SUMMARY OF PRODUCT CHARACTERISTICS, LABELLING AND PACKAGE LEAFLET

Transcription

1 SUMMARY OF PRODUCT CHARACTERISTICS, LABELLING AND PACKAGE LEAFLET 1 DK/H/718/ /MR

2 SUMMARY OF PRODUCT CHARACTERISTICS 2

3 1. NAME OF THE MEDICINAL PRODUCT Norspan 5 microgram/hour, 10 microgram/hour and 20 microgram/hour transdermal patch. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Norspan 5 microgram/hour Each transdermal patch contains 5 mg of buprenorphine in a 6.25 cm 2 area releasing a nominal 5 micrograms of buprenorphine per hour over a period of 7 days. Norspan 10 microgram/hour Each transdermal patch contains 10 mg of buprenorphine in a 12.5 cm 2 area releasing a nominal 10 micrograms of buprenorphine per hour over a period of 7 days. Norspan 20 microgram/hour Each transdermal patch contains 20 mg of buprenorphine in a 25 cm 2 area releasing a nominal 20 micrograms of buprenorphine per hour over a period of 7 days. For the full list of excipients, see section PHARMACEUTICAL FORM Transdermal patch. Beige coloured patch with rounded corners. Square patch marked Norspan 5 μg/h Rectangular patch marked Norspan 10 μg/h Square patch marked Norspan 20 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. Norspan is not suitable for the treatment of acute pain. Norspan is indicated in adults. 4.2 Posology and method of administration Posology Norspan should be administered every 7th day. Patients aged 18 years and over The lowest Norspan dose (Norspan 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. 3

4 Titration During initiation of treatment with Norspan, short-acting supplemental analgesics may be required (see section 4.5) as needed until analgesic efficacy with Norspan is attained. The dose of Norspan 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 Norspan. 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 Norspan can be used as an alternative to treatment with other opioids. Such patients should be started on the lowest available dose (Norspan 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 Norspan in children below 18 years of age has not been established. No data are available. Elderly No dosage adjustment of Norspan is required in elderly patients. Renal impairment No special dose adjustment of Norspan 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 Norspan. Patients with severe hepatic impairment may accumulate buprenorphine during Norspan treatment. Consideration of alternate therapy should be considered, and Norspan 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 Norspan 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. Norspan should be applied to a relatively 4

5 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. Norspan 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 Norspan should under no circumstances be administered for longer than absolutely necessary. If long-term pain treatment with Norspan 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 Norspan 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 Norspan is contraindicated 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 Norspan 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). 5

6 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 Norspan carefully titrated since a reduced dosage might be sufficient in these patients. Norspan 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. Norspan should not be used at higher doses than recommended. 4.5 Interaction with other medicinal products and other forms of interaction Norspan 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 (C max ) or total (AUC) buprenorphine exposure following Norspan with ketoconazole as compared to Norspan alone. The interaction between buprenorphine and CYP3A4 enzyme inducers has not been studied. Co-administration of Norspan 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 Norspan 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, 6

7 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 described to function as a pure mu receptor agonist. In Norspan clinical studies subjects receiving full mu agonist opioids (up to 90 mg oral morphine or oral morphine equivalents per day) were transferred to Norspan. There were no reports of abstinence syndrome or opioid withdrawal during conversion from entry opioid to Norspan (see section 4.4). 4.6 Fertility, pregnancy and lactation Pregnancy There are no or limited amounts of data from the use of Norspan 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 Norspan 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 in milk (see section 5.3). Therefore the use of Norspan 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 Norspan has a major influence on the ability to drive and use machines. Even when used according to instructions, Norspan 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. 4.8 Undesirable effects Serious adverse reactions that may be associated with Norspan 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). 7

8 System organ class MedDRA Immune system disorders Metabolic and nutritional disorders Psychiatric disorders Nervous system disorders Eye disorders Ear and labyrinth disorders Very common ( 1/10) Headache Dizziness Somnolence Common ( 1/100, <1/10) Anorexia Confusion Depression Insomnia Nervousness Anxiety Tremor Uncommon ( 1/1000, <1/100) Rare ( 1/10,000, <1/1000) Hypersensitivity Anaphylactic reaction Affect lability Sleep disorder Restlessness Agitation Euphoric mood Hallucinations Libido decreased Nightmares Aggression Sedation Dysgeusia Dysarthria Hypoaesthesia Memory impairment Migraine Syncope Coordination abnormal Disturbance in attention Paraesthesia Dry eye Blurred vision Tinnitus Vertigo Dehydration Psychotic disorder Balance disorder Speech disorder Visual disturbance Eyelid oedema Miosis Very rare (<1/10,000) Drug dependence Mood swings Involuntary muscle contractions Ear pain Not known (cannot be estimated from the available data) Anaphylactoi d reaction Depersonalis ation Seizures Cardiac disorders Vascular disorders Respiratory, thoracic and Dyspnoea Palpitations Tachycardia Hypotension Circulatory collapse Hypertension Flushing Cough Wheezing Angina pectoris Vasodilatation Orthostatic hypotension Respiratory depression 8

9 mediastinal disorders Hiccups Respiratory failure Asthma aggravated Hyperventilatio n Rhinitis Gastrointestin al disorders Constipation Nausea Vomiting Abdominal pain Diarrhoea Dyspepsia Dry mouth Flatulence Dysphagia Ileus Diverticulitis Hepatobiliary disorders Skin and subcutaneous tissue disorders Musculoskele tal and connective tissue disorders Pruritus Erythema Rash Sweating Exanthema Muscular weakness Dry skin Urticaria Dermatitis contact Myalgia Muscle spasms Face oedema Pustules Vesicles Biliary colic Renal and urinary disorders Reproductive system and breast disorders General disorders and administration site conditions Application site reaction 1 Tiredness Asthenic conditions Peripheral oedema Urinary incontinence Urinary retention Urinary hesitation Fatigue Pyrexia Rigors Oedema Drug withdrawal syndrome Application site dermatitis* Chest pain Erectile dysfunction Sexual dysfunction Influenza like illness Drug withdrawal syndrome neonatal Investigations Alanine aminotransfera se increased Weight 9

10 Injury, poisoning and procedural complications decreased Accidental injury Fall * In some cases delayed local allergic reactions occurred with marked signs of inflammation. In such cases treatment with Norspan 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 Norspan, 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 Norspan, 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 national reporting system listed in Appendix V. 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. Norspan demonstrated clinically significant reductions in pain scores (approximately 3 points on the BS- 11 scale) and significantly greater pain control compared with placebo. 10

11 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 Norspan, buprenorphine concentrations decline, decreasing approximately 50% in 12 hours (range h). Absorption Following Norspan application, buprenorphine diffuses from the patch through the skin. In clinical pharmacology studies, the median time for Norspan 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 Norspan 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 Norspan 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 Norspan 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 11

12 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 Norspan 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 55 l/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 Norspan 20 µg/h 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. 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, Norspan 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): 12

13 [(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 ) Adhesive matrix (without buprenorphine): Poly[acrylic acid-co-butylacrylate-co-(2-ethylhexyl) acrylate-co-vinylacetate] (5:15:75:5), not cross-linked (DuroTak ). 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. 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 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, 12 transdermal patches. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling 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 13

14 8. MARKETING AUTHORISATION NUMBER(S) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 10. DATE OF REVISION OF THE TEXT 14

15 LABELLING 15

16 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Norspan 5 microgram/hour Transdermal patch Buprenorphine 2. STATEMENT OF ACTIVE SUBSTANCE(S) One transdermal patch (active surface area 6.25 cm 2 ) contains 5 mg of buprenorphine and releases 5 micrograms/hour over a period of 7 days. 3. LIST OF EXCIPIENTS Polyacrylate, Levulinic acid, Oleyl oleate, Povidone, Polyethyleneterephthalate 4. PHARMACEUTICAL FORM AND CONTENTS Transdermal patch <1,2,3,4,5,8,10 or 12> patches 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. For use on the skin. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Do not use if the pouch seal is broken. 8. EXPIRY DATE Expiry date (month/year): 16

17 9. SPECIAL STORAGE CONDITIONS Do not store above 25 C 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 12. MARKETING AUTHORISATION NUMBER(S) 13. BATCH NUMBER Batch No. 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Norspan 5 <unit> 17

18 PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING POUCH 1. NAME OF THE MEDICINAL PRODUCT Norspan 5 microgram/hour Transdermal patch Buprenorphine 2. STATEMENT OF ACTIVE SUBSTANCE(S) One transdermal patch contains 5 mg of buprenorphine. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 1 transdermal patch 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. For use on the skin. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE Expiry date (month/year): 9. SPECIAL STORAGE CONDITIONS Do not store above 25 C 18

19 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 12. MARKETING AUTHORISATION NUMBER(S) 13. BATCH NUMBER Batch No. 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE 19

20 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Norspan 10 microgram/hour Transdermal patch Buprenorphine 2. STATEMENT OF ACTIVE SUBSTANCE(S) One transdermal patch (active surface area 12.5 cm 2 ) contains 10 mg of buprenorphine and releases 10 micrograms/hour over a period of 7 days. 3. LIST OF EXCIPIENTS Polyacrylate, Levulinic acid, Oleyl oleate, Povidone, Polyethyleneterephthalate 4. PHARMACEUTICAL FORM AND CONTENTS Transdermal patch <1,2,3,4,5,8,10 or 12> patches 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. For use on the skin. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Do not use if the pouch seal is broken. 8. EXPIRY DATE Expiry date (month/year): 20

21 9. SPECIAL STORAGE CONDITIONS Do not store above 25 C 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 12. MARKETING AUTHORISATION NUMBER(S) 13. BATCH NUMBER Batch No. 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Norspan 10 <unit> 21

22 PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING POUCH 1. NAME OF THE MEDICINAL PRODUCT Norspan 10 microgram/hour Transdermal patch Buprenorphine 2. STATEMENT OF ACTIVE SUBSTANCE(S) One transdermal patch contains 10 mg of buprenorphine. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 1 transdermal patch 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. For use on the skin. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE Expiry date (month/year): 9. SPECIAL STORAGE CONDITIONS Do not store above 25 C 22

23 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 12. MARKETING AUTHORISATION NUMBER(S) 13. BATCH NUMBER Batch No. 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE 23

24 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Norspan 20 microgram/hour Transdermal patch Buprenorphine 2. STATEMENT OF ACTIVE SUBSTANCE(S) One transdermal patch (active surface area 25 cm 2 ) contains 20 mg of buprenorphine and releases 20 micrograms/hour over a period of 7 days. 3. LIST OF EXCIPIENTS Polyacrylate, Levulinic acid, Oleyl oleate, Povidone, Polyethyleneterephthalate 4. PHARMACEUTICAL FORM AND CONTENTS Transdermal patch <1,2,3,4,5,8,10 or 12> patches 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. For use on the skin. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Do not use if the pouch seal is broken. 8. EXPIRY DATE Expiry date (month/year): 24

25 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 12. MARKETING AUTHORISATION NUMBER(S) 13. BATCH NUMBER Batch No. 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Norspan 20 <unit> 25

26 PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING POUCH 1. NAME OF THE MEDICINAL PRODUCT Norspan 20 microgram/hour Transdermal patch Buprenorphine 2. STATEMENT OF ACTIVE SUBSTANCE(S) One transdermal patch contains 20 mg of buprenorphine. 3. LIST OF EXCIPIENTS 4. PHARMACEUTICAL FORM AND CONTENTS 1 transdermal patch 5. METHOD AND ROUTE(S) OF ADMINISTRATION Read the package leaflet before use. For use on the skin. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE Expiry date (month/year): 9. SPECIAL STORAGE CONDITIONS Do not store above 25 C 26

27 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 12. MARKETING AUTHORISATION NUMBER(S) 13. BATCH NUMBER Batch No. 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE 27

28 PACKAGE LEAFLET 28

29 Package leaflet: Information for the patient Norspan 5 microgram/hour transdermal patches Norspan 10 microgram/hour transdermal patches Norspan 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: 1. What Norspan patches are and what they are used for 2. What you need to know before you use Norspan patches 3. How to use Norspan patches 4. Possible side effects 5. How to store Norspan patches 6. Contents of the pack and other information 1. What Norspan patches are and what they are used for Norspan 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, longlasting pain that requires the use of a strong painkiller. Norspan patches should not be used to relieve acute pain. Norspan 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 Norspan patches Do not use Norspan patches: if you are allergic to buprenorphine or any of the other ingredients of this medicine (listed 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. Norspan patches must not be used to treat symptoms associated with drug withdrawal. 29

30 Warnings and precautions Talk to your doctor, pharmacist or nurse before using Norspan 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 Norspan patches Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Norspan 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 Norspan patches may be reduced. Norspan 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. Norspan 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 Norspan 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 Norspan patches. Drinking alcohol whilst using Norspan patches may also affect your reaction time. Pregnancy, breast-feeding and fertility You should not use Norspan 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 30

31 Norspan 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 Norspan patches, or for 24 hours after removing the patch. 3. How to use Norspan 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. Three different strengths of Norspan patches are available. Your doctor will decide which strength of Norspan patch will suit you best. When people first start using Norspan, 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 Norspan 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. 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 Norspan 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 Norspan 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 Norspan 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 Norspan patch may be affected and your doctor will therefore check on you more closely. Before applying the Norspan patch 31

32 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 Norspan 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 Norspan 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. 32

33 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 Norspan 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 Norspan patches below). If you feel that the effect of the Norspan patch is too weak or too strong, talk to your doctor or pharmacist. If you use more Norspan 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 Norspan 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 Norspan patches If you stop using Norspan 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 Norspan 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 Norspan 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, Norspan patches can cause side effects, although not everybody gets them. 33

34 Serious side effects that may be associated with Norspan 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 Norspan patches. In patients treated with Norspan 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 Norspan patches. If you need to have blood tests remind your doctor that you are using Norspan patches. This is important because Norspan 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. 34

35 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 Norspan 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 the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Norspan patches Keep this medicine out of the sight and reach of children. Do not use Norspan 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 Norspan 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 35