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DEFINITION
Macrogol is the International Nonproprietary Name (INN) for polyethylene glycol.
Macrogols have been used as laxatives, i.e. to treat constipation.

They are also used as excipients in pharmaceutical products where lower molecular
weight variants are used as solvents in oral liquids and soft capsules. Solid variants
are used as ointment bases, tablet bindings, film coatings and lubricants.

Popular types include:
macrogol 3350
macrogol 4000
macrogol 6000
The number represents the average molecular weight of the polyethylene glycol.
Combining different molecular weights provides some control over the consistency.
Polyethylene glycol




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INTRODUCTION
Laxatives are a type of medicine that can help you empty your bowels if you
are having trouble going to the toilet.
They are widely used to treat constipation and are available over the counter
(without a prescription or 'OTC') from pharmacies and supermarkets.
Things to consider
Just because laxatives are available over the counter does not mean they are safe
and suitable for everyone.
Laxatives are not usually recommended for children unless advised by a doctor and
some types of laxatives may not be safe to use if you have a bowel condition such
as Crohns disease or ulcerative colitis.
You should always read carefully the patient information leaflet that comes with
medication to make sure it is safe for you to take.
Read more about the considerations regarding laxatives.
Types of laxatives
The four most widely used laxatives in England are:
osmotic laxatives which make your stools (poo) softer by increasing the
amount of water in your bowels
stimulant laxatives which speed up the movement of your bowel by
stimulating the muscles that line your digestive tract
bulk-forming laxatives, also known as fibre supplements, work in the same
way as dietary fibre; they increase the bulk of your stools by helping your
stools retain fluid
stool softener laxatives add water to your stools to lubricate them, making
them more slippery and easier to pass
Less commonly used types of laxatives include:
bowel cleansing solutions these are often given to people who are going to
have bowel surgery or a bowel examination to make sure that the bowel is
empty and are not seen as a routine treatment for constipation
peripheral opioid-receptor antagonists these are used to treat constipation in
people who are terminally ill where the constipation is the result of taking
powerful painkiller medications such as morphine
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prucalopride used to treat persistent constipation in women who have failed
to respond to treatment (it is unclear whether prucalopride is safe or effective
in men so its use in men is currently not recommended)
Dosage
Laxatives are available as:
tablets or capsules you swallow
sachets of powder you mix with water and then drink
suppositories a capsule you place inside your rectum (back passage) where
it will dissolve
Ideally, laxatives should only be used for short periods of time as prolonged use can
make your body dependent on them, so your bowel no longer functions normally
without them.
Recommendations can vary depending on the type of laxative but generally it is
recommended that you do not take laxatives for more than 5-7 days in a row.
If symptoms persist after this time contact your GP for advice.
You should take a laxative with plenty of water as this can help prevent unpleasant
side effects.
Side effects
Common side effects of laxatives include:
flatulence (breaking wind or farting)
bloating
abdominal pain
These side effects are usually mild and should pass once you stop taking the
laxatives.
The long-term use of laxatives can cause more troublesome side effects such as:
dehydration
unbalanced levels of salts and minerals in your body




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Alternatives
In many cases you can improve the symptoms of constipation without having to use
laxatives through lifestyle changes, such as:
increase your daily intake of fibre - you should eat at least 18-30g of fibre a
day; high-fibre foods include fruit, vegetables and cereals
add bulking agents, such as wheat bran, to your diet - these will help make
your stools softer and easier to pass.
drink plenty of water
get more exercise by going for a daily walk or run

Information specific to: Macrogol compound powder NPF.
About Macrogol compound powder NPF and how it works
This medicine is a laxative and is used to treat constipation, especially constipation
that is present for a long time. It is also used to help relieve the discomfort of
impacted faeces, where the stools are hard and compressed.
This medicine works by absorbing water into the stool and increases the volume and
water content of stools. This makes the stools easier to move through the bowel to
be emptied and hence relieves constipation. This medicine also contains electrolytes
which help balance water and salts in the body.
This medicine is available as a powder in a sachet.
You must not take this medicine for more than three days for treating faecal
impaction or for more than 14 days for treating constipation.
Speak to your doctor if your symptoms do not improve or if they get worse during
treatment with this medicine.



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Before using Macrogol compound powder NPF
This medicine may not be suitable for everyone and some people must never have
it. Check the leaflet that comes with your medicine to make sure that the medicine is
suitable before having it.
Always get advice from a healthcare professional before having this medicine if:
you are allergic or sensitive to or have had a reaction to any of the ingredients
in the medicine
this medicine is for a child under 12 years of age
you have inflammatory bowel problems such as ulcerative colitis or Crohn's
disease
you have toxic megacolon
you have ileus
you have an obstruction or perforated gut
you have not been diagnosed as having faecal impaction before
you have heart and circulation problems


Possible side effects of Macrogol compound powder NPF
Most medicines can cause some side-effects but not everyone having the same
medicine will get the same side-effects.
The following side-effects have been associated with people having this medicine:
electrolyte imbalances - stop taking this medicine and seek immediate
medical advice if you are short of breath, feel tired, are dehydrated or if you
develop oedema
diarrhoea - this may be caused by taking a dose that is too high and may be
relieved or prevented by taking a lower dose
allergic reactions
gastrointestinal effects such as stomach distension and pain, nausea, or
gurgling from the stomach or bowels




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Pregnancy and breast-feeding
If you are trying to become pregnant, are pregnant, or are breast-feeding, you should
seek medical advice before taking this medicine.

Other important information
Make sure that you read the leaflet that comes with your medicine to check what
dose you should take and if there is anything that you need to do if you take more
than the recommended dose. If you are in any doubt about whether this medicine is
suitable for you, speak to your doctor or pharmacist.
This medicine can affect the absorption of some medicines. If you are taking other
medicines by mouth, take them one hour before or one hour after taking Macrogol
compound powder NPF.
Keep all medicines out of the sight and reach of children.

Movicol (macrogol)
How does it work?
Movicol sachets contain macrogol (polyethylene glycol '3350'), which is a type of
medicine known as an osmotic laxative. Each sachet also contains sodium
bicarbonate, sodium chloride and potassium chloride. The contents of the sachets
are mixed with water to make a drink.
Macrogol is an inert substance that passes through the gut without being absorbed
into the body. It relieves constipation because it causes the water it is taken with to
be retained in the bowel instead of being absorbed into the body. This increases the
water content and volume of the stools in the bowel, making them softer and easier
to pass.
The sodium bicarbonate, sodium chloride and potassium chloride (electrolytes) are
included in this medicine to help ensure that the laxative works without causing the
body to gain or lose significant amounts of sodium, potassium or water.
This medicine is used to help people who have been constipated for a long time to
have a comfortable bowel movement. It is also used to relieve more severe
constipation known as faecal impaction.
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What is it used for?
Chronic constipation.
Build up of compressed and hardened stools (faeces) in the rectum as a
result of chronic constipation (faecal impaction).
How do I take it?
Take this medicine as directed by your doctor or pharmacist. The number of
sachets needed, how often they should be taken and for how long depends
on the severity of your constipation.
The contents of each sachet should be dissolved in 125ml of water before
taking. If needed you can add a flavour such as orange squash to the
solution. If you can't drink the solution straight away, it can be kept covered in
the fridge (2-8C) for up to six hours. Throw away any solution not used within
a six hour period.
The dose for constipation is normally one to three sachets a day, depending
on the severity of the constipation. The number of sachets used should be
spread over the day, eg one sachet three times a day. Using this medicine for
longer than two weeks is not usually recommended. However, your doctor
may recommend that you take it for longer than this if you have chronic
constipation that is a result of diseases such asParkinson's
disease or multiple sclerosis, or if you are taking regular medicines that cause
constipation, such as opioid painkillers (eg morphine), antispasmodic
medicines (eg hyoscine, atropine) or anticholinergic medicines for Parkinson's
symptoms (eg procyclidine).
For the treatment of faecal impaction the dose is eight sachets a day, all of
which should be taken within a six hour period. You can make up this dose all
at once (dissolve eight sachets in one litre of water) and keep it covered in the
fridge. Drink the total amount over six hours. (If you have a heart condition
you should divide the dose so that you don't take more than two sachets (one
quarter of the litre of made-up solution) in any one hour.) A course of
treatment for faecal impaction does not normally exceed three days.
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Warning!
Stop taking this medicine and consult your doctor if you begin to feel weak,
fatigued, breathless, very thirsty with a headache, or get swollen ankles while
taking this medicine. These symptoms may indicate that your fluid and
electrolyte levels are disturbed and your doctor may need to take a blood test
to check for this.
Use with caution in
Heart disease. If you have a heart condition you should not take more than
two sachets in any one hour.

Not to be used in
People with a hole in the gut (intestinal perforation).
People with a blockage in the gut (intestinal obstruction) caused by a
structural or functional disorder of the gut wall.
Inflammation of the bowel and back passage (ulcerative colitis).
Crohn's disease.
People with a sudden expansion of the large intestine, seen in advanced
ulcerative colitis or Crohn's disease (toxic megacolon).
Movicol should not be given to children under 12 years of age. Movicol
paediatric is available for treating this age group.
This medicine should not be used if you are allergic to one or any of its ingredients.
Please inform your doctor or pharmacist if you have previously experienced such an
allergy. If you feel you have experienced an allergic reaction, stop using this
medicine and inform your doctor or pharmacist immediately.


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Pregnancy and breastfeeding
Certain medicines should not be used during pregnancy or breastfeeding. However,
other medicines may be safely used in pregnancy or breastfeeding providing the
benefits to the mother outweigh the risks to the unborn baby. Always inform your
doctor if you are pregnant or planning a pregnancy, before using any medicine.
This medicine can be used during pregnancy, though as with all medicines
you should get medical advice from your doctor first. The medicine is not
absorbed into the bloodstream in significant amounts and no harmful effects
on a developing baby are expected.
This medicine can be used by women who are breastfeeding. The medicine is
not absorbed into the bloodstream in significant amounts and no harmful
effects on a nursing infant are expected. Seek further medical advice from
your doctor.

Label warnings
Dissolve or mix this medication with water before taking.
Side effects
Medicines and their possible side effects can affect individual people in different
ways. The following are some of the side effects that are known to be associated
with this medicine. Just because a side effect is stated here, it does not mean that all
people using this medicine will experience that or any side effect.
Abdominal pain.
Diarrhoea.
Feeling sick.
Vomiting.
Swelling or bloating of the abdomen.
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Abdominal rumbling and gurgling sounds due to movement in the intestines.
Wind (flatulence).
Anal discomfort.
Headache.
Disturbances in the levels of electrolytes (particularly potassium) in the blood.
See warning section above.
The side effects listed above may not include all of the side effects reported by the
medicines's manufacturer. For more information about any other possible risks
associated with this medicine, please read the information provided with the
medicine or consult your doctor or pharmacist.

How can this medicine affect other medicines?
It is important to tell your doctor or pharmacist what medicines you are already
taking, including those bought without a prescription and herbal medicines, before
you start treatment with this medicine. Similarly, check with your doctor or
pharmacist before taking any new medicines while taking this one, to make sure that
the combination is safe.
Large volumes of fluid can flush tablets and capsules through the gut without giving
them a chance to be absorbed into the body. For this reason, if you are taking a
large volume of this medicine in one go, you should avoid taking other tablets or
capsules in the hour before and after the dose. Ask your pharmacist for further
advice.




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Other medicines containing the same active ingredient
Laxido orange.
Molaxole.
Movicol-half.
Movicol liquid.
Movicol paediatric.
Macrogol oral powder is also available without a brand name, ie as
the generic medicine.

Dulcobalance
Information specific to: Dulcobalance.
About Dulcobalance and how it works
This medicine is a laxative and is used to treat constipation. It works by absorbing
water into the stool and increases the volume and water content of stools. This helps
relieve constipation as the stools pass through the bowel more easily.
This medicine is available as a powder in a sachet that is dissolved in water before
taking by mouth.
This medicine usually takes between 24-48 hours after first taken to have an effect. It
is best to take this medicine in the morning.
Children should not take this medicine for more than three months.
Speak to your doctor if your symptoms do not improve or if they get worse during
treatment with this medicine.



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Before using Dulcobalance
This medicine may not be suitable for everyone and some people must never have
it. Check the leaflet that comes with your medicine to make sure that the medicine is
suitable before having it.
Always get advice from a healthcare professional before taking this medicine if:
you are allergic or sensitive to or have had a reaction to any of the ingredients
in the medicine
this medicine is for a child under eight years of age
you have stomach pain and the cause is not known
you have inflammatory bowel problems such as ulcerative colitis or Crohn's
disease
you have toxic megacolon
you have ileus
you have or are at risk of having an obstruction of the stomach or small bowel
you have or are at risk of having a perforated gut
you have fructose intolerance
Medicines interactions
If you are taking more than one medicine they may interact with each other. This
medicine is unlikely to have any important interactions. But speak to your pharmacist
or doctor if you get any unusual symptoms while having this medicine with other
medicines.




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Possible side effects of Dulcobalance
Most medicines can cause some side-effects but not everyone taking the same
medicine will get the same side-effects.
The following side-effects have been associated with people taking this medicine:
hypersensitivity reactions such as bronchospasm, itching, urticaria, rash,
oedema and anaphylactic shock
diarrhoea - if severe this can lead to dehydration and electrolyte imbalances.
Diarrhoea may lead to soreness around the anus
stomach pain or distension
nausea
vomiting
faecal incontinence
urgent need to defaecate
bloated feeling
Pregnancy and breast-feeding
This medicine is not known to cause any problems during pregnancy or while breast-
feeding. However, as with all medicines, you should seek medical advice from your
doctor before taking this medicine if you are pregnant or are breast-feeding.
Other important information
Make sure that you read the leaflet that comes with your medicine to check what
dose you should take and if there is anything that you need to do if you take more
than the recommended dose. If you are in any doubt about whether this medicine is
suitable for you, speak to your doctor or pharmacist.
This medicine has an orange-grapefruit flavour.
Keep all medicines out of the sight and reach of children.
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LAXATIVE
Laxatives are medicines that are used to treat constipation. They can be taken by
mouth as liquids, tablets, or capsules, or they can be given via the rectum (back
passage). Laxatives are generally divided into four groups - depending on the way
they work. Some laxatives work quickly, within 15 to 30 minutes, and some take one
or two days to work. You should drink plenty of fluid when you are taking laxatives
(8-10 cups per day). Laxatives are usually taken for a few days until your bowel
movements have returned to normal. But a few people need to take them long-term.
What are laxatives?
Laxatives are a group of medicines that are used to treat constipation. They can be
taken by mouth as liquids, tablets, or capsules, or they can be given via the rectum
(back passage) - for example, suppositories, or enemas. Suppositories are pellet-
shaped laxatives that are inserted into the rectum, via the anus. An enema is a liquid
that is inserted into the rectum and lower colon, via the anus.

There are four main groups of laxatives that work in different ways. Each laxative
often comes in various different brand names:
Bulk-forming laxatives (also known as fibre supplements). For example,
ispaghula husk, methylcellulose, sterculia. Unprocessed bran is a cheap fibre
supplement.
Osmotic laxatives. For example, lactulose, macrogols, phosphate enemas,
and sodium citrate enemas.
Stimulant laxatives. For example, bisacodyl, dantron, docusate sodium,
glycerol, senna and sodium picosulfate.
Faecal softeners. For example, docusate sodium, arachis (peanut) oil
enemas, and liquid paraffin.


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What is constipation?
Constipation is when faeces (stools or motions) become hard, and difficult or painful
to pass. The time between toilet trips increases compared with your usual pattern.
(Note: there is a large range of normal bowel habit. Some people normally go to the
toilet to pass faeces 2-3 times per day. For others, 2-3 times per week is normal. It is
a change from your usual pattern that may mean that you are constipated.)
Sometimes crampy pains occur in the lower part of your abdomen. You may also
feel bloated and feel sick if you have severe constipation.

Constipation may be caused by not eating enough fibre, or not drinking enough
fluids. It can also be a side-effect of certain medicines, or related to an underlying
medical condition. In many cases, the cause is not clear.

For more information see separate leaflet called 'Constipation''.
How do laxatives work?
Bulk-forming laxatives are sometimes called fibre supplements. They increase the
bulk of your faeces in a similar way to fibre. They partly work by absorbing water (a
bit like blotting paper). The increase in the bulk of your faeces stimulates the
muscles in your gut to squeeze faeces along and out of the body. Fibre is the part of
plant food that is not digested. It stays in your gut and is passed in the stools
(faeces). Fibre adds bulk to the stools.

Osmotic laxatives work by retaining fluid in the large bowel by osmosis (so less
fluid is absorbed into the bloodstream from the large bowel).

Stimulant laxatives stimulate the nerves in the large bowel (the colon and rectum -
sometimes also called the large intestine). This then causes the muscle in the wall of
the large bowel to squeeze harder than usual. This pushes the faeces along and
out.


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Faecal softeners work by wetting and softening the faeces.
Which laxatives are usually prescribed or recommended?
Mostly, laxatives are taken by mouth (orally). In some cases, your doctor may prefer
to treat your constipation by giving medication via the anus (back passage). But the
choice of laxative usually depends on: what you would prefer, the symptoms of
constipation that you have, how severe your constipation is, the possible side-effects
of the laxative, your other medical conditions, and cost. As a general rule:
Treatment with a bulk-forming laxative is usually tried first.
If faeces remain hard despite using a bulk-forming laxative, then an osmotic
laxative tends to be tried, or used in addition to a bulk-forming laxative.
If faeces are soft but you still find them difficult to pass then a stimulant
laxative may be added in.
If you are pregnant or breast-feeding there are a number of laxatives that are thought
to be safe to take. If you do need to take a laxative when you are pregnant or breast-
feeding you should always ask your doctor or pharmacist for advice about which one
you should use.

Sometimes, an enema is needed in severe constipation and can be used to clear out
the lower bowel (rectum).

High doses of the macrogol osmotic laxatives are used to treat faecal loading and
impaction (severe constipation) - this should be under the supervision and advice of
a doctor.

Liquid paraffin used to be commonly used as a faecal softener. However, it is now
not recommended, as it may cause side-effects such as seeping from the anus and
irritating the skin, and it can interfere with the absorption of some vitamins from the
gut.
How long do laxatives take to work?
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Bulk-forming laxatives can have some effect within 12-24 hours but their full effect
may take several days to develop.

Osmotic laxatives such as lactulose can take up to two days to have any effect so
they are not suitable for the rapid relief of constipation. Macrogols act much faster,
and can also be used in high doses to clear faecal loading or impaction.

Stimulant laxatives usually work within 8-12 hours. A bedtime dose is
recommended so you are likely to feel the urge to go to the toilet sometime the
following morning. However, you may try taking it at different times in the day to find
the best time of day for you. Some people naturally have their bowel movements
later in the day rather than in the morning.

Faecal softeners usually work within 24 to 48 hours.

Laxatives that are given via the rectum (suppositories or enemas) usually work within
15 to 30 minutes. Stronger osmotic laxatives (such as magnesium salts and
phosphate enemas) can be used to clear the bowel quickly and in situations such as
before bowel surgery.
How long should I take a laxative for?
This depends on what type of constipation you have. Most people only need to take
a laxative for a short time, to get over a bout of constipation. Once the constipation
eases, you can normally stop the laxative. Some people get into the habit of taking a
laxative each day "to keep the bowels regular" or to prevent constipation. This is not
advised, especially for laxatives which are not bulk-forming.

Some people have chronic (persistent) constipation and this can be more difficult to
treat. So, in some situations, laxatives are needed for longer periods (sometimes
even indefinitely) and they should not be stopped suddenly. Chronic constipation is
sometimes complicated by a backlog of hard stools building up in the bowel (faecal
loading) or even partially blocking it (impaction). If loading and impaction occur they
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need to be treated first, often with much higher doses of laxatives. Then a normal
maintenance dose of laxatives is used to keep the bowels moving.
What are the side-effects?
It is not possible to list all the possible side-effects of each laxative in this leaflet.
However, as with all medicines, there are a number of side-effects that have been
reported with each of the different laxatives. If you want more information specific to
your laxative then you should read the information leaflet that comes with the
medicine.

Laxatives very rarely cause serious side-effects. Common side-effects include
flatulence, cramps, diarrhoea, nausea, and bloating. Most of the side-effects can be
avoided or reduced by starting off on a low dose and increasing the dose of oral
laxatives gradually.

Bulk-forming laxatives - you may notice an increase in wind (flatulence) and
abdominal bloating. This is normal and tends to settle down after a few weeks as the
gut becomes used to the increase in fibre (or bulk-forming laxative). Occasionally,
bulk-forming laxatives can make symptoms worse if you have very severe
constipation. This is because they may cause abdominal bloating and discomfort
without doing much to clear a lot of faeces which are stuck further down the gut. See
a doctor if you feel that bulk-forming laxatives are making your symptoms worse.

These medicines sometimes react with other medicines that you may take. So, make
sure your doctor knows of any other medicines that you are taking, including ones
that you have bought rather than been prescribed. See the leaflet that comes with
your particular brand for a full list of possible side-effects and cautions
When taking a laxative
Some important considerations are:
Drinking plenty of fluid.
Avoiding taking too much.
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Drinking plenty of fluid
It is important that you drink plenty of fluid when taking any laxative. At least two
litres per day (8-10 cups). An osmotic laxative can make you dehydrated. If you take
a bulk-forming laxative and you do not drink enough fluid this can cause a blockage
in the gut. The faeces may become dry and difficult to pass.

Avoid taking too much
Taking too much of some laxatives can lead to diarrhoea and losing too much salt
from the body. Taking too much of a bulk-forming laxative, or not drinking enough
fluid with a bulk-forming laxative, causes a blockage in the gut rather than diarrhoea.

If you take bran, it is best to build up the amount gradually. Start with two teaspoons
a day, and double the amount every five days until you reach about 1-3 tablespoons
per day. You can sprinkle bran on breakfast cereals, or mix it with fruit juices, milk,
stews, soups, crumbles, pastries, scones, etc.
Who cannot take laxatives?
In general, most people are able to take laxatives. You cannot take laxatives if you:
Have a blockage in your gut.
Have Crohn's disease or ulcerative colitis, unless specifically advised by your
doctor.
What about natural laxatives?
The information above is about laxatives that are commonly prescribed. However, it
is well known that certain foods have laxative properties and some people prefer to
try natural remedies. Foods that have laxative properties mainly work because they
are high in fibre but some foods may also have some stimulant or osmotic
properties. The following are two examples of natural laxatives.
Prunes
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Prunes (dried plums) have long been thought of as effective for constipation.
However, up until recently, there had been little scientific proof of this. But, a
research trial published in 2011 (cited at the end) lends support to the belief that
prunes are good for treating constipation. In the trial, 40 adults with persistent
constipation were studied as to the effect of prunes versus ispaghula (psyllium) - a
commonly used treatment for constipation. Briefly, on average, 50 g of prunes (about
six prunes) twice daily seemed to be better at easing constipation than 11 g
ispaghula taken twice daily. This is just one small trial, but does seem to confirm
many people's belief that prunes are good for easing constipation.
The Beverley-Travis Natural Laxative Mixture
This recipe (detailed below) was studied in a research trial that involved older people
in a care home. A treatment group was compared to a non-treatment group. The
conclusion of the study stated that "the Beverley-Travis Natural Laxative Mixture,
given at a dosage of 2 tablespoons twice daily, is easy to use, cost-effective, and
more effective than daily prescribed laxatives at producing normal bowel
movements". So, it may be worth a try:
Recipe ingredients - one cup each of: raisins; pitted prunes; figs; dates;
currants; prune juice concentrate.
Directions - combine contents together in a grinder or blender to a thickened
consistency. Store in refrigerator between uses.
Dose - two tablespoons twice a day. Increase or decrease the dose according
to consistency and frequency of bowel movements.






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How to use the Yellow Card Scheme
If you think you have had a side-effect to one of your medicines you can report this
on the Yellow Card Scheme. You can do this online at the following web
address:www.mhra.gov.uk/yellowcard.
The Yellow Card Scheme is used to make pharmacists, doctors and nurses aware of
any new side-effects that medicines may have caused. If you wish to report a side-
effect, you will need to provide basic information about:
The side-effect.
The name of the medicine which you think caused it.
Information about the person who had the side-effect.
Your contact details as the reporter of the side-effect.













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Use of macrogol 4000 in chronic constipation
Abstract
BACKGROUND:
Chronic constipation is a common functional disorder of the gastrointestinal tract,
affecting up to 35% of the general population, and especially the elderly. However,
its definition as perceived by the patient can vary, making it difficult to understand the
problem and find appropriate therapeutic measures. The approach to chronic
constipation, thus, needs a thorough understanding of the patient's complaint and
the main pathophysiological mechanism requiring treatment. Lifestyle changes do
not usually meet with complete patient satisfaction. Other treatments include
different types of laxatives. Of these, osmotic laxatives appear one of the most
effective and are, therefore, frequently prescribed.
DESIGN:
This review will cover the topic of osmotic laxatives, specifically focusing on
polyethylene glycol (PEG/macrogol 4000) in chronic constipation and as a key agent
for bowel cleansing prior to colonoscopy. PEG formulations, including macrogol
4000, are safe, effective treatments for constipation, even in children and elderly
patients. Macrogol 4000 may well be more palatable than combined formulations
(macrogol 3350 with electrolytes), which could help improve adherence to the long-
term treatment required for chronic constipation.
CONCLUSIONS:
PEG/macrogol is also recommended as an effective option for bowel cleansing prior
to colonoscopy. The improved cost-effectiveness of macrogol over other commonly
prescribed laxatives, such as lactulose, should be taken into consideration.




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Pharmacokinetic and pharmacodynamic drug interactions between digoxin
and macrogol 4000, a laxative polymer, in healthy volunteers
Abstract
AimsThe aim of this study was to examine the bioequivalence between a single oral
dose of digoxin administered alone and with a coadministration of macrogol 4000 (a
laxative polymer) in 18 healthy volunteers.
MethodsThis was an open, randomised, two-way cross-over study, with a single
dose oral administration of 0.5 mg digoxin administered alone or in combination with
macrogol 4000, 20 g day
1
during 8 days. Pharmacokinetics of digoxin, heart rate
and PR ECG interval at rest were assessed.
ResultsMacrogol 4000 coadministration was associated with a 30% decrease of
digoxin AUC and a 40% decrease in its C
max
(P<0.05). Digoxin t
max
and t
1/2,z
were not
significantly altered. Heart rate and PR interval did not differ during the two
therapeutic sequences, digoxin alone and digoxin in combination.
ConclusionsMacrogol 4000 coadministration interacts with single-dose digoxin
pharmacokinetics. This is most likely due to a reduction of the intestinal absorption of
digoxin. However, there was no consequence of this interaction on heart rate and AV
conduction.








MACROGOL 2014

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Introduction
Macrogol 4000 (Forlax

), a laxative polymer, has been registered for the

symptomatic treatment of functional constipation at the dosage of 1020 g daily.
Macrogol 4000 is not absorbed; it increases the osmotic pressure in the gut. These
osmotic effects could induce modifications in intestinal resorption of drugs.
Digoxin is a cardiac glycoside commonly used in the treatment of congestive heart
failure and atrial dysrhythmias, mainly eliminated by kidneys as unchanged drug with
a long elimination half-life of approximately 36 h (range: 3040 h) [ 1]. The intestinal
absorption of digoxin is incomplete, dependent upon formulation characteristics and
highly variable between individuals [ 2]. The therapeutic range of plasma
concentrations of digoxin is 0.8 ng ml
1
to 2.0 ng ml
1
[ 2[3][4]5].
Since an alteration in absorption of concomitantly administered drugs is theoretically
possible with macrogol 4000, and because digoxin is a widely prescribed drug with a
narrow therapeutic index, the objective of the study was to assess a possible
influence of macrogol 4000 on the pharmacokinetic profile of digoxin.
Methods
Study design
Eighteen healthy volunteers (10 males and 8 females) aged 22 years (1936) were
included in a double-blind, 2-period cross-over trial after giving their written informed
consent to participate. Local Ethics Committee approval for the study was obtained.
The two therapeutic sequences were performed in a randomised order and were
separated by 1125 days of washout. During one period, subjects received a single
oral dose of 0.5 mg digoxin (2 tablets of Digoxin Nativelle

). During the other period,

they received the same dose of digoxin coadministered with 20 g macrogol 4000,
preceded (4 days) and followed (3 days) by single administrations of macrogol 4000,
at the dosage of 20 g day
1
.
Blood samples for digoxin level determination were taken before digoxin
administration (t0), 15, 30, 45, 60, 90, 120, 150, 180 min and 4, 6, 9, 12, 16, 24, 32,
48, 58, 72, 82, 96, and 120 h after drug administration. The day of digoxin
administration, 12-lead ECG were recorded at the same evaluation times as plasma
MACROGOL 2014

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samples for determination of heart rate (RR interval) and PR interval at rest.
Subjects were hospitalized during the first 24 h following oral administration of
digoxin.
Drug assay
Plasma digoxin concentrations were measured with the use of a modified enzyme
multiplied digoxin immunoassay. The detection and quantification limits were 0.02
and 0.08 ng ml
1
, respectively [ 6].
Pharmacokinetic analysis
Model independent methods were used to estimate the pharmacokinetic parameters
of digoxin, using WinNonlin software, version 1.5 (Scientific Consulting Inc, USA).
The following parameters were calculated for each period: time of plasma peak
appearance (t
max
, h), maximum plasma concentration (C
max
, ng ml
1
), area under
plasma concentration time curve calculated from time 0 to the last sampling time (t)
and from 0 to infinity (AUC(0,t) and AUC(0, ) ng ml
1
h) by the linear trapezoidal
method, and apparent elimination half-life (t
1/2,z
, h).
Pharmacodynamic parameters
Heart rate and PR interval at rest were calculated, for each ECG recording at
50 mm s
1
, from three consecutive QRS intervals, using a digitizing table
(SummaSketch Professional MM II 1812, Summagraphics, Seymour, CT USA).
Statistical analysis
The pharmacokinetic parameters of digoxin with and without coadministration of
macrogol 4000 were compared by using an analysis of variance (anova) for a two-
period crossover design and a Dunnett-test (at the 0.05 significance level). Two one-
sided tests bioequivalence decision rule for log-transformed data was applied to
compare the magnitude of the differences observed in C
max
and AUC. The accepted
bioequivalence limits of the 90% confidence interval of the geometric mean ratio
were 0.801.25. Experimental t
max
were compared by using the sign test. The
maximal effects on heart rate and AV conduction observed under treatment were
MACROGOL 2014

26


compared using a paired Students t-test. Differences were considered to be st
Results
Pharmacokinetics
Figure 1 shows the time course profile of mean plasma concentrations of digoxin
obtained with and without macrogol 4000. The pharmacokinetic parameters are
summarized in Table 1.

Figure 1. Digoxin plasma concentration over time. Mean valuess.d. (n=18).
digoxin alone, digoxin+macrogol 4000.
Table 1. Digoxin pharmacokinetic parameters (means.d.).

The coadministration of macrogol 4000 resulted in a 40% decrease (P<0.05) in
mean C
max
values (2.50.7 and 1.40.4 ng ml
1
) with a 90% confidence interval of
the ratio of 0.490.70, outside the bioequivalence limits.
Similarly, the AUC(0,t) and AUC(0, ) mean values decreased by 30% (P<0.05) with
a 90% confidence interval of the ratio of, respectively, 0.610.80 and 0.620.79, both
outside of the bioequivalence limits.
However, the t
max
values were unaffected by macrogol 4000 with respective mean
values of 1.5[0.82.3] h (alone) and 1.5[1.02.0] h (combination) (NS). The digoxin
elimination half-life was not significantly different in the absence and the presence of
macrogol 4000 (33.88.8 h and 30.710.2 h, respectively).
Pharmacodynamic parameters
MACROGOL 2014

27


No modification of AV conduction under treatment was observed over the 24 h
hospitalization between the two therapeutic sequences. We observed a bradycardic
effect during the first 6 h following the digoxin administration, with a maximal
decrease of 18.98.1% alone and 16.98.6% in combination (NS).
atistically significant at P<0.05.
Discussion
Pharmacokinetics
The digoxin pharmacokinetic parameters observed in our study are in accordance
with those found in the literature in healthy volunteers with comparable doses [ 7, 8].
We observed a statistically significant difference between the two therapeutic
sequences for the C
max
and AUC values, without any difference for t
max
, suggesting
that macrogol 4000 coadministration interacts with single-dose digoxin
pharmacokinetics by reducing the absorption of the drug. These data are in
accordance with the results of Padoin et al. who previously showed a decreased
amoxicillin absorption with a coadministration of saline-macrogol in healthy
volunteers [ 9].
Macrogol 4000 is not absorbed and has a local osmotic intestinal action. Thus, the
decreased absorption rate of digoxin observed in our study could be explained by a
decreased concentration at the absorption site, resulting from an increased volume
of liquid in the intestinal lumen caused by macrogol 4000, or by local changes in pH
or electrolytes. However, no effect on stool hydratation, stool electrolytes output and
pH has been found in healthy volunteers treated by low doses of macrogol 4000
[ 10]. Another hypothesis could be a direct physicochemical interaction between
macrogol 4000 and digoxin. In fact, it is well known that such an interaction is
observed with liquid antacids, which coat digoxin tablets and thus interfere with their
dissolution [ 3], with kaolin and pectin which adsorb digoxin [ 2] and with
cholestyramine known to bind cardiac glycosides [ 3].
12-lead ECG
Digoxin is well known to have a depressor effect on the sinusal function and the AV
nodal conduction at rest [ 1, 11]. In this single-dose digoxin study, we observed a
MACROGOL 2014

28


bradycardia during the first hours after the digoxin administration, with no
consequence of macrogol 4000 coadministration. However, as there was no placebo
period, this mild bradycardia cannot be clearly related to digoxin administration. No
significant changes in AV conduction were observed in the subjects. Similar results
on PR interval were observed recently by Chaufour et al. in healthy volunteers, at the
dose of 0.25 mg of digoxin per day during 7 days [ 12]. These results could be
explained by the low dose of digoxin tested, which is below the loading dose
required to achieve a full therapeutic effect.
Clinical implications
Although there is considerable debate on the plasma concentration-effect
relationships during digoxin acute and chronic treatment [ 1, 5], a decrease in digoxin
digestive absorption could result in loss of therapeutic effect. We did not observe any
reduction in the pharmacodynamic response following a single dose administration
of 0.5 mg digoxin in normal subjects. The pharmacokinetic interaction observed in
this study has to be evaluated in patients during chronic digoxin treatment in order to
assess the therapeutic consequences of this drugdrug interaction.
Acknowledgements
his study was supported by a grant in aid from BEAUFOUR Laboratories










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Pharmaceutical Additives MACROGOL
The appearance of MACROGOL products varies depending on the molecular
weight. For example, MACROGOL 400 is a viscous liquid, while MACROGOL 1500
is a paste-like solid substance and MACROGOL 6000 is a waxy solid substance, the
later is available in either flakes or powder. Each MACROGOL product is water-
soluble, and has low toxicity.These features make MACROGOL ideal for use as a
base material for ointments and suppositories, tablet coating agents, tablet binders,
and other applications.
End Use Examples
Base Materials for Ointments
MACROGOL products are ideal as a base material for ointments (e.g. penicillin,
Terramycin, streptomycin, and other antibiotics; antihistamine, benzocaine, and
other narcotics; and for preservatives). These products can be used to adjust the
concentration and viscosity of pharmaceuticals to be applied to the skin. These
products make the pharmaceuticals easier to evenly apply, therefore allowing an
accurate amount to persistently permeate into the affected area. These products
also act to absorb body fluid oozing from the affected area.
Example formula for base materials of
water-soluble ointment
Materials (wt %)
MACROGOL 4000 20
Stearyl alcohol 37
Glycerin 30
Purified water 12
Sodium lauryl sulfate 1
Total 100



MACROGOL 2014

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Base Materials for Suppositories
We offer a wide range of MACROGOL products, from MACROGOL 400 that has a
freezing point of approximately 6C, to MACROGOL 20000 which has a freezing
point of approximately 60C. It is possible to mix two or more MACROGOL products
to produce a base material that has an ideal melting point and an ideal dissolving
rate for suppositories.
In general, thermal stability (storage stability) is improved at ambient temperature by
the use of MACROGOL products with a high average molecular weight.
Binders for Tablets
MACROGOL products can also be used as a tablet surface smoother, coating agent,
or binder.
MACROGOL 6000 (powder) has a shorter tablet coating time than the common
sugar coating agent. With this product, you can obtain a tablet that looks good
appearance and has a hard surface.
This product can also be used in tablets for diabetics.
Properties
Hygroscopic Properties
MACROGOL products are hygroscopic, and their hygroscopic properties decrease in
accordance with the increase in their molecular weight. For example, MACROGOL
200 has a high hygroscopic property similar to that of a propylene glycol, whereas
MACROGOL 4000 and MACROGOL 20000 have very low hygroscopic properties.
The following figure shows the equilibrium moisture regain of MACROGOL.



MACROGOL 2014

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Safety
MACROGOL products have low toxicity according to the following LD50 values for
rats.
Product Name
LD50
g/kg (oral, rat)
MACROGOL 200 28
MACROGOL 400 30.2
MACROGOL 1500 44.2
MACROGOL 4000 50
MACROGOL 6000(powder) 50
MACROGOL 6000(flake) 50
Registry of Toxic Effects of Chemical Substances, Feb. 2003 (NIOSH)(CD-ROM).

Other properties
MACROGOL is readily esterified and etherified, because it has primary
hydroxyl groups at both ends of its molecule.
MACROGOL's water solubility is not affected by the presence of an
electrolyte. It is solubule in hard water and aqueous salt solution, as well as in
acids and alkalis (except for extremely concentrated acids or alkalis).
MACROGOL and its aqueous solutions show excellent lubricity. It
decomposes at high temperatures, but no residue remains.
MACROGOL's temperature-kinematic viscosity curve and its aqueous
solutions' temperature-kinematic viscosity curves are shown below.




MACROGOL 2014

32















MACROGOL 2014

33


MACROGOL Lineup
The table below shows the MACROGOL products
Product Name
Appearance
205
Viscosity
mm
2
/s
(21F
*1
)
Molecular
Weight
Freezing
Point

Flash
*2

Point
C
pH
*3

MACROGOL 200 Colorless liquid 4 200 <-35 196 5.5
MACROGOL 400 Colorless liquid 7 400 6 230 5.5
MACROGOL 1500 White paste 16 *4 40 240 5.5
MACROGOL 4000 White flake 80 3,200 55 270 7.0
MACROGOL 6000
powder
White powder 800 8,300 59 256 7.0
MACROGOL 6000
flake
White flake 800 8,300 59 256 7.0
MACROGOL 20000 White flake 14,000 20,000 60 296 7.0
*1 Measured at 98.9C (210F).
*2 Measured according to the COC method.
*3 Measured as a 5 wt % aqueous solution.
*4 A mixture of equal amount of HOCH
2
(CH
2
OCH
2
)nCH
2
OH in which n is both 5 to 6
and 28 to 36

For Safe Material Handling
For further information, Safety Data Sheets (SDS) are available from Sanyo
Chemical.




MACROGOL 2014

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Compound Macrogol Oral powder Sachets - Sugar Free
Compound Macrogol Oral Powder is a laxative used to treat chronic constipation and
the build-up of hard faeces in your bowel. It works by softening your faeces, making
it easier to pass.

Product Discription
Compound Macrogol Oral Powder has electrolytes that help to maintain your
bodys normal levels of sodium, potassium and water while you are being treated for
constipation and it works by softening your faeces, making it easier to pass. In
general this drug is used for the treatment of constipation, especially if you have
been constipated for a long time. It is also used to treat the build-up of hard faeces in
your bowel, which can occur if you have been constipated for a long time.
Benefits of being on this drug can include relief from constipation
Listed below are the typical uses of macrogol
Chronic constipation
Build-up of hard faeces in the bowel (faecal impaction)

Usage / Instruction
How to take Compond Macrogol:
Please take Compond Macrogol as prescribed by your doctor or medical
professional.
Direction details will be available on your medication container








MACROGOL 2014

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Warning

Caution before taking Compound Macrogol Oral Powder:
The faecal impaction diagnosis should be confirmed by appropriate physical or
radiological examination of the rectum and abdomen.
Mild adverse drug reactions are possible such as allergic reactions, including
anaphylaxis, angioedema, dyspnoea, rash, erythema, urticaria, and pruritus;
metabolism and nutrition disorders; electrolyte disturbances, particularly
hyperkalaemia and hypokalaemia; nervous system disorders; headache;
gastrointestinal disorders; abdominal pain, diarrhoea, vomiting, nausea, dyspepsia,
abdominal distension, borborygmi, flatulence, anal discomfort; general disorders and
administration site conditions & peripheral oedema.
If patients develop any symptoms indicating shifts of fluids/electrolytes (e.g. oedema,
shortness of breath, increasing fatigue, dehydration, cardiac failure) Compound
Macrogol Oral Powder Sugar Free should be stopped immediately and electrolytes
measured and any abnormality should be treated appropriately.
The absorption of other medicinal products could transiently be reduced due to an
increase in gastro-intestinal transit rate induced by Compound Macrogol Oral
Powder Sugar Free.

Ingredients
Each Compond Macrogol sachet contains the following quantitative
composition of active ingredients:
Macrogol 335013.125g, Sodium Chloride 350.7mg, Sodium Hydrogen
Carbonate178.5mg, Potassium Chloride 46.6mg.


Macrogol Compound Npf
Brand Name(s) : Idrolax, Movicol, Laxido


MACROGOL COMPOUND NPF USES

Macrogol compound is a laxative used to treat chronic constipation and the build up
of hard faeces in your bowel. It works by softening your faeces, making it easier to
pass. The electrolytes help to maintain your bodys normal levels of sodium,
MACROGOL 2014

36


potassium and water while you are being treated for constipation.

In general this drug is used for the treatment of constipation, especially if you have
been constipated for a long time. It is also used to treat the build up of hard faeces in
your bowel, which can occur if you have been constipated for a long time.

Benefits of being on this drug can include relief from constipation.

Listed below are the typical uses of macrogol.

Chronic constipation
Build up of hard faeces in the bowel (faecal impaction).
Colonic clearance before examination or surgery requiring a clean colon.

HOW TO USE/TAKE

How often do I take it?

Dissolve the contents of a package in a glass of water (125ml) to take this
medication. For constipation, one sachet should be used one to three times a day,
for faecal impaction eight sachets should be taken within a six hour time frame (all
eight sachets may be dissolved in one litre of water.
Use this medication for the duration of prescription, and as instructed by your doctor
or pharmacist in order to get the most benefit from it.
Remember to use it at the same time each day - unless specifically told otherwise
by your doctor.
Certain medical conditions may require different dosage instructions as directed by
your doctor.

What dose?

Dosage is based on your age, gender, medical condition, response to therapy, and
use of certain interacting medicines.

Do I need to avoid anything?

Macrogol compound has no influence on the ability to drive or use machines.

When can I stop?

Always complete the full course as prescribed by your doctor.
Details
MACROGOL 2014

37


MACROGOL COMPOUND NPF INTERACTIONS

Your doctor or pharmacist may already be aware of any possible drug interactions
and may be monitoring you for them. Do not start, stop, or change the dosage of any
medicine before checking with them first.

Other medicines should not be taken orally for one hour before and for one hour
after taking macrogol compound.

Before using this medication, tell your doctor or pharmacist of all prescription and
non-prescription/herbal products you may use.

This information does not contain all possible interactions. Therefore, before using
macrogol compound, tell your doctor or pharmacist of all the products you use.


MACROGOL COMPOUND NPF SIDE EFFECTS

Allergic reaction (rash, itching, shortness of breath)
Changes in your body's fluid or electrolyte levels (swollen ankles, other swelling,
fatigue, dehydration, increased thirst with headache)
Abdominal pain
Mild diarrhoea
Nausea
Vomiting
Swollen abdomen
Stomach rumbling

If any of these persist or you consider them severe then inform your doctor or
pharmacist.

Tell your doctor immediately if you develop any of the following symptoms:

signs of an allergic reaction; signs of a change in your body's fluid or electrolyte
levels.

Remember that your doctor has prescribed this medication because he or she has
judged that the benefit to you is greater than the risk of side effects. Many people
using this medication do not have serious side effects.

A serious allergic reaction to this drug is unlikely, but seek immediate medical
attention if it occurs. Symptoms of a serious allergic reaction include: rash,
itching/swelling (especially of the face/tongue/throat), dizziness, trouble breathing.
MACROGOL 2014

38



This is not a complete list of possible side effects. If you notice other effects not
listed above, contact your doctor or pharmacist.

In the UK you may report side-effects to the MHRA


MACROGOL COMPOUND NPF OVERDOSE

If you take more macrogol compound than you should, you may experience severe
pains and swelling in your abdomen, or vomiting or diarrhoea. If this happens,
contact your doctor or pharmacist.

If you think you, or someone you care for, might have accidentally taken more than
the recommended dose of Macrogol compound or intentional overdose is suspected,
contact your local hospital, GP or if in the UK call NHS Direct on 0845 4647.

MISSED DOSE

If you miss a dose, take it as soon as you remember. If it is near the time of the next
dose, skip the missed dose and resume your usual dosing schedule. Do not double
the dose to catch up.


MACROGOL COMPOUND NPF PRECAUTIONS

Before taking macrogol compound, tell your doctor or pharmacist if you are allergic
to it; or to other laxatives; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before
using this medicine, consult your doctor or pharmacist if you have: blockage of the
intestine, perforation in the intestine, paralysis of the intestine, ulcerative colitis,
Crohn's disease, toxic megacolon, patients with allergies to any of the ingredients.

Before using this medication, tell your doctor or pharmacist your medical history,
especially any of the following: intestinal obstruction or perforation, severe
inflammatory conditions of the intestinal tract, allergies to macrogol compound or any
of the other ingredients.

Before having surgery, tell your doctor or dentist that you are taking this medication.

Alcohol intake does not appear to affect this drug.

MACROGOL 2014

39


The elderly: macrogol compound can be used in the elderly.

Pregnancy and breastfeeding - please ensure you read the detailed information
below

PREGNANCY

Pregnancy

Macrogol compound is not safe to take if you are, or are planning to become,
pregnant.

Ask your doctor or pharmacist if you have any doubts or questions about this.

It is sensible to limit use of medication during pregnancy whenever possible.
However, your doctor may decide that the benefits outweigh the risks in individual
circumstances and after a careful assessment of your specific health situation.

If you have any doubts or concerns you are advised to discuss the medicine with
your doctor or pharmacist.

BREAST FEEDING

breastfeeding

Macrogol compound is not safe to take if you are breastfeeding.

Ask your doctor or pharmacist if you have any doubts or questions about this.

It is sensible to limit use of medication during breastfeeding whenever possible.
However, your doctor may decide that the benefits outweigh the risks in individual
circumstances and after a careful assessment of your specific health situation.

If you have any doubts or concerns you are advised to discuss the medicine with
your doctor or pharmacist.


MACROGOL COMPOUND NPF WARNINGS

Macrogol compound should not be used for faecal impact unless the diagnosis has
been confirmed by your doctor.

It should not be used in:
MACROGOL 2014

40



blockage of the intestine, perforation in the intestine, paralysis of the intestine,
ulcerative colitis, Crohn's disease, toxic megacolon, patients with allergies to any of
the ingredients, other medicines should not be taken within an hour either before or
after taking macrogol compound.

Also see list of precautions and interactions

STORAGE

You should store unopened sachets below 25C.
Reconstituted Compound Macrogol Oral Powder solution can be covered and stored
in the refrigerator (2C to 8C), and should be used within six hours. After six hours,
any unused solution should be discarded.