BuTrans 5 micrograms/hour transdermal patch

Ireland - English - HPRA (Health Products Regulatory Authority)

Buy It Now

Active ingredient:
Buprenorphine
Available from:
Imbat Limited
ATC code:
N02AE; N02AE01
INN (International Name):
Buprenorphine
Dosage:
5 Microgram per hour
Pharmaceutical form:
Transdermal patch
Prescription type:
Product subject to prescription which may not be renewed (A)
Therapeutic area:
Oripavine derivatives; buprenorphine
Authorization status:
Authorised
Authorization number:
PPA1151/194/001
Authorization date:
2013-03-15

Page 1 of 2

PACKAGE LEAFLET: INFORMATION FOR THE USER

BuTrans

®

5 micrograms/hour

Transdermal Patch

(buprenorphine)

Your medicine is available using the name BuTrans 5 micrograms/

hour

Transdermal Patch but will be

referred to as BuTrans patches throughout this leaflet.

Read all of this leaflet carefully before you start using this medicine.

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

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

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

their symptoms are the same as yours.

If any of the side effects become serious, or if you notice any side effects not listed in this leaflet,

please tell your doctor or pharmacist.

In this leaflet:

1.

What BuTrans patches are and what they are used for

2.

Before you use BuTrans patches

3.

How to use BuTrans patches

4.

Possible side effects

5.

How to store BuTrans patches

6.

Further 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.

BEFORE YOU USE BUTRANS PATCHES

Do not use BuTrans patches:

if you are allergic (hypersensitive) to buprenorphine or any of the other ingredients of BuTrans

patches;

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

tranylcypromide, phenelzine, isocarboxazid, moclobamide 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.

Take special care with BuTrans patches

Before treatment with BuTrans patches tell your doctor or pharmacist:

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;

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.

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,

including medicines obtained without a prescription. If you use BuTrans patches with some other

medicines, the effect of BuTrans patches or the other medicine may be changed.

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

oxidase inhibitor (examples include tranylcypromide, phenelzine, isocarboxazid, moclobamide 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 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 not be used together with benzodiazepines (medicines used to treat anxiety

or to help you sleep). This combination may cause serious breathing problems which may be fatal.

Using BuTrans patches with 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 and breast-feeding

You should not use BuTrans patches if you are pregnant, likely to become pregnant or are breast-

feeding.

Ask your doctor or pharmacist for advice before taking any medicines.

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 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

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

BuTrans patch will suit you best. During treatment, your doctor may change the patch you use to a

smaller or larger one if necessary. You should not apply more than two patches at the same

time, regardless of the patch strength.

Always use the BuTrans patch exactly as your doctor has told you. You should check with your doctor

or pharmacist if you are not sure.

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

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

tearing where indicated. 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.

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.

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).

Page 2 of 2

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 reach and sight 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.

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, dry mouth, feeling or actually being sick.

Itching, redness, itching at application site.

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

Loss of appetite.

Confusion, depression, difficulty in sleeping, nervousness.

Tingling or numbness.

Flushing of the skin.

Shortness of breath.

Abdominal pain or discomfort, diarrhoea, indigestion.

Sweating, rash, skin eruptions.

Tiredness, a feeling of unusual weakness, muscle weakness, pain, chest pain, swelling of hands,

ankles or feet, redness or rash at the application site.

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

Dehydration.

Mood swings, restlessness, agitation, anxiety, feeling detached from oneself, a feeling of extreme

happiness, hallucinations, nightmares.

Changes in taste, difficulty in speaking, reduced sensitivity to pain or touch, loss of memory,

migraine, fainting, shaking, 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, angina (severe chest pain associated with heart disease), fast or

irregular heart beat.

Worsening of breathing problems associated with asthma, cough, hiccups, over breathing, reduced

oxygen in the blood, runny nose, wheezing.

Wind.

Weight loss.

Dry skin, swelling of the face.

Muscle cramps, spasms, aches and pains.

Difficulty in passing urine.

A flu like illness, high temperature, shivering, generally feeling unwell.

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)

Decreased sexual drive, mental disorder.

Difficulties with balance.

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

Difficulty in breathing.

Diverticulitis (inflammation of the intestine), difficulty in swallowing.

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

Decreased erection, sexual dysfunction.

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

Muscle twitching.

Ear pain.

Blisters.

If any of the side effects become serious, or if you notice any side effects not listed in this

leaflet, please tell your doctor or pharmacist.

5.

HOW TO STORE BUTRANS PATCHES

Keep 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 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.

If your medicine appears to be discoloured or shows any other signs of deterioration, please return to

your pharmacist who will advise you further.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to

dispose of medicines no longer required. These measures will help to protect the environment.

6.

FURTHER INFORMATION

What BuTrans patches contain

The active ingredient is buprenorphine.

One transdermal patch (active surface area 6.25cm

contains 5mg of buprenorphine and releases

5 micrograms/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

BuTrans are square, beige coloured patches with rounded corners marked BuTrans

5 mg 5 μg/h.

BuTrans patches are available in packs containing 2 or 4 patches.

Manufacturer

BuTrans patches are manufactured by:

Bard Pharmaceuticals Limited, Cambridge Science Park, Milton Road, Cambridge, CB4 0GW, UK

Mundipharma DC B.V., De Wel 20, 3871 MV Hoevalaken, The Netherlands.

Procured from within the EU by the PPA holder:

Imbat Ltd., Unit L2, North Ring Business Park, Santry, Dublin 9.

Repackaged by: Doncaster Pharmaceuticals Group Ltd., Kirk Sandall, Doncaster, DN3 1QR, UK.

Distributed by: Eurodrug Ltd., Santry, Dublin 9.

PPA No: 1151/194/1

Leaflet revision and issue dated (ref): 17.04.14

BuTrans

is a registered trademark of Mundipharma AG.

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

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

BuTrans 5 micrograms/hour transdermal patch

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

5 µg/h transdermal patch contains: 5 mg buprenorphine

Area containing active substance: 6.25 cm

Nominal release rate:

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

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Transdermal patch.

Product imported from: UK

Square, beige coloured patch with rounded corners marked: BuTrans

5 mg 5 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.

4.2 Posology and method of administration

BuTrans should be administered every 7th day.

Patients aged 18 years and over:

The lowest BuTrans dose (BuTrans 5 µg/h 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:

During initiation and titration with BuTrans, patients should use the usual recommended doses of short-acting

supplemental analgesics (see section 4.5) as needed until analgesic efficacy with BuTrans is attained.

The dose should not be increased before 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, regardless of the patch strength.

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.

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

section 4.5) during titration, as required.

Patients under 18 years of age:

As BuTrans has not been studied in patients under 18 years of age the use of BuTrans in patients below this age is not

recommended.

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.

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.

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.

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.

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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.

4.3 Contraindications

BuTrans is contra-indicated in:

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 convulsive disorders,

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).

Significant

respiratory depression has been associated with buprenorphine,

particularly by the intravenous route.

number

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.

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 have,

or suspected of

having, a history of drug abuse.

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.

4.5 Interaction with other medicinal products and other forms of interaction

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.

aA drug interaction study 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.

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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:

Benzodiazepines:

This combination can potentiate respiratory depression of

central

origin,

with risk of

death (see

section 4.4).

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.

Buprenorphine is a partial mu-receptor agonist but it is described to function as a pure mu receptor agonist at typical

analgesic doses.

These doses produce buprenorphine exposures comparable to or

greater

than those produced by

BuTrans 5, 10, and 20 µg/h transdermal patches.

In BuTrans clinical studies, where 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. Long-term administration of buprenorphine during the last three months of pregnancy

may cause a withdrawal syndrome in the neonate.

Therefore BuTrans should not

be used during pregnancy and in women of childbearing potential

who are not

using

effective contraception.

Lactation

Studies in rats have shown that buprenorphine may inhibit lactation.

Excretion of buprenorphine into the milk in rats

has been observed. Data on excretion into human milk are not available. Therefore the use of BuTrans during lactation

should be avoided.

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.

In patients who are affected, such as during treatment initiation or titration to a higher dose, these patients should not

drive or use machines, not for at least 24 hours after the patch has been removed.

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).

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Immune system disorders

Uncommon:

hypersensitivity

Very rare:

anaphylactic reaction, anaphylactoid

reaction

Metabolism and nutrition disorders

Common:

anorexia

Uncommon:

dehydration

Psychiatric disorders

Common:

confusion, depression, insomnia,

nervousness,

Uncommon:

sleep disorder, restlessness, agitation,

depersonalisation, euphoric mood,

affect lability, anxiety, hallucinations,

nightmares

Rare:

psychotic disorder, decreased libido

Very rare:

drug dependence, mood swings

Nervous system disorders

Very common:

headache, dizziness, somnolence

Common:

paraesthesia

Uncommon:

sedation, dysgeusia, dysarthria,

hypoaesthesia, memory impairment,

migraine, syncope, tremor, abnormal

co-ordination, disturbance in attention

Rare:

balance disorder, speech disorder,

Very rare:

involuntary muscle contractions

Eye disorders

Uncommon:

dry eye, blurred vision

Rare:

visual disturbance, eyelid oedema,

miosis

Ear and labyrinth disorders

Uncommon:

tinnitus, vertigo

Very rare:

ear pain

Cardiac/disorders

Uncommon:

angina pectoris, palpitations,

tachycardia

Vascular disorders

Common:

vasodilatation

Uncommon:

hypotension, circulatory collapse,

hypertension, flushing

Respiratory, thoracic and mediastinal disorders

Common:

dyspnoea

Uncommon:

asthma aggravated, cough, hypoxia,

rhinitis, wheezing, hyperventilation,

hiccups

Rare:

respiratory depression, respiratory

failure

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

In such cases treatment

with BuTrans should be terminated.

Buprenorphine has a low risk of physical dependence. After discontinuation of BuTrans withdrawal symptoms are

unlikely.

This may be due to the very slow 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.

Gastrointestinal disorders

Very common:

constipation, dry mouth, nausea,

vomiting

Common:

abdominal pain, diarrhoea, dyspepsia

Uncommon:

flatulence

Rare:

diverticulitis, dysphagia, ileus

Hepatobiliary disorders

Rare:

biliary colic

Skin and subcutaneous tissue disorders

Very common:

pruritus, erythema

Common:

rash, sweating, exanthema

Uncommon:

dry skin, face oedema, urticaria

Very rare:

pustules, vesicles

Musculoskeletal and connective tissue disorders

Uncommon:

muscle cramp, myalgia, muscular

weakness, muscle spasms

Renal and urinary disorders

Uncommon:

urinary retention, micturition disorder

Reproductive system and breast disorders

Rare:

erectile dysfunction, sexual dysfunction

General disorders and administration site conditions

Very common:

application site pruritus, application site

reaction

Common:

tiredness, asthenia, pain, peripheral

oedema, application site erythema,

application site rash, chest pain

Uncommon:

fatigue, influenza like illness, pyrexia,

rigors, malaise, oedema, drug

withdrawal syndrome

Rare:

application site inflammation*

Investigations:

Uncommon:

alanine aminotransferase increased,

weight decreased

Injury, poisoning and procedural complications

Uncommon:

accidental injury, fall

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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. The dose of naloxone may be

in the range 5 to 12 mg intravenously.

The onset

of the naloxone effect

may be delayed by 30 minutes or more.

Maintenance of adequate ventilation is more important than treatment with naloxone.

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 five 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 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 µg/h” 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.

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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.

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.

5.3 Preclinical safety data

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.

No teratogenic effects were

observed in rats

rabbits.

However,

perinatal

mortality was

reported in the

literature

rats

treated with

buprenorphine.

A standard battery of genotoxicity tests indicated that buprenorphine is non-genotoxic.

In long-term studies in rats and mice there was no evidence of any carcinogenic potential relevant for humans.

Toxicological data available did not indicate a sensitising potential of the additives of the transdermal patches.

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6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Polyacrylate (Durotak 387-2051 & 387-2054)

Levulinic acid

Oleyl Oleate

Povidone

Polyethylenterephthalate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

The shelf

life expiry date of this product shall be the date shown on the pouches and outer carton of the product as

marketed in the country of origin.

6.4 Special precautions for storage

Do not store above 25

6.5 Nature and contents of container

Cardboard outer containing 2 or 4 sealed pouches.

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 PARALLEL PRODUCT AUTHORISATION HOLDER

Imbat Limited

Unit L2, North Ring Business Park

Santry

Dublin 9

8 PARALLEL PRODUCT AUTHORISATION NUMBER

PPA 1151/194/001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 15th March 2013

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10 DATE OF REVISION OF THE TEXT

May 2014

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