- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Patients aged 18 years and over:The lowest BuTrans dose (BuTrans 5 μg/h transdermal patch) should be used as the initial dose. Consideration should be given to the previous opioid history of the patient (see section 4.5) as well as to the current general condition and medical status of the patient.
Titration:During initiation and titration with BuTrans, patients should use the usual recommended doses of short-acting supplemental analgesics (see section 4.5) as needed until analgesic efficacy with BuTrans is attained.The dose should not be increased before 3 days, when the maximum effect of a given dose is established. Subsequent dosage increases may then be titrated based on the need for supplemental pain relief and the patient's analgesic response to the patch.To increase the dose, a larger patch should replace the patch that is currently being worn, or a combination of patches should be applied in different places to achieve the desired dose. It is recommended that no more than two patches are applied at the same time, regardless of the patch strength. A new patch should not be applied to the same skin site for the subsequent 3-4 weeks (see section 5.2). Patients should be carefully and regularly monitored to assess the optimum dose and duration of treatment.
Conversion from opioids:BuTrans can be used as an alternative to treatment with other opioids. Such patients should be started on the lowest available dose (BuTrans 5 μg/h transdermal patch) and continue taking short-acting supplemental analgesics (see section 4.5) during titration, as required.
Patients under 18 years of age:As BuTrans has not been studied in patients under 18 years of age the use of BuTrans in patients below this age is not recommended.
Elderly:No dosage adjustment of BuTrans is required in elderly patients.
Renal impairment:No special dose adjustment of BuTrans is necessary in patients with renal impairment.
Hepatic impairment:Buprenorphine is metabolised in the liver. The intensity and duration of its action may be affected in patients with impaired liver function. Therefore patients with hepatic insufficiency should be carefully monitored during treatment with BuTrans.Patients with severe hepatic impairment may accumulate buprenorphine during BuTrans treatment. Consideration of alternate therapy should be considered, and BuTrans should be used with caution, if at all, in such patients.
Patch application:BuTrans should be applied to non-irritated, intact skin of the upper outer arm, upper chest, upper back or the side of the chest, but not to any parts of the skin with large scars. BuTrans should be applied to a relatively hairless or nearly hairless skin site. If none are available, the hair at the site should be cut with scissors, not shaven. If the application site must be cleaned, it should be done with clean water only. Soaps, alcohol, oils, lotions or abrasive devices must not be used. The skin must be dry before the patch is applied. BuTrans should be applied immediately after removal from the sealed sachet. Following removal of the protective layer, the transdermal patch should be pressed firmly in place with the palm of the hand for approximately 30 seconds, making sure the contact is complete, especially around the edges. If the edges of the patch begin to peel off, the edges may be taped down with suitable skin tape.The patch should be worn continuously for 7 days.Bathing, showering, or swimming should not affect the patch. If a patch falls off, a new one should be applied.
Duration of administration:BuTrans should under no circumstances be administered for longer than absolutely necessary. If long-term pain treatment with BuTrans is necessary in view of the nature and severity of the illness, then careful and regular monitoring should be carried out (if necessary with breaks in treatment) to establish whether and to what extent further treatment is necessary.
Discontinuation:After removal of the patch, buprenorphine serum concentrations decrease gradually and thus the analgesic effect is maintained for a certain amount of time. This should be considered when therapy with BuTrans is to be followed by other opioids. As a general rule, a subsequent opioid should not be administered within 24 hours after removal of the patch. At present, only limited information is available on the starting dose of other opioids administered after discontinuation of the transdermal patch (see section 4.5).
Patients with fever or exposed to external heat:While wearing the patch, patients should be advised to avoid exposing the application site to external heat sources, such as heating pads, electric blankets, heat lamps, sauna, hot tubs, and heated water beds, etc., as an increase in absorption of buprenorphine may occur. 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.
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.A drug interaction study with the CYP3A4 inhibitor ketoconazole did not produce clinically relevant increases in mean maximum (Cmax) or total (AUC) buprenorphine exposure following BuTrans with ketoconazole as compared to BuTrans alone.The interaction between buprenorphine and CYP3A4 enzyme inducers has not been studied. Co-administration of BuTrans and enzyme inducers (e.g. phenobarbital, carbamazepine, phenytoin and rifampicin) could lead to increased clearance which might result in reduced efficacy.Reductions in hepatic blood flow induced by some general anaesthetics (e.g. halothane) and other medicinal products may result in a decreased rate of hepatic elimination of buprenorphine.
Pharmacodynamic interactions:BuTrans should be used cautiously with: Benzodiazepines: This combination can potentiate respiratory depression of central origin, with risk of death (see section 4.4). Other central nervous system depressants: other opioid derivatives (analgesics and antitussives containing e.g. morphine, dextropropoxyphene, codeine, dextromethorphan or noscapine). Certain antidepressants, sedative H1-receptor antagonists, alcohol, anxiolytics, neuroleptics, clonidine and related substances. These combinations increase the CNS depressant activity.Buprenorphine is a partial mu-receptor agonist but it is described to function as a pure mu receptor agonist at typical analgesic doses. These doses produce buprenorphine exposures comparable to or greater than those produced by BuTrans 5, 10, and 20 µg/h transdermal patches. In BuTrans clinical studies, where subjects receiving full mu agonist opioids (up to 90 mg oral morphine or oral morphine equivalents per day) were transferred to BuTrans, there were no reports of abstinence syndrome or opioid withdrawal during conversion from entry opioid to BuTrans (see section 4.4).
PregnancyThere are no data from the use of BuTrans in pregnant women. Studies in animals have shown reproductive toxicity (see Section 5.3). The potential risk for humans is unknown.Towards the end of pregnancy high doses of buprenorphine may induce respiratory depression in the neonate even after a short period of administration. Long-term administration of buprenorphine during the last three months of pregnancy may cause a withdrawal syndrome in the neonate. Therefore BuTrans should not be used during pregnancy and in women of childbearing potential who are not using effective contraception.
LactationStudies in rats have shown that buprenorphine may inhibit lactation. Excretion of buprenorphine into the milk in rats has been observed. Data on excretion into human milk are not available. Therefore the use of BuTrans during lactation should be avoided.
|Immune system disorders|
|Very rare:||anaphylactic reaction, anaphylactoid reaction|
|Metabolism and nutrition disorders|
|Common:||confusion, depression, insomnia, nervousness,|
|Uncommon:||sleep disorder, restlessness, agitation, depersonalisation, euphoric mood, affect lability, anxiety, hallucinations, nightmares|
|Rare:||psychotic disorder, decreased libido|
|Very rare:||drug dependence, mood swings|
|Nervous system disorders|
|Very common:||headache, dizziness, somnolence|
|Uncommon:||sedation, dysgeusia, dysarthria, hypoaesthesia, memory impairment, migraine, syncope, tremor, abnormal co-ordination, disturbance in attention|
|Rare:||balance disorder, speech disorder,|
|Very rare:||involuntary muscle contractions|
|Uncommon:||dry eye, blurred vision|
|Rare:||visual disturbance, eyelid oedema, miosis|
|Ear and labyrinth disorders|
|Very rare:||ear pain|
|Uncommon:||angina pectoris, palpitations, tachycardia,|
|Uncommon:||hypotension, circulatory collapse, hypertension, flushing|
|Respiratory, thoracic and mediastinal disorders|
|Uncommon:||asthma aggravated, cough, hypoxia, rhinitis, wheezing, hyperventilation, hiccups|
|Rare:||respiratory depression, respiratory failure|
|Very common:||constipation, dry mouth, nausea, vomiting|
|Common:||abdominal pain, diarrhoea, dyspepsia|
|Rare:||diverticulitis, dysphagia, ileus|
|Skin and subcutaneous tissue disorders|
|Very common:||pruritus, erythema|
|Common:||rash, sweating, exanthema|
|Uncommon:||dry skin, face oedema, urticaria|
|Very rare:||pustules, vesicles|
|Musculoskeletal and connective tissue disorders|
|Uncommon:||muscle cramp, myalgia, muscular weakness, muscle spasms|
|Renal and urinary disorders|
|Uncommon:||urinary retention, micturition disorder|
|Reproductive system and breast disorders|
|Rare:||erectile dysfunction, sexual dysfunction|
|General disorders and administration site conditions|
|Very common:||application site pruritus, application site reaction|
|Common:||tiredness, asthenia, pain, peripheral oedema, application site erythema, application site rash, chest pain|
|Uncommon:||fatigue, influenza like illness, pyrexia, rigors, malaise, oedema, drug withdrawal syndrome|
|Rare:||application site inflammation*|
|Uncommon:||alanine aminotransferase increased, weight decreased|
|Injury, poisoning and procedural complications|
|Uncommon:||accidental injury, fall|
Absorption:Following BuTrans application, buprenorphine diffuses from the patch through the skin. In clinical pharmacology studies, the median time for BuTrans 10 μg/h to deliver detectable buprenorphine concentrations (25 picograms/ml) was approximately 17 hours. Analysis of residual buprenorphine in patches after 7-day use shows 15% of the original load delivered. A study of bioavailability, relative to intravenous administration, confirms that this amount is systemically absorbed. Buprenorphine concentrations remain relatively constant during the 7-day patch application.
Application site:A study in healthy subjects demonstrated that the pharmacokinetic profile of buprenorphine delivered by BuTrans is similar when applied to upper outer arm, upper chest, upper back or the side of the chest (midaxillary line, 5th intercostal space). The absorption varies to some extent depending on the application site and the exposure is at the most approximately 26 % higher when applied to the upper back compared to the side of the chest.In a study of healthy subjects receiving BuTrans repeatedly to the same site, an almost doubled exposure was seen with a 14 day rest period. For this reason, rotation of application sites is recommended, and a new patch should not be applied to the same skin site for 3-4 weeks. In a study of healthy subjects, application of a heating pad directly on the transdermal patch caused a transient 26 - 55% increase in blood concentrations of buprenorphine. Concentrations returned to normal within 5 hours after the heat was removed. For this reason, applying direct heat sources such as hot water bottles, heat pads or electric blankets directly to the patch is not recommended. A heating pad applied to a BuTrans site immediately after patch removal did not alter absorption from the skin depot.
Distribution:Buprenorphine is approximately 96% bound to plasma proteins.Studies of intravenous buprenorphine have shown a large volume of distribution, implying extensive distribution of buprenorphine. In a study of intravenous buprenorphine in healthy subjects, the volume of distribution at steady state was 430 l, reflecting the large volume of distribution and lipophilicity of the active substance.Following intravenous administration, buprenorphine and its metabolites are secreted into bile, and within several minutes, distributed into the cerebrospinal fluid. Buprenorphine concentrations in the cerebrospinal fluid appear to be approximately 15% to 25% of concurrent plasma concentrations.
Biotransformation and elimination:Buprenorphine metabolism in the skin following BuTrans application is negligible. Following transdermal application, buprenorphine is eliminated via hepatic metabolism, with subsequent biliary excretion and renal excretion of soluble metabolites. Hepatic metabolism, through CYP3A4 and UGT1A1/1A3 enzymes, results in two primary metabolites, norbuprenorphine and buprenorphine 3-O-glucuronide, respectively. Norbuprenorphine is glucuronidated before elimination. Buprenorphine is also eliminated in the faeces. In a study in post-operative patients, the total elimination of buprenorphine was shown to be approximately 55l/h.Norbuprenorphine is the only known active metabolite of buprenorphine.
Effect of buprenorphine on the pharmacokinetics of other active substances:Based on in vitro studies in human microsomes and hepatocytes, buprenorphine does not have the potential to inhibit metabolism catalysed by the CYP450 enzymes CYP1A2, CYP2A6 and CYP3A4 at concentrations obtained with use of BuTrans 20µg/h transdermal patch. The effect on metabolism catalysed by CYP2C8, CYP2C9 and CYP2C19 has not been studied.
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.
Napp Pharmaceuticals Limited
Cambridge Science Park, Milton Road, Cambridge, Cambridgeshire, CB4 0GW
+44 (0)1223 424 444