Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Sandoz Limited, Park View, Riverside Way, Watchmoor Park, Camberley, Surrey, GU15 3YL, United Kingdom
Buprenorphine transdermal patches should be used with particular caution in patients with acute alcohol intoxication, head injury, shock, a reduced level of consciousness of uncertain origin, intracranial lesions or increased intracranial pressure, or in patients with severe hepatic impairment (see section 4.2).
Buprenorphine may lower the seizure threshold in patients with a history of seizure disorder.
Significant respiratory depression has been associated with buprenorphine, particularly by the intravenous route. A number of overdose deaths have occurred when addicts have intravenously abused buprenorphine, usually with benzodiazepines concomitantly. Additional overdose deaths due to ethanol and benzodiazepines in combination with buprenorphine have been reported (see section 4.5).
Concomitant use of buprenorphine and sedative medicinal products such as benzodiazepines or related medicinal products may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicinal products should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe buprenorphine concomitantly with sedative medicinal products, the lowest effective dose should be used, and the duration of treatment should be as short as possible.
The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).
Concomitant administration of buprenorphine and other serotonergic agents, such as selective serotonin re-uptake inhibitors (SSRIs), serotonin norepinephrine re-uptake inhibitors (SNRIs) or tricyclic antidepressants may result in serotonin syndrome, a potentially life-threatening condition (see section 4.5).
If concomitant treatment with other serotonergic agents is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.
Symptoms of serotonin syndrome may include mental-status changes, autonomic instability, neuromuscular abnormalities, and/or gastrointestinal symptoms.
If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy should be considered depending on the severity of the symptoms.
Buprenorphine transdermal 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.
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 medicinal 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.
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.
Buprenorphine transdermal patches should not be used at higher doses than recommended.
While wearing the transdermal 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.
Athletes must be aware that this medicinal product may cause a positive reaction to sports doping control tests. Use of Reletrans as a doping agent may become a health hazard.
Buprenorphine transdermal patches must not be used concomitantly with MAOIs or in patients who have received MAOIs within the previous two weeks (see section 4.3).
Buprenorphine is primarily metabolised by glucuronidation and to a lesser extent (about 30%) by CYP3A4. Concomitant treatment with CYP3A4 inhibitors may lead to elevated plasma concentrations with intensified efficacy of buprenorphine.
Studies with the CYP3A4 inhibitor ketoconazole did not produce clinically relevant increases in mean maximum (Cmax) or total (AUC) buprenorphine exposure following use of buprenorphine transdermal patches with ketoconazole as compared to buprenorphine transdermal patches alone.
The interaction between buprenorphine and CYP3A4 enzyme inducers has not been studied. Co-administration of buprenorphine transdermal patches 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.
Reletrans should be used cautiously when co-administered with:
At typical analgesic doses buprenorphine is described to function as a pure mu receptor agonist. In buprenorphine transdermal patch clinical studies subjects receiving full mu agonist opioids (up to 90 mg oral morphine or oral morphine equivalents per day) were transferred to buprenorphine transdermal patches. There were no reports of abstinence syndrome or opioid withdrawal during conversion from entry opioid to buprenorphine transdermal patches (see section 4.4).
There are no or limited amounts of data from the use of buprenorphine transdermal patches 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 newborn infant even after a short period of administration. Prolonged use of buprenorphine during pregnancy can result in neonatal opioid withdrawal syndrome. Therefore, Reletrans should not be used during pregnancy and in women of childbearing potential who are not using effective contraception.
Buprenorphine is excreted in human milk. Studies in rats have shown that buprenorphine may inhibit lactation. Available pharmacodynamic/toxicological data in animals have shown excretion of buprenorphine in milk (see section 5.3). Therefore, the use of Reletrans during lactation should be avoided.
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).
This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:
Reletrans has a major influence on the ability to drive and use machines.
Even when used according to instructions, buprenorphine transdermal patches 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 adverse reactions (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 transdermal patch has been removed.
Serious adverse reactions that may be associated with buprenorphine transdermal patches 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 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very rare (<1/10,000), Not known (cannot be estimated from the available data).
Uncommon: hypersensitivity
Rare: anaphylactic reaction
Frequency not known: anaphylactoid reaction
Common: anorexia
Rare: dehydration
Common: confusion, depression, insomnia, nervousness, anxiety
Uncommon: affect lability, sleep disorder, restlessness, agitation, euphoric mood, hallucinations, libido decreased, nightmares, aggression
Rare: psychotic disorder
Very rare: drug dependence, mood swings
Frequency not known: depersonalisation
Very common: headache, dizziness, somnolence
Common: tremor
Uncommon: sedation, dysgeusia, dysarthria, hypoaesthesia, memory impairment, migraine, syncope, abnormal coordination, disturbance in attention, paraesthesia
Rare: balance disorder, speech disorder
Very rare: involuntary muscle contractions
Frequency not known: seizures
Uncommon: dry eye, blurred vision
Rare: visual disturbance, eyelid oedema, miosis
Uncommon: tinnitus, vertigo
Very rare: ear pain
Uncommon: palpitations, tachycardia
Rare: angina pectoris
Uncommon: hypotension, circulatory collapse, hypertension, flushing
Rare: vasodilatation, orthostatic hypotension
Common: dyspnoea
Uncommon: cough, wheezing, hiccups
Rare: respiratory depression, respiratory failure, asthma aggravated, hyperventilation, rhinitis
Very common: constipation, nausea, vomiting
Common: abdominal pain, diarrhoea, dyspepsia, dry mouth
Uncommon: flatulence
Rare: dysphagia, ileus
Frequency not known: diverticulitis
Frequency not known: biliary colic
Very common: pruritus, erythema
Common: rash, sweating, exanthema
Uncommon: dry skin, urticaria, dermatitis contact
Rare: face oedema
Very rare: pustules, vesicles
Common: muscular weakness
Uncommon: myalgia, muscle spasms
Uncommon: urinary incontinence, urinary retention, urinary hesitation
Rare: erectile dysfunction, sexual dysfunction
Very common: application site reaction, including erythema, oedema, pruritus, rash
Common: tiredness, asthenia, peripheral oedema
Uncommon: fatigue, pyrexia, rigors, oedema, drug withdrawal syndrome, application site dermatitis*, chest pain
Rare: influenza like illness
Frequency not known: drug withdrawal syndrome neonatal
Uncommon: alanine aminotransferase increased, weight decreased
Uncommon: accidental injury, fall
* In some cases delayed local allergic reactions occurred with marked signs of inflammation. In such cases treatment with Reletrans should be terminated.
Buprenorphine has a low risk of physical dependence. After discontinuation of buprenorphine transdermal patches, 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 buprenorphine transdermal patches, 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 suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website:www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Not applicable.
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