
glycol-electrolyte lavage day before
solution (PEG-ES) (n=92) procedure,
advised to
eat a
normal
breakfast
in the
EMA/HMPC/228759/2016 Page 75/133
subjects
morning
and a light
liquid
lunch;
afterwards,
only clear
liquids
were
allowed
until 2 h
before
colonoscop
y
Amato et al. Prospective 12 tablets, each containing 12 296 Referred 1. Aronchick scoring scale and Descriptive Supportive
(2010) randomised mg calciumsalts of sennosides for elective the incidence of preparation- evidence for
investigator- A+B from a standardised colono- related abdominal pain well-
blind extract of senna leaves; scopy established
extraction solvent: methanol 2. Patients' compliance with use
66% (V/V) contains 12 mg of the cleansing regimen, overall
concentrated extract of tolerability, prevalence of
sennoside A and B as calcium predefined side effects, and
salts and 2 l of PEG-ES (half- quality of right colon
dose group, HDG), n=151 cleansing
24 tablets of senna divided in half doses of PEG-ES and

two doses (senna group, SG) senna provides high-quality
the day before colonoscopy, bowel preparation and
n=145 acceptable patient tolerance,
with less abdominal pain
compared to high-dose senna
Kelly et al. Prospective Low-volume PEG(2 l), n=86 258 Referred Overall cleansing grades of Fisher exact Contribution
(2012) (female, for elective preparations used: patient test to evidence
Bowel Standard volume PEG (4 l), 138; colono- compliance, taste, and for well-
preparation n=91 53.5%) scopy acceptability Unpaired established
for colono-
EMA/HMPC/228759/2016 Page 76/133
subjects
scopy Magnesium citrate plus 1 The overall cleansing efficacy testing use
sachet Senna (no further across the 3 groups (those
information), n=81 with grades A or B) was P value was
73.9%, 74.5%, and 86.5% <0.05
for PEG 4 l, PEG 2 l, and
Senna/magnesium citrate
Senna/magnesium citrate
proved significantly better at
bowel cleansing than PEG 4 l
(P<0.05) and it showed a
trend toward better cleansing
when compared with PEG 2 l
(P=0.08)
Manukyan et Prospective Sodium phosphate 2x45 ml 99 Referred Time taken to complete the SPSS 10.0 Supportive
al. (2011) (“phosphor-soda”), n=53 for elective colonoscopy and the segment Chi2 Test evidence for
randomised colono- of the colon examined were well-
Sennoside A+B 150 ml=150 scopy recorded sennoside A+B Student t-test, established
mg (HAD), n=46 calcium is more effective in Fisher exact use
some of the colonic segmental test
cleansing, causes fewer
changes on serum electrolyte
levels, and is better tolerated
Ergül et al. Randomised Sennoside tablet 80 mg daily 129 Scheduled Aronchick scale CI 95% Supportive
(2014) controlled, for 3 days;senna solution 150 for elective evidence for
single blind ml (300 mg senna) the night colono- Cecal intubation time was well-
before colonoscopy, n=65 scopy significantly shorter in the established
gum-chewing group (8.6±5.1 use
To chew sugarless gum half and 7.1±2.8 minutes,
an hour three-times daily P=0.03)
after meals for these 3 days
sennoside tablet 80 mg daily Gum chewing enhances
for 3 days;senna solution 150 colonoscopy bowel
ml (300 mg senna) the night preparation quality
EMA/HMPC/228759/2016 Page 77/133
subjects
before colonoscopy, n=64
Altinbas et Retrospec- Sennoside a+b calcium 500 185 Elective Ottawa Bowel preparation SPSS 13.0 Study not
al. (2015) tive single mg/250 ml, n=91 patients; colono- Scale Score relevant for
blind 53.4±13.4 scopy (SPSS Inc., establishment
4 l of PEG-ELS, n=94 years A large proportion of patients Chicago, IL, of the
(53.7±15.0 (75.3%) in Group 1 and half USA). P<0.05 monograph
in Group 1, of the patients in Group 2 was accepted
52.42±11. (46.2%) would agree to drink as the cut-off
8 in Group the same regime again value for
2, statistical
P=0.255), significance.
and 89.3% Chi-square,
and 95.8% Kruskal–
respectivel Wallis, and
y, Mann–Whitney
(P=0.545) U tests
of the
patients in
the groups
were male
Taylor et al. Controlled Reduced-laxative (13 g 95 patients Scheduled Two radiologists graded Questionnaire Supportive
(2008) randomised sachet of senna granules/18 g (50 to undergo residual stool (1: responses evidence for
magnesium citrate) prior to female), afternoon none/scattered to 4: >50% compared well-
Optimum CT colonography tagging mean age diagnostic circumference) and tagging using Fischer’s established
barium- regimens: 64 years, colono- efficacy for stool (1: untagged exact test. use
based range 50– scopy for to 5: 100% tagged) and fluid False-positive
reduced- 20 ml 40% w/v barium 85 years) symptoms (1: untagged, 2: layered, 3: numbers were
laxative sulphate: regimen two days of suggestive tagged), noting the compared
tagging low residue of Hounsfield units of tagged using one-way
regimen A: four doses,
diet colorectal fluid ANOVA
prior to CT B: three doses, neoplasia
colono- Preparation was good (76-
graphy C: three doses plus 220 ml 94% segments graded 1),
although best for regimen D
EMA/HMPC/228759/2016 Page 78/133
subjects
2.1% barium sulphate, or (P=0.02). Across all

regimens, stool tagging
D: three doses plus 15 ml quality was high (mean 3.7-
diatriazoate megluamine 4.5) and not significantly
different among regimens.
Reduced-laxative with three
doses of 20 ml 40% barium
sulphate is as effective as
more complex regimens,
retaining adequate diagnostic
accuracy
Hookey et Prospective 120 mg (HAD) oral 171 Referred 1. Ottawa scale Tolerance and Supportive
al. (2006) randomised sennosides syrup followed by patients for elective efficacy in a χ2 evidence for
investigator- 2 l PEG, n=79 with a clear colonoscop 2. Patients' compliance with test, to detect well-
blind fluid diet y the cleansing regimen, overall a 20% established
4 l PEG, n=81 the day tolerability, prevalence of difference in use.
before predefined side effects effectiveness
colono- A significant difference of colon
scopy between the two preparations cleansing and
in the quality of colon patient
cleansing was seen in favour tolerance,
of PEG (P=0.03) low-volume with an alpha
PEG plus sennosides was of 0.05 and
better tolerated than PEG 80%
(P<0.001) confidence
level, 80
patients/group
<80 mg HAD
Iida et al. Uncontrolled Drink 2 l of PEG-ELS on the 297 Referred Bowel cleanliness was No Uncontrolled
(1992) day of examination by taking examinees for colono- assessed as ‘excellent’ or information therefore only
36 mg of sennosides (no (219 male scopy ‘good’ in 90% to 97% of the available weakly
further information of the and 78 patients at all sites in the supportive to
formulation) orally in the female; well-
EMA/HMPC/228759/2016 Page 79/133
subjects
evening before colonoscopy. mean age colon and rectum established

57 years) use
Chilton et al. Randomised, 75 mg syrup; 50 ml contains 132 Referred Endoscopists assessed bowel Nonparametric Limited
(2000) single-blind sennoside B, 7.5 mg/5 patients; for colono- cleanliness by a 4-stage score statistics, the relevance for
ml+sodium picosulphate 10 scopy (excellent, good, chi-squared monograph
mg at 2 pm. + PEG-ELS 1 l at Low intermediate, poor) test was used because of low
6 pm. on the day before residue to compare posology
colonoscopy when diet for 48 “Time to caecum” proportions
colonoscopy took place before hours;
liquid only The triple regimen patients
12 am., n=81 had significantly cleaner
24 hours
75 mg sennosides A+B at 2 prior to colons than patients who
pm.+sodium picosulphate 10 exami- received Phospho-soda
mg at 6 pm.+ PEG-ELS 1 l at nation (p=0.037, Mann-Whitney U-
7 am. on the day of test). Although the median
colonoscopy when The (range) cleanliness scores
colonoscopy took place after doubling of were identical for both
12 hours, n=81 the groups groups, 73% of the triple
is due to regimen group scored 1 or 2,
Sodium phosphate solution 45 the time compared with 57% of the
ml at 8 am. and 45 ml at 8 frame of Phospho-soda group
pm. on the day before examin-
colonoscopy when ation Median time to caecum was
colonoscopy took place before 11 minutes (range 5-50) in
12 hours; n=51 the triple regimen group and
16 minutes (range 5-65) in
Sodium phosphate solution 45 the Phospho-soda group,
ml at 8 pm. and at 8 am. in (p=0.08)
the morning of the
colonoscopy when
colonoscopy took place after
12 am. (n=51)
Haapamäki Single- 2 l PEG combined with 36 mg n=490 Referred 1. Ottawa score Differences in Limited
et al. (2011) center, senna glycosides in tablets for elective categorical relevance for
prospective Avoided colono- 2. Subjective grading of data between monograph
EMA/HMPC/228759/2016 Page 80/133
subjects
and n=244; ITT=203 solid food scopy patients of ease of taking the groups were because of low
randomised after 3 pm. large-bowel preparation, tested with posology
investigator- 4 l PEG for bowel preparation, the day frequency of need for the two-sided
blind n=246; ITT=196 before repeated colonoscopy because chi-square
colono- of insufficient view, and test; CI 95%
scopy were frequency of incomplete
allowed to intake of bowel preparation
drink clear
liquids Significantly more cases with
poor or inadequate bowel
cleansing after the low-
volume alternative with senna
and 2 l PEG (22/203)
compared with after 4 l PEG
(8/196, p=0.027)
Patients’ subjective grading of
ease of taking the bowel
preparation:
Difficult and impossible
25/231 senna
55/238 4 l PEG
Postgate et Prospective "Standard" (fluid restriction 150 Healthy 1. gastric transit time (GTT); Descriptive Limited
al. (2009) single-blind then nothing by mouth 12 volunteers small-bowel transit time relevance for
randomised hours before the procedure, (SBTT), completion rates monograph
To evaluate controlled water and simethicone at (CR), view quality, and because of low
the capsule ingestion [S]) patient acceptability posology
usefulness of
bowel "Standard"+10 mg oral 2. positive findings, diagnostic
purgatives metoclopramide before the yield
and procedure (M)
prokinetics Bowel purgatives and
in small- Magnesium citrate+senna prokinetics did not improve
bowel bowel-purgative regimen the CRs or view quality at CE, and
bowel purgatives reduce
EMA/HMPC/228759/2016 Page 81/133
subjects
Capsule evening before CE (CS), n=40 patient acceptability

Endoscopy
CE Magnesium citrate+senna+10
mg metoclopramide, n=37
before the procedure (CSM).
Kashyap et Prospective, 4 Senna tablets, no further 25 Healthy The % of subjects with a descriptive No relevance
al. (2015) single- specification volunteers clinically significant change in statistics (for for
center, to colon serum chemistry at the last continuous monograph
single-arm 4 l of PEG (split dose) capsule test and the adverse event variables) or
10 mg metoclopramide, endoscopy (AE) rate frequencies
(CCE) and
2 oral sulfate solution no serious AEs, three percentages
boosters (6 oz. and 3 oz.) moderate AEs related to the (for
bowel preparation (nausea, categorical
10 mg bisacodyl headache, elevated variables)
creatinine) and two mild
unrelated AEs (chills,
abdominal cramping)
Poyrazoglu Prospective 90 ml of oral NaP (NaP group) 137 Referred Patients questionnaire ITT;CI=95% No relevance
and Yalniz randomised ITT= 66 consecutiv for for
(2015) single-blind e patients colonoscop Bowel cleansing Descriptive monograph
Senna solution (500 ml, y
1,000 mg of sennosides A and Drop out: 9 The patients’ compliance to
B calcium +66.6 g of sorbitol) in senna the bowel-cleansing regimen,
in two divided doses 1 day group, 5 in as well as any gastrointestinal
before the procedure: 250 ml NaP group or other unfavorable
at 4 pm. and 250 ml at 6 symptoms (nausea, vomiting,
pm., ITT=62 abdominal pain, and
dizziness) induced by these
regimens, was assessed, and
patients’ responses were
graded using a four-point
scoring system: 1=no
trouble; 2=mild;
EMA/HMPC/228759/2016 Page 82/133
subjects
3=moderate; and 4=severe

The number of patients with
excellent bowel cleansing
according to the general
appraisal of colonoscopic
evaluation was significantly
higher in the NaP regimen
group than in the senna group
(46 [78%] vs 25 [43.1%],
P<0.001)
Vradelis et Prospective Magnesium citrate 2 sachets 345 adult Referred The combined citramag/senna χ2-test CI 95 Limited
al. (2009) at 11.6 g magnesium out for regimen proved superior in supportive
carbonate and 17.8 g patients; endoscopy bowel cleansing as it achieved evidence
anhydrous citric acid, n=160 “adequate” colon visualisation because
Low-fiber (quality of colon cleansing Senna
2 sachets at 11.6 g diet for 2 rated as “good” or medication
magnesium carbonate and days; clear “satisfactory” in 148/182 only partly
17.8 g anhydrous citric acid fluids 1 day (81.3%) compared to specified
1 sachet senna granules no 108/160 (67.5%)
further information, n=182 colonoscopies using the
citramag protocol (P=0.004)
The combined citramag/senna
regimen proved superior in
bowel cleansing as it achieved
“adequate” colon visualisation
(quality of colon cleansing
rated as “good” or
“satisfactory” in 148/182
(81.3%) compared to
108/160 (67.5%)
colonoscopies using the
citramag protocol (P=0.004;
EMA/HMPC/228759/2016 Page 83/133
Table 8: Clinical studies on humans, in postoperative constipation
Reference Study Test Product(s): Number of Type of Outcomes Statistical Clinical relevance
Design subjects analysis
subjects
Patel et al. Prospective Placebo, n=45 96 patients After pelvic First bowel movement CI=95% One study on first
(2010) randomised reconstructive (BM) postoperative use bowel movement in
Senna 8.6 mg with surgery of magnesium citrate postoperative
docusate 50 mg, were compared constipation. Data
n=48 are not sufficient
There was a significant
difference in the time to
first BM in those
receiving senna with
docusate vs placebo
(3.00±1.50 vs
4.05±1.50 days;
P<.002). More subjects
in the placebo group
needed to use
magnesium citrate to
initiate a bowel
movement (43.6% vs
7.0%; P<.001)
Table 9: Clinical studies, in postoperative opioid-induced constipation
Reference Study Test Product(s): Number of Type of Outcomes Statistical Clinical

Design subjects analysis relevance
subjects
Marciniak et al. Double Lubiprostone , orally 64 adults No information 1.Patient assessment of ITT; CI 95% One study on
(2014) blind, twice a day 24 µg available constipation (PAC)- postoperative
randomised 56 participants symptoms (PAC-SYM) and opioid-induced
active Senna (generic) two (28 in each the PAC-quality of life constipation.
comparator capsules group) had (PAC-QOL) scales No further
trial administered daily for baseline and measured at baseline and conclusion with
six days follow up day 7 respect to the
Random.: measures and
EMA/HMPC/228759/2016 Page 84/133
Reference Study Test Product(s): Number of Type of Outcomes Statistical Clinical
Design subjects analysis relevance
subjects
1:1 ratio in were included in 2. Bristol stool scale bowel monograph

blocks of 4 the intention to consistency, specific bowel
treat (ITT) symptom score (Nausea,
efficacy of analyses. 43 cramping, straining,
lubipros- participants completeness, abdominal
tone completed the pain, time per lavatory
compared study, 21 in the attempt, assistance
to Senna on active group needed), adverse events
bowel and rescue medications
symptoms required
and
constipation Both lubiprostone and
in post- senna improved
operative constipation-related
orthopedic symptoms and QOL in
patients opioid-induced
treated with constipation, with no
opioids significant between-group
differences
Table 10: Clinical studies, in chemotherapy-induced constipation
Reference Study Test Product(s): Number of Type of subjects Outcomes Statistical Clinical
Design analysis relevance
subjects
Tao et al. No data Senna extract in the 82 patients Constipation after Effective rates of CI 95% Data are not
(2012) available 1st chemotherapeutic chemotherapy relieving sufficient to
course and the crude chemotherapy-induced draw further
fiber diet in the 2nd constipation by senna conclusions
chemotherapeutic extract and by the
course crude fiber diet; the
differences of the
Vice versa digestive tract reaction
and the hematotoxicity
EMA/HMPC/228759/2016 Page 85/133
subjects
reaction were compared

The effective rate of
constipation by taking
senna extract was
92.68% and that by the
crude fiber diet was
10.93%, with statistical
difference shown
(P<0.01).
Table 11: Clinical studies, in constipation in people receiving palliative care

subjects
Ramesh et al. Controlled Purified senna extract 50 patients (30- Management of opioid- Bowel movement Descriptive Data are not
(1998) open 60 mg containing 12 70 years) induced constipation in sufficient to
mg senna glycosides as advanced cancer No difference draw further
calcium salts(2 tablets Senna: 9 conclusions
at night; 4 tablets at dropouts (4
night; 2 tablets in the irreg. admin.; 2
morning+4 tablets at lost follow-up; 2
night every 2 days, morphine
n=25; step 1: 2 tablets withdrawal; 1
at night; step 2: 4 bowel
tablets at night; step 3: movement
2 tablets b. Morning; 4 spontaneous )
tablets at night Liquid 5 drop
A liquid Ayurvedic outs (2†; 2 lost
(herbal) preparation follow-up; 1
(Misrakasneham; 21 irreg. admin.)
herbs), n=25
Increasing in 3 steps;
EMA/HMPC/228759/2016 Page 86/133
subjects
2,5 ml; 5 ml; 10 ml
Agra et al. Randomi- Senna derivatives 0.4 91; By the end Terminal cancer The mean morphine Not relevant
(1998) sed, open, ml (12 mg) for senna of the 27 days, patients treated with dose at which for
parallel – (no other information 37 patients opioids; When a patient laxatives proved T-test establish-
group trial of the formulation were lost: 21 in reached the ceiling of necessary was 84.1 ment of the
available) intake in two the senna group his respective laxative mg (SD 72.3 mg) monograph
doses; every 3 days and 16 in the and had a defaecation-
lactulose group. free period of 3 days, No differences in the
Maximum doses were Three developed he was maintained on respective
1.6 ml (48 mg), n=43 vomiting, five that dose and, in the defaecation-free 72-
refused to absence of side effects, hr intervals as a
Lactulose 15 ml (10 g) function of opioid
every 3 days; continue in the he was also given the
maximum doses 60 ml protocol, 17 initial dose of the other
(40 g), n=48 died, and 12 laxative, which could
were then be increased at 3-
hospitalised day intervals until
reaching the
experimental maximum
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4.3. Clinical studies in special populations (e.g. elderly and children)
Children
Constipation within childhood is an common problem. Despite the widespread use of osmotic and
stimulant laxatives by health care professionals to manage constipation in children, there has been a
long standing paucity of high quality evidence to support this practice.
Perkin (1977) treated 21 children under 15 years' of age with chronic constipation in a crossover trial
lasting 3 weeks. In the first week they received either lactulose (10-15 ml) or senna (a standardised
syrup, no further information 10-20 ml) in the next week no treatment, and in the third week the
alternative treatment. Patient diaries were kept by parents on the number and character of stools
passed, and of side-effects reported, during the 3 weeks. There was a significant difference, in favour
of lactulose, in the number of days on which normal stools were passed during the treatment weeks.
The number and frequency of the side effects reported in the senna treatment week were much higher
(p less than 0.001) than in the lactulose week. Lactulose is recommended as an effective and well
tolerated treatment for the constipated child.
Nolan et al. (1991) in an open controlled trial randomly allocated 169 children with encopresis and
evidence of stool on plain abdominal radiograph to receive multimodal (MM) therapy (laxatives plus
behaviour modification; n=83) or behaviour modification only (BM; n=86). The protocol for the MM
group used laxative therapy in two phases. The initial disimpaction phase consisted of 3-day cycles of
5 ml (sodium citrate 90 mg, sodium lauryl sulphoacetate 9 mg, sorbic acid 5 mg, glycerol, sorbitol,
distilled water) on day 1, one 5 mg bisacodyl suppository after school and one in the evening on day 2,
and a 5 mg bisacodyl tablet after school and one in the evening on day 3. Up to 4 cycles (12 days)
were undertaken. Further cycles were prescribed if there was later evidence of stool reaccumulation.
The subsequent maintenance phase consisted of a mixture (liquid paraffin, phenolphthalein, benzoic
acid, sorbic acid) 5-30 ml once or twice each day, senna granules, and/or bisacodyl tablets. Doses
were adjusted to maintain at least daily defaecation and were increased if there was persistent or
recurrent stool retention. By 12 months follow-up 42 (51%) of the MM group and 31 (36%) of the BM
group (p=0.079) had achieved remission (at least one 4 week period with no soiling episodes) and 52
(63%) vs 37 (43%) (p=0.016) had achieved at least partial remission (soiling no more than once a
week). MM subjects achieved remission significantly sooner than BM subjects. The authors concluded
that this study shows a clear advantage overall for the use of laxative medication, although the benefit
may not be as great for children, who are able to maintain regular bowel habits.
Assessor’s comment:
Only poor information concerning senna is given in the publication. Neither evaluation of the efficacy,
nor of the safety or tolerability is possible. Furthermore, this is a special study population, which
cannot be compared with constipated children.
Bliesner et al. (1978) reported his experiences with a senna preparation in children. One hundred
and eleven patients between 0.5 and 15 years undergoing bowel cleansing before radiological
examination were enrolled and 107 completed this prospective uncontrolled study (44 patients
between 0.5–5 years; 47 between 6–10; 20 between 11–15). They received 1 ml=2 mg/kg body
weight of the senna preparation (1.26-1.85 g dry extract of Sennae fructus acutifoliae corresponding to
150 mg hydroxyanthracene glycosides, calculated as sennoside B; DER 3-5:1, extraction solvent
water) at 7 pm. in the evening prior to radiological examination. According to the authors, the
preparation method was well accepted even by the younger (<5 years) children. Excellent radiographic
visualisation was obtained in most patients (87%) and diagnosis was possible in all patients. The
preparation method was well tolerated.
Assessment report on Senna alexandrina Mill., (Cassia senna L.; Cassia angustifolia
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Other specific clinical experience was reported by Blair et al. (1996). Despite proper technique, pull-
through operations for Hirschsprung's disease (congenital aganglionic megacolon) sometimes fail to
deliver normal or effective bowel evacuation. Ten patients, described herein, had had a pull-through
procedure – a minimally invasive approach to treat Hirschsprung's disease uses only four to five small
incisions. The procedure is done with an endoscope. Sometimes this approach is used only to remove
the blockage and tissue that is lacking nerves. The healthy sections of bowel are then reconnected. The
procedures had been performed by various pediatric surgeons. Five cases had been diagnosed in the
newborn period and had undergone colostomies. The remainder had been diagnosed later (at 2 months
to 2 years of age). They too had undergone colostomy initially, and all had an elective pull-through
procedure. The techniques varied; two had Soave procedures, seven had Duhamel procedures, and
one had a Kimura-Soave procedure (the only case of total colonic Hirschsprung's disease in the series).
All the patients had manifested difficulty in passing stools after the pull-throughs. The problem was
described as "severe constipation", "obstipation", or "fecal retention". Four patients had been treated
with many laxatives, suppositories, enema routines, and diet regimens for years, with no success. All
had been examined radiographically to detect megarectum or megacolon. All had additional biopsies to
confirm the presence of ganglia in the pulled-through segments. At 21 months to 12 years of age,
these patients underwent full posterior internal sphincterotomies. Nine of the 10 had a good or
excellent outcome, with resolution of the megarectum or megacolon. Three patients still require small
doses of senna compound, which are being decreased continuously. Therapy failed for a patient with
Down's syndrome and a, Duhamel pull-through, and a stoma was required.
Dahshan et al. (1999) performed a prospective, randomised, single-blind study in children

undergoing colonoscopy to evaluate the acceptance and efficacy of three different bowel preparations.
Seventy patients (ages 3–20 years, 38 male) were randomly assigned to one of the three study
preparations: Group A: magnesium citrate with a senna preparation, 1.26-1.85 g dry extract of Sennae
fructus acutifoliae corresponding to 150 mg hydroxyanthra-cene glycosides, calculated as sennoside B;
DER 3-5:1, extraction solvent water and clear liquid diet for 2 days. Group B: bisacodyl for 2 days and
enema without dietary restriction. Group C: PEG-ELS 20 ml/kg (up to 1 l) per hour for 4 hours with
clear liquid diet for 1 day. Endoscopists blinded to bowel preparation graded the adequacy of colon
cleansing. The preparations were rated by patients for tolerance, willingness to retake them, adverse
effects, and compliance. Data analysis using Fisher exact test and trend test showed that colon
cleansing in groups A and C was superior to that in group B (p<0.0001) and better in group C than A
(p<0.075). Overall tolerance and compliance were significantly better for groups A and B than group C
(p<0.003), but not different between A and B. More of group B patients were willing to retake the
preparation than in group C (p<0.002) and group A (p<0.05), but this was not different between
groups A and C. Adverse effects were reported more frequently by patients in group C than in groups A
and B (p<0.01). The authors concluded that although the least well tolerated, PEG-ELS provided the
best cleansing. Bisacodyl without dietary restriction provided unsatisfactory colon cleansing.
Magnesium citrate with senna preparation was acceptable and provided good cleansing. This
investigation cannot prove the efficacy of senna because it was given in combination with magnesium
citrate and the study groups were very small.
There are several reports of local intolerance of a senna extract (1.26-1.85 g dry extract of Sennae
fructus acutifoliae corresponding to 150 mg hydroxyanthracene glycosides, calculated as sennoside B;
DER 3-5:1, extraction solvent water) on skin in children wearing napkins. These skin irritations were
bullous and comparable with skin irritations caused by scalds (Sitzmann et al., 1979).
The majority of children who experience constipation and whose care-givers seek medical care are
seen by primary care physicians such as pediatricians or family physicians. Little is known about how
primary care physicians treat childhood constipation or about the success of their treatments.
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Borowitz et al. (2005) prospectively examined which treatments primary care physicians prescribe
to children who present for the first time with constipation and how effective those treatments are in
an observational study. A total of 119 children participated in this study. They were between 2 and 7
years of age (mean: 44.1±13.6 months) and presented to 26 different primary care physicians (15
pediatricians and 11 family physicians) for the treatment of constipation for the first time. Parents
completed daily diaries of their child's bowel habits for 2 weeks before starting treatment
recommended by their primary care physician and again 2 months after treatment. The prescribed
treatment was identified by reviewing office records of the treating physicians. After 2 months of
treatment, 44 (37%) of 119 children remained constipated. In the majority (87%) of cases, physicians
prescribed some form of laxative or stool softener. The most commonly prescribed laxatives were
magnesium hydroxide (77%), senna syrup (23%), mineral oil (8%), and lactulose (8%). In nearly all
cases, a specific fixed dose of laxative was recommended; in only 5% of cases were parents instructed
clearly to adjust the dose of laxative up or down to get the desired effect. In approximately half of the
cases, physicians recommended some sort of dietary intervention. Some form of behavioral
intervention was mentioned in the office records of approximately one third of cases; however, in most
cases, little detail was provided. In 45% of cases, physicians prescribed disimpaction using oral
cathartics, enemas, or suppositories followed by daily laxatives. In 35% of cases, physicians prescribed
daily laxatives without any disimpaction procedure. In the remainder, physicians prescribed only
dietary changes (5%), the use of intermittent laxatives (9%), or no therapy (7%). Treatment success
corresponded to how aggressively the child was treated. Specifically, children who underwent some
form of colonic evacuation followed by daily laxative therapy were more likely to have responded to
treatment than were those who were treated less aggressively. Primary care physicians tend to
undertreat childhood constipation. After 2 months of treatment, nearly 40% of constipated children
remain symptomatic.
A prospective study of 62 children was performed by Martinez-Costa et al., 2005 using a standard
questionnaire (onset-age, regular toilet use, encopresis, complications, dietary habits and
environmental and psychological factors) and physical and anthropometric assessment. Functional
constipation (FC) was defined as a stool frequency of less than 3 bowel movements/week, with
passage of large or scybalous stools, with or without 2 or more soiling episodes per week, without
underlying disease. Treatment included demystification, behavioral modification and drugs (mineral oil
and senna). Each child was periodically re-evaluated, and treatment was considered successful when
the defecation rate was 3 or more bowel ovements/week, discomfort was absent, and fecal soiling
frequency was 2 or fewer episodes/ month. FC accounted for 13% of all first consultations (60% boys,
40% girls; mean age at diagnosis 6.1 years). The most frequent manifestations were painful
defecation (60%), rectorrhagia (42%), obstructive episodes (34%) and anal fissure or hemorrhoids
(17%); 19 patients (31%) had encopresis. Nutritional assessment revealed that 84% of the patients
was well nourished and 16% was overweight. Fiber intake was deficient in more than 60%. Sixteen
(26%) patients underwent successful relief of impaction with senna (20-30 mg/dose; no more
information on senna available) combined with mineral oil. Maintenance treatment included mineral oil
(15-30 mlper day) and senna at the minimum effective dose (5-15 mg per day, no more information
on senna available). Satisfactory results were achieved 1 month later in 32% of the children, 3-6
months later in 71%, and 6-12 months later in 85%; successful response was closely related to
regular toilet habits, dietary modification and a shift in the family's attitude.
Many protocols of bowel preparation are available for use in children; however, none of them is
commonly accepted. The aim of a study by Kierkus et al. (2013) was to evaluate the efficacy and
acceptability of high-volume polyethylene glycol (PEG) versus low-volume PEG combined with
bisacodyl (BPEG) vs sennosides for colonoscopy preparation in children. Participants 10 to 18 years of
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age were randomly assigned to receive either PEG 60 or PEG 30 ml/kg per day plus oral bisacodyl 10
to 15 mg per day or sennosides 2 mg/kg per day for 2 days. A blinded assessment of bowel cleansing
was made by the endoscopist according to the Aronchick and Ottawa scales (Aronchick et al., 2000).
Patient acceptability was evaluated with the visual-analog scale. Analysis was done on an available
case analysis basis. Of 240 patients enrolled in the study 234 patients were available for analysis of
the efficacy of colon cleansing. There were no significant differences found among the 3 groups for the
proportions of participants with excellent/good (PEG: 35/79, BPEG: 26/79, sennosides 25/76) and
poor/inadequate (PEG: 20/79, BPEG: 28/79, sennosides 28/76) bowel preparation evaluated with the
Aronchick scale and for the mean Ottawa total score (PEG: 5.47 ± 3.63, BPEG: 6.22 ± 3.3, sennosides:
6.18 ± 3.53). Acceptability of bowel cleansing protocol was similar in all of the groups (P = 0.8). All 3
cleansing methods showed similar efficacy and tolerability; however, none of them was satisfactory.
Safety and effectiveness of large-volume polyethylene glycol-based solution (PEG-ES) have been
documented, but the taste and volume can be barriers to successful colonoscopy preparation. Efficacy
and safety of small-volume electrolyte-free (PEG-P) preparation for colonoscopy preparation have been
rarely studied, although presently used at many paediatric centers. The primary objective of a study by
Terry et al. (2013) was to determine whether PEG-P results in a more efficacious and safe
colonoscopy preparation as compared with senna. The study design was prospective, randomised, and
single-blinded. Patients ages 6 to 21 years were randomised to a 2-day clean-out regimen of PEG-P at
a dose of 1.5 g/kg divided twice per day for 2 days versus senna 15 ml daily (ages 6-12) (26,4 mg
sennosides) or 30 ml daily (ages 12-21)(52,8 mg sennosides) for 2 days. Both preparations required 1
day of clear liquids whereas senna preparation required an additional day of full liquid diet. A blinded
endoscopist graded the quality of preparation with a standardised cleanliness tool (Aronchick scale,
Aronchick et al. 2000). Serum chemistry panels were obtained. Patients or parents rated symptoms
and ease of preparation. The anticipated number of subjects was 166; however, the interim analysis
demonstrated inferiority of senna preparation. Thirty patients were evaluated in the present study. Of
the patients in the PEG-P arm, 88% (14/16) received an excellent/good score compared with 29%
(4/14), with the senna preparation (P=0.0022). Both preparations were well-tolerated by patient-
graded ease of preparation. Demographics and laboratory values did not differ significantly across the
2 groups. No serious adverse events were noted. PEG-P is an effective colonoscopy preparation
whereas senna preparation was insufficient. Both were well-tolerated and appear safe in a pediatric
population.
The authors of a Cochrane review (Gordon et al., 2013) set out to evaluate the efficacy and safety
of osmotic and stimulant laxatives used to treat functional childhood constipation. The search in 2012
was standardised and not limited by language and included electronic searching (MEDLINE, EMBASE,
Cochrane Central Register of Controlled Trials, Cochrane Inflammatory Bowel Disease and Functional
Bowel Disorders Group Specialized Trials Register), reference searching of all included studies,
personal contacts and drug companies. Randomised controlled trials (RCTs) which compared osmotic
or stimulant laxatives with either placebo or another intervention, with patients aged 0 to 18 years old
were considered for inclusion. The primary outcome was frequency of defecation. Secondary endpoints
included faecal incontinence, disimpaction, need for additional therapies and adverse events. Relevant
papers were identified and the authors independently assessed the eligibility of trials. Methodological
quality was assessed using the Cochrane risk of bias tool. The Cochrane RevMan software was used for
analyses. Patients with final missing outcomes were assumed to have relapsed. For continuous
outcomes a mean difference (MD) and 95% confidence interval (CI) was calculated using a fixed-effect
model. For dichotomous outcomes an odds ratio (OR) and 95% confidence intervals (95% CI) was
calculated using a fixed-effect model. The chi square and I (2) statistics were used to assess statistical
heterogeneity. A random-effects model was used in situations of unexplained heterogeneity. Eighteen
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RCTs (1643 patients) were included in the review. Nine studies were judged to be at high risk of bias
due to lack of blinding, incomplete outcome data and selective reporting. Meta-analysis of two studies
(101 patients) comparing polyethylene glycol (PEG) with placebo showed a significantly increased
number of stools per week with PEG (MD 2.61 stools per week, 95% CI 1.15 to 4.08). Common
adverse events in the placebo-controlled studies included flatulence, abdominal pain, nausea,
diarrhoea and headache. Meta-analysis of 4 studies with 338 participants comparing PEG with lactulose
showed significantly higher frequency of stools per week with PEG (MD 0.95 stools per week, 95% CI
0.46 to 1.44), although follow up was short. Patients who received PEG were significantly less likely to
require additional laxative therapies. Eighteen per cent of PEG patients required additional therapies
compared to 30% of lactulose patients (OR 0.49, 95% CI 0.27 to 0.89). No serious adverse events
were reported with either agent. Common adverse events in these studies included diarrhoea,
abdominal pain, nausea, vomiting and pruritis ani. Meta-analysis of 3 studies with 211 participants
comparing PEG with milk of magnesia showed that the stools per week was significantly higher with
PEG (MD 0.69 stools per week, 95% CI 0.48 to 0.89). However, the magnitude of this difference is
quite small and may not be clinically significant. One child was noted to be allergic to PEG, but there
were no other serious adverse events reported. Meta-analysis of 2 studies with 287 patients comparing
liquid paraffin (mineral oil) with lactulose revealed a relatively large statistically significant difference in
the number of stools per week favouring paraffin (MD 4.94 stools per week, 95% CI 4.28 to 5.61). No
serious adverse events were reported. Adverse events included abdominal pain, distention and watery
stools. No statistically significant differences in the number of stools per week were found between PEG
and enemas (1 study, 90 patients, MD 1.00, 95% CI -1.58 to 3.58), dietary fibre mix and lactulose (1
study, 125 patients, P=0.481), senna and lactulose (1 study, 21 patients, P>0.05), lactitol and
lactulose (1 study, 51 patients, MD -0.80, 95% CI -2.63 to 1.03), and PEG and liquid paraffin (1 study,
158 patients, MD 0.70, 95% CI -0.38 to 1.78). The pooled analyses suggest that PEG preparations
may be superior to placebo, lactulose and milk of magnesia for childhood constipation. GRADE
analyses indicated that the overall quality of the evidence for the primary outcome (number of stools
per week) was low or very low due to sparse data, inconsistency (heterogeneity), and high risk of bias
in the studies in the pooled analyses. Thus, the results of the pooled analyses should be interpreted
with caution because of quality and methodological concerns, as well as clinical heterogeneity, and
short follow up. However, PEG appears safe and well tolerated. There is also evidence suggesting the
efficacy of liquid paraffin (mineral oil), which was also well tolerated. There is no evidence to
demonstrate the superiority of lactulose when compared to the other agents studied, although there is
a lack of placebo controlled studies.
The authors concluded that further research is needed to investigate the long-term use of PEG for
childhood constipation, as well as the role of liquid paraffin. There is limited value of this study for the
HMPC specific assessment of senna pods and senna leaves.
A randomised controlled crossover design clinical trial, including a washout period, was conducted,
including children with corrected anorectal malformations with fecal continence and constipation
(Santos-Jasso et al., 2017). The sample size was calculated for proportions (n=28) according to
available data for senna. Effectiveness of laxative therapy was measured with a three variable
construct: 1) daily bowel movement, 2) fecal soiling, 3) a “clean” abdominal x-ray. Data analysis
included descriptive statistics and a Fisher's exact test for the outcome variable (effectiveness). The
study was terminated early because the interim analysis showed a clear benefit toward senna
(p=0.026). The maximum daily dose of senna (sennosides A and B) was 38.7 mg and 17 g for
polyethylene glycol. No adverse effects were identified. The authors concluded that therapy with senna
should be the laxative treatment of choice as part of a bowel management program in children with
repaired anorectal malformations and constipation, since the stimulation of colonic propulsion waves
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could lead to stool evacuation without modification of its consistency which can affect faecal
continence. The study was including children with repaired anorectal malformations and constipation.
The data are not sufficient to draw general conclusions.
Conclusion on clinical studies in special populations
The data available are not sufficient to show the efficacy and safety of senna leaves or pods to treat
constipated children, if change of nutrition and increase of daily fibre intake is not effective. The
Cochrane (Gordon et al. 2013) review showed the vast amount of data regarding the use of osmotic
laxatives whereas the data on senna containing stimulants are marginal. They do not provide strong
evidence supporting a recommendation for bowel cleansing for colonoscopy in children.
4.4. Overall conclusions on clinical pharmacology and efficacy
There are no recent clinical studies available, which evaluate senna leaves or fruits alone and not in
combination with other laxatives in a representative study population in the indication constipation.
The postulated laxative effect is mainly based on the pharmacological data, experts’ opinions and
clinical experiences. The results of several studies show a clear laxative effect additionally to fibre
intake.
The study of Hübner and Moser (2002) cannot prove the efficacy of senna leaves in irritable bowel
syndrome. The study treatment was a combination product and the differences between the groups
concerning the primary efficacy parameter were not statistically significant. Based on the results of this
study, it is not possible to recommend the specific indication “irritable bowel syndrome”.
PEG-EL, which is the goldstandard agent for precolonoscopic bowel preparation, has an important
problem to be overcome: its large volume. In accordance with the literature, only 70% of patients
were able to finish the whole PEG-EL solution before the colonoscopic procedure. For this reason,
investigators have worked on how to reduce the PEG-EL solution volume in recent years (Altinbas et
al., 2015).
The indication for pre-examinative bowel cleansing and the method of administration (3 days of clear
soups or fluids, 150 mg HAD±enema is especially supported by the trial of Krakamp et al. (1996).
There are 6 different clinical trials towards the indication of bowel cleansing with additional supply of 2
l fluid (saline or not) with or without enema. Three of them have been performed with a dry extract
(1.26–1.85 g from sennae fructus acutifoliae standardised to 150 mg hydroxyanthracene derivatives
calculated as sennoside B. DER 3-5:1 extraction solvent water) covering 150 mg hydroxyanthracene
derivatives (Ziegenhagen et al., 1991; Schanz et al. 2008; Bokemeyer et al. 2000), with 120 mg
hydroxyanthracene derivatives as calcium sennosides (Hookey et al. 2006), three further trials are
done with Pursennid (1 tablet: corr. to 12 mg sennaglycosides as calcium salts from a concentrated
extract of senna leaves (extraction solvent: methanol 66% (V/V)) receiving 144 mg
hydroxyanthracene derivatives (Amato et al. 2010; Arezzo et al. 2000) as well as taking 288 mg
hydroxyanthracene derivatives (Amato et al., 2010; Radaelli et al., 2005), which proved to be less
tolerable.
Radaelli et al. (2005) in the trial from 90.6% of the patients taking 144 mg hydroxyanthracene
derivatives as calcium sennosides were excellently or well prepared.
All of these patients had to drink additionally 2 l of PEG-ELS, magnesium sulphate or clear liquid.
Therefore, also the following indication is supported for a single usage of higher dosages:
“Herbal medicinal product for bowel cleansing prior to clinical procedures requiring bowel preparation”.
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Because of the unique therapeutic approach with a single dose and the very rare application to an
individuum, the higher amount of exposure to hydroxyanthracene derivatives can be accepted for a
single application.
Regarding the database of 430 patients from the different studies the recommended single dose is:
150 mg HAD (Ziegenhagen et al., 1991; Bokemeyer et al., 2000; Hookey et al., 2006; Amato et al.,
2010; Arezzo et al., 2000). Basically 30% of the patients are not able to complete the bowel cleansing
with 4 l of cleansing fluid. The preparation with senna preparations is slightly inferior but better
tolerable. Actually the additional indication is especially to be considered for therapy of elderly patients
with heart insufficiency, patients suffering from renal insufficiency, as far as they are restricted in fluid
uptake, patients with a migraine and those who are not able to drink 4 l of fluid in the recommended
time.
The potential indications of postoperative or opioid-induced constipation including palliative care are
not included into the monographs due to too heterogenous indications and study conditions in different
patientgroups with immanent high drop out rates within the palliative care patients.
5. Clinical Safety/Pharmacovigilance
5.1. Overview of toxicological/safety data from clinical trials in humans
Bowel cleansing
The following table of tolerability is exemplarily showing the differences in tolerability (senna n=190;
PEG-ES n=191) in bowel cleansing trials:
Radaelli et al. (2005): Tolerability of procedure
Mean Score ( SD) Easy Bothersome Distressing Severely distressing
Senna 1.66 0.74 91 (47.9) 77 (40.5) 18 (9.5) 4 (2.1)
PEG-ES 2.13 0.82 44 (23.0) 87 (45.6) 51 (26.7) 9 (4.7)

(p<0.001)
Colorectal cancer
Satia et al. (2009) evaluated whether education, physical activity, smoking status, BMI, fruit and
vegetable consumption, use of non-fiber laxatives (never/<1 per year, 1-4 times per year, 5-11 times
per year, 1-3 times per month, ≥1 time per week), NSAID use, sigmoidoscopy use in the past 10 years
(yes, no), current multivitamin use, previous history of cancer, and first-degree family history of
colorectal cancer (yes, no) were confounders of the herbal/specialty supplement-colorectal cancer
associations in models already adjusted for age and gender. Colorectal cancer patients used non-fiber
laxatives more frequently (14% vs. 9% at 1-4 times per year) than controls. There was no further
specification of substances. The final model for all the herbal and specialty supplements included age,
gender, education, physical activity, BMI, fruit and vegetable consumption, NSAID use, and
sigmoidoscopy. Glucosamine, chondroitin, and methylsulfonylmethane (MSM) were further adjusted for
history of arthritis.
Dukas et al. (2000) prospectively examined the association between bowel movement frequency,
laxative use, and the risk of colorectal cancer in 84,577 women of the Nurses' Health Study living in
the United States, 36-61 years of age and free of cancer in 1982. Between 1984 and 1996, 611
incident cases of colorectal cancer were documented. After controlling for age, body mass index, fiber
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intake, postmenopausal status and hormone use, physical activity, and use of laxatives, the relative
risks associated with having bowel movements every third day or less, compared with those with
bowel movements once daily, were 0.94 (95% confidence interval (CI): 0.69, 1.28) for colorectal
cancer, 0.88 (95% CI: 0.62, 1.26) for colon cancer, and 1.18 (95% CI: 0.63, 2.20) for rectal cancer.
Compared with women who never used laxatives, the multivariate relative risks associated with weekly
to daily laxative use were 1.00 (95% CI: 0.72, 1.40) for colorectal cancer, 1.09 (95% CI: 0.76, 1.57)
for colon cancer, and 0.68 (95% CI: 0.29, 1.57) for rectal cancer. These findings do not support an
association between infrequent bowel movement, laxative use, and risk of colorectal cancer and
indicate that simple questions directed at bowel movement frequency are unlikely to enhance our
ability to predict colorectal cancer risk.
Urothelial cancer
Bronder et al. (1999) reported on 766 cases of urothelial cancers (98% confirmed by histology) in
Berlin, Germany, between 1990 and 1994. A control group (1:1) was obtained by sampling, from the
West Berlin Population Registry, persons of German nationality who had lived in Germany for at least
20 years and matched with the patients for sex and age. Through a standardised questionnaire
completed by 648 patients and 647 controls, social class was recorded as well as consumption of
analgesics, laxatives and tobacco. After adjustment for tobacco use and social class, the risk of
urothelial carcinoma was increased in laxative users. Use of contact laxatives was reported by 63
urothelial cancer patients versus 29 controls (odds ratio, 2.5; 95% CI, 1.5–4.2) and 13 renal pelvis
and ureter cancer patients versus two controls (odds ratio, 9.3; 95% CI, 1.1–83.3). For different
laxatives, the corresponding figures (urothelial cancer patients versus controls) were: chemical and
anthranoid laxatives, five versus two (odds ratio, 2.7; 95% CI, 0.47–16); anthranoid laxatives alone,
37 versus 20 (odds ratio, 2.0; 95% CI, 1.1–3.7); aloe, 16 versus 11 (odds ratio, 1.6; 95% CI, 0.66–
3.7); senna, 26 versus 13 (odds ratio, 2.4; 95% CI, 1.1–5.0); and rhubarb, eight versus four (odds
ratio, 2.6; 95% CI, 0.68–9.6). The Working Group noted that no results for laxatives adjusted for use
of analgesics were presented.
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Table 12: Clinical safety data from clinical trials
Reference Study Test Product(s): Number of Type of subjects Adverse reactions Comments
subjects
Pharmacological studies
Ewe et al. Prospective Loperamid to double transit 24 volunteers Healthy None Loperamide prolonged
(1993) time (A) colonic transit from
27±0.7 to 72±12 hours.
Purified sennosides 20 mg (B) This effect was abolished
A fibre product containing 20 g by (B) (30±5 hours) and
Plantago ovata seeds/husks 30 (D) (27±1 hours)
g (C) (p<0.005), but not by (C)
(64±13 hours). Colonic
A combination of 5.4 g transit was reduced by
Plantago ovata (B) and by (D) from 39±4
seeds/husks+1.2 g senna pod hours to 17±3 hours
with a sennoside content of 30 (p<0.005)
mg (D)
Buhmann Prospective 180 ml warm Senna tea (1.7 g 15 volunteers Healthy None The use of functional cine
et al. Sennes leaves=30 mg MRI utilising a prokinetic
(2005a) hydroxyanthra-cene glycoside stimulus allowed
visualisation and
quantification of large
bowel motility
Emeriau et Observational Sennosides 20 mg daily 14 elderly Constipation None Long-term laxative

al. (1983) treatments do not
necessarily induce
significant intestinal
protein and potassium
losses
Constipation
Pers et al. Prospective 2.6 g Semen plantaginis ovata, 20; 1 drop out Severe No AEs Due to small number of
(1983) randomised 0.11 g Ispaghula husk and 0.62 constipation patients only limited
g Sennae fructus angustifolie information
equivalent to 15 mg glycoside
EMA/HMPC/228759/2016 Page 96/123
subjects
A+B per sachet of 5 g”)

(“3.3 g Testa ispaghula ‘Tika’
and 25 mg glycoside sennae
A+B per sachet”)
1 week prior
2 weeks Prep A
2 weeks Prep B
Marlett et Controlled, Ispaghula husk (7.2 g per day), 42 adults Constipation 1½-2 psyllium plus The adverse reactions
al. (1987) n=20 senna; cramps; observed are reflecting
Randomised, bloating; nausea the known spectrum of
single-blind Psyllium plus senna (6.5 g+1.5 adverse events
g per day) for 1 week, n=22
Passmore Randomised, ispaghula 54.2%, senna 12.4% 77 elderly History of chronic Cramps, The adverse reactions
et al. double-blind, (m/m)) and lactulose patients constipation urgency,flatulence, observed are reflecting
(1993) crossover (average age: Nausea, bloated the known spectrum of
study Senna-fibre combination 10 ml 82.9 years) headache; no adverse events
daily with lactulose-active difference between
senna-fibre combination 10 ml groups
daily with lactulose placebo 15
ml twice daily
Active lactulose 15 ml twice
daily with senna-fibre placebo
10 ml daily for two 14 day
periods
Maximum daily dose for active
or placebo senna-fibre was 20
ml (10 ml twice daily) and for
lactulose or lactulose placebo
60 ml
Kinnunen Open, Plantago ovata seed 521.6 mg 30 long-stay Chronic No AEs No AEs; seems to be a
et al. randomised (bulk forming), Fructus cassiae elderly constipation problem of definition
and controlled angustifoliae 138 mg patients aged
EMA/HMPC/228759/2016 Page 97/123
subjects
(1993) crossover (stimulant) 65–94 years

study (mean 81.8)
Levolac 30 ml lactulose
In period I, 21
patients
received
senna
combination
and 9 patients
lactulose; in
period II, 7
patients
received
senna
combination
and 18
patients
lactulose
Irritable Bowel Syndrome
Hübner 12-week CL+(containing as active 284 patients irritable bowel 50 AEs CL+42 The adverse reactions
and Moser double blind, ingredients “180 mg Carbo between 19 syndrome (IBS) observed are reflecting
(2002) controlled, ligni”, i.e. vegetable, non- and 70 years CL; as in IBS the known spectrum of
randomised, activated charcoal, “105 mg Rome criteria for adverse events
multicentre Fol. Sennae, 25 mg rhubarb IBS
and extract” 2.65–3.95 mg
prospective anthraquinone per tablet)
clinical trial (n=145) compared to Carbo
ligni (CL) containing tablets
(n=139). Adaptation from one
to eight tablets per day
Bowel cleansing 150–300 mg HAD without enema
Ziegenhag Prospective The day before endoscopy 120 Referred for Patient tolerance The adverse reactions
en et al. randomised either extractum sennae outpatients, colonoscopy was similar in both observed are reflecting
(1991) investigator (n=60) or a placebo solution all patients groups with 86.7% the known spectrum of
EMA/HMPC/228759/2016 Page 98/123
subjects
blind (n=60) was given underwent vs. 83.3% of adverse events

whole gut subjects rating the
irrigation with preparation as
(PEG-ELS) tolerable. Severe
adverse events were
not observed
Frigerio et Randomised, 1 dose of senna fruit dry 473 patients Referred for 150/300 mg HAD The adverse reactions
al. (1996) single-blind extract preparation (225 males colonoscopy observed are reflecting
study corresponding to 150 mg and 248 abdominal pain the known spectrum of
hydroxyanthracene glycosides, females with a 19/17 adverse events.
calculated as sennoside B, per mean age of nausea 2/5
single dose) for colon cleansing 59.7 years,
(n=250) range 14–96 fainting 3/1
years)
2 doses, one at mid-day and headache 0/1
one on the evening prior to the liquids orally
examination, equivalent to 300 according to
mg sennosides (n=223) need, no
enema
Schanz et Randomised, Sodium phosphate solution, 355 Referred to Discomfort of fluid The adverse reactions
al. (2008) multicenter, n=128 (A) consecutive colonoscopy 39.8% A; 46.6% B observed are reflecting
observer- out patients 54.5% C the known spectrum of
blind Sodium phosphate solution and (18 and 75 adverse events
a senna fruit dry extract years). Tolerability A: good
preparation corresponding to 72%, moderate
150 mg hydroxyanthracene Drinking 21.6% bad 6.4%
glycosides, calculated as volumes (L)
sennoside B, per single dose), (A=4.33+1.2, B: 72.2% good,
n=133 (B) B=4.56+1.18, mod: 20.3% bad
C=4.93+1.71) 7.5%
PEG-ELS and senna were different
preparation, n=94 (C) C: good: 83.7%
(p=0.005) mod: 10.9%, bad
5.4%
Kositchaiw Prospective 180 mg senna tablet -95 ml 134 Referred for 4 AEs ; senna 1 The mentioned AEs are
at et al. randomised sodium phosphate solution on elective sigmoid perforation, the usual risks of
1 polypectomy colonoscopy, they are not
EMA/HMPC/228759/2016 Page 99/123
subjects
(2006) single blind the day before colonoscopy colonoscopy bleeding to be associated with the
application of senna
Valverde Prospective, Sennosides A+B 120 mg or 240 523 patients Colonic or rectal Sennoside group The adverse reactions
et al. randomised, mg in obese patients, senna carcinoma or 262 observed are reflecting
(1999) observer- preparation evening before 5% povidone sigmoid the known spectrum of
blind, parallel, surgery, n=262 iodine diverticular disease Complete tolerance adverse events. The
multicentre antiseptic undergoing 206; vomiting 12; higher incidence
study Polyethylene glycol (PEG) (2 enemas (2 l) elective colonic or abdominal pain 35; correlates to the daily
packages diluted in 2–3 l of the evening rectal resection distension 8 doses
water, ColoPeg®), n=261 and the followed by
morning immediate
before surgery anastomosis
Bowel cleansing 150 mg HAD with enema
Hanggartn Prospective 4 l of PEG-ELS; n=100 300 patients Referred for Vomiting 6/98 The adverse reactions
er et al. randomised colonoscopy observed are reflecting
(1989) 2 l of PEG-ELS combined with Exclusion of Nausea 39/98 the known spectrum of
Cascara-Salax, n=102 prior colonic adverse events
surgery Abdominal cramps
1.26-1.85 g dry extract Sennae 62/98
fructus acutifoliae
corresponding to 150 mg Hunger 57/98
hydroxyanthra-cene glycosides, Vertigo 22/98
calculated as sennoside B; DER
3-5:1, extraction solvent water Sleeplessness 30/98
for colon cleansing combined
with an enema, n=98
Krakamp randomised PEG-ELS-recepture 3 l; 3 150 out- Referred for Cramps The adverse reactions
et al. simple-blind hours, n=50 patients colonoscopy observed are reflecting
(1996) study Abdominal fullness the known spectrum of
PEG-ELS, 4 l; 4 hours, n=50 Group 3 three adverse events
days eating No frequency
Senna preparation 150mg HAD, restrictions; 1
n=50 day clear
fluids 1 enema
1 hour before
EMA/HMPC/228759/2016 Page 100/123
subjects
procedure.
57±19 years
in group 1,
55±15 years
in group 2 and
57±17 years
in group 3
Bokemeyer Open PEG-ELS, 2 l on the day before 300 Referred for 1-6; tolerability The adverse reactions
et al. prospective colonoscopy and 2 l on the day outpatients colonoscopy around 2 for all observed are reflecting
(2000) study of colonoscopy p.o., n=41 groups the known spectrum of
adverse events
PEG-ELS-RSS, 3 l on the day of
colonoscopy p.o.), n=40
Sodium phosphate solution (45
ml on the day before and 45 ml
on the day of colonoscopy
p.o.), n=44
A senna fruit dry extract
preparation corresponding to
150 mg hydroxyanthracene
glycosides, calculated as
sennoside B, per single dose,
and an enema and 2 l PEG-ELS
on the day before colonoscopy
p.o. and an enema in the
morning before colonoscopy),
n=40
Calcium sennosides (120-300 mg HAD)
Arezzo Randomised Senna compound (group 1; 12 300 patients Referred for Senna tolerability The adverse reactions
(2000) observer- tablets each containing 12 mg colonoscopy good 87; medium observed are reflecting
blind, parallel sennosides A+B at 10 am. and 10; scarce 3 the known spectrum of
study magnesium sulfate 15 g at 5 adverse events
pm. on the day before
EMA/HMPC/228759/2016 Page 101/123
subjects
colonoscopy p.o., n=100

PEG lavage (group 2; 4 l at 4
pm. on the day before
colonoscopy p.o., n=100
An oral sodium phosphate
solution (group 3; 40 ml at 6
pm. on the day before and 40
ml at 6 am. on the day of
colonoscopy, n=100
Radaelli et Prospective Oral high dose of senna 24 283 patients Referred for Senna The adverse reactions
al. (2005) randomised tablets of senna (12 mg extract elective observed are reflecting
single blinded of sennoside A and B colonoscopy Nausea 54/190 the known spectrum of
Vomiting 13/190 adverse events.
divided into two doses at 1 pm.
and 9 pm. (n=191), Abd. pain 141/190
Conventional polyethylene Headache 27/190
glycol-electrolyte lavage
solution (PEG-ES) (n=92) Dizziness 37/190
Tolerability see
Table 6
Amato et Randomised 12 tablets of 12 mg senna and 296 Referred for Nausea 31/151 The adverse reactions
al. (2010) investigator- 2 l of PEG-ES (half-dose group, elective observed are reflecting
blinded HDG), n=151 colonoscopy Vomiting 15/151 the known spectrum of
Abd. pain 60/151 adverse events
24 tablets of senna divided in
two doses (senna group, SG) Headache 33/151
the day before colonoscopy,
n=145 Dizziness 25/151
Nausea 41/145
Vomiting 13/145
Abd. pain 66/145
EMA/HMPC/228759/2016 Page 102/123
subjects
Headache 30/145
Dizziness 18/145
Kelly et al. Prospective Low-volume polyethylene glycol 258 (female, Referred for AEs (mean) The adverse reactions
(2012) (2 l Moviprep; Norgine 138; 53.5%) elective observed are reflecting
Pharmaceuticals), n=86 colonoscopy 1.65 Senna citramag the known spectrum of
1.94 Klean Prep adverse events
Standard volume polyethylene
glycol (4 l), n=91 1.89 Moviprep
Magnesium citrate plus
stimulant laxative, n=81
Manukyan Prospective Sodium phosphate, n=53 99 Referred for Nausea 26% The adverse reactions
et al. elective observed are reflecting
(2011) Sennoside A+B, n=46 colonoscopy Vomiting 6% the known spectrum of
Abd. pain 52% adverse events
Headache 14%
Ergül et al. Randomised Sennoside tablet 80 mg daily 129 Scheduled for Nausea 7.7%, 3.2% The adverse reactions
(2014) controlled, for 3 days; senna solution 150 elective observed are reflecting
single blinded ml (300 mg senna) the night colonoscopy Vomiting 1.5%, the known spectrum of
before colonoscopy, n=65 (1) 1.6% adverse events
To chew sugarless gum half an Abd. pain 9.2%,

hour three-times daily after 4.7%
meals for these 3 days Fatigue 1.5%, -
sennoside tablet 80 mg daily
for 3 days;senna solution 150 Dizziness 4.6%,
ml (300 mg senna) the night 1.6%
before colonoscopy, n=64 (2)
For treatment 1 or
2, respectively
Altinbas et Retrospective Sennoside a+b calcium 500 185 patients; Elective No statistical Single administration
al. (2015) single blinded mg/250 ml, n=91 53.4±13.4 colonoscopy differences without specific AE
years
4 l of PEG-EL, n=94 (53.7±15.0 in Nausea 1-2%
EMA/HMPC/228759/2016 Page 103/123
subjects
Group 1, Abdominal cramps

52.42±11.8 in
Group 2, 9-14%
P=0.255);
89.3% and
95.8%,
respectively,
of the patients
in the groups
1 and 2 were
male,
(P=0.545)
Taylor et Controlled Reduced-laxative (13 g sachet 95 patients Scheduled to Red prep: Single administration
al. (2008) randomised of senna granules HAD/18 g (50 female, undergo afternoon without specific AE
magnesium citrate) CTC prior mean age diagnostic Nausea/ Vomiting
to CT colonography 64 years, colonoscopy for 29%
range 50– symptoms Dizziness 29%
tagging regimens: 85 years), two suggestive of
20 ml 40% w/v barium days of low colorectal Abd. pain 55%
sulphate: regimen A: four residue diet neoplasia
Soreness 49%
doses
B: three doses
C: three doses plus 220 ml
2.1% barium sulphate
D: three doses plus 15 ml

diatriazoate megluamine
Hookey et Prospective 120 mg oral sennosides syrup 171 patients, Referred for No significant The adverse reactions
al. (2006) randomised followed by 2 l PEG a clear fluid elective differences in observed are reflecting
investigator- diet the day colonoscopy symptom scores for the known spectrum of
blind 4 l PEG before nausea, vomiting, adverse events
colonoscopy chest or abdominal
pain, dizziness or
bloating
EMA/HMPC/228759/2016 Page 104/123
subjects
< 80 mg HAD
Iida et al. Uncontrolled Drink 2 l of PEG-ELS on the day 297 Referred for Nausea 10%; The adverse reactions
(1992) of examination by taking 36 mg examinees colonoscopy abdominal fullness observed are reflecting
of sennosides (no further (219 male and 24%; 54 no the known spectrum of
information of the formulation) 78 female; symptoms adverse events
orally in the evening before mean age 57
colonoscopy years)
Haapamäki Single-center, 2 l PEG combined with 36 mg 490 Referred for No information As no information on
et al. prospective senna glycosides in tablets elective adverse reactions, study
(2011) randomised colonoscopy allows no further
investigator- 4 l PEG for bowel preparation conclusion
blind study
Kashyap et Prospective, 4 senna tablets 25 volunteers Healthy; colon No serious AEs, Single administration
al. (2015) single-center, capsule endoscopy three moderate AEs without specific AE
single-arm 4 l of PEG (split dose) (CCE) related to the bowel
10 mg metoclopramide preparation (nausea,
headache, elevated
2 oral sulfate solution boosters creatinine) and two
(6 oz. and 3 oz.) mild unrelated AEs
(chills, abdominal
10 mg bisacodyl
cramping
Poyrazoglu Prospective 90 ml of oral NaP (NaP group), 137 Referred for Nausea and vomiting Single administration with
and Yalniz randomised n=66 consecutive colonoscopy less in sennagroup the usual AEs; less
(2015) single-blinded patients; 5 p=0.05; no nausea and vomiting in
500 ml of 1,000 mg of NaP; 4 senna differences in Senna group
sennosides A and B calcium excluded abdominal pain;
+66.6 g of sorbitol (senna dizziness; headache
group), n=62
Vradelis et Prospective Magnesium citrate 2 sachets á 345 Referred for Nausea vomiting The adverse reactions
al. (2009) 11.6 g magnesium carbonate consecutive endoscopy bloating and observed are reflecting
and 17.8 g anhydrous citric adult out headache the known spectrum of
acid, n=160 patients adverse events
Abdominal cramps
2 sachets at 11.6 g magnesium Low-fiber diet were less in the
EMA/HMPC/228759/2016 Page 105/123
subjects
carbonate and 17.8 g for 2 days; citramag group

anhydrous citric acid clear fluids 1
day
1 sachet senna granules no
further information, n=182
Postoperative constipation
Patel et al. Prospective Placebo, n=45 96 patients After pelvic Cramping bloating The adverse reactions
(2010) randomised after pelvic reconstructive 6/39 observed are reflecting
Senna 8.6 mg with docusate 50 reconstructive surgery the known spectrum of
mg, n=48 surgery adverse events
Postoperative opioid-induced constipation
Marciniak Double blind, Lubiprostone , orally twice a 64 adults, 56 Postoperative Relative frequency The adverse reactions
et al. randomised, day 24 mg participants opioid-induced observed are reflecting
(2014) active (28 in each constipation Nausea 0.46 the known spectrum of
comparator Senna (generic) two capsules group) had adverse events
administered daily for six days Cramping 0.11
trial randomi- baseline and
sation: 1:1 follow up Straining 0.75
ratio in blocks measures and
Abd. pain 0.04
of 4 were included
in the No differences
intention to
treat (ITT)
analyses. 43
participants
completed the
study, 21 in
the active
group
Chemotherapy-induced constipation
Tao et al. Senna extract in the 1st 82 patients Constipation after Abdominal Pain The adverse reactions
(2012) chemotherapeutic course and chemotherapy 8.54% observed are reflecting
the crude fiber diet in the 2nd the known spectrum of
No differences
EMA/HMPC/228759/2016 Page 106/123
subjects
chemotherapeutic course between groups adverse events

Vice versa
Constipation in people receiving palliative care
Ramesh et Controlled Purified senna extract 60 mg 50 patients Management of No nausea and The adverse reactions
al. (1998) open containing 12 mg senna (30-70years), opioid-induced vomiting in senna observed are reflecting
glucosides as calcium salts (2 constipation in group the known spectrum of
tablets at night; 4 tablets at Senna: 9 advanced cancer adverse events
night;2 tablets in the morning dropouts (4
+4 tablets at night every 2 irreg. admin.;
days, n=25; 2 lost follow-
up; 2
step 1: 2 tablets at night; morphine
withdrawal; 1
step 2: 4 tablets at night; bowel
step 3: 2 tablets in the movement
morning; 4 tablets at night spontaneous )
A liquid Ayurvedic (herbal) Liquid: 5 drop

preparation (Misrakasneham; outs (2†; 2
21 herbs), n=25 lost follow-up;
1 irregular
Increasing in 3 steps; 2.5 ml; 5 administrat.)
ml; 10 ml
Agra et al. Randomised, Senna derivatives 0.4 ml (12 91 terminal Terminal cancer First 7 days, 6 The adverse reactions
(1998) open, parallel mg) for senna (no other cancer patients (3 treated observed are reflecting
–group trial information of the formulation patients 16 with senna and 3 the known spectrum of
available) intake in two doses; patients treated with adverse events
every 3 days dropped out lactulose) presented
during the adverse effects
Maximum doses were 1.6 ml first 4 days (diarrhoea,
(48 mg), n=43 vomiting, and
37 patients cramps)
Lactulose 15 ml (10 g) every 3 were lost: 21
days; maximum doses 60 ml in the senna
(40 g), n=48 group and 16
EMA/HMPC/228759/2016 Page 107/123
subjects
in the
lactulose
group 3
vomiting; 5
refusals; 17
deaths; 12
hospitalised
Urothelial cancer
Bronder et Retrospective Analgesics and laxatives as 766 cases of Standardised Use of contact Further studies are
al. (1999) case-control risks for the induction of urothelial questionnaire laxatives was needed; no results for
study urothelial cancer in renal pelvis, cancers (98% reported by 63 laxatives adjusted for use
ureter and bladder confirmed by 648 patients and urothelial cancer of analgesics
histology) 647 controls, social patients versus 29
Phenacetin, aaracetamol, class was recorded controls (odds ratio,
acetylsalicylic acid (ASA) and Control group as well as 2.5; 95% CI, 1.5–
pyrazolones (1:1) was consumption of 4.2) and 13 renal
obtained by analgesics, pelvis and ureter
sampling, laxatives and cancer patients
from the West tobacco versus two controls
Berlin (odds ratio, 9.3;
Population 95% CI, 1.1–83.3).
Registry, For different
persons of laxatives, the
German corresponding
nationality figures (urothelial
who had lived cancer patients
in Germany versus controls)
for at least 20 were: chemical and
years and anthranoid laxatives,
matched with five vs. two (odds
the patients ratio, 2.7; 95% CI,
for sex and 0.47–16);
age anthranoid laxatives
alone, 37 vs. 20
(odds ratio, 2.0;
95% CI, 1.1–3.7);
EMA/HMPC/228759/2016 Page 108/123
subjects
aloe, 16 vs. 11
(odds ratio, 1.6;
95% CI, 0.66–3.7);
senna, 26 vs. 13
(odds ratio, 2.4;
95% CI, 1.1–5.0);
and rhubarb, eight
vs. four (odds ratio,
2.6; 95% CI, 0.68–
9.6)
EMA/HMPC/228759/2016 Page 109/123
Children
No data are available on the safety of senna use in children <6 years of age. To describe the clinical
outcomes of exposure to unintentional ingestion of senna-containing laxatives in young children, all
ingestion exposures of senna-containing laxatives in children <5 years of age from 6 poison centers
over a 9-month period were evaluated. Inclusion criteria required 24-hour follow-up and the presence
of diarrhea to confirm ingestion. Parents were told routinely that severe diaper rash was possible and
to protect the perianal area with frequent cleansing and a barrier ointment if the child was wearing
diapers. During the study period, 111 cases were reported: 19 children experienced no diarrhea, 4
were lost to follow-up, and 88 exposures were evaluated. Fifty two children (59%) were </=2 years
old. Fifty children remained in diapers, 28 children were fully toilet trained, and 10 wore diapers (pull-
up pants) overnight. Twenty nine children (33%) experienced severe diaper rash. The mean±SD time
to recognition of the diaper rash was 15.6±8.6 hours. Ten children (11%) had blisters and skin
sloughing. There was a significant increase in severe diaper rash (p<0.05) and onset of blisters and
skin breakdown (p<0.05) in children wearing diapers versus those who were fully toilet trained. The
mean time to onset of blisters was 14.5±6.8 hours. Skin burns and loss were seen primarily on the
buttocks and perineum, loosely following the diaper area. It was concluded that unintentional ingestion
of senna-containing laxatives in young children may potentially cause severe diaper rash, blisters, and
skin sloughing (Spiller et al. 2003).
5.2. Patient exposure
Aside from its market presence and the data from clinical studies in humans (3939 patients treated
with different posologies from 30 mg HAD to 300 mg HAD from the studies mentioned in this
assessment report) the mostly mentioned adverse events are headache, nausea, vomiting, abdominal
cramps, fatigue and dizziness, to be estimated in the category of very common >1/10) to common
(>1/100 to<1/10).
Siegers et al. (1993 b) reported about a retrospective study of 3,049 patients, who underwent
diagnostic colorectal endoscopy. The incidence of pseudomelanosis coli, which is regarded as a reliable
indicator of chronic anthranoid laxative abuse (use for more than nine to 12 months), was 3.13% in
patients without pathological changes. In those with colorectal adenomas, the incidence increased to
8.64% (p<0.01), and in those with colorectal carcinomas it was 3.29%. This lower rate was probably
caused by incomplete documentation of pseudomelanosis coli in those with carcinoma. In a prospective
study of 1,095 patients, the incidence of pseudomelanosis coli was 6.9% for patients with no
abnormality seen on endoscopy, 9.8% (p=0.068) for patients with adenomas and 18.6% for patients
with colorectal carcinomas. From these data a relative risk of 3.04 (1.18, 4.9; 95% confidence
interval) can be calculated for colorectal cancer as a result of chronic anthranoid laxative abuse.
Kune et al. (1988) and Kune (1993) reported about the “Melbourne Colorectal Cancer Study”.
Commercial laxative use as a risk factor in colorectal cancer was investigated as one part of this large
population based epidemiological study of colorectal incidence, aetiology and survival. Commercial
laxative use was similar in 685 colorectal cancer patients and 723 age/sex matched community-based
controls. Also, when laxatives were subdivided into various groups containing anthraquinones,
phenolphthalein, mineral salts and others, previous laxative intake was similar between cases and
controls. Previous use of anthraquinone laxatives and of phenolphthalein containing laxatives was not
associated with the risk of colorectal cancer. Furthermore the results of this study suggest that chronic
constipation, diarrhoea, and the frequency and consistency of bowel motions are unlikely to be
etiologic factors in the development of colorectal cancer. They indicate that it is the diet and not the
constipation that is associated with the risk of large-bowel cancer. Additionally, a highly statistically
EMA/HMPC/228759/2016 Page 110/123
significant association (p=0.02) with the risk of colorectal cancer was found in those who reported
constipation and also had a high fat intake.
In a retrospective study a cohort of 2,277 patients was defined by colonoscopy. Among other factors
Nusko et al. (1993) tested whether in these patients laxative use or the endoscopically diagnosed
presence of melanosis coli were risk factors related to colorectal neoplasm. In comparison to patients
taking no laxatives, there was no significant increase in colorectal cancer rate either in laxatives users
or in patients with melanosis coli. However, there was a statistically significant association between the
occurrence of colorectal adenomas and laxative use (relative risk of all patients exposed to
laxatives=1.72; of patients exposed to laxatives without melanosis coli=1.47). The relative risk of
adenoma development in patients with melanosis coli was 2.19. Taking into account that polyps can be
diagnosed in the dark mucosa of melanosis coli patients more easily, the authors concluded that even
this relative risk of 2.19 seems to be related to a generally enhanced risk of laxative intake rather than
to a special group of (anthranoid-containing) laxatives.
Jacobs and White (1998) examined the associations of colon cancer with constipation and use of
commercial laxatives in a case control study among men and women aged 30–62 years (424 incident
cases and 414 random-digital-dial controls). Constipation was defined by “feeling constipated to the
point of having to take something”. The adjusted relative risk (RR) was 2.0 [95% confidence interval
(CI)=1.2-3.6] for constipation 12-51 times per year, and 4.4 (95% CI=2.1-8.9) for constipation 52 or
more times a year. Cumulative lifetime use of commercial laxatives was also associated with increased
risk of colon cancer. When adjusted for constipation, commercial laxative use was no longer associated
with increased risk (RR=0.3, 95% CI=0.1-0.9 for less than 350 uses; RR=0.9, 95% CI=0.4-2.3 for
350 or more uses). The association with constipation remained. In this study, no subject reported use
of anthranoid-containing laxatives.
Van Gorkom et al. (2000) performed a controlled study to evaluate the effects of a senna extract
(1.26-1.85 g dry extract of Sennae fructus acutifoliae corresponding to 150 mg hydroxyanthracene
glycosides, calculated as sennoside B; DER 3-5:1, extraction solvent water) on cell proliferation and
crypt length in the entire colon and to clarify the mechanism of the suggested cancer-promoting effects
of long-term senna ingestion. One hundred and seventy one outpatients were randomised into 2
groups. Eighty patients received 1 ml/kg (maximum 75 ml) senna extract taken orally 18 hours before
colonoscopy. This was followed 3 hours later by the oral intake of 2 l lavage solution containing
polyethylene glycol and electrolytes. Another 1–3 l of this lavage solution was given on the morning of
the colonoscopy. The same bowel preparation, but without senna, was given to 87 patients. From 32
randomised patients (15 with senna, 17 without senna) biopsies were taken. A massive acute loss of
cells was found in the senna group (presumably due to induced, uninhibited apoptosis), with a
shortening in the crypts and an increase in cell proliferation. The authors interpreted these effects as
possible signs of a carcinogenic effect, but also pointed out that in this study patients were treated
with a single high dose of senna extract, which is normally not used for repeated treatment, the
number of participated patients was very small while these effects have not been confirmed by any
other studies (Hallmann 2000).
A review by Hallmann (2000) summarised toxicological data of stimulant laxatives and other freely
available compounds such as lactulose. He reported on possible connections between the increased
incidence of (colon) cancer and the use of senna preparations. In retrospective studies, only a
relationship with long-term use of the laxative could be demonstrated.
Since individual case-control studies have failed to resolve the question whether constipation and use
of cathartics represent significant risk factors of colorectal cancer, a meta-analysis was performed. The
method by Peto was used to calculate pooled odds ratios of the cancer risk among exposed and
EMA/HMPC/228759/2016 Page 111/123
unexposed subjects. The analysis of 14 previously published case-control studies revealed statistically
significant risks for colorectal cancer associated with both constipation and use of cathartics, the
pooled odds ratios and their 95% confidence intervals being 1.48 (1.32-1.66) and 1.46 (1.33-1.61),
respectively. The increased risk applied similarly to both sexes, it was higher in cancer of the colon
than rectum. Since constipation and cathartics are associated with much lower odds ratios than various
dietary components, such as fat, meat, alcohol, and low-vegetable or low-residue diets, it appears that
their risk reflects the confounding influence of underlying dietary habits (Sonnenberg and Mueller
1993).
Nusko et al. (2000) performed a prospective case control study at the University of Erlangen to
investigate the risk of anthranoid laxative use for the development of colorectal adenomas or
carcinomas. A total of 202 patients with newly diagnosed colorectal carcinomas, 114 patients with
adenomatous polyps, and 238 patients (controls) with no colorectal neoplasm who had been referred
for total colonoscopy were studied. The use of anthranoid preparations was assessed by standardised
interview, and endoscopically visible or microscopic melanosis coli was studied by histopathological
examination. There was no statistically significant risk of anthranoid use for the development of
colorectal adenomas (unadjusted odds ratio 1.0; 95% CI 0.5-1.9) or carcinomas (unadjusted odds
ratio 1.0; 95% CI 0.6-1.8). Even after adjustment for the risk factors age, sex, and blood in the stools
by logistic regression analysis the odds ratio for adenomas was 0.84 (95% CI 0.4-1.7) and for
carcinomas 0.93 (95% CI 0.5-1.7). Also, there were no differences between the patient and control
groups for duration of intake. Macroscopic and high grade microscopic melanosis coli were not
significant risk factors for the development of adenomas or carcinomas.
Roberts et al. conducted in 2003 a population-based, case control study, with equal representation by
white and black men and women aged 40–80 years. Constipation, defined as fewer than three reported
bowel movements per week, was associated with a higher than two-fold risk of colon cancer (OR 2.36;
95% CI=1.41-3.93) adjusted for age, race, sex, and relevant confounders. The OR for constipation
was slightly higher for distal than for proximal colon cancers. There was no association with laxative
use (OR 0.88; 95% CI=0.69-1.11). The authors did not explicitly mention anthraquinone-containing
laxatives. They mentioned the group “stimulants, fibers, natural remedies, stool softeners, oils,
osmotic agents, enemas, suppositories, and unknown”. They mentioned in particular phenolphthalein
and magnesium.
Nilsson et al. examined 2004 the impact of constipation and laxative treatment on the blood levels of
homocysteine, folate and cobalamine in a population-based sample of aged people. Elevated plasma
homocysteine secondary to reduced supply of folate and cobolamine might indicate an increased risk of
cancer, and cardiovascular and neurological diseases. The homocysteine level depends on the supply of
folate and cobalamine, which constipation and/or laxative treatment might compromise. The study was
based on biochemical tests in 341 females and 183 males aged 82 years and older. The concentrations
of homocysteine (plasma), folate, cobalamine and urea (serum) were measured in subjects with and
without ongoing treatment with laxative substances. Values were adjusted for age, gender and frailty,
as well as for clinical diagnoses and medicinal therapies known to affect homocysteine levels.
Homocysteine levels were increased and those of folate reduced in aged subjects on laxatives.
Homocysteine remained elevated after adjusting for frailty and various neurological disorders. There
was no significant effect on homocysteine and folate in constipated subjects without laxatives.
5.3. Adverse events, serious adverse events and deaths
Farah et al. (2000) published a review article where they presented details of reported adverse events
with herbal medicines received at the Uppsala Monitoring Center of the WHO during the period from
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1968–1997 (8985 individual reports). One hundred one cases were reported in connection with senna
products. The symptoms listed were epileptic seizures (5 times), circulatory disorders (4), death (3),
intestinal perforation (4), vomiting (6), facial oedema (3), hypertension (3), apnoea (2), hepatitis (2),
bloody stools (2), anaphylactic reaction/shock (2), diarrhoea (11), abdominal pain (9), nausea (8),
pruritus (7), erythema (7), skin rash (5), syncope (5), urticaria (5), vesicular eruption (4).
Due to poor information the data do not permit any meaningful analysis. It is not clear whether these
adverse events occurred with mono-preparations or with combination products; furthermore the
combination partners are not known. A further problem in analysing the database arises from the use
of incomplete or incorrect names for the herbal medicines. In addition, the review article provides no
information about dosage and the patients’ medical history. Adverse events like abdominal pain,
nausea and allergic reactions are known (see above).
Reports of adverse events of epileptic seizures, circulatory disorders and anaphylactic reactions/shocks
were also received by the German Health Authority. These adverse reactions only occurred after
ingestion of high doses of senna preparations for bowel cleansing.
Since 1990 the German Health Authority received in total 41 reports of adverse events concerning
mono-preparations and 4 reports concerning combination products of senna leaves and fruits. There
are 23 reports concerning ingestion of high dose of senna preparations for bowel cleansing. In 6
reports, when the senna preparation was administered without co-medication, hypersensitive reactions
(angiooedema, skin irritations, dyspnoea) occurred. Hypersensitive reactions are not depending on the
administered doses in principle. Therefore these adverse reactions have to be also mentioned in case
of low dose as administered for short-term use in cases of occasional constipation. The remaining 22
reports concern the use for constipation. In 19 cases co-medication was administered and an objective
evaluation is therefore not possible. The other 3 reports are related to laxative abuse: albuminuria and
haematuria (nephrolithiasis known), vomiting (gastrointestinal infection was diagnosed later on),
abdominal pain (suspicion of ileus, colonoscopy showed melanosis coli).
Senna leaves and pods
Administration of senna leaves and pods can cause adverse effects such as abdominal cramps and
diarrhea in humans (Langmeade and Rampton 2001).
Major symptoms of overdose/abuse are griping pain and severe diarrhoea with consequent losses of
fluid and electrolyte, which should be replaced. Diarrhoea may cause potassium depletion, in
particular. Potassium depletion may lead to cardiac disorders and muscular asthenia, particularly
where cardiac glycosides, diuretics or adrenocorticosteroids 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.
Furthermore chronic ingestion of overdoses of anthranoid-containing medicinal products may lead to

toxic hepatitis (see below).
Hepatitis
Beuers et al. (1991) reported a case of toxic hepatitis related to abuse of senna glycosides in a 26-year
old female, who had taken an extract of senna fruits corresponding to 100 mg of sennoside B daily in
addition to the usual dose of 10 g senna leaves twice a week in a laxative tea. When the patient
stopped taking senna, aminotransferases fell by 70% within a week and ranged from 20–40 U/l
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subsequently. When the patient took senna alkaloids again, 2 months later, liver function rapidly
deteriorated and improved once more when the product was stopped.
Vanderperren et al. (2005) reported a case of a 52-year-old woman who had ingested, for >3 years,
one liter of an herbal tea each day made from a bag containing 70 g of dry senna fruits, developed
acute hepatic failure and renal impairment requiring intensive care therapy. The severity of the hepatic
failure was reflected by the increase in prothrombin time (international normalised ratio >7) and the
development of encephalopathy. Relevant laboratory data included blood glucose 40 mg/dL,
hemoglobin 17.9 g/dL, urea 63 mg/dL, creatinine 3.2 mg/dL, uric acid 6.7 mg/dL, sodium 138 mEq/l,
chloride 96 mEq/l, calcium 10.2 mg/dL, phosphorus 6 mg/dL, aspartate aminotransferase (AST) 6640
IU/l, alanine aminotransferase (ALT) 9160 IU/l, γ-glutamyl transferase 160 IU/l, bilirubin 6.2 mg/dL,
international normalized ratio (INR) 5.27, and factor V 19%. Arterial blood gas analysis revealed pH
7.18, pCO2 23 mm Hg, total CO2 8 mmol/l, base deficit 19 mmol/l, and lactate 14.8 mmol/l. Urine
analysis showed pH 5.5, density 1020, ++protein, glucose 1.5 g/l, and granular casts. She was
admitted to the intensive care unit (ICU). Common causes of acute hepatitis were ruled out by
laboratory investigations. She had been consuming, for >3 years, one liter of an herbal tea containing
70 g of dry senna products that were made from the fruit of Cassia angustifolia, also known as
Tinnevelly Senna. Liver transplantation was discussed, but the patient ultimately recovered with
supportive therapy. Renal impairment was consistent with proximal tubular acidosis, also with marked
polyuria refractory to vasopressin administration. Suprisingly, large amounts of cadmium were
transiently recovered in the urine.
Severe hepatotoxicity after senna use is unusual. The cause of senna-related hepatotoxicity is unclear
but could be explained by the exposure of the liver to unusual amounts of toxic metabolites of
anthraquinone glycosides. To asses these two cases of liver impairment, the Roussel UCLAF causality
assessment method was used. In 1993, an international group of experts published the so-called
Rucam score to evaluate cases of hepatotoxicity (Danan et al., 1993). The score was validated and the
results published (Benichou et al., 1993).
Beuers et al. (1991).
Rucam Score +10 highly probable: Patient had an hepatocellular type hepatitis. One month before the
first signs of hepatitis, the patient had increased the dose of senna alkaloids by taking an extract of
senna fruits corresponding to 100 mg sennoside B daily on top of her usual dose of 10 g Folia sennae
twice a week in a laxative tea. At this time she was taking 10 times the recommended dose. When she
stopped taking senna ALT decreased by 70% within a week. When she took senna again 2 months
later, ALT again increased (>280 U/l; normal range<19 U/l). ALT decreased once more when the drug
was again stopped. No concomitant use of other medication could be detected. There was no evidence
for viral, autoimmune, or metabolic disease (rated with+2 points within the Rucam Score). The
histological picture suggested toxic damage.
Vanderperren et al. (2005)
Rucam Score +4 possible: Although the value of alkaline phosphatase (AP) is not given, it is assumed
that it was a hepatocellular type of hepatitis (ALT=9160 IU/l; normal range 14–63 IU/l). ALT
decreased>50% within 8 days. The authors were unable to document chronic hepatotoxicity prior to
this episode because the patient had never consulted a physician and had no laboratory workup. The
patient regularly took vitamin supplements. Common causes of acute hepatitis were ruled out by
laboratory investigations (no special information). Interpretation is that the non-drug related causes of
the first group were ruled out (rated with+1 point within the Rucam Score).
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A 42-year-old woman was admitted to the emergency department with a five-day history of worsening
epigastric pain, anorexia, episodic vomiting, and intermittent fever. She reported that she had boiled
dried senna leaves (unreported daily dose) she had bought from herbalists and drank approximately
200 ml daily for two years. Color Doppler screening found an echogen thrombus obliterating portal vein
bifurcation and the right branch. The lumen was obstructed at this level and there was no blood flow
through it. Treatment with thrombolytics was unsuccessful. Chronic use of Cassia angustifolia may
rarely be associated with portal vein thrombosis (Soyuncu et al., 2008).
Assessor’s comment
According to the Rucam score, the hepatotoxic cases are related to the chronic ingested overdoses.
Nephritis
Nephritis as a response to large doses of anthraquinones is mentioned by Brunton (1996) without any
further information or references.
As mentioned above, Vanderperren et al. (2005) reported one case with acute liver failure and renal
impairment related to the abuse of senna anthraquinone glycosides. The renal dysfunction in this
patient had the characteristics of secondary mixed proximal and distal renal tubular acidosis. It is
caused by an impairment of bicarbonate reabsorption in the proximal tube. This defect is either
hereditary or secondary to administration of drugs or toxin e.g. cadmium. The tubular defect in this
case is transient. Significant amounts of cadmium were found in the patient’s urine. In the present
case the source of cadmium remained unknown. The authors did not identify metals in a sample of the
herbal tea drunken by the patient.
The relationship between this abuse of senna and the renal impairment is too weak to be mentioned in
the European Union herbal monograph.
Finger clubbing
Silk et al. (1975) reported a case of a 26-year old female, who was investigated for severe diarrhoea,
which occurred after laparotomy with division of the ligament of Treitz because of a duodenal ileus and
a second laparotomy with a duodenojejunostomy because of persisting vomiting. No organic cause
could be revealed. During the course of her illness the patient had developed finger clubbing. During a
recent hospitalisation more than 2,000 tablets (standardised senna concentrate; each tablet contains
8.6 mg sennosides) were found in her bedside locker, and a subsequent analysis of her urine showed
that high concentrations of anthranquinone excretion products were present. After this finding the
psychiatric assessment revealed that the patient exhibited many features typically associated with
anorexia nervosa. On stopping the purgatives, her diarrhoea improved and her finger clubbing
regressed. But vomiting and diarrhoea recurred and she admitted to take 100 to 200 senna tablets a
day. Her finger clubbing also returned 2 to 3 months after she admitted to re-ingesting purgatives.
Prior and White (1978) reported on a 24-year old woman with anorexia nervosa. Over the past 4 years
she was taking increasing quantities of senna (up to 50 tablets daily) to produce a regular stool. She
denied diarrhoea. The patient was thin. She had scoliosis and the fingers and toes were clubbed. She
presented tetany, probably caused by a combination of hypokaliaemia and hyperventilation. The
patient refused to cease laxative abuse.
Malmquist et al. (1980) reported the case of a young woman with a previous history of anorexia
nervosa (body weight minimum 26 kg, height 1.56 m) and of abuse of alcohol and sedatives presented
with severe finger clubbing. Urine samples intermittently contained significant amounts of
aspartylglucosamine. Liver biopsy showed abnormal cytoplasmic inclusions in phagocytic cells. The
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patient reluctantly admitted the daily intake of 2 to 5 tablets of a senna preparation (each containing
12 mg calcium salts of sennosides A+B from a standardised extract of senna leaves, extraction
solvent: methanol 66% (V/V)) continuously for 10 years. Although she was strongly advised to
discontinue, she could not because attempts to do so cause severe constipation according to what the
patient said.
Levine et al. (1981) reported the case of a 64-year old woman, who had lost more than 45% of her
healthy weight. She had had repeated urinary infections with renal stones over many years, but
diarrhoea had been the chief symptom since 1972. Finger clubbing and hypokaliaemia were observed
in 1975. Hypogammaglobulinaemia and a B-cell deficit were diagnosed. When hospitalised over 200
Senokot® tablets were found in her locker. Stopping ingestion of senna and increasing food intake
with enteral proprietary supplements led to rapid weight gain. Serum levels of immunoglobulins rose
and a repeat lymphocyte analysis showed B cells in normal numbers. In an interview with a clinical
psychologist, she gave a history of probable anorexia nervosa in early adult life, since when she had
apparently retained the idea that a low bodyweight was desirable.
Armstrong et al. (1981) presented a case of a 21-year old woman with a 9-month history of painful
swelling of both ankles followed by painful swelling and morning stiffness affecting proximal and distal
interphalangeal joints of both hands without rheumatic family history. She had intermittent diarrhoea
of three years’ duration. On examination she weighed 49.1 kg. There was clubbing of fingers and toes
with pronounced periungual erythema. Both ankles were swollen, red, and tender, and there was
tenderness of interphalangeal joints of fingers. Radiographs of knees and ankles showed striking
symmetrical bilateral periosteal new bone formation, affecting particularly the ends of the long bones.
The patient confessed to habitually taking at least 3 senna tablets daily to control her weight. She also
admitted to a period of secondary amenorrhoea of several months’ duration a year before. Her weight
increased to 57.2 kg when she stopped taking the laxatives. Within 6 months the clubbing had
disappeared. Her rheumatic symptoms were less severe and controlled by NSAID, though the
radiological bone abnormalities did not regress.
These cases only show symptoms of an overdose and abuse. But all these reported cases have in
common a history of anorexia nervosa with an abuse of senna to control weight. The causality of the
finger clubbing and all other disturbances with this misuse seems to be dubious. The main disease is
anorexia nervosa, which can cause life-threatening disturbances. At this moment, available data are
not strong enough and these effects are not introduced in the European Union herbal monograph.
Melanosis coli caused by senna and a combination of aloe, rheum and frangula
Willems et al. (2003) described a case of melanosis coli, which occurred in a 39-year old liver
transplant patient, who took an over-the-counter product containing aloe, rheum and frangula. The
typical brownish pigmentation of the colonic mucosa developed in a period of ten months. The
anthranoid medication was stopped and follow-up colonoscopy one year later showed normal looking
mucosa once more. However, in contrast to previous examinations, a sessile polypoid lesion was found
in the transverse colon. Histology showed tubulovillous adenoma with extensive low-grade dysplasia.
Since there had been preliminary reports suggesting a possible role of anthranoid-containing laxatives
in the development of colorectal adenomas and cancer, the authors discouraged their use.
Ewing et al. (2004) reported the case of an 83-year old man, who underwent a left hemicolectomy for
colonic adenocarcinoma and was found incidentally to have melanosis coli associated with long-term
use of a herbal laxative, a senna leaves preparation, not only in his colonic mucosa, but also in the
colonic submucosa and in his pericolonic lymph nodes. Four more cases were described in the
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literature (Hall and Eusebi, 1978) in which spindle-shaped, yellow-brown bodies were seen in the
mesentric lymph nodes of patients with melanosis coli. The authors concluded that this implies that the
melanosis pigment-laden macrophages formed in the lamina propria of the colon pass to the regional
lymph nodes and may explain the observation of similar pigment-laden macrophages in other sites. In
addition the authors demanded further studies to determine whether there is a relation between the
prolonged use of this herbal laxative and colonic adenocarcinoma.
5.4. Laboratory findings
No specific data available. The laboratory data from some of the clinical trials show no critical changes
neither in the indication constipation nor in bowel cleansing.
5.5. Safety in special populations and situations
Elderly
In order to check the long-term tolerance of a laxative treatment, Emeriau et al. (1983) supervised
during six months a group of 14 elderly people (12 women and 2 men) with a mean age of 81.3 years
suffering from long-standing constipation without any organic cause. The laxative was given in a daily
dosage corresponding to 20 mg of sennosides. Alpha 1-antitrypsin (alpha 1-AT) clearance and
exchangeable potassium pool (PPE) were measured, at the beginning (T0), and at the end of the third
(T3) and the sixth (T6) months of the study. No abnormal variation of intestinal protein loss (alpha 1-
AT: T0, 6.74±3.16; T3, 2.96±1.35; T6, 4.15±1.45 ml/24 hours; T0-T3; p less than 0.05, T0-T6, T3-
T6: NS) and exchangeable potassium pool (PPE: T0, 19.54±2.55; T3, 20.29±3.46, T6, 23.56±4.92
mEq/kg; T0-T3, T0-T6, T3-T6: NS) was observed. Long-term laxative treatments do not necessarily
induce significant intestinal protein and potassium losses.
5.5.1. Use in children and adolescents
The use in children is contraindicated (see section 5.5.2).
5.5.2. Contraindications
During processing steps such as drying, cutting, weighing and filling, senna occasionally causes an
inhalation allergy involving the mucous membranes of the respiratory organs (Roth et al., 1988).
Isolated cases of various anaphylactic reactions have also been reported in connection with senna
administration. Senna leaves and pods should therefore not be used by patients with known
hypersensitivity to senna leaves or pods.
Furthermore, senna leaves and pods should not be used in 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 states with water and electrolyte depletion
(Kommission E, 1993; Bundesinstitut für Arzneimittel und Medizinprodukte 1996). Sossai et al. (2007)
published a case report of an 85 year old man suffering from constipation who took a tisane containing
Cassia angustifolia leaves and fruits liquorice, mallow, fennel, balm and caraway in unreported doses
from a health food store. He suffered at hospital admission from a paralytic ileus. After suspension of
the cassia containing product and conventional therapy including enema, nose tube and fuid supply
with potassium supplementation the patient recovered fully. Colonoscopy showed a colic melanosis.
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Senna leaves and pods preparations are contraindicated in children under 12 years of age, because
lack of data regarding constipation and bowel cleansing in children and because of general safety
concerns.
The use of preparations containing senna leaves and pods are contraindicated in pregnant and
lactating women, because potential genotoxicity has not been fully excluded. Furthermore, after
administration of anthranoids, active metabolites, such as rhein, were excreted in breast milk in small
amounts.
5.5.3. Special warnings and precautions for use
Senna leaves preparation should only be used if a therapeutic effect cannot be achieved by a change of
diet or the administration of bulk forming agents (Kommission E, 1993).
Mueller-Lissner (2005) concluded in his review that the warnings about laxative-induced damage to the
autonomous nervous system of the colon are based on poorly documented experiments and that, in
contrast, the investigations that do not support such damage are well done. The studies in the cited
references (Smith 1968; Riemann et al., 1980; Riemann and Schmidt, 1982; Berkelhammer et al.,
2002; Meisel et al., 1977; Pockros and Foroozan, 1985) showed abnormalities observed in humans
(damage to enteric nerves, smooth muscle atrophy; distension or ballooning of axons, reduction of
nerve-specific cell structures and increase in lysosomes, and sometimes a total degeneration of whole
nerve fibers; short-lived superficial damage to the mucosa). These were uncontrolled observations and
the author therefore concluded that the cause of these damages can also be the constipation itself or
pre-existing changes of unknown aetiology.
The only study comparing the morphology of the autonomous nervous system of constipated patients
taking anthraquinones (aloe) to that of an appropriate control group of constipated patients without
laxative intake (Riecken et al., 1990) did not support the hypothesis that anthraquinone-containing
laxatives are able to provoke relevant degenerative changes in the colonic nerve tissue. But this
investigation was conducted in 11 matched pairs only.
It cannot be assessed definitely if a longer than a brief period of treatment with stimulant laxatives
leads to dependence requiring increasing quantities of the medicinal product, to an atonic colon with
impaired function and to aggravation of the constipation. Precautionally the long-term use of stimulant
laxatives should be avoided.
The following warnings and precautions for use are recommended:
Long-term use of stimulant laxatives should be avoided, as use for more than a brief period of
treatment may lead to impaired function of the intestine and dependence on laxatives. If laxatives are
needed every day the cause of the constipation should be investigated. Senna pod/leaf preparations
should only be used if a therapeutic effect cannot be achieved by a change of diet or the administration
of bulk forming agents.
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/leaves concomitantly.
Like all laxatives, senna leaves/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).
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When preparations containing senna leaves are administered to incontinent adults, pads should be
changed more frequently to prevent extended skin contact with faeces (Sitzmann et al., 1979; Spiller
et al., 2003).
Patients with kidney disorders should be aware of possible electrolyte imbalance.
5.5.4. Drug interactions and other forms of interaction
Seybold et al. (2004) reported a case of a 28-year-old woman, who presented a 2-week history of
fatigue, myalgias, epigastric pain, pyrosis, and nausea. For 2 days, she had noted yellowish eyes and
dark urine. Recently, she had been consuming 3 to 4 l of beer per week. The patient declined liver
biopsy. Ultrasonography showed only increased hepatic echogenicity. After the patient stopped
drinking alcohol, liver function levels initially decreased but, after 4 weeks, increased again. The
patient recalled that she had been found to be homozygous for the CYP2D6*4 variant while
participating in a scientific study. She also reported drinking a herbal tea containing senna leaves. She
stopped drinking the tea, and her laboratory results gradually returned to normal. Twelve months
later, a controlled tea reexposure was performed. Within 7 days, liver function levels increased
dramatically. The tea was withdrawn, and the values slowly decreased. One month later, another
increase in liver function levels was noted after moderate alcohol consumption. Without further senna
or alcohol ingestion, all laboratory values normalised after 7 more weeks. Rhein levels in stored serum
samples were as follows: 330 ng/ml after 11 months of tea consumption, 130 ng/ml 2 weeks after the
patient stopped drinking the tea, 200 ng/ml at 2 weeks after 1 week of reexposure, and less than 100
ng/ml (lower limit of quantification) 3 weeks later. Serum rhein levels in this patient 24 hours after the
last senna dose were 2 to 10 times higher than in the investigation of Krumbiegel et al., 1993. The
authors assumed that the toxic effects in this patient were caused by a small dose of sennosides that
would not have harmed persons with normal metaboliser status. Furthermore, the exact amount of
ingested sennosides is not given in the publication and the first duration of administration was 11
months. The role of the alcohol consumption cannot be evaluated definitely. On the other side, a re-
exposition resulted in an increase in liver function levels. It cannot be assessed if CYP2D6*4 played a
key role. This can be regarded as a signal. Until there are further data available, no information
referring to this publication is given in the European Union herbal monograph.
The monograph makes reference to the particular effects, which may arise from interaction with
potassium metabolism in sections 4.4 and 4.5. The wording in the revised monographs is based on the
data presented here, development of the wording from the first versions and consideration of
consistency with other revisions of monographs on hydroxyanthracene containing herbal substances.
Chronic use or abuse of senna leaves may lead to hypokalaemia. This hypokalaemia and the increased
loss of potassium may increase the activity of cardiac glycosides and interfere with the action of
antiarrythmic agents (interaction with antiarrhythmic medicinal products, which induce reversion to
sinus rhythm, e.g. quinidine) and medicinal products inducing QT-prolongation (Haverkamp et al.
2002). Concomitant use with medicinal products inducing hypokalaemia (e.g. diuretics,
adrenocorticosteroids and liquorice root) may aggravate electrolyte imbalance.
The hypokalaemia can be aggravated by thiazide diuretics and by loop diuretics, in particular, but not
by potassium-sparing diuretics such as amiloride. However, the patient cannot always differentiate
between the different kinds of diuretics. All kind of diuretics should therefore be mentioned. Because
the mechanism, which this interaction is based on, is described in the SmPC, the doctor can decide
whether the concomitant use of a given diuretic is dangerous or not.
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5.5.5. Fertility, pregnancy and lactation
There are no recent investigations available.
There are also no new, systematic preclinical tests for senna leaves or preparations thereof. There are
some preclinical data that refer to an extract of senna pods 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 to isolated active constituents, rhein or sennosides A and B. The
following in vivo studies were conducted using this extract:
Bauer (1977) administered a combination to 95 pregnant women suffering from constipation: 3 g of

this preparation contain 0.9 g methyl cellulose, 0.3 g frangula bark (13.5 mg hydroxyanthracene
derivatives), 0.3 g senna leaves (7.5 mg hydroxyanthracene derivatives), 0.15 g rhubarb root (6.75
mg hydroxyanthracene derivatives) and 0.015 g achillea extract. Fourteen pregnant women were in
the first trimester, 15 in the second one, and 66 women in the third trimester. On average the
combination was administered for 61.4 days and the complaints disappeared in 3.9 days with a daily
dose of 3.9 g. Efficacy was very good in 55 patients, good in 31 patients, satisfactory in 7 patients and
insufficient in 2 patients. This result was not analysed with regard to the different trimesters. 4
patients (4.2%) complained about adverse reactions. Twelve women in the second group were
gynaecologically treated because of a threatening abortion. Only one of these women miscarried.
There is no information about the state of the new-borns. This investigation cannot prove the safe use
of senna preparations in general in pregnancy.
Shelton (1980) reported that a successful treatment of constipation in the immediate postpartum
period in 93% of white patients and 96% of coloured patients was achieved in a clinical randomised
controlled trial of “standardised senna tablets”. The time of the first spontaneous normal bowel action
was taken as the criterion. If this occurred within the first 24 hours after delivery or on the following
day (i.e. within 48 hours of delivery) the response was regarded as successful. This result was
significantly better than the success rates of 51% and 59% in white and coloured patient controls
treated with placebo. Minor abdominal cramps occurred in some 13% of the patients treated with
senna and in 4% of the controls given the placebo. Furthermore the author reported that there was no
evidence to suggest that standardised senna had any effect on a breast-fed baby if taken by the
mother.
Faber et al. (1988) investigated the excretion of rhein in 100 breast milk samples of 20 post-partum
women after intake of a “standardised senna laxative”, which also contains Plantago ovata seeds/husks
as bulk substances. After daily doses of 5 g of the senna laxative containing 15 mg sennosides for 3
days, the rhein concentration in milk samples from every lactation during 24 hours post-dose varied
between 0 and 27 ng/ml with values below 10 ng/ml in 94%. Based on median values, 0.007% of the
sennoside intake (calculated as rhein) was excreted in breast milk. None of the breast-fed infants had
an abnormal stool consistency. Assuming theoretically a complete metabolism of sennosides to rhein in
the mother, the amount of rhein delivered to the infant (ng/kg b.w.) is by the factor 10-3 below the
rhein intake of the mother.
The possible teratogenic effect of frequently used laxative drug had not been checked in case-control
epidemiological study, previously. Therefore, the objective of the study of Ács et al. (2009) was the
comparison of cases with congenital abnormalities (CAs) and their matched controls without CAs in the
population-based large data set of the Hungarian Case-Control Surveillance System of Congenital
Abnormalities. Of 22,843 cases with CA, 506 (2.2%) had mothers with senna treatment, while of
38,151 control newborn infants without CA, 937 (2.5%) were born to mothers with senna treatment
(adjusted OR with 95% CI: 1.0, 0.9-1.1), and of 834 malformed controls with Down syndrome, 26
EMA/HMPC/228759/2016 Page 120/123
(3.1%) had mothers with the use of senna (OR with 95% CI: 0.7, 0.5-1.1). The range of senna doses
was between 10 mg and 30 mg, but most pregnant women used 20 mg daily. The mothers with senna
treatment showed the characteristics of pregnant women with constipation (elder with larger
proportion of primiparae). There was no higher risk for 23 different CA groups after the senna
treatment during the second and/or third gestational month of 260 mothers, i.e. during the critical
period of most major CAs, compared with their 500 matched controls. The gestational age at delivery
was somewhat longer (0.2 week). Furthermore, the rate of preterm birth was lower (6.6% vs. 9.2%)
in newborn infants without CA born to mothers with senna treatment compared with babies born to
mothers without senna treatment. In conclusion, senna treatment did not associate with a higher risk
of CAs in the offspring of pregnant women with constipation.
Conclusion on fertility, pregnancy and lactation
Use during pregnancy and lactation is contraindicated due to preclinical data regarding potential
genotoxicity of anthranoids as well as there are insufficient data on the excretion of metabolites in
breast milk, respectively. Small amounts of active metabolites (rhein) are excreted in breast milk. A
laxative effect in breast fed babies has not been reported.
No fertility data available.
5.5.6. Overdose
The section overdose of the monographs refers to major symptoms of chronic use and abuse such as
griping pain and severe diarrhoea with consequent losses of fluid and electrolytes and also the risk of
toxic hepatitis (see also section 5.3 and section 5.5.4).
5.5.7. Effects on ability to drive or operate machinery or impairment of

mental ability
No studies on the effect on the ability to drive and use machines have been performed.
5.5.8. Safety in other special situations
No data available.
5.6. Overall conclusion on clinical safety
Because of the possible genotoxicity in experimental investigations and the results of Siegers (1993 b),
pharmacovigilance actions for anthranoid-containing laxatives (BfArM, 1996) were initiated in
Germany. By these pharmacovigilance actions the daily dose and the duration of administration were
limited. The use in children and nursing mothers was contraindicated. The use during pregnancy was
linked to special conditions.
The results of the more recent clinical studies are inconsistent and the question of a possible
carcinogenic risk of long-term use of anthranoid-containing laxatives is still open. Some studies
revealed a risk for colorectal cancer 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. Therefore the conditions determined in the pharmacovigilance actions for anthranoid-containing
laxatives have to be maintained for the moment.
Long-term administration of anthranoid-containing medicinal products over a period of 4-13 months

leads to the development of pseudomelanosis coli–pigmentation of the gut wall in the caecum and
EMA/HMPC/228759/2016 Page 121/123
colon. This condition is produced by the accumulation of macrophages that have stored a brown
pigment from the breakdown products of anthranoid (probably lipofuscin) and consequently cause the
mucosa to appear brown to blackish-brown in colour. Prevalence among patients with chronic
constipation is reported to be 12-31%, and 62% following chronic ingestion of anthraquinone-
containing laxatives. This finding disappears 6-12 months after stopping chronic laxative administration
(Mascolo et al., 1998).
6. Overall conclusions (benefit-risk assessment)

Senna leaf preparations and senna pods preparations fulfil well-established medicinal use according to
Article 10a of Directive 2001/83/EC in the following indications:
- short-term use in cases of occasional constipation (pods and leaves)
- for bowel cleansing prior to clinical procedures requiring bowel preparation (pods)
WHO ATC: A06AB06 and V04CZ01/05
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
on constipation combinations of senna with fibre were investigated. For bowel cleansing high doses of
a senna preparation were tested. In the European Union herbal medicinal products have been
authorised for more than ten years. There have been over hundred scientific publications during the
last ten years and the data on effects and efficacy are coherent.
There is no well-designed non-experimental descriptive study with a mono-preparation of senna leaves

and pods available which investigates the short-term use of occasional constipation. Evidence is
obtained from pharmacological data, experts’ 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. In total, 23 clinical trials have been performed
with different settings of preparations for bowel cleansing prior to any clinical procedures requiring a
clean bowel e.g. bowel endoscopy or radiology. The data available on use for bowel cleansing in a high
dose are consistent. (see conclusions in section 4.2.2.3), a dosage equivalent to 150 mg sennosides is
sufficient.
It is up to the health care professional to integrate the use of senna pod preparations into an adequate
preparatory scheme such as for instance described by Krakamp et al. (1996), “The preparation starts
with a three days diet of clear fluids, the herbal preparation is to be applied between 2 pm. and 4 pm.
of the day before the examination followed by a glass of water and drinking of 2 l of clear fluids until
bedtime. No solid food intake until examination.”). When deciding about appropriateness of application
of senna pod preparations in this indication it must be considered that standard therapies with sodium
phosphate or PEG-solutions were slightly more effective, but senna preparations were better tolerated.
For senna preparations less vomiting but more frequent spasms have been observed. Application of
senna pod preparations may be a reasonable and effective therapeutic option for patient groups with
limitations in intake of high volumes of fluids.
Furthermore pharmacological studies in humans are available (Ewe et al., 1993; Buhmann et al.,
2005; Symposium Antrachinon-Laxantien, 1985), even if they show some shortcomings, e.g. a not
validated technique (Buhmann et al., 2005). The studies with combination products clearly identify the
additional effect of the senna fraction in the combination products.
EMA/HMPC/228759/2016 Page 122/123
The results of the studies with combination preparations show a clear laxative effect additionally to
fibre intake.
The use in children under 12 years of age, pregnant and lactating women is contraindicated.
The duration of use is limited to a maximum of one week (for short-term use in cases of occasional
constipation) to consider adverse effects of long-term misuse and also the potential genotoxicity and
carcinogenicity of anthraquinones and derivatives.
In the indications described in the European Union monograph the benefit/risk ratio is considered
positive.
Hydroxy-anthracene derivatives are considered by the HMPC as constituents with known therapeutic
activity.
Annex
List of references
EMA/HMPC/228759/2016 Page 123/123

EMA-HMPC-228759. Assessment Report On Senna Alexandrina Mill. (Cassia Senna L. Cassia Angustifolia Vahl) Folium and Fructus, 2016

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25 September 2018

Assessment report on Senna alexandrina Mill. (Cassia

Based on Article 10a of Directive 2001/83/EC (well-established use)

Herbal preparation(s) Comminuted herbal substance or herbal

Pharmaceutical form(s) Standardised herbal substance as herbal tea for

Rapporteur(s) W. Knoess (revision), C. Werner (first version)

Assessor(s) C. Werner (revision), B. Merz (first version)

30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom

Annex ................................................................................................................................ 123

1.1. Description of the herbal substance(s), herbal preparation(s) or

• Combinations of herbal substance(s) and/or herbal preparation(s) including a description of

1.2. Search and assessment methodology

Search engines used: Google

Scientific databases: PubMed, DIMDI, SciFinder

Toxicological databases: ToxLine

Pharmacovigilance resources: Vigilance central

Other resources: Historical literature according to list of references

2. Data on medicinal use

2.1. Information about products on the market

2.1.1. Information about products on the market in the EU/EEA Member

Table 1: Overview of data obtained from marketed medicinal products

Active substance Indication Pharmaceutical form Regulatory Status

folium, extraction ¼-½ bar per day

Cassiae Sennae L. folii Symptomatic Coated tablets 28/10/2002;

Sennae folium Symptomatic Powder for oral use 01/11/1977;

Use for more than 1-2

Sennae folium Herbal medicinal 1 tea bag (1 g of the WEU, 1996; CZ

Use for more than 1-2

Sennae folium Herbal medicinal 1 g of the herbal WEU, 1996; CZ

Use for more than 1-2

sennoside B 1-2 weeks

Sennae folium Herbal medicinal Tea bags WEU, 2002; Standard

Use for more than 1-2

Calcium sennosides As a laxative for the Syrup Full MA; IE

Children over 6 years:

New users should start

Once regularity has

Duration of use: 1-2

Contraindicated for use

Use for more than 1-2

Contraindicated for use

Use for more than 1-2

Contraindicated for use

Use for more than 1-2

Standardised dry Constipation Coated tablet WEU, 1991; AT

Standardised dry Constipation Film-coated tablet WEU, 1969; AT

Standardised dry Cleaning of bowels Oral solution WEU, 1971; AT

Use for more than 1-2

senna pods, extraction constipation derivatives

1 bag contains 40 g Herbal medicinal Ethanolic extract; WEU, 1978; DE

250-318 mg Herbal medicinal Tablets; adults and WEU, 1978; DE

Use for more than 1-2

Comminuted herbal Herbal medicinal Tablets MA 1997; HR

1 g tea contains: Herbal medicinal Herbal tea MA 1995; MA 1996;

Use for more than 1-2

Adults and adolescents

tablet daily; one week

Use for more than 1-2

Senna pods powdered As a laxative in the Tablet Full MA; 2003; CZ