Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Qdem Pharmaceuticals Limited, Cambridge Science Park, Milton Road, Cambridge, CB4 0AB, United Kingdom
Butec is contra-indicated in:
Butec should be used with particular caution in patients with severely impaired respiratory function, sleep apnoea, acute alcohol intoxication, head injury, shock, a reduced level of consciousness of uncertain origin, intracranial lesions or increased intracranial pressure, severe hepatic impairment (see section 4.2) or constipation.
The primary risk of opioid excess is respiratory depression.
Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.
Concomitant use of Butec and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Butec concomitantly with sedative medicines, 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).
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.
Concomitant administration of Butec 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.
Application site reactions usually present as a mild to moderate skin inflammation (contact dermatitis) with erythema, oedema, pruritis, rash, vesicles and pain or a burning sensation at the application site. The reaction typically resolves spontaneously following removal of the Butec patch. Adherence to the method of administration given in section 4.2 reduces the risk of skin reactions at the application site.
Butec patches may also cause skin sensitisation and subsequent immune-mediated, type IV hypersensitivity reaction allergic contact dermatitis. Allergic contact dermatitis may develop with a significant delay of up to several months following initiation of treatment with Butec patches. This may manifest either with symptoms similar to irritant contact dermatitis or with more severe symptoms, including burn-like lesions with bullae and discharge which spread beyond the application site and may not resolve rapidly following removal of the patch. Patients and caregivers should be instructed to monitor the application site for such reactions.
If allergic contact dermatitis is suspected, relevant diagnostic procedures should be performed to determine whether sensitisation has occurred and is caused by the patches. If allergic contact dermatitis is confirmed treatment should be discontinued (see section 4.3). Continued treatment with Butec patches in patients experiencing allergic contact dermatitis may lead to complications, including blistering of the skin, open wound, bleeding, ulceration and subsequent infections. Mechanical injuries during patch removal, such as laceration, are also possible in patients with fragile skin. Chronic inflammation may lead to long-lasting sequelae such as post-inflammatory hyper- and hypopigmentation, as well as dry and thick scaly lesions which may closely resemble scars.
Buprenorphine may lower the seizure threshold in patients with a history of seizure disorder.
Since CYP3A4 inhibitors may increase concentrations of buprenorphine (see section 4.5), patients already treated with CYP3A4 inhibitors should have their dose of Butec carefully titrated since a reduced dosage might be sufficient in these patients.
Butec 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.
For all patients, prolonged use of this product may lead to drug dependence (addiction), even at therapeutic doses. The risks are increased in individuals with current or past history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g. major depression).
Additional support and monitoring may be necessary when prescribing for patients at risk of opioid misuse.
A comprehensive patient history should be taken to document concomitant medications, including over-the-counter medicines and medicines obtained on-line, and past and present medical and psychiatric conditions.
Patients may find that treatment is less effective with chronic use and express a need to increase the dose to obtain the same level of pain control as initially experienced. Patients may also supplement their treatment with additional pain relievers. These could be signs that the patient is developing tolerance. The risks of developing tolerance should be explained to the patient.
Overuse or misuse may result in overdose and/or death. It is important that patients only use medicines that are prescribed for them at the dose they have been prescribed and do not give this medicine to anyone else.
Patients should be closely monitored for signs of misuse, abuse, or addiction.
The clinical need for analgesic treatment should be reviewed regularly.
Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with buprenorphine.
Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take weeks to months.
Withdrawal syndrome, when it occurs, is generally mild, begins after 2 days and may last up to 2 weeks. The opioid drug withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms may also develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate.
If women take this drug during pregnancy, there is a risk that their newborn infants will experience neonatal withdrawal syndrome.
Hyperalgesia may be diagnosed if the patient on long-term opioid therapy presents with increased pain. This might be qualitatively and anatomically distinct from pain related to disease progression or to breakthrough pain resulting from development of opioid tolerance. Pain associated with hyperalgesia tends to be more diffuse than the pre-existing pain and less defined in quality. Symptoms of hyperalgesia may resolve with a reduction of opioid dose.
Butec should not be used at higher doses than recommended.
Butec must not be used concomitantly with MAOIs or in patients who have received MAOIs within the previous two weeks (see section 4.3).
Butec should be used cautiously when co-administered with serotonergic medicinal products, such as selective serotonin re-uptake inhibitors (SSRIs), serotonin norepinephrine re-uptake inhibitors (SNRIs) or tricyclic antidepressants as the risk of serotonin syndrome, a potentially life-threatening condition, is increased (see section 4.4).
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 Butec with ketoconazole as compared to Butec alone.
The interaction between buprenorphine and CYP3A4 enzyme inducers has not been studied. Co-administration of Butec 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.
Butec should be used cautiously with other central nervous system depressants such as other opioid derivatives (analgesics and antitussives containing e.g. morphine, codeine or dextromethorphan), certain antidepressants, sedative H1-receptor antagonists, alcohol, anxiolytics, neuroleptics, clonidine and related substances. These combinations increase the CNS depressant activity.
The concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use should be limited (see section 4.4).
There are no data from the use of Butec in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Therefore Butec should not be used during pregnancy and in women of childbearing potential who are not using effective contraception.
Towards the end of pregnancy high doses of buprenorphine may induce respiratory depression in the neonate even after a short period of administration.
Regular use during pregnancy may cause drug dependence in the foetus, leading to withdrawal symptoms in the neonate.
If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
Administration during labour may depress respiration in the neonate and an antidote for the child should be readily available.
Administration to nursing women is not recommended as buprenorphine is secreted in breast milk and may cause respiratory depression in the infant.
Studies in rats have shown that buprenorphine may inhibit lactation. Available pharmacodynamic/toxicological data in animals has shown excretion of buprenorphine into the milk (see section 5.3). Therefore the use of Butec 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).
Butec has a major influence on the ability to drive and use machines. Even when used according to instructions, Butec 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, nor for at least 24 hours after the patch has been removed.
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:
Details regarding a new driving offence concerning driving after drugs have been taken in the UK may be found here: https://www.gov.uk/drug-driving-law.
Serious adverse reactions that may be associated with Butec therapy in clinical use are similar to those observed with other opioid analgesics, including respiratory depression (especially when used with other CNS depressants) (see section 4.4).
The following frequency categories form the basis for classification of the undesirable effects:
| Term | Frequency |
| 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 |
| Frequency 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, decreased libido, nightmares, aggression.
Rare: psychotic disorder.
Very rare: mood swings.
Frequency not known: drug dependence (see section 4.4), depersonalisation.
Very common: headache, dizziness, somnolence.
Common: tremor.
Uncommon: sedation, dysgeusia, dysarthria, hypoaesthesia, memory impairment, migraine, syncope, abnormal co-ordination, disturbance in attention, paraesthesia.
Rare: balance disorder, speech disorder.
Very rare: involuntary muscle contractions.
Frequency not known: seizure, hyperalgesia, sleep apnoea syndrome.
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: vasodilation, 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: pruritis, erythema.
Common: rash, sweating, exanthema.
Uncommon: dry skin, urticaria.
Rare: face oedema.
Very rare: pustules, vesicles.
Frequency not known: Dermatitis contact, skin discolouration.
Common: muscular weakness.
Uncommon: myalgia, muscle spasms.
Uncommon: urinary incontinence, urinary retention, urinary hesitation.
Rare: erectile dysfunction, sexual dysfunction.
Very common: application site skin reactions*.
Common: tiredness, asthenic conditions, peripheral oedema.
Uncommon: fatigue, pyrexia, rigors, oedema, drug withdrawal syndrome, chest pain.
Rare: influenza-like illness.
Frequency not known: neonatal drug withdrawal syndrome, drug tolerance.
* Includes common signs and symptoms of contact dermatitis (irritative or allergic): erythema, oedema, pruritis, rash, vesicles and pain/burning sensation at the application site. In some cases late onset allergic contact dermatitis has occurred with marked signs of inflammation. In such cases treatment with Butec patches should be terminated.
Uncommon: alanine aminotransferase increased, weight decreased.
Uncommon: accidental injury, fall
After discontinuation of Butec, withdrawal symptoms are uncommon. 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).
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 at: www.mhra.gov.uk/yellowcard.
Not applicable.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
