COMMUNITY HERBAL MONOGRAPH ON
PLANTAGO OVATA
FORSSK., SEMEN
To be specified for the individual finished product.
1 2
Well-established use
Traditional use
With regard to the marketing authorisation
application of Article 10a of Directive
2001/83/EC as amended
With regard to the registration application of
Article 16d(1) of Directive 2001/83/EC as
amended
Plantago ovata
Forssk. (
P. ispaghula
Roxb.),
semen (ispaghula seed)
•
Herbal substance
- dried ripe seeds
•
Herbal preparation
- powdered herbal substance
Well-established use
Traditional use
Herbal substance or herbal preparation in solid
dosage forms such as granules or powders for oral
use.
The pharmaceutical form should be described by
the European Pharmacopeia full standard term.
4.1.
Therapeutic indications
Well-established use
Traditional use
Herbal medicinal product
None
a)
for the treatment of habitual constipation;
b)
in conditions in which easy defaecation with
soft stools is desirable, e.g. in cases of painful
defaecation after rectal or anal surgery, anal
fissures or haemorrhoids.
1
The material complies with the Ph. Eur. monograph.
2
The declaration of the active substance(s) should be in accordance with relevant herbal quality guidance.
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4.2.
Posology and method of administration
Well-established use
Traditional use
Posology
Oral use
Adolescents over 12 years of age, adults, elderly
8 - 40 g herbal substance or corresponding amount
of herbal preparation (daily dose) in 2 - 3 single
doses
Children from 6 to 12 years of age
Half to two-thirds of the adult dose (4 - 25 g
herbal substance or corresponding amount of
herbal preparation, daily dose) in 2 – 3 single
doses.
Method of administration
Mix approximately x g of the [pharmaceutical
form] (amount corresponding to 1 g herbal
substance) with at least 30 ml of water, milk, fruit
juice or similar aqueous liquid; stir briskly and
swallow as quickly as possible. Alternatively the
herbal substance can be taken and swallowed with
sufficient quantity (at least 30 ml per g of herbal
substance) of water, milk, fruit juice or similar
aqueous liquid; then maintain adequate fluid
intake. The product should be taken during the day
at least ½ to 1 hour before or after intake of other
medicines. The effect starts 12 - 24 hours later.
Warning: not to be taken immediately prior to bed-
time.
Duration of use
If the constipation does not resolve within 3 days,
a doctor or a pharmacist should be consulted.
See also section 4.4 Special warnings and
precautions for use.
4.3.
Contraindications
Well-established use
Traditional use
Ispaghula seed should not be used by patients with
a sudden change in bowel habit that persists for
more than 2 weeks, undiagnosed
rectal bleeding
and failure to defaecate following the use of a
laxative.
Ispaghula seed should also not be used by patients
suffering from abnormal constrictions in the
gastro-intestinal tract, with diseases of the
oesophagus and cardia, potential or existing
intestinal blockage (ileus), paralysis of the
intestine, or megacolon, diabetes mellitus, which
is difficult to regulate.
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This product should not be taken by patients who
have difficulty in swallowing or any throat
problems.
Patients with known hypersensitivity to the active
substance should not use ispaghula seed and its
preparations.
4.4.
Special warnings and precautions for use
Well-established use
Traditional use
As there is insufficient experience available, use is
not recommended in children below the age of
6 years. Laxative bulk producers should be used
before using other purgatives if change of nutrition
is not successful.
Ispaghula seed should not be used by patients with
faecal impaction and symptoms such as abdominal
pain, nausea and vomiting unless advised by a
doctor because these symptoms can be signs of
potential or existing intestinal blockage (ileus).
If abdominal pain occurs or in cases of any
irregularity of faeces, the use of ispaghula seed
should be discontinued and medical advice must
be sought.
A sufficient amount of liquid should always be
taken e.g. 30 ml of water per 1 g of herbal
substance.
In the package leaflet, the patient is informed
about the following warning:
Warning
Take each single dose of this product with at least
x ml (x is to be replaced by the amount which
corresponds to 30 ml per 1 g of the herbal
substance or corresponding amount of the herbal
preparation) of water or similar aqueous fluid.
Taking this product without adequate fluid may
cause it to swell and block your throat or
oesophagus and may cause choking. Intestinal
obstruction may occur if adequate fluid intake is
not maintained. If you experience chest pain,
vomiting, or difficulty in swallowing or breathing
after taking this product, seek immediate medical
attention. The treatment of debilitated patients
requires medical supervision. The treatment of
elderly patients should be supervised.
4.5.
Interaction with other medicinal products and other forms of interaction
Well-established use
Traditional use
Enteral absorption of concomitantly administered
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medicines such as minerals, vitamins (B 12),
cardiac glycosides, coumarin derivatives,
carbamazepine and lithium may be delayed. For
this reason the product should not be taken ½ to 1
hour before or after intake of other medicinal
products.
If the product is taken together with meals by
insulin dependent diabetic patients it may be
necessary to reduce the insulin dose.
Use of ispaghula seed concomitantly with thyroid
hormones requires medical supervision because
the dose of the thyroid hormones may have to be
adjusted.
In order to decrease the risk of gastrointestinal
obstruction (ileus) ispaghula seed should be used
together with medicinal products known to inhibit
peristaltic movement (e.g. opioids, loperamide)
only under medical supervision.
4.6.
Pregnancy and lactation
Well-established use
Traditional use
No restriction.
Laxative bulk producers should be used before
using other purgatives if change of nutrition is not
successful.
4.7.
Effects on ability to drive and use machines
Well-established use
Traditional use
Not relevant.
4.8.
Undesirable effects
Well-established use
Traditional use
Flatulence may occur with the use of the product,
this generally disappears in the course of the
treatment. Abdominal distension and risk of
intestinal or oesophageal obstruction and faecal
impaction may occur, particularly if swallowed
with insufficient fluid.
Due to the allergic potential of ispaghula, patients
must be aware of reactions of hypersensitivity
including very rare anaphylaxis-like reactions.
If other adverse reactions not mentioned above
occur, a doctor or a pharmacist should be
consulted.
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Well-established use
Traditional use
Overdose with ispaghula seed may cause
abdominal discomfort, flatulence and possibly
intestinal obstruction. Adequate fluid intake
should be maintained and management should be
symptomatic.
5.1.
Pharmacodynamic properties
Well-established use
Traditional use
Pharmacotherapeutic group: Laxatives – Bulk
Producers
ATC-Code: A 06 AC
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended.
The active ingredient ispaghula seed consists of
the dried ripe seeds of
Plantago ovata
Forssk.
Ispaghula seed is particularly rich in alimentary
fibres and mucilages. Ispaghula seed is capable of
absorbing up to 10 times its own weight in water.
Ispaghula seed consists of 20 – 30 % mucilages,
which are located in the episperms. It is partly
fermentable (
in vitro
72 % unfermentable residue)
and acts by hydration in the bowel. Gut motility
and transit rate can be modified by ispaghula
through mechanical stimulation of the gut wall as
a result of the increase in intestinal bulk by water
and the decrease in viscosity of the luminal
contents or by contact with rough fibre particles.
When taken with a sufficient amount of liquid (at
least 30 ml per 1 g of herbal substance) ispaghula
produces an increased volume of intestinal
contents due to its highly bulking properties and
hence a stretch stimulus, which triggers
defaecation; at the same time the swollen mass of
mucilage forms a lubricating layer, which makes
the transit of intestinal contents easier.
Progress of action
: Ispaghula seed usually acts
within 12 to 24 hours after single administration.
Sometimes the maximum effect is reached after 2
to 3 days.
5.2.
Pharmacokinetic properties
Well-established use
Traditional use
The material hydrates and swells to form a
Not required as per Article 16c(1)(a)(iii) of
3
Scientific data available do not always differentiate the investigated preparations exactly whether the
investigated herbal substance was ispaghula husk or seed or psyllium seed and often indicate "psyllium" as
investigated herbal substance. If a differentiation was not possible the term "psyllium" is used.
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mucilage because it is only partially solubilised.
Polysaccharides, such as those which dietary
fibres are made of, must be hydrolysed to
monosaccharides before intestinal uptake can
occur. The sugar residues of the xylan backbone
and the side chains of psyllium are joined by ß-
linkages, which cannot be broken by human
digestive enzymes.
Less than 10 % of the mucilage gets hydrolysed in
the stomach, with formation of free arabinose.
Intestinal absorption of the free arabinose is
approximately 85
% to 93 %.
To varying degrees, dietary fibre is fermented by
bacteria in the colon, resulting in production of
carbon dioxide, hydrogen, methane, water, and
short-chain fatty acids, which are absorbed and
brought into the hepatic circulation. In humans,
psyllium reaches the large bowel in a highly
polymerised form that is fermented to a limited
extent, resulting in increased faecal concentration
and excretion of short-chain fatty acids.
Directive 2001/83/EC as amended.
5.3.
Preclinical safety data
Well-established use
Traditional use
There are only data for ispaghula husk and
psyllium without defining the exact test
preparation available.
Single dose toxicity
The LD50 in rats was greater than the highest dose
tested corresponding to 3,360 mg/kg ispaghula
husk administered by gavage of an aqueous
suspension. The LD50 in mice was greater than
the highest dose tested corresponding to
2,940 mg/kg ispaghula husk also administered by
gavage of an aqueous suspension. These studies
were conducted prior to the establishment of good
laboratory practices.
Not required as per Article 16c(1)(a)(iii) of
Directive 2001/83/EC as amended, unless
necessary for the safe use of the product.
Subchronic toxicity
Psyllium was fed to rats at levels high as 10 % of
the diet for periods up to 13 weeks (three 28-day
studies, one 13-week study). Psyllium
consumption ranged from 3,876 to
11,809 mg/kg/day. Because the absorption of
psyllium is very limited, histopathological
evaluations were limited to the gastrointestinal
tract, liver, kidneys and gross lesions without
observing any treatment-related effect. Effects
considered to be biologically significant and
related to psyllium supplementation were lower
serum total protein, albumin, globulin, total iron-
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binding capacity, calcium, potassium, and
cholesterol; and higher aspartate transaminase
(AST) and alanine transaminase (ALT) activities
relative to control. Several of these effects are
considered to be secondary effects to others. The
reasons for the lower serum total protein, albumin
and globulin are not clear, but the absence of any
increases in urinary protein, any evidence of
gastrointestinal pathology, which could account
for protein loss, and any differences in growth or
feed efficiency in psyllium fed rats may give
evidence that there are no adverse effect of
psyllium on protein metabolism.
Reproductive toxicity
A rat multigeneration reproduction/teratology
study showed no evidence of any adverse effects
of psyllium on reproduction or development.
Psyllium as 0, 1.25, or 5% (w/w) of the diet was
administered in a standard (NIH-07) rat and mouse
meal diet
ad libitum
through gestation of the third
generation.
A segment II study in rabbits also showed no
evidence of any adverse effect. Psyllium as 0, 2.5,
5 or 10% (w/w) of diet was administered in a
purine certified rabbit chow diet for days 2 - 20 of
gestation.
Genotoxicity and carcinogenicity
Tests on genotoxicity and carcinogenicity have not
been performed.
Well-established use
Traditional use
Not applicable.
26 October 2006
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Assessment Report
T
ABLE OF CONTENTS
I.
Introduction
3
II. Clinical Pharacology
3
II.1 Pharmacokinetics
3
II.2 Pharacodynaics
4
II.2.1 ode of action
4
II.2.2 Interactions
6
III. Clinical Efficacy
7
III.1 Dosage
7
III.2 Clinical studies
7
III.2.1 Laxative effect
7
III.2.2 Antidiarrhoeal effect
8
III.2.3 Effect on irritable bowel syndrome
8
III.2.4 Effect on blood lipids levels
9
III.3 Clinical studies in special populations
9
III.3.1 Use in children
9
III.4 Traditional use
III.3.2 Use during pregnancy and lactation
10
IV. Safety
11
IV.1 Undesirable effects
11
IV.2 Contraindications
11
IV.3 Special warnings and precautions for use
11
IV.4 Interactions with other medicinal products and other forms of interaction
12
V. Overall conclusions
12
Counity herbal onograph
annex
References
annex
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10
I. Introduction
This assessment report reviews the scientific data available for ispaghula seed (
Plantago ovata
Forssk., semen), primarily the clinical data. When special clinical data are lacking, results of
investigations in animals are given. This report was prepared on the basis of the assessment report on
ispaghula husk. Scientific publications do not always differentiate precisely the investigated
preparations i.e. whether the investigated herbal substance was ispaghula husk or ispaghula seed or
psyllium seed. They often refer to “psyllium” as the investigated herbal substance. If a differentiation
was not possible use is made in this report of the term “psyllium”. In the more recent investigations,
ispaghula husk was used predominantly.
The literature presented by the European Scientific Cooperative on Phytotherapy (ESCOP) and
supporting the monograph “Plantaginis ovatae semen” (Ispaghula Seed) (ESCOP Monographs, second
edition 2003) was also taken into account.
Constipation is a common complaint in 1 – 6% of the middle-aged population and 20 – 80 % of the
elderly people, and may be treated by laxatives. Functional constipation is the most common type,
without any specific etiology (1). The most commonly used laxatives are either stimulant laxatives
(containing anthracenic derivatives from senna, frangula or cascara), lubricant laxatives (e.g. mineral
oils) or bulk forming agents such as ispaghula husk and ispaghula seed.
Ispaghula seed is a natural substance and belongs to the bulk forming agents. It is used:
a)
for the treatment of habitual constipation,
b)
in conditions in which easy defaecation with soft stool is desirable, e.g. in cases of painful
defaecation after rectal or anal surgery, anal fissures and haemorrhoids.
These indications are scientifically substantiated by the pharmacological effects of ispaghula seed.
Preparations of ispaghula seed have to be regarded as herbal medicinal products with a “well-
established medicinal use” in these indications with respect to the application of Directive 2001/83/EC
of the Parliament and of the Council on the Community code relating to medicinal products for human
use as amended.
II.
Clinical Pharmacology
II.1 Pharmacokinetics
Ispaghula seed consists of the whole dried ripe seeds of
Plantago ovata
Forsk (
Plantago ispaghula
Roxb). The herbal substance has to comply with the monograph “Ispaghula Seed” of the European
Pharmacopoeia (ref. 01/2005:1333).
Ispaghula seeds contain 20 – 30 % mucilages, which are a highly branched acidic arabinoxylan (2)
(see also chapter II.2.1 Mode of action).
For data concerning absorption, metabolism and excretion, see corresponding chapters of the
assessment report on
Plantago ovata
Forssk., seminis tegumentum (ispaghula husk).
Conclusion
The pharmacokinetics of psyllium are essentially those of an inert unabsorbed substance; only small
amounts of monosaccharides become available for systemic absorption through limited digestion of
the few available α-linkages and fermentation by colonic bacteria.
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II.2 Pharmacodynamics
II.2.1 Mode of action
•
Laxative effect
The active ingredients, the mucilages, are identical in ispaghula husk and ispaghula seed. Ispaghula
seed consists of the whole seeds and not only of the episperm and collapsed adjacent layers removed
from the seeds as is the case for ispaghula husk. The seeds contain 20 – 30 % mucilages, which are
located in the epidermis of the husks (2). The seeds also contain proteins, fixed oil, sterols and the
trisaccharide planteose (3, 4, 5).
The German Pharmacopoiea indicates that ispaghula seed has to be capable of absorbing at least 9
times its own weight in water. The British Pharmacopoiea indicates at least 12 times. The European
Pharmacopoeia requests a swelling index of minimum 9. High-quality seeds are capable of absorbing
14 to 19 times their own weight of water (2).
Leng-Peschlow E 1991
(6) compared in rats the effects of a 4-week supplementation of a fibre-free
elemental diet with 100 or 200 g
Plantago ovata
seeds/kg with that of the husks and wheat bran. The
seeds increased faecal fresh weight up to 100 %, faecal dry weight up to 50 % and faecal water content
up to 50 %. The husks, at the high concentration only, were more effective than the seeds and wheat
bran less effective. Faecal bacterial mass as estimated from the 2,6-diaminopimelic acid output was
increased to the greatest extent by the seed-containing diet and by the high concentration of husks, but
to a lesser extent by the wheat bran. Faecal and caecal protein content was enhanced by the seeds and
wheat bran, but to a lesser extent by the husks. Total acetate in caecal contents or faeces was highest
on the seeds and husks diet and not elevated by wheat bran. Total faecal bile acid excretion was
stimulated and beta-glucuronidase activity reduced by both
Plantago ovata
preparations, but not by
wheat bran. Mucosal digestive enzyme activities were inhibited to different degrees by all dietary
fibres in jejunum, and sometimes activated in the ileum. The author concluded that these results
suggest that
Plantago ovata
seed is a partly-fermentable dietary supplement, which increases stool
bulk; metabolic and mucosa-protective effects are also probable.
Progress of action: Ispaghula seed usually acts within 12 to 24 hours after single administration.
Sometimes the maximum effect is not reached before 2 or 3 days.
Conclusion
As for ispaghula husk, gut motilility and transit rate can be modified by ispaghula seed through
mechanical stimulation of the gut wall as a result of the increase in intestinal bulk by water and a
decrease in viscosity of the luminal contents. When taken with a sufficient amount of liquid (at least
30 ml per 1 g of herbal substance) ispaghula seed produces an increased volume of intestinal contents
due to their highly bulking properties and hence a stretch stimulus that triggers defaecation; at the
same time the swollen mass of mucilage forms a lubricating layer, which eases the transit of intestinal
contents (2).
•
Effect on diarrhoea
There are no specific data available for ispaghula seed.
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•
Effect on blood lipids levels
Kritchevsky D
et al
. 1995
(7) investigated the influence of psyllium preparations on plasma and liver
lipids of cholesterol-fed rats. Rats were fed a semi purified diet containing 0.5% cholesterol and 10%
fibre (cellulose, pectin, psyllium seed or defatted psyllium husk). One additional group of rats was fed
cholesterol (0.5%) as part of a fibre-free diet; the sixth group was fed a fibre free diet without
cholesterol. Cellulose had virtually no effect on serum or liver lipids. Pectin had a lipid lowering
effect. Psyllium seed exerted an effect on total serum cholesterol equal to that of pectin but gave
higher levels of high-density-lipoprotein (HDL) cholesterol. The effects of psyllium seed on liver
lipids were more pronounced than those of pectin. Defatted psyllium husk feeding virtually normalised
liver size and serum triglyceride levels and produced lower serum total cholesterol levels and higher
HDL cholesterol than observed in normal controls. Feeding with defatted psyllium husk also yielded
liver lipid values, which were in the normal range. Faecal wet and dry weights were significantly
higher in rats fed either psyllium preparation.
Gelissen IC
et al.
1994
(8) investigated the effect of
Plantago ovata
(psyllium) husk and seed on
sterol metabolism in normal and ileostomy subjects. The diet of 6 normal and 5 ileostomy subjects
was supplemented with 10 g/d
Plantago ovata
(psyllium) husk for 3 weeks (experiment 1) while 6
normal and 4 ileostomy subjects received 10 g/d psyllium seed (experiment 2). A control period of 1
week preceded the treatment period. Faecal output and ileostomy output, sterol excretion, serum
cholesterol, and triglycerides were measured before and after supplementation. The husk had no effect
on cholesterol or triglyceride concentrations in either normal or ileostomy subjects. Total and HDL
cholesterol concentrations were reduced on average by 6.4% and 9.3%, respectively, in the normal
group after seed supplementation. The average estimated low-density-lipoprotein (LDL) cholesterol
value was reduced by 10.1 % but this reduction was not statistically significant. The HDL-LDL ratio
remained unchanged. No effect on faecal bile acid excretion in the normal subjects was found after
both regimes. Ileostomy bile acids were increased (on average 25%) after seed supplementation,
whereas no effect on cholesterol concentrations was found. The authors concluded that these results
suggest that psyllium seed might be more effective than the husk in reducing serum cholesterol, and
that this cholesterol-lowering effect is not mediated by increased faecal bile acid losses.
•
Effect on blood glucose levels
Due to delayed intestinal absorption of carbohydrates, ispaghula seed influences the glucose
metabolism by reducing peak levels of blood glucose.
Mahapatra SC
et al.
1988
(9) investigated the effect of cellulose and ispaghula on the intestinal
function of hamsters. Everted intestinal sacs were prepared from three groups of developing hamsters,
which had been maintained on diets of varying fibre content. Irrespective of the dietary background of
the animals, presence of fibre in the mucosal solution reduced the rate of transfer of monosaccharides
from the mucosal to the serosal side in proximal and distal intestinal segments, but generally not in the
middle segments. The transfer in the absence of any fibre in the mucosal solution, which can be
considered to reflect the maximum absorptive capacity of the segment, was at a maximum in the
proximal segments and at a minimum in the distal segments in the group of fibre-free diet. On the
other hand, in fibre-fed groups, the transfer was maximum in the distal segment and minimum in the
proximal segment.
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•
Effect on gastrointestinal enzymes
Leng-Peschlow E 1989
(10) incubated dietary fibres (
Plantago ovata
seed,
Plantago ovata
husk,
wheat bran, alfalfa, pectin, xylan)
in vitro
with gastrointestinal enzymes (pepsin, trypsin,
chymoptrypsin, lipase, alpha-amylase, maltase, lactase) in buffer solutions at concentrations of 1 – 5%
for 10 – 30 min at 37 °C. All fibres sometimes induced pronounced changes in enzyme activity, but
the effect of the different fibres on the various enzymes varied individually and was not predictable.
Both
Plantago ovata
preparations had either no actions (pepsin, trypsin, alpha-amylase) or only
stimulating (chymotrypsin, lipase, lactase) actions whereas all other fibres showed inhibiting as well
as stimulating influences. Wheat bran induced the most pronounced alterations increasing lipase,
maltase and lactase activity and inhibiting alpha-amylase activity. Pectin and xylan were comparable
in decreasing lipase and pepsin activity and in increasing chymotrypsin activity bud had opposite
effects on maltase activity. Alfalfa was able to stimulate lactase and lipase activity but depressed
trypsin and alpha-amylase activity. The inactivation of enzymes by dietary fibres can, at least partly,
be explained by adsorption to the fibre or by the presence of enzyme inhibitors especially in natural
compounds.
II.2.2 Interactions
Because of their pharmacodynamic properties, all bulk forming laxatives may delay the enteral
absorption of concomitantly administered medications. Ispaghula seed should therefore be taken at
least ½ to 1 hour before or after intake of other medicinal products.
There are no specific data on interactions between ispaghula seed and medicinal products. Because
seeds and husks have the same origin and comparable ingredients, it is assumed that ispaghula seed
interacts with the same medicinal products as ispaghula husk. Resulting from the assessment of data
on interactions available for ispaghula husk, the following information should be included in the
product information of ispaghula seed containing medicinal products:
- Enteral absorption of concomitantly administered medicines such as minerals (e.g lithium), vitamins
(B 12), cardiac glycosides, coumarin derivates, and carbamazepine may be delayed. For this reason
the product should not be taken ½ to 1 hour before or after intake of other medicinal products.
- If the product is taken together with meals by insulin dependent diabetic patients it may be necessary
to reduce the insulin dose.
- Use of ispaghula seed concomitantly with thyroid hormones requires medical supervision because
the dose of the thyroid hormones may have to be adjusted.
- In order to decrease the risk of gastrointestinal obstruction (ileus) ispaghula seed should be used
together with medicinal products known to inhibit peristaltic movement (e.g. opioids, loperamide)
only under medical supervision.
III.
Clinical Efficacy
III.1 Dosage
There are no dose-finding studies available.
As a laxative for adults, elderly and children over 12 years of age, experts (2, 11) recommend 12 –
40 g in 1 –3 doses daily.
Even if ispaghula seed has only nearly 25 % to 45 % of the water-binding capacity of ispaghula husk
(see above), which implies that the daily dose of ispaghula seed should be higher than the daily dose
of ispaghula husk, the clinical data presented below justify a minimal daily dose of 8 g. A range of 8 –
40 g herbal substance or corresponding amount of herbal preparation daily is recommended by the
Committee on Herbal Medicinal Products because there are different qualities of seeds available and
the Ph. Eur. only recommends a swelling index of minimum 9.
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The amount of 8 – 40 g herbal substance or corresponding amount of herbal preparation (daily dose)
should be taken in 2 – 3 single doses daily because the amount of the fluid, which has to be taken with
the single dose, is otherwise too high.
III.2 Clinical studies
III.2.1 Laxative effect
Numerous clinical practice summaries, dating back to as early as 1935, recommended the use of fibre
supplementation for the management and treatment of chronic constipation. Between 1976 and the
present, numerous studies involving over 900 patients have been published; they evaluated the effects
of psyllium intake on symptoms of constipation in a population specifically identified as “chronically
constipated” and meeting the definition of less than three bowel movements per week for more than 3
months.
These studies were predominantly carried out with ispaghula husk; in other cases the investigated
herbal substance was not exactly defined.
These studies are described in the assessment report on ispaghula husk.
There are however some studies available with a combination of ispaghula husk and seed (Agiocur®);
100 g of this preparation contains 65 g ispaghula semen and 2.2 g ispaghula husk.
Sölter H and Lorenz D 1983
(22) conducted short-term trials of 7 days and long-term trials of up to
12 weeks. At 15 trial centers 669 patients (266 males and 403 females) ranging in age from 13 to 90
years were treated with Prodiem Plain® for 7 days. 28 patients were excluded because of uncertainty
of diagnosis, administration of other laxatives and inadequately completed protocols. At three centers
139 patients (59 males and 80 females, ranging in age from 9 to 80 years) were treated with Prodiem
Plain® over periods up to 12 weeks. Most of these patients were suffering from constipation, some
from haemorrhoids, fistula in ano, anal fissures and abscesses. Very few patients were suffering from
colonic diverticulosis, irritable bowel syndrome (IBS) and others. The most dominant symptoms were
gaseous distension and abdominal pain. The standard dosage was 2 teaspoonsful taken before the
evening meal. If necessary, an extra teaspoonful could be taken before breakfast. Individual increases
or decreases in dosage were permitted, if needed. Prodiem Plain® is described as a product containing
psyllium mucilloid as its active constituent. In the short-term trials a response to treatment in the form
of at least one daily bowel evacuation was achieved in nearly 56.8 % on the first day, in 89.7 % on the
third day, in 93.3 % of the fourth day and in 92.4 % of the end of the study. Furthermore the faecal
consistency was measured (1 = liquid; 2 = semi-liquid; 3 = soft but formed; 4 = hard, 5 = no
evacuation). As described in the publication the effect of treatment was significant in 7 trials (p<0.01).
A change in consistency of a least 0.69 scale units was achieved. The aim for the long-term trials was
a daily bowel evacuation with a soft but formed stool. 123 patients (88.4%) were successfully treated,
9 patients were treated without success, 2 patients were excluded because of lack of compliance, 1
dropped out due to a change of physician and 4 patients with dentures had difficulties in taking the
product.
A post-evaluation of these studies concerning the dosage applied was done by Madaus 2005 (23).
Prodiem Plain® seems to be identical to Agiocur®. According to Madaus 1 teaspoonful corresponds
to 5 g Agiocur®, which contain 3.25 g ispaghula husks and 0.11 g ispaghula seeds. The data of each
single patient included in the short-term studies (641 patients) were evaluated. The 85 patients with a
negative outcome had received 2.6 teaspoonsful with 8.4 g ispaghula seeds and 0.29 g ispaghula husks
as mean daily dose. The 556 patients with a positive outcome had received 2.4 teaspoonsful with 7.8 g
ispaghula seeds and 0.26 g ispaghula husks as mean daily dose. No case report forms of the 3 long-
term studies were available, only summarising reports without any information about the individual
dosage.
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Conclusion
The use of ispaghula seed as a laxative is based on experts’ testimony and scientifically substantiated
by pharmacological data (see above). The clinical investigations of Sölter and Lorenz support the
efficacy of ispaghula seeds, even if these investigations were uncontrolled and unblinded, a
combination preparation was used, and the information given in the publication are poor. The amount
of ispaghula husk was very small, approximately 4 % of the recommended minimal daily dose (7 g). It
can therefore be concluded that the main efficacy was due to the amount of ispaghula seeds and that
already 8 g ispaghula seeds are effective. The active ingredients in ispaghula seeds are the same as in
ispaghula husk. In conclusion, the clinical data on ispaghula husk support the use of ispaghula seed as
laxative and in conditions in which easy defaecation with soft stool is desirable.
III.2.2 Antidiarrhoeal effect
Sölter H and Lorenz D 1983
(22)
also conducted a study in 84 hospital inpatients (48 psychiatric
patients and 36 residents of a nursing home) with diarrhoea. They were treated for up to 3 days with a
dose of 2 teaspoonsful Prodiem Plain® 3 times daily, if necessary. Twenty eight of the psychiatric
patients were suffering from chronic diarrhoea. During Prodiem Plain® treatment, a good response
was noted in 16 cases and an adequate response in 8 others. The average daily frequency of bowel
movements diminished from 3.4 before treatment to 1.5 after one week of treatment. The stool
consistency changed from liquid or semi-liquid to soft but formed, or solid. When Prodiem Plain®
was discontinued, increased frequency of bowel evaluations recurred in 7 out of the 28 patients within
7 days. In the 20 patients with acute diarrhoea, stool frequency decreased from an average of 4.7 daily
pre-treatment to 2.3 on the third day of treatment, and to 1.6 on the seventh day. The nursing home
patients were all suffering from acute diarrhoea. The stool frequency decreased from an average of
6.94 daily pre-treatment to 3.28 on the first day, 1.67 on the 2
nd
day, and 0.81 on the 3
rd
day. Liquid
stools ceased on the 2
nd
and on the 3
rd
treatment day.
The post-evaluation of Madaus (23) stated that no other information than the publication was
available. A further individual analysis of the daily dosage was not possible.
In an open pilot study
Hamouz W 1984
(12) investigated the effect of Agiocur® (5 g of granula i.e.
1 teaspoon) containing ispaghula seed = 3.25 and ispaghula husk = 0.11 g) on acute or chronic
diarrhoea of 50 hospitalised patients of a psychiatric department. The patients received Agiocur® for
7 days (2 teaspoonsful 3 times daily for 3 days following an individual dosage). The median number
of stools decreased from 4.7 to 1.6 in the 22 patients with acute diarrhoea and from 3.4 to 1.5 in the 28
patients with chronic diarrhoea. Stool consistency changed from loose to soft formed after one week
treatment in all patients. All 28 patients with chronic diarrhoea had already been treated with other
antidiarrhoeal agents before. Only moderate success or no success at all could be achieved with this
prior treatment. The switch to treatment with Agiocur® brought success in 24 of the 28 cases.
This publication seems to deal with the same study, which was reported by Sölter and Lorenz (22).
Conclusion
Although these investigations suggest that ispaghula seed might exert an antidiarrhoeal effect, these
data are not sufficient to prove the efficacy in this indication. There are only uncontrolled studies with
a combination of ispaghula husk and seed; in addition acute diarrhoea is often a self-limited disease
and a placebo-controlled study is therefore necessary. There are no detailed information available on
the effective dosage.
III.2.3 Effect on irritable bowel syndrome
Ligny G 1988
(24) tested the efficacy of Agiocur® in the three types of IBS in a randomised placebo-
controlled study. 30 out of 60 patients were administered 5 g Agiocur® 4 times daily for 30 days. The
daily dose contains 13 g ispaghula seeds and 0.44 g ispaghula husks. No special diet was required. In
the Agiocur® group, only 3 patients were suffering from diarrhoea predominant IBS (Type I), 8
patients were suffering from constipation predominant IBS (Type II) and 19 patients from IBS with
alternate occurrence of diarrhoea and constipation (Type III). In the placebo group, 4 patients were
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suffering from IBS Type I, 9 patients from IBS Type II, and 17 from IBS Type III. During the study
patients were permitted to take an antispasmodic (Visceralgine® forte – methyl sulphate). The number
of tablets was recorded. The severity of the condition was assessed on a scale from 0 to 4 scores for
seven symptoms (intensity of pain, abdominal pain, flatulence, cardiac palpitation, asthenia, number of
evacuation, severity of constipation). Baseline was the severity of the symptoms and the use of
antispasmodics during the last 15 days before treatment. After 15 days treatment, there was a
symptomatic improvement in both groups. After 30 days treatment, 27 out of 30 patients in the
Agiocur® group reported symptomatic improvement and their need for antispasmodic medication
dropped by more than 50%. In the placebo group, 10 out of 30 patients showed a symptomatic
improvement, but their antispasmodic intake remained just as high as before the trial.
Conclusion
The data available are not sufficient to prove the efficacy of ispaghula seed for the indication irritable
bowel syndrome. Only 30 patients suffering from IBS were treated with a combination of ispaghula
seed and husk (even if the amount of ispaghula husk was clearly below the amount of ispaghula seed).
The various types of IBS were not represented equally and were not assessed separately.
III.2.4 Effect on blood lipids levels
Segawa K
et al.
1998
(13) examined the association of urea and lipid metabolism in 28 mild
hypercholesterolemic male and female adults treated with psyllium seed for 3 months. The total serum
cholesterol, LDL cholesterol and atherogenic index significantly decreased, but levels of HDL
cholesterol, triglyceride and urea nitrogen did not. To determine the parameters associated with the
cholesterol-lowering effect in the subjects’ backgrounds, both biochemical and haematological
parameters, the authors statistically examined the correlation between pretreatment parameters and the
absolute change of total cholesterol level. The absolute change of total cholesterol level showed a
direct correlation with the triglyceride level at pretreatment (r=0.41, p=0.03) and had an inverse
correlation with urea nitrogen level (r= -0.46, p=0.01) but not with the total cholesterol level
(r= -0.18). The change in urea nitrogen level had an inverse correlation with the urea nitrogen level
itself at pretreatment (r= -0.82, p= 7x 10
-8
) and had a direct correlation with the triglyceride level
(r=0.43, p=0.02). The change in triglyceride level had an inverse correlation with urea nitrogen level
(r= -0.48, p=0.008). Furthermore the change in total cholesterol level had direct correlations with
changes in the triglyceride level (r=0.56, p=0.002) and the urea nitrogen level (r=0.51, p=0.006), but
these changes in triglyceride and urea nitrogen levels did not correlate significantly. The authors
concluded that these findings suggest the close associated of urea nitrogen and lipid metabolism in
hyperlipidemia and psyllium seed treatment.
Conclusion
Pharmacological data as mentioned in chapter II.2.1 Mode of action suggest that ispaghula seed has a
positive effect on blood lipid levels but the clinical data are insufficient. The clinical data available for
ispaghula husk and mentioned in the assessment report on ispaghula husk cannot be extrapolated to
ispaghula seed because the exact mechanism of action and the involved active ingredient are still
unknown. As the clinical data are insufficient, it is not possible to recommend a specific indication.
III.3 Clinical studies in special populations
III.3.1 Use in children
There are numerous publications, which indicate that the potential health benefits of increased dietary
fibre in childhood outweigh the potential risks, especially in highly industrialised countries (14). A
review of the scientific literature by
Williams CL et al. 1995
(15) suggests that a small loss of energy,
protein, and fat may occur with a high intake of dietary fibre but that a moderate increase in dietary
fibre is more likely to be healthy than harmful, especially in children with constipation (16).
According to the recommendations from a conference on dietary fibre in childhood, children older
than 2 years of age should increase their daily intake of dietary fibre (increased consumption of a
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variety of fruits, vegetables, cereal and other grain product) to an amount equal or greater than their
age plus 5 g (e.g. 8 g/day at age 3) (14).
Conclusion
Considering these remarks, laxative bulk producers should be used before using other purgatives in
children, if change of nutrition is not successful. As a general precaution and because clinical data are
lacking, the use is not recommended in children below the age of 6 years.
Children from 6 to 12 years of age should take half to two-thirds of the adult dose (4 – 25 g herbal
substance or corresponding amount of herbal preparation, daily dose) in 2 – 3 single doses according
to general recommendations of posology for children of this age derived from the adult dose.
III.2.2 Use during pregnancy and lactation
There are no recent data available available for the use of ispaghula seed during pregnancy and
lactation.
Bishop C 1978
(17) concluded that bulk-forming laxatives appear to be safe and effective in
pregnancy. The author referred to 2 studies, which compared bulk-forming laxatives to irritant
laxatives in antenatal women (see below).
Greenhalf JO
et al.
1973
(18) stated that constipation was corrected in a higher percentage of patients
using irritant laxatives but normalisation of bowel habit was similiar (statistically) in all groups (an
irritant, an emollient/irritant combination, a bulk forming/mild irritant combination, and a bulk
forming agent). The side effects were higher in the irritant group than the bulk forming group.
Fianu S
et al.
1975
(100) compared psyllium hydrophilic mucilloid (ViSiblin®) with irritant laxatives
in 199 pregnant women (plus control patients) and observed no significant differences between irritant
laxatives and psyllium. Psyllium when given to the mothers appeared to have had no effect on the
defaecation of their new-born infants.
Conclusion
The following advice that “Laxative bulk producers should be used before using other purgatives if
change of nutrition is not successful” should appear in the section ‘Pregnancy and lactation’ of the
product information of ispaghula seed containing products. Medicinal products should be avoided
during pregnancy and lactation if possible; caution is recommended when administered.
III.4 Traditional use
Please refer to the corresponding chapter of the assessment report on ispaghula husk, which concludes
as follows:
Older references do not mention
Plantago ovata
because this plant is native to Iran and India.
The use of ispaghula husk and other kinds of Plantago in traditional medicine is similiar to the use of
linseed, but such traditional use is not described as well and so consistently as for linseed.
Furthermore, no precise posology is mentioned.
None of the uses can therefore be accepted for inclusion in the ‘Community list of herbal substances,
preparations and combinations thereof for use in traditional herbal medicinal products’
.
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IV. Safety
Please refer to the corresponding chapter of the assessment report on ispaghula husk. No specific data
on the safety of ispaghula seed are available.
IV.1 Undesirable effects
Flatulence may occur with the use of ispaghula seed.
Ispaghula seed contains potent allergens. Exposure to these allergens is possible through the oral route
or through contact. Ispaghula seed should be considered as a possible cause of anaphylaxis from
laxatives. Reactions of hypersensitivity including anaphylaxis-like reactions may occur very rarely.
Ispaghula seed is not to be used by patients with known hypersensitivity to ispaghula (19, 20, 21).
IV.2 Contraindications
Pharmacological data suggest that ispaghula seed lowers peak blood glucose levels due to delayed
intestinal absorption of carbohydrates, like ispaghula husk (see chapter II.2.1 Mode of action). Cases
of diabetes mellitus where insulin adjustment is difficult constitute therefore a contraindication to the
administration of ispaghula seed preparations. The following should appear in the product information
of such preparations:
Ispaghula seed should not be used by patients with diabetes mellitus, which is difficult to regulate.
Furthermore, the product information should contain a statement, as already pointed out in chapter
II.2.2 Interactions, that it may be necessary to reduce the insulin dose if the product is taken together
with meals by insulin dependent diabetic patients.
Ispaghula seed is a bulk forming agent and several other contraindications for this kind of agents must
be respected:
Ispaghula seed should not be used by patients with a sudden change in bowel habit that persists for
more than 2 weeks, undiagnosed
rectal bleeding and failure to defaecate following the use of a
laxative. Ispaghula seed should also not be used by patients suffering from abnormal constrictions
in the gastro-intestinal tract, with diseases of the esophagus and cardia, potential or existing
intestinal blockage (ileus), or megacolon.
Ispaghula seed preparations should not be taken by patients who have difficulty in swallowing or
who have any throat problems.
Ispaghula seed should finally not be used by patients with known hypersensitivity to ispaghula.
IV.3 Special warnings and precautions for use
There are several warnings to be included in the product information of ispaghula seed containing
medicinal products:
Ispaghula seed should not be used by patients with faecal impaction and symptoms such as
abdominal pain, nausea and vomiting unless advised by a doctor because these symptoms can be
signs of potential or existing intestinal blockage (ileus).
Furthermore the following advice should be given:
If the constipation does not resolve within 72 hours or if abdominal pain occurs or in case of any
irregularity of faeces, the use of ispaghula seed should be discontinued and medical advice must be
sought.
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Special warnings for bulk forming agents must be included, too.
IV.4 Interactions with other medicinal products and other forms of interaction
See chapter II.2.2.
IV.
Overall conclusions
Indication a): For the treatment of habitual constipation
The use of ispaghula seed as a laxative is mainly based on experts’ testimony and is scientifically
substantiated by pharmacological data. The clinical investigations of Sölter and Lorenz support the
efficacy of ispaghula seeds. The active ingredients are the same as in ispaghula husk; the clinical data
on ispaghula husk support therefore the use of ispaghula seed as laxative. It can be concluded that the
use as a laxative is a well-established use. Taking into account the investigations of Sölter and Lorenz,
the current level of evidence
1
can be identified as level III to IV.
Indication b): In conditions in which easy defaecation with soft stool is desirable, e.g. in cases of
painful defaecation after rectal or anal surgery, anal fissures and haemorrhoids
The use in condition in which easy defaecation with soft stool is desirable is scientifically
substantiated by the well-known laxative effects but there are no specific data available. The level of
evidence in this indication is therefore level IV.
1
As referred to in the HMPC ‘Guideline on the assessment of clinical safety and efficacy in the preparation of
Community herbal monographs for well-established and of Community herbal monographs/entries to the
Community list for traditional herbal products/substances/preparations’ (EMEA/HMPC/104613/2005)
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Source: European Medicines Agency
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