SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Butec 10 microgram/hour transdermal patch

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each transdermal patch contains 10 mg of buprenorphine in a 12.5 cm² 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 Butec 10 pg/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

Butec is not suitable for the treatment of acute pain.

Butec is indicated in adults.

4.2 Posology and method of administration

Posology

Butec should be administered every 7th day.

Patients aged 18 years and over :

The lowest Butec dose (Butec 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:

During initiation of treatment with Butec, short-acting supplemental analgesics may be required (see section 4.5) as needed until analgesic efficacy with Butec is attained.

The dose of Butec 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 :

Butec can be used as an alternative to treatment with other opioids. Such patients should be started on the lowest available dose (Butec 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 Butec in children below 18 years of age has not been established. No data are available.

Elderly:

No dosage adjustment of Butec is required in elderly patients.

Renal impairment:

No special dose adjustment of Butec 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 Butec.

Patients with severe hepatic impairment may accumulate buprenorphine during Butec treatment. Consideration of alternate therapy should be considered, and Butec should be used with caution, if at all, in such patients.

Method of administration Route of administration

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

Patch application:

Butec 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. Butec 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. Butec 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:

Butec should under no circumstances be administered for longer than absolutely necessary. If long-term pain treatment with Butec 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 Butec 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.

4.3 Contraindications

Butec 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

Butec 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 Butec carefully titrated since a reduced dosage might be sufficient in these patients.

Butec 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 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.

Butec should not be used at higher doses than recommended.

4.5 Interaction with other medicinal products and other forms of interaction

Butec 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 Butec with ketoconazole as compared to Butec alone.

The interaction between buprenorphine and CYP3A4 enzyme inducers has not been studied.

Co-administration of Butec 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:

Butec 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).

At typical analgesic doses buprenorphine is a partial mu-receptor agonist but it is described to function as a pure mu receptor agonist. In Butec clinical studies subjects receiving full mu agonist opioids (up to 90 mg oral morphine or oral morphine equivalents per day) were transferred to Butec. There were no reports of abstinence syndrome or opioid withdrawal during conversion from entry opioid to Butec (see section 4.4).

4.6 Pregnancy and lactation

Pregnancy

There are no data from the use of Butec 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 Butec 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 Butec 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

Butec has a major influence on the ability to drive and use machines. Even when used according to instructions, Butec 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, nor for at least 24 hours after the patch has been removed.

This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

•    The medicine is likely to affect your ability to drive.

•    Do not drive until you know how the medicine affects you.

•    It is an offence to drive while you have this medicine in your body over a specified limit unless you have a defence (called the ‘statutory defence’). This defence applies when:

•    The medicine has been prescribed to treat a medical or dental problem; and

•    You have taken it according to the instructions given by the prescriber and in the information provided with the medicine.

•    Please note that it is still an offence to drive if you are unfit because of the medicine (i.e. your ability to drive is being affected).”

Details regarding a new driving offence concerning driving after drugs have been taken in the UK may be found here: https: //www. gov.uk/drug-driving-law

4.8 Undesirable effects

Serious adverse reactions that may be associated with Butec 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			Hypers ens itivity	Anaphylactic reaction		Anaphylactoid reaction
Metabolic and nutritional disorders		Anorexia		Dehydration
Psychiatric disorders 1		Confusion Depression Insomnia Nervousness Anxiety	Affect liability Sleep disorder Restlessness Agitation Euphoric mood Hallucinations Libido decreased Nightmares Aggression	Psychotic disorder	Drug dependence Mood swings	Depersonalisation
Nervous system disorders	Headache Dizziness	Tremor	Sedation Dysgeusia	Balance disorder Speech disorder	Involuntary muscle	Convulsions

1	Somnolence		Dysarthria Hypoaesthesia Memory impairment Migraine SyncopeCo-ordin		contractions
						, - - -( Deleted:
			ation abnormal Disturbance in attention Paraesthesia
Eve 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 Flushing	Vasodilatation Orthostatic hypotension
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 uridary disorders			Urinary incontinence Urinary retention Urinary hesitation
Reproductive system and breast disorders				Erectile dysfunction Sexual dysfunction
General disorders and administration site conditions	Application site reaction1	Tiredness Asthenic conditions Peripheral oedema	Fatigue Pyrexia Rigors Oedema Drug withdrawal syndrome Application site	Influenza like illness		Drug withdrawal syndrome neonatal

			dermatitis* Chest pain
Investigations			Alanine aminotransferase increased Weight decreased
Injury, poisoning and procedural complications			Accidental injury Fall

Serious adverse reactions that may be associated with Butec 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).

* In some cases delayed local allergic reactions occurred with marked signs of inflammation. In such cases treatment with Butec should be terminated.

¹ Includes application site erythema, application site oedema, application site pruritus, application site rash.

Buprenorphine has a low risk of physical dependence. After discontinuation of Butec, 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 Butec, 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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

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 p-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. Butec 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 5 mg dose, 35% on the 10 mg dose and 48% on the 20 mg 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 Butec, buprenorphine concentrations decline, decreasing approximately 50% in 12 hours (range 10-24 h).

Absorption:

Following Butec application, buprenorphine diffuses from the patch through the skin. In clinical pharmacology studies, the median time for “Butec 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 Butec 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 Butec 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 Butec 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 Butec 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 Butec 20 microgram/hour transdermal patch. The effect on metabolism catalysed by CYP2C8, CYP2C9 and CYP2C19 has not been studied.

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.

Carcinogenicitv

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:

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.

Incompatibilities

Not applicable

Shelf life

2 years

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

Sealed sachet, composed of identical top and bottom layers of heat-sealable laminate, comprising (from outside to inside) paper, LDPE, aluminium and poly(acrylic acid-co-ethylene).

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

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

Qdem Pharmaceuticals Limited Cambridge Science Park Milton Road Cambridge CB4 0AB

United Kingdom

MARKETING AUTHORISATION NUMBER(S)

PL 40431/0025

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

18 June 2015

DATE OF REVISION OF THE TEXT

24/08/2016

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