NAME OF THE MEDICINE

Buprenorphine base (active). The structural formula is:

CAS Registry Number

: 52485-79-7

The inactive ingredients in NORSPAN transdermal drug delivery system (patch) are levulinic acid, oleyl oleate, povidone, Duro Tak 387-2051, Duro Tak 387-2054 and polyethylene terephthalate.

DESCRIPTION

Buprenorphine is a white or almost white powder and is very slightly soluble in water, freely soluble in acetone, soluble in methanol and ether and slightly soluble in cyclohexane. The pKa is 8.5. The chemical name of buprenorphine is (2S)-2-[17-(cyclopropylmethyl)-4, 5a- epoxy-3-hydroxy-6-methoxy-6a, 14-ethano-14a-morphinan-7a-yl]-3, 3-dimethylbutan-2-ol. The molecular weight is 467.6 and the empirical formula is C29H41NO4. NORSPAN patches are either a rectangular (10 micrograms per hour), or square (5 and 20 micrograms per hour), beige-coloured, matrix patch with rounded corners, marked with the trade name and consisting of a protective liner and functional layers. Proceeding from the outer surface towards the surface adhering to the skin, the layers are (1) a beige-coloured web backing layer of polyester material; (2) an adhesive matrix rim without buprenorphine; (3) a separating foil over the adhesive matrix; (4) the buprenorphine-containing adhesive matrix; and (5) a release liner (see Figure 1). Before use the release liner covering the adhesive layer is removed and discarded. NORSPAN patches are available in three strengths: 5 micrograms per hour, 10 micrograms per hour and 20 micrograms per hour. The composition of all three strengths is identical except for patch size. The proportion of buprenorphine in the adhesive matrix is the same in each strength (10% by weight). The amount of buprenorphine released from each system per hour is proportional to the surface area of the patch. The skin is the limiting barrier to diffusion from the system into the bloodstream.

FIGURE 1

Cross section drawing of NORSPAN patch

PHARMACOLOGY

Pharmacodynamics

Buprenorphine is a partial opioid agonist, acting at mu-opioid receptors. The opioid agonist activities are dose related. Buprenorphine also has antagonistic activity at the kappa-opioid receptor. It is classified as a psychotropic substance under international convention. Like other opioid agonists, buprenorphine produces dose-related analgesia, however a ceiling effect to analgesia is well documented. Buprenorphine binds to and dissociates from the mu- receptor slowly, which may account for the prolonged duration of analgesia and, in part, for the limited physical dependence potential observed with the drug. Buprenorphine produces similar effects to other opioids on the central nervous, cardio- vascular, respiratory and gastrointestinal systems, although the intensity and duration of the effects may vary when compared with other opioids. Opioids may also influence the hypothalamic-pituitary-adrenal or -gonadal axes, including an increase in serum prolactin and decreases in plasma cortisol and testosterone, which can manifest in clinical symptoms. Since kappa-receptor agonist activity is related to psychotomimetic and dysphoric effects, buprenorphine is expected to produce fewer psychotomimetic and dysphoric effects than drugs with kappa-agonist activities. Like other opioid agonists, buprenorphine may produce increases in cerebrospinal fluid pressure, cause altered mentation, mental clouding or amnesia. Buprenorphine acts to reduce blood pressure in a manner similar to other opioids. NORSPAN patch application resulted in transient decreases in blood pressure in healthy young and elderly subjects, without clinical adverse events. Like other opioid analgesics, buprenorphine has a potential of respiratory depression. Respiratory depression is less common than with full mu-agonists, such as morphine and there appears to be a ceiling effect. However, evidence suggests that buprenorphine is a partial agonist with respect to its respiratory depressant activity. When respiratory depression occurs it appears to have a slower onset and longer duration compared with morphine. Administration of buprenorphine to persons who are physically dependent on full mu-opioid agonists may precipitate an abstinence syndrome depending on the level of physical dependence, and the timing and dose of buprenorphine. Like other opioids buprenorphine may cause nausea, vomiting, constipation and an increase in biliary tract pressure. Effects on the immune system were seen with natural opioids like morphine in in vitro and animal studies, although the clinical significance of these is unknown. It is not known whether buprenorphine, a semi-synthetic opioid, has immunological effects similar to morphine. Buprenorphine can cause dose-related miosis and urinary retention in some patients.

Pharmacokinetics

Each NORSPAN patch provides a steady delivery of buprenorphine for up to seven days. Steady state is achieved by day three following the first application. After removal of a NORSPAN patch, buprenorphine concentrations decline, decreasing approximately 50% in 12 hours (range 10 to 24 hours). NORSPAN patches 5 micrograms per hour, 10 micrograms per hour and 20 micrograms per hour provide dose-proportional increases in total exposure (AUC) over the seven-day application period. Dose-proportional increases in plasma concentrations occur at steady state with NORSPAN patch application for up to 60 days. Accumulation of plasma buprenorphine did not occur during the 60 days. The rate of buprenorphine release from each patch is proportional to the surface area. Each NORSPAN patch 5 micrograms releases 5 micrograms of buprenorphine per hour, and contains a total of 5 mg of buprenorphine. Each NORSPAN patch 10 micrograms releases 10 micrograms of buprenorphine per hour and contains a total of 10 mg of buprenorphine. Each NORSPAN patch 20 micrograms releases 20 micrograms of buprenorphine per hour and contains a total of 20 mg of buprenorphine.

Absorption

Following NORSPAN patch application, buprenorphine diffuses from the patch through the skin. In clinical pharmacology studies, the median time for NORSPAN patch 10 micrograms to deliver detectable buprenorphine concentrations (25 picograms/mL) was approximately 17 hours. The bioavailability of buprenorphine from a NORSPAN patch relative to IV dosing is 15% (for all three strengths).

Accidental oral ingestion: Measurable systemic levels of buprenorphine were demonstrated in dogs given NORSPAN patches by oral administration.

Distribution:

Buprenorphine is approximately 96% bound to plasma proteins. In a study of IV buprenorphine in healthy subjects, the volume of distribution at steady state was 430 L, which is indicative of the high lipophilicity of the drug. Following IV administration, buprenorphine and its metabolites are secreted into bile, and within several minutes distribute into the cerebrospinal fluid (CSF). CSF concentrations appear to be approximately 15% to 25% of concurrent plasma concentrations.

Metabolism and elimination:

Buprenorphine metabolism in the skin following NORSPAN patch application is negligible. 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; norbuprenorphine is also glucuronidated prior to elimination. Buprenorphine is eliminated in the faeces within seven days. Norbuprenorphine is the only known active metabolite of buprenorphine. It has been shown to be a respiratory depressant in rats at concentrations at least 50-fold those seen following application of NORSPAN patch 20 micrograms per hour. In a study in postoperative patients the total clearance of buprenorphine was 55 L/h.

Application site:

A study in healthy subjects demonstrated that the pharmacokinetic profile of buprenorphine delivered by NORSPAN patch is similar when applied to the upper outer arm, upper chest, upper back or the side of the chest (midaxillary line, 5th intercostal space). In a study of healthy subjects applying NORSPAN patches repeatedly to the same site, immediate reapplication caused increased absorption, without clinical adverse events. For this reason, rotation of application sites is recommended (see DOSAGE AND ADMINISTRATION). In another study in healthy subjects, application of a heating pad directly on the NORSPAN patch caused a transient, 26 to 55% increase in blood concentrations of buprenorphine. Concentrations returned to normal within five hours after the heat was removed. For this reason, applying heat sources such as hot water bottles, heat pads or electric blankets directly to the NORSPAN patch is not recommended. A heating pad applied to a NORSPAN patch site directly after patch removal did not alter absorption from the skin depot.

CLINICAL TRIALS

The safety and efficacy of NORSPAN patches in the management of chronic pain has been studied in 10 clinical trials [1,698 patients treated with NORSPAN patches]. The active and placebo-controlled clinical trials included patients with moderate to severe chronic pain of osteoarthritis, low back and non-cancer pain requiring opioid analgesia. A single trial examined the safety of three doses of NORSPAN patches given for 72 hours to patients following orthopaedic surgery. No trials have been conducted in patients with cancer-related pain.

BUPN.CLIN0001

was a randomised, double-blind, double-dummy, parallel, equivalence study comparing the efficacy and tolerability of NORSPAN patches 5, 10 and 20 mg applied every seven days with sublingual buprenorphine tablets 200 and 400 micrograms [Temgesic] in 238 patients with moderate to severe pain due to osteoarthritis [hip and/or knee, 85% > one year]. Patients were titrated to optimum pain control over 21 days, and continued at this level for 28 days. Paracetamol was permitted for breakthrough pain and all usage recorded. The primary efficacy variable was pain intensity recorded during the

assessment period [Days three and seven, BS-11 scale, refer Table 1]. The Per Protocol (PP) population mean reductions in pain scores ranged from 2.6 to 3.6 across the three daily rating assessments [morning, midday, evening] and the estimated mean difference between both active treatment arms was minimal [range 0.001 to 0.13]. The 95% confidence intervals for the difference between treatments were within the range -1 to 1, compared with the pre- specified equivalence margins of -1.5 to 1.5. This demonstrated equivalent efficacy. At study completion 70% [40/51] of patients on the patch and 75% [42/51] on tablets rated their pain relief as good or very good. Table 1 Pain intensity scores in study BUPN.CLIN0001

There was no difference in escape medication usage and the incidence of discontinuation due to lack of efficacy was similar between the two treatment groups [9% Temgesic vs 14% NORSPAN patch]. The most common adverse events reported were those commonly associated with the use of opioids [nausea, vomiting, dizziness, somnolence, headache and constipation]. BP98-1201 was a randomised, double-blind trial comparing the efficacy and safety of NORSPAN patches 5, 10 and 20 mg, applied every seven days, with hydrocodone/paracetamol [2.5 mg/250 mg] tablets four times a day (qid) in 270 patients with chronic moderate to severe back pain [pain intensity > 5 BS-11 scale], not controlled by non-opioid analgesia alone [ibuprofen 400 mg qid]. Patients were titrated to optimum pain control over 21 days, and continued at this level for 35 days. The primary efficacy variables were average pain intensity [BS-11 scale *] and patient satisfaction with medication over Days 21-56+, refer Table 2. The Intention to Treat (ITT) population mean baseline pain intensity was 7.74 [NORSPAN patch group] compared with 7.65, which reduced through Days 21-56 to 5.96 and 6.04, respectively. The difference [and 95% confidence interval] in average pain intensity between the two treatments was -0.08 [-0.06 to 0.44]. The difference between the two treatments in patient global satisfaction was 0.16 [-0.08 to 0.39]. NORSPAN patches were equally effective as hydrocodone/paracetamol tablets in relieving pain and for patient satisfaction. Table 2 Pain intensity scores in study BP98-1201

The majority of adverse events reported were mild or moderate in severity and were typically associated with opioid therapy. Withdrawals due to lack of efficacy was similar for both groups (15% for NORSPAN patch and 14% for hydrocodone/paracetamol). No changes in laboratory values were considered related to treatment, and no clinically important changes were reported for pulse rate, respiratory rate or physical examinations.

* Pain intensity was assessed by the BS-11 pain scale, an 11-point scale for rating current pain, where 0 = "no pain" and 10 = "pain as bad as you can imagine".

+

Patient global satisfaction with medication was assessed on a 4-point scale, with the question "Rate the study medication you received for pain".

CONTRAINDICATIONS

NORSPAN patches are contraindicated in patients with known hypersensitivity to buprenorphine or any components of the patch, myasthenia gravis, delirium tremens and pregnancy. NORSPAN patches are contraindicated in patients with severely impaired respiratory function and in patients concurrently receiving non-selective monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping treatment with non-selective MAOIs. NORSPAN patches must not be used for the treatment of opioid dependence and opioid withdrawal.

PRECAUTIONS

General

NORSPAN patches 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 and severe hepatic impairment. Buprenorphine may lower the seizure threshold in patients with a history of seizure disorder. Use with caution in patients with hypotension, hypovolaemia, biliary tract disease, pancreatitis, inflammatory bowel disorders, prostatic hypertrophy, adrenocortical insufficiency, chronic renal and hepatic disease and debilitated patients. As with all opioids, a reduction in dosage may be advisable in hypothyroidism.

Use in surgery

NORSPAN patches are 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. As with all opioid preparations, patients who are to undergo cordotomy or other pain-relieving surgical procedures should not use NORSPAN patches for at least 24 hours prior to surgery. NORSPAN patches should be used with caution following abdominal surgery, as opioids are known to impair intestinal motility.

Respiratory depression

Significant respiratory depression has been associated with buprenorphine, particularly by the intravenous route. A number of deaths have occurred when addicts have intravenously abused buprenorphine, usually with benzodiazepines concomitantly. Additionally, overdosage deaths due to ethanol and benzodiazepines in combination with buprenorphine have been reported. Caution should be exercised when prescribing NORSPAN patches to patients known to have, or suspected of having, problems with drug or alcohol abuse or serious mental illness.

Prolongation of QT interval

In a positive-controlled study of the effect of NORSPAN patches on the QTc interval in healthy males, therapeutic dosages (10 micrograms per hour) had no effect on the QTc interval but higher dosages (40 micrograms per hour) were associated with a mean prolongation of the QTc interval of 5.9 ms. This observation should be considered when prescribing NORSPAN patches for patients with congenital QT prolongation and for patients taking antiarrhythmic medications in either Class 1A, Class III or any other medication which prolongs the QT interval (see INTERACTIONS WITH OTHER MEDICINES).

Febrile illness

A kinetic study indicated no alteration of buprenorphine plasma concentrations in subjects with mild fever induced by endotoxin administration. However, because increased blood flow to the skin may enhance absorption, severe febrile illness may increase the rate of buprenorphine absorption from the patch and thus, patients with severe febrile illness should be monitored for side effects and may require dose adjustment.

Drug dependence

Controlled human and animal studies indicate that buprenorphine has a lower dependence liability than pure agonist analgesics. In man 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 personal or family drug or alcohol abuse. Chronic use of buprenorphine can result in the development of physical dependence. Withdrawal (abstinence syndrome), when it occurs, is generally mild, begins after two days and may last up to two weeks.

Use in opioid-dependent patients

Physicians should be careful not to prescribe NORSPAN patches for known or suspected opioid-dependent patients. Administration of buprenorphine to persons who are physically dependent on full u-opioid agonists may precipitate an abstinence syndrome depending on the level of physical dependence, and the timing and dose of buprenorphine.

Opioid-naive patients

The lowest dose available, NORSPAN patch 5 micrograms, should be used as the starting dose in opioid-naive patients.

Renal impairment

No dose adjustment is necessary in patients with renal impairment.

Hepatic impairment

Buprenorphine is metabolised in the liver. No dose adjustment is necessary in patients with mild to moderate hepatic impairment, however, the intensity and duration of its action may be affected in patients with impaired liver function. Patients with severe hepatic impairment may accumulate buprenorphine during NORSPAN patch treatment. Consideration should be given to alternative therapy and NORSPAN patches should be used with caution, if at all, in such patients.

Paediatric use

The safety and efficacy of NORSPAN patches in patients under 18 years of age has not been established.

Driving and operating dangerous machinery

NORSPAN patch has a major influence on the ability to drive and use machines. Even when used according to instructions, buprenorphine may modify patients' reactions to a varying extent depending on the dosage and individual susceptibility such that road safety and the ability to operate machinery may be impaired. This applies particularly in the beginning of treatment, during titration to a higher dose and in conjunction with other centrally acting substances including alcohol, tranquilisers, sedatives and hypnotics. If affected, patients should not drive or operate machinery nor for at least 24 hours after the patch has been removed.

Genotoxicity

Buprenorphine showed no evidence of genotoxic activity in assays for gene mutations (reverse mutations in bacterial cells, forward mutations in mammalian cells and yeast), chromosomal damage (human lymphocytes, mouse micronucleus test, Chinese hamster cell in vivo and in vitro) or gene conversion (yeast). However, in other assays, buprenorphine was positive for frame-shift mutations in Ames test and caused inhibition of normal DNA synthesis and increases in unscheduled DNA synthesis in studies using mouse testes.

Carcinogenicity

The carcinogenic potential of buprenorphine is currently unknown. No carcinogenicity studies of NORSPAN patch have been conducted. No evidence for carcinogenicity due to buprenorphine was noted in lifetime studies in mice at orally administrated ( PO) doses up to 100 mg/kg/day. In rats, however, an increased incidence of testicular tumours was observed at doses greater than 5.5 mg/kg/day. The no-effect level in both studies are at least 80 times greater than the expected daily systemic dose of buprenorphine in humans during treatment with NORSPAN patch 20 mg, on a surface area basis.

Effects on fertility

Reproduction studies of buprenorphine in rats demonstrated no evidence of impaired fertility at daily PO doses up to 80 mg/kg/day or daily subcutaneous (SC) doses up to 5 mg/kg/day. These doses are at least 75 times greater than the expected daily systemic dose of buprenorphine in humans during treatment with NORSPAN patch 20 mg, on a surface area basis.

Use in pregnancy

Australian Categorisation of Medicines in Pregnancy: Category C. Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details. Buprenorphine has been shown to cross the placenta in humans and has been detected in newborn blood, urine and meconium. Opioid analgesics, including buprenorphine, may cause respiratory depression in the newborn infant. Withdrawal symptoms in newborn infants have been reported with prolonged use of this class of drugs. There are no adequate and well- controlled studies of buprenorphine or NORSPAN patches in pregnant women. In pregnant rabbits, buprenorphine produced statistically significant pre-implantation losses at PO doses >= 1 mg/kg/day and post-implantation losses at intravenous (IV) doses >= 0.2 mg/kg/day (drug exposure in animals about 6 times the expected daily systemic dose of buprenorphine in humans during treatment with NORSPAN patch 20 mg, on a surface area basis). Dystocia was noted in pregnant rats treated with intramuscular (IM) buprenorphine doses >= 1 mg/kg/day (approximately 17 times the expected human daily dose during treatment with NORSPAN patch 20 mg). Fertility and peri-and postnatal development studies with buprenorphine in rats showed increases in neonatal mortality after doses of 0.8 mg/kg/day PO, 0.5 mg/kg/day IM or 0.1 mg/kg/day SC (approximately 14, 9 and 1.7 times, respectively, the human daily dose during treatment with NORSPAN patch 20 mg on a mg/m2 basis). No-effect doses for neonatal mortality were not established. Delays in the occurrence of righting reflex and startle response were noted in rat pups at a buprenorphine dose >= 8 mg/kg/day PO (> 100 times the expected human daily dose during treatment with NORSPAN patch 20 mg on a mg/m2 basis). No evidence for teratogenic activity was observed in animal studies at buprenorphine doses ranging from 14 to > 100 times the expected human daily dose during treatment with NORSPAN patch 20 mg, on a surface area basis. No effects on embryofoetal development were noted in studies with topically applied NORSPAN patches in rats and rabbits (systemic exposure to buprenorphine up to about 30 and 6 times, respectively, the expected human daily dose during treatment with NORSPAN patch 20 mg, on a surface area basis). However, systemic absorption was demonstrated only during late gestation in rabbits.

Use in lactation

Animal studies indicate buprenorphine has the potential to inhibit lactation or milk production. Decreases in postnatal survival, growth and development were also observed in animals treated with buprenorphine during lactation. Buprenorphine passes into mother's milk at low concentrations and therefore NORSPAN patches should not be used by breast- feeding women.

Effect on laboratory tests

Increased alanine aminotransferase levels.

INTERACTIONS WITH OTHER MEDICINES

Anti-arrhythmic medications

Higher doses (40 micrograms per hour) of buprenorphine may increase the QTc interval. This should be considered when prescribing NORSPAN patches for patients with congenital QT prolongation or those taking anti-arrhythmic medications in either class IA (e.g. quinidine, procainamide) or in Class III (e.g. amiodarone, sotalol) or any other medication which prolongs the QT interval.

Anti-ulcer medication

In clinical trial patients there were no apparent effects on NORSPAN patch exposure when used concomitantly with various H2-antagonists or proton pump inhibitors.

CNS depressants

NORSPAN patches, like all opioid analgesics, should be used with caution in patients who are currently taking other CNS depressants or other drugs that may cause respiratory depression, hypotension, profound sedation or potentially result in coma. Such agents include sedatives or hypnotics, general anaesthetics, other opioid analgesics, phenothiazines, centrally acting anti-emetics, benzodiazepines and alcohol.

CYP inhibitors and inducers

Buprenorphine is both a substrate for, and an inhibitor of, CYP3A4. Specific inhibitors of CYP3A4 (ketoconazole, ritonavir, indinavir) have been shown to inhibit formation of the buprenorphine metabolite, norbuprenorphine, in human liver microsomes. One drug interaction study with ketoconazole did not produce clinically relevant increases in mean maximum or total buprenorphine exposure; however, caution is advised when NORSPAN patches are administered concurrently with inhibitors of CYP3A4 (e.g. protease inhibitors, some drug classes of azole antimycotics, calcium channel antagonists and macrolide antibiotics) as this might lead to increased levels with increased efficacy of buprenorphine with concomitant increased toxicity. Unlike NORSPAN patches, oral dose buprenorphine-containing formulations refer to an interaction study of buprenorphine with ketoconazole (a potent inhibitor of CYP3A4) that resulted in increased Cmax and AUC of buprenorphine (approximately 50% and 70% respectively) and, to a lesser extent, of norbuprenorphine. Patients should be closely monitored, and may require a dose reduction if combining oral dose buprenorphine-containing formulations with CYP3A4 inhibitors. The interaction between buprenorphine and CYP3A4 enzyme inducers has not been studied; however, co- administration of NORSPAN patches and enzyme inducers (e.g. phenobarbitone, carbamazepine, phenytoin, rifampicin) could lead to increased clearance which might result in reduced efficacy. Buprenorphine has also been shown to be a CYP2D6 inhibitor in vitro.

General anaesthetics

Reductions in hepatic blood flow induced by some general anaesthetics (e.g. halothane) and other drugs may result in a decreased rate of hepatic elimination of buprenorphine.

Monoamine oxidase inhibitors

Non-selective MAOIs intensify the effects of opioid drugs which can cause anxiety, confusion and respiratory depression. NORSPAN patches must not be used concomitantly with non- selective MAOIs or in patients who have received non-selective MAOIs within the previous 14 days. As it is unknown whether there is an interaction between selective MAOIs (e.g. selegiline) and buprenorphine, caution is advised with this drug combination.

Warfarin

The potential exists for international normalized ratio (INR) elevation in patients who are concomitantly taking warfarin. A retrospective safety analysis and benefit-risk assessment was performed evaluating the interaction between buprenorphine and warfarin. The analysis revealed very limited data was available and that there was a more likely interaction between buprenorphine and phenprocoumon than warfarin. However, there is not sufficient information for inclusion of the medicine interaction between buprenorphine and phenprocoumon.

DOSAGE AND ADMINISTRATION

For application to the skin (transdermal use) only over 7 days.

Adults:

The lowest dose, NORSPAN patch 5 micrograms per hour, should be used as the initial dose. Consideration should be given to the previous opioid history of the patient, including opioid tolerance, if any, as well as current general condition and medical status of the patient. No dosage adjustment is necessary in the elderly.

Titration:

During initiation and titration with NORSPAN patch, patients should take the usual recommended doses of short-acting supplemental analgesics as needed until analgesic efficacy with NORSPAN patch is attained. The dose of NORSPAN patch should not be increased at less than 3-day intervals when steady state levels are attained and the maximum effect of a given dose is established. Changes in NORSPAN patch dosage may be individually titrated based on the need for supplemental PRN analgesia and the patient's response to NORSPAN patch. To increase the dose, the patch that is currently being worn should be removed and a higher strength of NORSPAN patch or a combination of patches should be applied at a different skin site to achieve the required dose. A new patch should not be applied to the same skin

site for three to four weeks

. It is recommended that no more than two patches be applied at the same time, regardless of strength.

Patients should be carefully and regularly monitored to assess the optimum dose and duration of treatment. Titration should continue every three to seven days until adequate analgesia and improvement in function is achieved. If adequate pain relief cannot be achieved with maximal doses of NORSPAN patch, the patient should be converted to an around-the-clock strong opioid.

Opioid-naive patients

In situations when it is clinically indicated to initiate opioid therapy with a maintenance (around-the-clock) opioid in an opioid-naive patient, clinical trials have shown that NORSPAN patch is an appropriate opioid product. The lowest dose available (NORSPAN patch 5 micrograms per hour) should be used as the initial dose. If the patient is taking supplemental analgesics, these may be continued on a PRN basis as the dose of NORSPAN patch is adjusted.

Conversion from opioid or fixed-ratio opioid/non-opioid combination drugs

NORSPAN patches have been used as an alternative in patients taking lower doses of opioids (up to 90 mg of oral morphine equivalents a day) and combination analgesics. Such patients should be started on a low dose of NORSPAN patch and continue with the same dose and dosing scheduling of their previous daily regimen during titration.

Children

Use in children is not recommended due to lack of clinical safety and efficacy data in patients under 18 years of age.

Renal and hepatic impairment

No dosage adjustment is required in patients with renal impairment or mild to moderate hepatic impairment. Patients with severe hepatic impairment may accumulate buprenorphine and NORSPAN patch should be used with caution, if at all, in such patients.

Discontinuation

After removal of a NORSPAN patch, buprenorphine serum concentrations decrease gradually, and the analgesic effect is maintained for a certain amount of time. This needs to be considered when use of NORSPAN patch is to be followed by other opioids. As a general rule, a subsequent opioid should not be administered within 24 hours of removal of a NORSPAN patch.

Method of application

NORSPAN patches 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. Application sites should be rotated whenever a patch is replaced or added. Application sites should be re-used at no less than three-week intervals. NORSPAN patches 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 should not be used. The skin should be dry before the patch is applied. NORSPAN patches should be applied immediately after removal from the sealed pouch packaging. Following removal of the release liner, the 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, they 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. While wearing the NORSPAN patch patients should be advised to avoid exposing the application site to direct external heat sources, such as heating pads, electric blankets, heat lamps etc. as an increase in the absorption of buprenorphine may occur. The effects of use in hot tubs and sauna have not been studied. When changing a patch, patients should be instructed to remove the used NORSPAN patch, fold it over on itself (bringing the adhesive sides together) and dispose of safely, out of reach of children.

OVERDOSAGE

Symptoms of overdose

Symptoms similar to other centrally acting analgesics are to be expected and are an extension of the pharmacological actions. These include respiratory depression including apnoea, sedation, drowsiness, nausea, vomiting, cardiovascular collapse and marked miosis although respiratory depression has been absent in some cases of buprenorphine overdosage.

Treatment of overdose

Remove any patch in contact with the patient and dispose of it properly. 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 mu-agonists. Treatment with continuous intravenous naloxone should begin with the usual doses but high doses may be required. The onset of naloxone's effect may be delayed by 30 minutes or more. Please refer to naloxone hydrochloride injection product information for further information. There are literature which suggests that the dose response of buprenorphine-induced respiratory depression to treatment with naloxone is bell shaped with higher doses of naloxone providing less effective treatment of respiratory depression than intermediate ones. Maintenance of adequate ventilation is more important than treatment with naloxone. Please phone the Poisons Information Centre on 13 11 26 for advice on managing overdose.

PRESENTATION AND STORAGE CONDITIONS

Rectangular or square, beige- coloured transdermal matrix patches with rounded corners. Available in three strengths/sizes: NORSPAN(r) patch 5 Each patch releases buprenorphine 5 micrograms per hour The area containing the active substance: 6.25 cm2 Total buprenorphine content: 5 mg NORSPAN(r) patch 10 Each patch releases buprenorphine 10 micrograms per hour The area containing the active substance: 12.5 cm2 Total buprenorphine content: 10 mg NORSPAN(r) patch 20 Each patch releases buprenorphine 20 micrograms per hour The area containing the active substance: 25 cm2 Total buprenorphine content: 20 mg Each NORSPAN(r) patch is printed with the trade name and the strength in blue ink. NORSPAN(r) patch is supplied in cartons containing two individually packaged patches. Store below 25degC.

NAME AND ADDRESS OF THE SPONSOR

Mundipharma Pty Limited ABN 087 081 322 509 50 Bridge Street SYDNEY, NSW 2000 Further information may be obtained from Mundipharma's Medical Information Department 1800 188 009.

POISON SCHEDULE OF THE MEDICINE

S8

DATE OF FIRST INCLUSION IN THE AUSTRALIAN REGISTER OF THERAPEUTIC GOODS (THE ARTG)

9 May 2005

DATE OF MOST RECENT AMENDMENT

18 March 2013 (r): NORSPAN is a Registered Trademark