MACROGOL 2014

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

INTRODUCTION

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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 Crohn’s 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

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

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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

Alternatives

In many cases you can improve the symptoms of constipation without having to use laxatives through lifestyle changes, such as:

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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.

Before using Macrogol compound powder NPF

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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

Pregnancy and breast-feeding

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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.

What is it used for?

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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 (2-8ºC) 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.

Warning!

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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.

Pregnancy and breastfeeding

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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.

Abdominal rumbling and gurgling sounds due to movement in the intestines.

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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.

Other medicines containing the same active ingredient

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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.

Before using Dulcobalance

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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.

Possible side effects of Dulcobalance

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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.

LAXATIVE

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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.

What is constipation?

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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. 

Faecal softeners work by wetting and softening the faeces.

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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?

Bulk-forming laxatives can have some effect within 12-24 hours but their full effect

may take several days to develop.

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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

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?

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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.

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

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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

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

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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.

How to use the Yellow Card Scheme

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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.

Use of macrogol 4000 in chronic constipation

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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

Aims The 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.

Methods This 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.

Results Macrogol 4000 coadministration was associated with a 30% decrease of

digoxin AUC and a 40% decrease in its Cmax(P<0.05). Digoxin tmax and t1/2,z were not

significantly altered. Heart rate and PR interval did not differ during the two

therapeutic sequences, digoxin alone and digoxin in combination.

Conclusions Macrogol 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.

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MACROGOL 2014

Introduction

Macrogol 4000 (Forlax® ), a laxative polymer, has been registered for the

symptomatic treatment of functional constipation at the dosage of 10–20 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: 30–40 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 (19–36) 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 11–25 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

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MACROGOL 2014

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 (tmax, h), maximum plasma concentration (Cmax, 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 (t1/2,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 Cmax and AUC. The accepted

bioequivalence limits of the 90% confidence interval of the geometric mean ratio

were 0.80–1.25. Experimental tmax were compared by using the sign test. The

maximal effects on heart rate and AV conduction observed under treatment were

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MACROGOL 2014

compared using a paired Student’s 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 values±s.d. (n=18). □

digoxin alone, ▾ digoxin+macrogol 4000.

Table 1.  Digoxin pharmacokinetic parameters (mean±s.d.).

The coadministration of macrogol 4000 resulted in a 40% decrease (P<0.05) in

mean Cmax values (2.5±0.7 and 1.4±0.4 ng ml−1 ) with a 90% confidence interval of

the ratio of 0.49–0.70, 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, 0.61–0.80 and 0.62–0.79, both

outside of the bioequivalence limits.

However, the tmax values were unaffected by macrogol 4000 with respective mean

values of 1.5[0.8–2.3] h (alone) and 1.5[1.0–2.0] h (combination) (NS). The digoxin

elimination half-life was not significantly different in the absence and the presence of

macrogol 4000 (33.8±8.8 h and 30.7±10.2 h, respectively).

Pharmacodynamic parameters

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MACROGOL 2014

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 18.9±8.1% alone and 16.9±8.6% 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 Cmax and AUC values, without any difference for tmax, 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

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MACROGOL 2014

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 drug–drug interaction.

Acknowledgements

his study was supported by a grant in aid from BEAUFOUR Laboratories

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MACROGOL 2014

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 ofwater-soluble ointment

Materials (wt %)

MACROGOL 4000 20

Stearyl alcohol 37

Glycerin 30

Purified water 12

Sodium lauryl sulfate 1

Total 100

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MACROGOL 2014

Base Materials for Suppositories

We offer a wide range of MACROGOL products, from MACROGOL 400 that has a freezing point of approximately 6ºC, to MACROGOL 20000 which has a freezing point of approximately 60ºC. 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.

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MACROGOL 2014

Safety

MACROGOL products have low toxicity according to the following LD50 values for rats.

Product NameLD50

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.

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MACROGOL 2014

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MACROGOL 2014

MACROGOL Lineup

The table below shows the MACROGOL products

Product NameAppearance（20±5℃）

Viscositymm2/s(21°F*1)

MolecularWeight

FreezingPoint℃

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 98.9°C (210°F).*2 Measured according to the COC method.*3 Measured as a 5 wt % aqueous solution.*4 A mixture of equal amount of HOCH2(CH2OCH2)nCH2OH 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.

Compound Macrogol Oral powder Sachets - Sugar Free

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MACROGOL 2014

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 body’s 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

Warning

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MACROGOL 2014

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 body’s normal levels of sodium, 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

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MACROGOL 2014

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 COMPOUND NPF INTERACTIONS

Your doctor or pharmacist may already be aware of any possible drug interactions

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MACROGOL 2014

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.

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

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MACROGOL 2014

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.

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

Pregnancy and breastfeeding - please ensure you read the detailed information

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MACROGOL 2014

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:

 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

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MACROGOL 2014

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

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