Uses/Indications: Partial opioid agonist. Mod to severe pain
Contraindications: Severe respiratory impairment; nonselective MAOIs (within 14 days of stopping MAOI)
Precautions: Not for narcotic dependence treatment, postop use, situations with a narrow therapeutic index, rapidly varying analgesia need; inflammatory bowel, convulsive disorders; head injury; impaired consciousness (undiagnosed); intracranial lesion; raised ICP; respiratory, hepatic, renal, biliary disease; hypotension, hypovolaemia, shock; pancreatitis; prostatic hypertrophy; adrenocortical insufficiency; debility; 24 hrs prior to pain relieving surgery incl cordotomy; after abdominal surgery; drug, alcohol abuse; serious mental illness; congenital QT prolongation; severe febrile illness; hypothyroidism; withdrawal; narcotic dependence; opioid naive; avoid excess heat to patch site; debility; pregnancy, lactation, children < 18 yrs
Adverse Reactions: Respiratory depression; QT prolongation; euphoria; dependence; GI upset esp constipation; anorexia; sweating; dizziness; headache; somnolence; confusion; pruritus; erythema; rash; application site reaction; anxiety; insomnia; nervousness; paraesthesia; depression; vasodilation; oedema; dyspnoea; taste perversion; asthenia; pain; others, see full PI
Drug Interactions: Nonselective MAOIs (see Contra); selective MAOIs; CNS depressants (eg sedatives, hypnotics, general anaesthetics, other opioids, phenothiazines, centrally acting antiemetics, benzodiazepines, alcohol); drugs that prolong QT (eg antiarrhythmics), cause respiratory depression, hypotension; drugs affecting hepatic metabolism; CYP3A4 inhibitors (eg protease inhibitors, azole antimycotics, Ca channel antagonists, macrolides); enzyme inducers (eg phenobarbitone, carbamazepine, phenytoin, rifampicin); warfarin (poss)
NORSPAN 5 TRANSDERMAL PATCH (Transdermal patch) Prescription required. S8 This product may cause drowsiness.
Buprenorphine (equiv. 5 mcg/hr); gluten free;
Dose: Apply patch every 7 days to intact skin (sites, skin prep, application, removal: see full PI); initially commence with Norspan 5. Titrate; incr at intervals greater than or equal to 3 days as needed by replacing or adding patch (max 2 concurrent patches). Give other analgesics during initiation, titration; change to other analgesic if analgesia inadequate on max Norspan dose. Rotate sites, avoid other opioids 24 hrs after patch removal (see full PI)
Uses/Indications: Partial opioid agonist. Mod to severe pain
Contraindications: Severe respiratory impairment; nonselective MAOIs (within 14 days of stopping MAOI)
Precautions: Not for narcotic dependence treatment, postop use, situations with a narrow therapeutic index, rapidly varying analgesia need; inflammatory bowel, convulsive disorders; head injury; impaired consciousness (undiagnosed); intracranial lesion; raised ICP; respiratory, hepatic, renal, biliary disease; hypotension, hypovolaemia, shock; pancreatitis; prostatic hypertrophy; adrenocortical insufficiency; debility; 24 hrs prior to pain relieving surgery incl cordotomy; after abdominal surgery; drug, alcohol abuse; serious mental illness; congenital QT prolongation; severe febrile illness; hypothyroidism; withdrawal; narcotic dependence; opioid naive; avoid excess heat to patch site; debility; pregnancy, lactation, children < 18 yrs
Adverse Reactions: Respiratory depression; QT prolongation; euphoria; dependence; GI upset esp constipation; anorexia; sweating; dizziness; headache; somnolence; confusion; pruritus; erythema; rash; application site reaction; anxiety; insomnia; nervousness; paraesthesia; depression; vasodilation; oedema; dyspnoea; taste perversion; asthenia; pain; others, see full PI
Drug Interactions: Nonselective MAOIs (see Contra); selective MAOIs; CNS depressants (eg sedatives, hypnotics, general anaesthetics, other opioids, phenothiazines, centrally acting antiemetics, benzodiazepines, alcohol); drugs that prolong QT (eg antiarrhythmics), cause respiratory depression, hypotension; drugs affecting hepatic metabolism; CYP3A4 inhibitors (eg protease inhibitors, azole antimycotics, Ca channel antagonists, macrolides); enzyme inducers (eg phenobarbitone, carbamazepine, phenytoin, rifampicin); warfarin (poss)
NORSPAN 5 TRANSDERMAL PATCH (Transdermal patch) Prescription required. S8 This product may cause drowsiness.
Buprenorphine (equiv. 5 mcg/hr); gluten free;
Dose: Apply patch every 7 days to intact skin (sites, skin prep, application, removal: see full PI); initially commence with Norspan 5. Titrate; incr at intervals greater than or equal to 3 days as needed by replacing or adding patch (max 2 concurrent patches). Give other analgesics during initiation, titration; change to other analgesic if analgesia inadequate on max Norspan dose. Rotate sites, avoid other opioids 24 hrs after patch removal (see full PI)
Chemical name: (2S)-2-[17-(cyclopropylmethyl)- 4, 5alpha-epoxy-3- hydroxy-6-methoxy-6alpha, 14-ethano-14alpha- morphinan-7alpha-yl]-3, 3-dimethylbutan-2-ol. Molecular formula: C29H41NO4. MW: 467.6. CAS: 52485-79-7. 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.
Norspan Transdermal Patch is a rectangular (10 microgram/hour) or square (5 and 20 microgram/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. Please refer to figure 1.
Norspan Transdermal Patch transdermal system is available in three different strengths: 5, 10 and 20 microgram/hour. The composition of all three strengths is identical except for 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 system. The skin is the limiting barrier to diffusion from the system into the bloodstream.
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Pharmacology. Buprenorphine is a partial opioid agonist, acting at the mu-opioid receptor. It also has antagonistic activity at the kappa-opioid receptor. The opioid agonist activities of buprenorphine are dose related.
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 system, and the cardiovascular, 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 hypothalamic pituitary 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 Transdermal Patch application resulted in transient decreases in blood pressure in healthy young and elderly subjects, without clinical adverse events.
Respiratory depression is less common than with full mu agonists, such as morphine, and there appears to be a ceiling effect. When respiratory depression occurs it appears to have a slower onset and longer duration compared to morphine.
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 semisynthetic opioid, has immunological effects similar to morphine.
Buprenorphine can cause dose related miosis and urinary retention in some patients.
Pharmacokinetics. Each Norspan Transdermal Patch provides a steady delivery of buprenorphine for up to seven days. Steady state is achieved by day 3 following the first application. After removal of the Norspan Transdermal Patch, buprenorphine concentrations decline, decreasing approximately 50% in 12 hours (range 10 to 24 hours).
Norspan Transdermal Patch 5, 10 and 20 microgram/hour provide dose proportional increases in total exposure (AUC (area under the curve)) over the seven day application period. Dose proportional increases in plasma concentrations occur at steady state with Norspan Transdermal 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 Transdermal Patch 5 microgram/hour releases buprenorphine 5 microgram per hour and contains a total of buprenorphine 5 mg. Each Norspan Transdermal Patch 10 microgram/hour releases buprenorphine 10 microgram per hour and contains a total of buprenorphine 10 mg. Each Norspan Transdermal Patch 20 microgram/hour releases buprenorphine 20 microgram per hour and contains a total of buprenorphine 20 mg.
Absorption. Following Norspan Transdermal Patch application, buprenorphine diffuses from the patch through the skin. In clinical pharmacology studies, the median time for Norspan Transdermal Patch 10 microgram/hour to deliver detectable buprenorphine concentrations (25 picogram/mL) was approximately 17 hours. The bioavailability of buprenorphine from a Norspan Transdermal Patch relative to IV (intravenous) is 15% (for all three strengths).
Accidental oral ingestion. Measurable systemic levels of buprenorphine were demonstrated in dogs given Norspan Transdermal Patch 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 Transdermal 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 the primary metabolites, norbuprenorphine and buprenorphine 3-O-glucuronide, respectively. Norbuprenorphine is also glucuronidated prior to elimination. Buprenorphine is also eliminated in the faeces within seven days.
In a study in postoperative patients the total clearance of buprenorphine was 55 L/hour.
Norbuprenorphine is the only known active metabolite of buprenorphine. It has been shown to be a respiratory depressant in rats at concentration at least 50-fold those seen following application of Norspan Transdermal Patch 20 microgram/hour.
Specific inhibitors of CYP450 (e.g. ketoconazole, gestodene, nifedipine, norfluoxetine, ritonavir) inhibited formation of the buprenorphine metabolite norbuprenorphine in human microsomes.
Application site. A study in healthy subjects demonstrated that the pharmacokinetic profile of buprenorphine delivered by Norspan Transdermal 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 Transdermal Patch 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 Transdermal 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 Transdermal Patch is not recommended. A heating pad applied to a Norspan Transdermal Patch site directly after patch removal did not alter absorption from the skin depot.
