BuTrans 10 micrograms/hour transdermal patch

Ireland - English - HPRA (Health Products Regulatory Authority)

Buy It Now

Active ingredient:
Buprenorphine
Available from:
Mundipharma Pharmaceuticals Limited
ATC code:
N02AE; N02AE01
INN (International Name):
Buprenorphine
Dosage:
10 milligram(s)
Pharmaceutical form:
Transdermal patch
Prescription type:
Product subject to prescription which may not be renewed (A)
Therapeutic area:
Oripavine derivatives; buprenorphine
Authorization status:
Marketed
Authorization number:
PA1688/002/002
Authorization date:
2005-06-24

Package leaflet: Information for the patient

BuTrans

®

5 microgram/hour transdermal patches

BuTrans

®

10 microgram/hour transdermal patches

BuTrans

®

15 microgram/hour transdermal patches

BuTrans

®

20 microgram/hour transdermal patches

Buprenorphine

Read all of this leaflet carefully before you start using this medicine because it contains

important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor, pharmacist or nurse.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,

even if their signs of illness are the same as yours.

If you get any side effects talk to your doctor, pharmacist or nurse. This includes any possible

effects not listed in this leaflet. See section 4.

What is in this leaflet:

What BuTrans patches are and what they are used for

What you need to know before you use BuTrans patches

How to use BuTrans patches

Possible side effects

How to store BuTrans patches

Contents of the pack and other information

1.

What BuTrans patches are and what they are used for

BuTrans patches contain the active ingredient buprenorphine which belongs to a group of medicines

called strong analgesics or ‘painkillers’. They have been prescribed for you by your doctor to relieve

moderate, long-lasting pain that requires the use of a strong painkiller.

BuTrans patches should not be used to relieve acute pain.

BuTrans patches act through the skin. After application, buprenorphine passes through the skin into

the blood. Each patch lasts for seven days.

2.

What you need to know before you use BuTrans patches

Do not use BuTrans patches:

if you are allergic to buprenorphine or any of the other ingredients of this medicine (list in

section 6);

if you have breathing problems;

if you are addicted to drugs;

if you are taking a type of medicine known as a monoamine oxidase inhibitor (examples include

tranylcypromine, phenelzine, isocarboxazid, moclobemide and linezolid), or you have taken this

type of medicine in the last two weeks;

if you suffer from myasthenia gravis (a condition in which the muscles become weak);

if you have previously suffered from withdrawal symptoms such as agitation, anxiety, shaking

or sweating upon stopping taking alcohol.

BuTrans patches must not be used to treat symptoms associated with drug withdrawal.

Warnings and precautions

Talk to your doctor, pharmacist or nurse before using BuTrans patches:

if you suffer from seizures, fits or convulsions;

if you have a severe headache or feel sick due to a head injury or increased pressure in your

skull (for instance due to brain disease). This is because the patches may make symptoms

worse or hide the extent of a head injury;

if you are feeling light-headed or faint;

if you have severe liver problems;

if you have ever been addicted to drugs or alcohol;

if you have a high temperature, as this may lead to larger quantities of the active ingredient

being absorbed into the blood than normal.

If you have recently had an operation, please speak to your doctor before using these patches.

Children and adolescents

Do not give this medicine to children below 18 years.

Other medicines and BuTrans patches

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

BuTrans patches must not be used together with a type of medicine known as a monoamine

oxidase inhibitor (examples include tranylcypromine, phenelzine, isocarboxazid, moclobemide

and linezolid), or if you have taken this type of medicine in the last two weeks.

If you take some medicines such as phenobarbital or phenytoin (medicines commonly used to

treat seizures, fits or convulsions), carbamazepine (a medicine to treat seizures, fits or

convulsions and certain pain conditions), or rifampicin (a medicine to treat tuberculosis) the

effects of BuTrans patches may be reduced.

BuTrans patches may make some people feel drowsy, sick or faint or make them breathe more

slowly or weakly. These side effects may be made worse if other medicines that produce the

same effects are taken at the same time. These include certain medicines to treat pain,

depression, anxiety, psychiatric or mental disorders, medicines to help you sleep, medicines to

treat high blood pressure such as clonidine, other opioids (which may be found in painkillers or

certain cough mixtures e.g. morphine, dextropropoxyphene, codeine, dextromethorphan,

noscapine), antihistamines which make you drowsy, or anaesthetics such as halothane.

BuTrans patches must be used with caution if you are also taking benzodiazepines (medicines

used to treat anxiety or to help you sleep). This combination may cause serious breathing

problems.

Using BuTrans patches with food drink and alcohol

Alcohol may make some of the side effects worse and you may feel unwell if you drink alcohol whilst

wearing BuTrans patches. Drinking alcohol whilst using BuTrans patches may also affect your

reaction time.

Pregnancy breast-feeding and fertility

You should not use BuTrans patches if you are pregnant or are breast-feeding, think you may be

pregnant or are planning to have a baby.

Ask your doctor or pharmacist for advice before taking this medicine.

Driving and using machines

BuTrans patches may affect your reactions to such an extent that you may not react adequately or

quickly enough in the event of unexpected or sudden occurrences. This applies particularly:

at the beginning of treatment;

if you are taking medicines to treat anxiety or help you sleep;

if your dose is increased.

If you are affected (e.g. feel dizzy, drowsy or have blurred vision), you should not drive or operate

machinery whilst using BuTrans patches, or for 24 hours after removing the patch.

3.

How to use BuTrans patches

Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor

or pharmacist if you are not sure.

Different strengths of BuTrans patches are available. Your doctor will decide which strength of

BuTrans patch will suit you best.

When people first start using BuTrans, they often experience some nausea and vomiting (see section

4). This usually passes after the first week of treatment. It’s a good idea to book a follow-up

appointment with your doctor a week or two after you first start using BuTrans patches to ensure that

you are taking the correct dose and to manage any side effects.

During treatment, your doctor may change the patch you use to a smaller or larger one if necessary or

tell you to use a combination of up to two patches. Do not cut or divide the patch or use a higher dose

than recommended. You should not apply more than two patches at the same time, up to a

maximum total dose of 40 micrograms/hour.

Adults and elderly patients

Unless your doctor has told you differently, attach one BuTrans patch (as described in detail below)

and change it every seventh day, preferably at the same time of day. Your doctor may wish to adjust

the dose after 3-7 days until the correct level of pain control has been found. If your doctor has

advised you to take other painkillers in addition to the patch, strictly follow the doctor’s instructions,

otherwise you will not fully benefit from treatment with the BuTrans patch. The patch should be

worn for 3 full days before increasing the dose, this is when the maximum effect of a given dose is

established.

Patients under 18 years of age

BuTrans patches should not be used in patients below the age of 18 years.

Patients with kidney disease/dialysis patients

In patients with kidney disease, no change in dose is necessary.

Patients with liver disease

In patients with liver disease, the effects and period of action of the BuTrans patch may be affected

and your doctor will therefore check on you more closely.

Before applying the BuTrans patch

Choose an area of non-irritated, intact skin on your upper arm, outer arm, upper chest, upper

back or side of the chest. (See illustrations below). Ask for assistance if you cannot apply the

patch yourself.

The BuTrans patch should be applied to a relatively hairless or nearly hairless skin site. If no

suitable hair free sites are available the hairs should be cut off with a pair of scissors. Do not

shave them off.

Avoid skin which is red, irritated or has any other blemishes, for instance large scars.

The area of skin you choose must be dry and clean. If necessary, wash it with cold or lukewarm

water. Do not use soap, alcohol, oil, lotions or other detergents. After a hot bath or shower,

wait until your skin is completely dry and cool. Do not apply lotion, cream or ointment to the

chosen area. This might prevent your patch from sticking properly.

Applying the patch

Wearing the patch

You should wear the patch for seven days. Provided that you have applied the patch correctly, there is

little risk of it coming off. If the edges of the patch begin to peel off, they may be taped down with a

suitable skin tape. You may shower, bathe or swim whilst wearing it.

Do not expose the patch to extreme heat (e.g. heating pads, electric blanket, heat lamps, sauna, hot

tubs, heated water beds, hot water bottle, etc) as this may lead to larger quantities of the active

ingredient being absorbed into the blood than normal. External heat may also prevent the patch from

sticking properly. If you have a high temperature this may alter the effects of BuTrans patches (see

“Take special care” section above).

In the unlikely event that your patch falls off before it needs changing, do not use the same patch

again. Stick a new one on straight away (see “Changing the patch” below).

Changing the patch

Take the old patch off.

Fold it in half with the sticky side inwards.

Open and take out a new patch. Use the empty pouch to dispose of the old patch. Now discard

the pouch safely.

Even used patches contain some active ingredient that may harm children or animals, so make

sure your used patches are always kept out of the sight and reach of them.

Stick a new patch on a different appropriate skin site (as described above). You should not

apply a new patch to the same site for 3-4 weeks.

Remember to change your patch at the same time of day. It is important that you make a note of

the time of day.

Step 3:

Stick the patch on to the area of skin you have chosen and remove the

remaining foil.

Step 4:

Press the patch against your skin with the palm of your hand and count

slowly to 30. Make sure that the whole patch is in contact with your skin,

especially at the edges.

Step 1: Each patch is sealed in a pouch. Just before use, cut the pouch

along the dotted line with scissors. Be careful not to damage the

transdermal patches with the scissors. Take out the patch. Do not use the

patch if the pouch seal is broken.

Step 2: The sticky side of the patch is covered with a silvery protective

foil. Carefully peel off half the foil. Try not to touch the sticky part of the

patch.

Duration of treatment

Your doctor will tell you how long you should be treated with the BuTrans patch. Do not stop

treatment without consulting a doctor, because your pain may return and you may feel unwell (see also

“If you stop using BuTrans patches” below).

If you feel that the effect of the BuTrans patch is too weak or too strong, talk to your doctor or

pharmacist.

If you use more BuTrans patches than you should

As soon as you discover that you have used more patches than you should, remove all patches and call

your doctor or hospital straight away. People who have taken an overdose may feel very sleepy and sick.

They may also have breathing difficulties or lose consciousness and may need emergency treatment in

hospital. When seeking medical attention make sure that you take this leaflet and any remaining patches

with you to show to the doctor.

If you forget to apply the BuTrans patch

Stick a new patch on as soon as you remember. Also make a note of the date, as your usual day of

changing may now be different. If you are very late changing your patch, your pain may return. In

this case, please contact your doctor.

Do not apply additional patches to make up for the forgotten application.

If you stop using BuTrans patches

If you stop using BuTrans patches too soon or you interrupt your treatment your pain may return. If

you wish to stop treatment please consult your doctor. They will tell you what can be done and

whether you can be treated with other medicines.

Some people may have side effects when they have used strong painkillers for a long time and stop

using them. The risk of having effects after stopping BuTrans patches is very low. However, if you

feel agitated, anxious, nervous or shaky, if you are overactive, have difficulty sleeping or digestive

problems, tell your doctor.

The pain relieving effect of BuTrans patch is maintained for some time after removal of the patch.

You should not start another opioid analgesic (strong painkiller) within 24 hours after removal of the

patch.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

4.

Possible side effects

Like all medicines BuTrans patches can have side effects, although not everybody gets them.

Serious side effects that may be associated with BuTrans patches are similar to those seen with other

strong painkillers and include difficulty in breathing and low blood pressure.

This medicine can cause allergic reactions, although serious allergic reactions are rare. Remove the

patch and tell your doctor immediately if you get any sudden wheeziness, difficulties in breathing,

swelling of the eyelids, face or lips, rash or itching especially those covering your whole body.

As with all strong painkillers, there is a risk that you may become addicted or reliant on BuTrans

patches.

In patients treated with BuTrans patches, the following other side effects have been reported:

Very common (probably occurring in more than 1 in 10 people)

Headache, dizziness, drowsiness.

Constipation, feeling or actually being sick.

Itchy skin.

Rash, redness, itching, inflammation or swelling of the skin at the application site.

Common (probably occurring in between 1 and 10 out of every 100 people)

Loss of appetite.

Confusion, depression, anxiety, difficulty in sleeping, nervousness, shaking (tremors).

Shortness of breath.

Abdominal pain or discomfort, diarrhoea, indigestion, dry mouth.

Sweating, rash, skin eruptions.

Tiredness, a feeling of unusual weakness, muscle weakness, swelling of hands, ankles or feet.

Uncommon (probably occurring in between 1 and 10 out of every 1,000 people)

Mood swings, restlessness, agitation, a feeling of extreme happiness, hallucinations, nightmares,

decreased sexual drive, aggression.

Changes in taste, difficulty in speaking, reduced sensitivity to pain or touch, tingling or

numbness.

Loss of memory, migraine, fainting, problems with concentration or co-ordination.

Dry eyes, blurred vision.

A ringing or buzzing sound in the ears, a feeling of dizziness or spinning.

High or low blood pressure, chest pain, fast or irregular heart beat.

Cough, hiccups, wheezing.

Wind.

Weight loss.

Dry skin.

Spasms, aches and pains.

Difficulty in beginning the flow of urine.

Fever.

An increase in accidental injuries (e.g. falls).

Withdrawal symptoms such as agitation, anxiousness, sweating or shaking upon stopping using

BuTrans patches.

If you need to have blood tests remind your doctor that you are using BuTrans patches. This is

important because BuTrans patches may change the way your liver works and this could affect the

results of some blood tests.

Rare (probably occurring in between 1 and 10 out of every 10,000 people)

Angina (chest pain associated with heart disease).

Mental disorder.

Difficulties with balance.

Swelling of the eyelids or face, a reduction in size of the pupils in the eye.

Difficulty in breathing, worsening of asthma, over breathing.

A feeling of faintness, especially on standing up.

Difficulty in swallowing.

Local allergic reaction with marked signs of swelling (in such cases treatment should be

stopped).

Swelling and irritation inside the nose.

Decreased erection, sexual dysfunction.

A flu like illness.

Flushing of the skin.

Dehydration.

Very rare (probably occurring in fewer than 1 out of every 10,000 people)

Muscle twitching.

Ear pain.

Blisters.

Not known (frequency cannot be estimated from the available data)

Seizures, fits or convulsions.

Inflammation of the bowel wall. Symptoms may include fever, vomiting and stomach pain or

discomfort.

Colicky abdominal pain or discomfort.

Feeling detached from oneself.

Withdrawal symptoms in babies born to mothers who have been given BuTrans in pregnancy

may include high-pitched crying, irritability and restlessness, shaking (tremor), feeding

difficulties, sweating and not putting on weight.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist or nurse. This includes any possible side

effects not listed in this leaflet. You can also report side effects directly via;

HPRA Pharmacovigilance,

Earlsfort Terrace,

IRL - Dublin 2;

Tel: +353 1 6764971;

Fax: +353 1 6762517.

Website: www.hpra.ie; E-mail: medsafety@hpra.ie

By reporting side effects you can help provide more information on the safety of this medicine.

5.

How to store BuTrans patches

Keep this medicine out of the sight and reach of children.

Do not use BuTrans patches after the expiry date which is stated on the carton and on the pouch. The

expiry date refers to the last day of that month. After the expiry date, take any unused patches to a

pharmacy.

Do not store BuTrans patches above 25°C.

Do not use the patch if the pouch seal is broken.

Used patches must be folded over on themselves with the adhesive layer inwards, and discarded safely

out of sight and reach of children.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to

throw away medicines you no longer use. These measures will help protect the environment.

6.

Contents of the pack and other information

What BuTrans patches contain

The active ingredient is buprenorphine.

BuTrans 5 microgram/hour transdermal patch

Each transdermal patch contains 5 mg of buprenorphine in a patch size of 6.25 cm

and releases about

5 micrograms of buprenorphine per hour (over a period of 7 days).

BuTrans 10 microgram/hour transdermal patch

Each transdermal patch contains 10 mg of buprenorphine in a patch size of 12.5 cm

and releases

about 10 micrograms of buprenorphine per hour (over a period of 7 days).

BuTrans 15 microgram/hour transdermal patch

Each transdermal patch contains 15 mg of buprenorphine in a patch size of 18.75 cm

and releases

about 15 micrograms of buprenorphine per hour (over a period of 7 days).

BuTrans 20 microgram/hour transdermal patch

Each transdermal patch contains 20 mg of buprenorphine in a patch size of 25 cm

and releases about

20 micrograms of buprenorphine per hour (over a period of 7 days).

The other ingredients are:

Polyacrylate (Durotak 387-2051 & 387-2054)

Levulinic acid

Oleyl oleate

Povidone

Polyethyleneterephthalate

What BuTrans patches look like and contents of the pack

Transdermal patch

5 microgram/hour: square, beige coloured patch with rounded corners marked BuTrans 5 μg/h

10 microgram/hour: rectangular, beige coloured patch with rounded corners marked BuTrans 10 μg/h

15 microgram/hour: rectangular, beige coloured patch with rounded corners marked BuTrans 15 μg/h

20 microgram/hour: square, beige coloured patch with rounded corners marked BuTrans 20 μg/h

BuTrans patches are available in cartons containing 2 or 4 child resistant pouches each containing a

single patch.

Marketing Authorisation Holder:

Mundipharma Pharmaceuticals Limited, Millbank House, Arkle Road, Sandyford, Dublin 18, Ireland.

Manufacturers:

Mundipharma DC B.V., Leusderend 16, 3832 RC Leusden, The Netherlands.

This medicinal product is authorised in the Member States of the EEA under the following names:

Austria

Norspan

Belgium

Norspan

Czech Republic

Norspan

Denmark

Norspan

Estonia

Norspan

Finland

Norspan

Germany

Norspan

Hungary

Norspan

Iceland

Norspan

Latvia

Norspan

Lithuania

Norspan

Luxembourg

Norspan

Netherlands

BuTrans

Norway

Norspan

Poland

Norspan

Portugal

Norspan

Republic of Ireland

BuTrans

Slovak Republic

Norspan

Sweden

Norspan

United Kingdom

BuTrans

This leaflet is also available in large print, Braille or as an audio CD. To request a

copy, please call the RNIB Medicine Information line on:

0044 1733 37 5370

You will need to give details of the product name and reference number.

These are as follows:

Product name: BuTrans patches

Reference number: 1688/2/1

This leaflet was last revised in July 2018

® BUTRANS, MUNDIPHARMA and the ‘mundipharma’ logo are registered trade marks of

Mundipharma.

© 2007-2018 Napp Pharmaceuticals Ltd.

You can also get support and information about arthritis from Arthritis Care:

Phone free: 0808 800 4050 12pm to 4pm Monday to Friday (or 020 7380 6555 10 am to 4pm standard

call charges apply).

Or write to: Helplines, Arthritis Care, 18 Stephenson Way, London, NW1 2HD.

Or email helplines@arthritiscare.org.uk

Health Products Regulatory Authority

23 January 2019

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Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

BuTrans 10 micrograms/hour transdermal patch

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each transdermal patch contains 10 mg of buprenorphine in a 12.5 cm

area

releasing a nominal 10 micrograms of buprenorphine per hour over a period of 7

days.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Transdermal patch.

Beige coloured patch with rounded corners.

Rectangular patch marked BuTrans 10 μg/h

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Treatment of non-malignant pain of moderate intensity when an opioid is necessary

for obtaining adequate analgesia

BuTrans is not suitable for the treatment of acute pain.

BuTrans is indicated in adults.

4.2 Posology and method of administration

Posology

BuTrans should be administered every 7th day.

Patients aged 18 years and over

The lowest BuTrans dose (BuTrans 5 microgram/hour transdermal patch) should be

used as the initial dose. Consideration should be given to the previous opioid history

of the patient (see section 4.5) as well as to the current general condition and

medical status of the patient.

Titration

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During initiation of treatment with BuTrans, short-acting supplemental analgesics

may be required (see section 4.5) as needed until analgesic efficacy with BuTrans is

attained.

The dose of BuTrans may be titrated upwards as indicated after 3 days, when the

maximum effect of a given dose is established. Subsequent dosage increases may

then be titrated based on the need for supplemental pain relief and the patient’s

analgesic response to the patch.

To increase the dose, a larger patch should replace the patch that is currently being

worn, or a combination of patches should be applied in different places to achieve

the desired dose. It is recommended that no more than two patches are applied at

the same time, up to a maximum total dose of 40 microgram/ hour. A new patch

should not be applied to the same skin site for the subsequent 3-4 weeks (see

section 5.2). Patients should be carefully and regularly monitored to assess the

optimum dose and duration of treatment.

Conversion from opioids

BuTrans can be used as an alternative to treatment with other opioids. Such

patients should be started on the lowest available dose (BuTrans 5 microgram/hour

transdermal patch) and continue taking short-acting supplemental analgesics (see

section 4.5) during titration, as required.

Paediatric population

The safety and efficacy of BuTrans in children below 18 years of age has not been

established. No data are available.

Elderly

No dosage adjustment of BuTrans is required in elderly patients.

Renal impairment

No special dose adjustment of BuTrans is necessary in patients with renal

impairment.

Hepatic impairment

Buprenorphine is metabolised in the liver. The intensity and duration of its action

may be affected in patients with impaired liver function. Therefore patients with

hepatic insufficiency should be carefully monitored during treatment with BuTrans.

Patients with severe hepatic impairment may accumulate buprenorphine during

BuTrans treatment. Consideration of alternate therapy should be considered, and

BuTrans should be used with caution, if at all, in such patients.

Method of administration

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Route of administration

Transdermal patch to be worn for 7 days. The patch must not be divided or cut

into pieces.

Patch application

BuTrans should be applied to non-irritated, intact skin of the upper outer arm, upper

chest, upper back or the side of the chest, but not to any parts of the skin with large

scars. BuTrans should be applied to a relatively hairless or nearly hairless skin site. If

none are available, the hair at the site should be cut with scissors, not shaven.

If the application site must be cleaned, it should be done with clean water only.

Soaps, alcohol, oils, lotions or abrasive devices must not be used. The skin must be

dry before the patch is applied. BuTrans should be applied immediately after

removal from the sealed sachet. Following removal of the protective layer, the

transdermal patch should be pressed firmly in place with the palm of the hand for

approximately 30 seconds, making sure the contact is complete, especially around

the edges. If the edges of the patch begin to peel off, the edges may be taped down

with suitable skin tape to ensure a 7 day period of wear. The patch should be worn

continuously for 7 days. Bathing, showering, or swimming should not affect the

patch. If a patch falls off, a new one should be applied and worn for 7 days.

Duration of administration

BuTrans should under no circumstances be administered for longer than absolutely

necessary. If long-term pain treatment with BuTrans is necessary in view of the

nature and severity of the illness, then careful and regular monitoring should be

carried out (if necessary with breaks in treatment) to establish whether and to what

extent further treatment is necessary.

Discontinuation

After removal of the patch, buprenorphine serum concentrations decrease gradually

and thus the analgesic effect is maintained for a certain amount of time. This should

be considered when therapy with BuTrans is to be followed by other opioids. As a

general rule, a subsequent opioid should not be administered within 24 hours after

removal of the patch. At present, only limited information is available on the starting

dose of other opioids administered after discontinuation of the transdermal patch

(see section 4.5).

Patients with fever or exposed to external heat

While wearing the patch, patients should be advised to avoid exposing the

application site to external heat sources, such as heating pads, electric blankets, heat

lamps, sauna, hot tubs, and heated water beds, etc., as an increase in absorption of

buprenorphine may occur. When treating febrile patients, one should be aware that

fever may also increase absorption resulting in increased plasma concentrations of

buprenorphine and thereby increased risk of opioid reactions.

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4.3 Contraindications

patients with known hypersensitivity to the active substance buprenorphine or to

any of the excipients (see section 6.1)

opioid dependent patients and for narcotic withdrawal treatment

conditions in which the respiratory centre and function are severely impaired or may

become so

patients who are receiving MAO inhibitors or have taken them within the last two

weeks (see section 4.5)

patients suffering from myasthenia gravis

patients suffering from delirium tremens.

4.4 Special warnings and precautions for use

BuTrans should be used with particular caution in patients with acute alcohol

intoxication, head injury, shock, a reduced level of consciousness of uncertain origin,

intracranial lesions or increased intracranial pressure, or in patients with severe

hepatic impairment (see section 4.2).

Buprenorphine may lower the seizure threshold in patients with a history of seizure

disorder.

Significant respiratory depression has been associated with buprenorphine,

particularly by the intravenous route. A number of overdose deaths have occurred

when addicts have intravenously abused buprenorphine, usually with

benzodiazepines concomitantly. Additional overdose deaths due to ethanol and

benzodiazepines in combination with buprenorphine have been reported.

Since CYP3A4 inhibitors may increase concentrations of buprenorphine (see section

4.5), patients already treated with CYP3A4 inhibitors should have their dose of

BuTrans carefully titrated since a reduced dosage might be sufficient in these

patients.

BuTrans is not recommended for analgesia in the immediate post-operative period

or in other situations characterised by a narrow therapeutic index or a rapidly varying

analgesic requirement.

Controlled human and animal studies indicate that buprenorphine has a lower

dependence liability than pure agonist analgesics. In humans limited euphorigenic

effects have been observed with buprenorphine. This may result in some abuse of

the product and caution should be exercised when prescribing to patients known to

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have, or suspected of having, a history of drug abuse or alcohol abuse or serious

mental illness.

As with all opioids, chronic use of buprenorphine can result in the development of

physical dependence. Withdrawal (abstinence syndrome), when it occurs, is generally

mild, begins after 2 days and may last up to 2 weeks. Withdrawal symptoms include

agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal

disorders.

BuTrans should not be used at higher doses than recommended.

4.5 Interaction with other medicinal products and other forms of interactions

BuTrans must not be used concomitantly with MAOIs or in patients who have

received MAOIs within the previous two weeks (see section 4.3).

Effect of other active substances on the pharmacokinetics of buprenorphine

Buprenorphine is primarily metabolised by glucuronidation and to a lesser extent

(about 30%) by CYP3A4 . Concomitant treatment with CYP3A4 inhibitors may lead to

elevated plasma concentrations with intensified efficacy of buprenorphine.

Studies with the CYP3A4 inhibitor ketoconazole did not produce clinically relevant

increases in mean maximum (Cmax) or total (AUC) buprenorphine exposure

following BuTrans with ketoconazole as compared to BuTrans alone.

The interaction between buprenorphine and CYP3A4 enzyme inducers has not been

studied.

Co-administration of BuTrans and enzyme inducers (e.g. phenobarbital,

carbamazepine, phenytoin and rifampicin) could lead to increased clearance which

might result in reduced efficacy.

Reductions in hepatic blood flow induced by some general anaesthetics (e.g.

halothane) and other medicinal products may result in a decreased rate of hepatic

elimination of buprenorphine.

Pharmacodynamic interactions

BuTrans should be used cautiously with:

Other central nervous system depressants: other opioid derivatives (analgesics and

antitussives containing e.g. morphine, dextropropoxyphene, codeine,

dextromethorphan or noscapine). Certain antidepressants, sedative H1-receptor

antagonists, alcohol, anxiolytics, neuroleptics, clonidine and related substances.

These combinations increase the CNS depressant activity. Benzodiazepines: This

combination can potentiate respiratory depression of central origin (see section 4.4).

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At typical analgesic doses buprenorphine is described to function as a pure mu

receptor agonist. In BuTrans clinical studies subjects receiving full mu agonist

opioids (up to 90 mg oral morphine or oral morphine equivalents per day) were

transferred to BuTrans. There were no reports of abstinence syndrome or opioid

withdrawal during conversion from entry opioid to BuTrans (see section 4.4).

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of BuTrans in pregnant women. Studies in animals

have shown reproductive toxicity (see Section 5.3). The potential risk for humans is

unknown.

Towards the end of pregnancy high doses of buprenorphine may induce respiratory

depression in the neonate even after a short period of administration. Prolonged use

of buprenorphine during pregnancy can result in neonatal opioid withdrawal

syndrome.

Therefore BuTrans should not be used during pregnancy and in women of

childbearing potential who are not using effective contraception.

Breastfeeding

Buprenorphine is excreted in human milk. Studies in rats have shown that

buprenorphine may inhibit lactation. Available pharmacodynamic/ toxicological data

in animals has shown excretion of buprenorphine into the milk (see section 5.3).

Therefore the use of BuTrans during lactation should be avoided.

Fertility

No human data on the effect of buprenorphine on fertility are available. In a fertility

and early embryonic development study, no effects on reproductive parameters were

observed in male or female rats (see section 5.3).

4.7 Effects on ability to drive and use machines

BuTrans has a major influence on the ability to drive and use machines. Even when

used according to instructions, BuTrans may affect the patient’s reactions to such an

extent that road safety and the ability to operate machinery may be impaired. This

applies particularly in the beginning of treatment and in conjunction with other

centrally acting substances including alcohol, tranquillisers, sedatives and hypnotics.

An individual recommendation should be given by the physician. A general

restriction is not necessary in cases where a stable dose is used.

Patients who are affected and experience side effects (e.g. dizziness, drowsiness,

blurred vision) during treatment initiation or titration to a higher dose should not

drive or use machines for at least 24 hours after the patch has been removed.

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4.8 Undesirable effects

Serious adverse reactions that may be associated with BuTrans therapy in clinical use

are similar to those observed with other opioid analgesics, including respiratory

depression (especially when used with other CNS depressants) and hypotension (see

section 4.4).

The following undesirable effects have occurred:

Very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare

(≥1/10,000, <1/1000), very rare (<1/10,000), not known (cannot be estimated from

the available data).

System organ

class

MedDRA

Very

common

(≥1/10)

Common

(≥1/100,

<1/10)

Uncommon

(≥1/1000,

<1/100)

Rare (≥1/10,000,

<1/1000)

Very rare

(<1/10,000)

Not known

(cannot be

estimated from

the available data)

Immune system

disorders

Hypersensitivity

Anaphylactic

reaction

Anaphylactoid

reaction

Metabolic and

nutritional

disorders

Anorexia

Dehydration

Psychiatric

disorders

Confusion

Depression

Insomnia

Nervousness

Anxiety

Affect lability

Sleep disorder

Restlessness

Agitation

Euphoric mood

Hallucinations

Libido decreased

Nightmares

Aggression

Psychotic

disorder

Drug

dependence

Mood

swings

Depersonalisation

Nervous system

disorders

Headache

Dizziness

Somnolence

Tremor

Sedation

Dysgeusia

Dysarthria

Hypoaesthesia

Memory

impairment

Migraine

Syncope

Co‑ordination

abnormal

Disturbance in

attention

Paraesthesia

Balance disorder

Speech disorder

Involuntary

muscle

contractions

Seizures

Eye disorders

Dry eye

Blurred vision

Visual

disturbance

Eyelid oedema

Miosis

Ear and labyrinth

disorders

Tinnitus

Vertigo

Ear pain

Cardiac disorders

Palpitations

Tachycardia

Angina pectoris

Vascular

disorders

Hypotension

Circulatory

collapse

Hypertension

Vasodilatation

Orthostatic

hypotension

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Flushing

Respiratory,

thoracic and

mediastinal

disorders

Dyspnoea

Cough

Wheezing

Hiccups

Respiratory

depression

Respiratory

failure

Asthma

aggravated

Hyperventilation

Rhinitis

Gastrointestinal

disorders

Constipation

Nausea

Vomiting

Abdominal

pain

Diarrhoea

Dyspepsia

Dry mouth

Flatulence

Dysphagia

Ileus

Diverticulitis

Hepatobiliary

disorders

Biliary colic

Skin and

subcutaneous

tissue disorders

Pruritus

Erythema

Rash

Sweating

Exanthema

Dry skin

Urticaria

Dermatitis

contact

Face oedema

Pustules

Vesicles

Musculoskeletal

and connective

tissue disorders

Muscular

weakness

Myalgia

Muscle spasms

Renal and urinary

disorders

Urinary

incontinence

Urinary retention

Urinary hesitation

Reproductive

system and

breast disorders

Erectile

dysfunction

Sexual

dysfunction

General disorders

administration

site conditions

Application

site

reaction

Tiredness

Asthenic

conditions

Peripheral

oedema

Fatigue

Pyrexia

Rigors

Oedema

Drug withdrawal

syndrome

Application site

dermatitis* Chest

pain

Influenza like

illness

Drug withdrawal

syndrome

neonatal

Investigations

Alanine

aminotransferase

increased

Weight decreased

Injury, poisoning

and procedural

complications

Accidental injury

Fall

* In some cases delayed local allergic reactions occurred with marked signs of inflammation. In such cases

treatment with BuTrans should be terminated.

Includes application site erythema, application site oedema, application site pruritus, application site rash.

Buprenorphine has a low risk of physical dependence. After discontinuation of

BuTrans, withdrawal symptoms are unlikely. This may be due to the very slow

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dissociation of buprenorphine from the opioid receptors and to the gradual decrease

of buprenorphine plasma concentrations (usually over a period of 30 hours after

removal of the last patch). However, after long-term use of BuTrans, withdrawal

symptoms similar to those occurring during opioid withdrawal, cannot be entirely

excluded. These symptoms include agitation, anxiety, nervousness, insomnia,

hyperkinesia, tremor and gastrointestinal disorders.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is

important. It allows continued monitoring of the benefit/risk balance of the medicinal

product. Healthcare professionals are asked to report any suspected adverse

reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2;

Tel: +353 1 6764971; Fax: +353 1 6762517.

Website: www.hpra.ie;

E-mail: medsafety@hpra.ie.

4.9 Overdose

Symptoms: Symptoms similar to those of other centrally acting analgesics are to be

expected. These include respiratory depression, sedation, drowsiness, nausea,

vomiting, cardiovascular collapse and marked miosis.

Treatment: Remove any patches from the patient’s skin. Establish and maintain a

patent airway, assist or control respiration as indicated and maintain adequate body

temperature and fluid balance. Oxygen, intravenous fluids, vasopressors and other

supportive measures should be employed as indicated.

A specific opioid antagonist such as naloxone may reverse the effects of

buprenorphine, although naloxone may be less effective in reversing the effects of

buprenorphine than other µ-opioid agonists. Treatment with continuous intravenous

naloxone should begin with the usual doses but high doses may be required.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Analgesics, opioids; ATC code: N02 AE01

Buprenorphine is a partial agonist opioid, acting at the mu opioid receptor. It also

has antagonistic activity at the kappa opioid receptor.

Efficacy has been demonstrated in seven pivotal phase III studies of up to 12 weeks

duration in patients with non-malignant pain of various aetiologies. These included

patients with moderate and severe OA and back pain. BuTrans demonstrated

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clinically significant reductions in pain scores (approximately 3 points on the BS-11

scale) and significantly greater pain control compared with placebo.

A long term, open-label extension study (n=384) has also been performed in patients

with non-malignant pain. With chronic dosing, 63% of patients were maintained in

pain control for 6 months, 39% of patients for 12 months, 13% of patients for 18

months and 6% for 21 months. Approximately 17% were stabilised on the 5mg dose,

35% on the 10mg dose and 48% on the 20mg dose.

5.2 Pharmacokinetic properties

There is evidence of enterohepatic recirculation.

Studies in non-pregnant and pregnant rats have shown that buprenorphine passes

the blood-brain and placental barriers. Concentrations in the brain (which contained

only unchanged buprenorphine) after parenteral administration were 2-3 times

higher than after oral administration. After intramuscular or oral administration

buprenorphine apparently accumulates in the foetal gastrointestinal lumen –

presumably due to biliary excretion, as enterohepatic circulation has not fully

developed.

Each patch provides a steady delivery of buprenorphine for up to seven days. Steady

state is achieved during the first application. After removal of BuTrans,

buprenorphine concentrations decline, decreasing approximately 50% in 12 hours

(range 10–24 h).

Absorption

Following BuTrans application, buprenorphine diffuses from the patch through the

skin. In clinical pharmacology studies, the median time for BuTrans 10

microgram/hour to deliver detectable buprenorphine concentrations (25

picograms/ml) was approximately 17 hours. Analysis of residual buprenorphine in

patches after 7-day use shows 15% of the original load delivered. A study of

bioavailability, relative to intravenous administration, confirms that this amount is

systemically absorbed. Buprenorphine concentrations remain relatively constant

during the 7-day patch application.

Application site

A study in healthy subjects demonstrated that the pharmacokinetic profile of

buprenorphine delivered by BuTrans is similar when applied to upper outer arm,

upper chest, upper back or the side of the chest (midaxillary line, 5th intercostal

space). The absorption varies to some extent depending on the application site and

the exposure is at the most approximately 26 % higher when applied to the upper

back compared to the side of the chest.

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In a study of healthy subjects receiving BuTrans repeatedly to the same site, an

almost doubled exposure was seen with a 14 day rest period. For this reason,

rotation of application sites is recommended, and a new patch should not be applied

to the same skin site for 3-4 weeks.

In a study of healthy subjects, application of a heating pad directly on the

transdermal patch caused a transient 26 - 55% increase in blood concentrations of

buprenorphine. Concentrations returned to normal within 5 hours after the heat was

removed. For this reason, applying direct heat sources such as hot water bottles, heat

pads or electric blankets directly to the patch is not recommended. A heating pad

applied to a BuTrans site immediately after patch removal did not alter absorption

from the skin depot.

Distribution

Buprenorphine is approximately 96% bound to plasma proteins.

Studies of intravenous buprenorphine have shown a large volume of distribution,

implying extensive distribution of buprenorphine. In a study of intravenous

buprenorphine in healthy subjects, the volume of distribution at steady state was 430

l, reflecting the large volume of distribution and lipophilicity of the active substance.

Following intravenous administration, buprenorphine and its metabolites are

secreted into bile, and within several minutes, distributed into the cerebrospinal

fluid. Buprenorphine concentrations in the cerebrospinal fluid appear to be

approximately 15% to 25% of concurrent plasma concentrations.

Biotransformation and elimination

Buprenorphine metabolism in the skin following BuTrans application is negligible.

Following transdermal application, buprenorphine is eliminated via hepatic

metabolism, with subsequent biliary excretion and renal excretion of soluble

metabolites. Hepatic metabolism, through CYP3A4 and UGT1A1/1A3 enzymes,

results in two primary metabolites, norbuprenorphine and buprenorphine

3-O-glucuronide, respectively. Norbuprenorphine is glucuronidated before

elimination. Buprenorphine is also eliminated in the faeces. In a study in

post-operative patients, the total elimination of buprenorphine was shown to be

approximately 55l/h.

Norbuprenorphine is the only known active metabolite of buprenorphine.

Effect of buprenorphine on the pharmacokinetics of other active substances

Based on in vitro studies in human microsomes and hepatocytes, buprenorphine

does not have the potential to inhibit metabolism catalysed by the CYP450 enzymes

CYP1A2, CYP2A6 and CYP3A4 at concentrations obtained with use of BuTrans

20µg/h transdermal patch. The effect on metabolism catalysed by CYP2C8, CYP2C9

and CYP2C19 has not been studied.

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5.3 Preclinical safety data

Reproductive and developmental toxicity

No effect on fertility or general reproductive performance was observed in rats

treated with buprenorphine. In embryofoetal developmental toxicity studies

conducted in rats and rabbits using buprenorphine, no embryofoetal toxicity effects

were observed. In a rat pre- and post-natal developmental toxicity study with

buprenorphine there was pup mortality, decreased pup body weight and

concomitant maternal reduced food consumption and clinical signs.

Genotoxicity

A standard battery of genotoxicity tests indicated that buprenorphine is

non-genotoxic.

Carcinogenicity

In long-term studies in rats and mice there was no evidence of any carcinogenic

potential relevant for humans.

Systemic toxicity and dermal toxicity

In single- and repeat-dose toxicity studies in rats, rabbits, guinea pigs, dogs and

minipigs, BuTrans caused minimal or no adverse systemic events, whereas skin

irritation was observed in all species examined. Toxicological data available did not

indicate a sensitising potential of the additives of the transdermal patches.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Adhesive matrix (containing buprenorphine):

[(Z)-octadec-9-en-1-yl] (Oleyl oleate),

Povidone K90,

4-oxopentanic acid, (Levulinic Acid)

Poly[acrylic acid-co-butylacrylate-co-(2-ethylhexyl)acrylate-co-vinylacetate]

(5:15:75:5), cross

linked (DuroTak 387-2054)

Adhesive matrix (without buprenorphine):

Poly[acrylic acid-co-butylacrylate-co-(2-ethylhexyl) acrylate-co-vinylacetate]

(5:15:75:5), not

cross-linked (DuroTak 387-2051).

Separating foil between the adhesive matrices with and without buprenorphine:

Poly(Ethyleneterephthalate) – foil.

Backing layer:

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Poly(Ethyleneterephthalate) – tissue.

Release liner (on the front covering the adhesive matrix containing buprenorphine)

(to be removed before applying the patch):

Poly(Ethyleneterephthalate) – foil, siliconised, coated on one side with aluminium.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

Sealed child resistant sachet, composed of identical top and bottom layers of

heat-sealable laminate, comprising (from outside to inside) paper, PET,

polyethylene-based copolymer, aluminium and poly(acrylic acid-co-ethylene).

Pack Sizes: 1, 2, 3, 4, 5, 8, 10, 12 transdermal patches.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal of a used medicinal product or waste

materials derived from such medicinal product and other handling of the

product

The patch should not be used if the seal is broken.

Disposal after use:

When changing the patch, the used patch should be removed, the adhesive layer

folded inwards on itself, and the patch disposed of safely and out of sight and reach

of children.

7 MARKETING AUTHORISATION HOLDER

Mundipharma Pharmaceuticals Limited

Millbank House

Arkle Road

Sandyford

Dublin 18

Ireland

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8 MARKETING AUTHORISATION NUMBER

PA1688/002/002

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 24 June 2005

Date of last renewal: 16 July 2008

10 DATE OF REVISION OF THE TEXT

January 2019

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