Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Sun Pharmaceutical Industries Europe B.V., Polarisavenue 87, 2132 JH, Hoofddorp, The Netherlands
Due to lack of data in adolescents (age 16-18), buprenorphine should be used only with caution in this age group.
Buprenorphine sublingual tablets are indicated only for the treatment of opioid drug dependence. It is also recommended that treatment is prescribed by a physician who ensures comprehensive management of the drug addicted patient(s).
When initiating buprenorphine treatment, the physician should be aware of the partial agonist profile of buprenorphine and that it can precipitate withdrawal in opioid-dependent patients. If administered before the agonist effects resulting from recent opioid use or misuse have subsided. To avoid precipitated withdrawal, induction should be undertaken when objective signs and symptoms of moderate withdrawal are evident (see section 4.2). Buprenorphine binds to the μ and κ opiate receptors.
Due to misuse risk, especially by intravenous route, and posology adaptation, prescription duration should be brief particularly at the beginning of the treatment. If possible, a controlled or partial dispensing should be implemented in order to favour also treatment compliance. Discontinuation of treatment may result in a withdrawal syndrome that may be delayed.
Buprenorphine can be misused or abused in a manner similar to other opioids, legal or illicit. Some risks of misuse and abuse include overdose, spread of blood borne viral or localised infections, respiratory depression and hepatic injury. Buprenorphine misuse by someone other than the intended patient poses the additional risk of new drug dependent individuals using buprenorphine as the primary drug of abuse, and may occur if the medicine is distributed for illicit use directly by the intended patient or if the medicine is not safeguarded against theft.
Sub-optimal treatment with buprenorphine may prompt medication misuse by the patient, leading to overdose or treatment dropout. A patient who is under-dosed with buprenorphine may continue responding to uncontrolled withdrawal symptoms by self-medicating with opioids, alcohol or other sedative-hypnotics such as benzodiazepines.
Diversion: diversion refers to the introduction of sublingual buprenorphine into the illicit market either by patients or by individuals who obtain the medicinal product through theft from patients or pharmacies. This diversion may lead to new addicts using sublingual buprenorphine as the primary drug of abuse with the risk of overdose, spread of blood borne viral infections, respiratory depression and hepatic injury.
To minimise the risk of misuse, abuse and diversion, physicians should take appropriate precautions when prescribing and dispensing buprenorphine, such as to avoid prescribing multiple refills early in treatment and to conduct patient follow-up visits with clinical monitoring that is appropriate to the patient’s level of stability.
Buprenorphine is a partial agonist at the mu-opiate receptor and chronic administration produces dependence of the opioid type. Studies in animals, as well as clinical experience, have demonstrated that buprenorphine may produce dependence, but at a lower level than a full agonist.
Abrupt discontinuation of treatment is not recommended as it may result in a withdrawal syndrome that may be delayed in onset.
A number of cases of death due to respiratory depression have been reported, particularly when buprenorphine was used in combination with benzodiazepines (see section 4.5) or when buprenorphine was not used according to prescribing information. Deaths have also been reported in association with concomitant administration of buprenorphine and other depressants such as alcohol or other opioids. If buprenorphine is administered to some non-opioid dependent individuals who are not tolerant to the effects of opioids, potentially fatal respiratory depression may occur.
Buprenorphine should be used with care in patients with respiratory insufficiency (e.g. chronic obstructive pulmonary disease, asthma, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, pre-existing respiratory depression or kyphoscoliosis).
Buprenorphine may cause severe, possibly fatal, respiratory depression in children and non-dependent persons who accidentally or deliberately ingest it. Protect children and non-dependent persons against exposure.
Cases of acute hepatic injury have been reported in opioid-dependent addicts both in clinical trials and in post-marketing adverse event reports. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of cytolytic hepatitis, hepatic failure, hepatic necrosis, hepatorenal syndrome, hepatic encephalopathy and death. In many cases the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant use of other potentially hepatotoxic drugs and ongoing injecting drug use may have a causative or contributory role. These underlying factors must be taken into consideration before prescribing buprenorphine and during treatment. When a hepatic event is suspected and the causality is unknown, further evaluation is required.
Depending on the findings, buprenorphine may be discontinued cautiously so as to prevent withdrawal symptoms and to prevent a return to illicit drug use.
If buprenorphine is suspected to be the cause of hepatic necrosis or jaundice, it must be discontinued as rapidly as the patient’s clinical condition permits. All patients should have liver function tests performed at regular intervals. Serious cases of acute hepatic injury have also been reported in a context of misuse, especially by intravenous route. These hepatic injuries have mainly been observed at the high doses and could be due to a mitochondrial toxicity (genetic diseases, viral infections particularly chronic C hepatitis, alcohol abuse, anorexia, associated mitochondrial toxins, e.g. aspirin, isoniazid, valproate, amiodarone, antiretroviral nucleoside analogues, and the concurrent use of other potentially hepatotoxic medicinal products).
Because CYP3A4 inhibitors (see section 4.5) may increase concentrations of buprenorphine, patients already treated with CYP3A4 inhibitors should have their dose of buprenorphine titrated carefully since a reduced dosing may be sufficient in these patients.
Buprenorphine can precipitate withdrawal symptoms in opioid-dependent patients particularly if administered less than 4-6 hours after the last use of heroin or other short-acting opioids, or if administered less than 24 hours after the last dose of methadone.
This product can cause drowsiness, which may be exacerbated by other centrally acting agents, such as: alcohol, tranquillisers, sedatives, hypnotics (see Section 4.5).
This product can cause orthostatic hypotension.
Studies in animals, as well as clinical experience, have shown that buprenorphine may produce dependence but at a lower level than morphine. Consequently, it is important to follow the recommendations for initiating treatment, dosage adjustment and monitoring of the patient (see section 4.2).
Athletes should be aware that this medicinal product may cause a positive reaction to "anti-doping tests."
The effects of hepatic impairment on the pharmacokinetics of buprenorphine were evaluated in a post marketing study. Buprenorphine is extensively metabolized in the liver, plasma levels were found to be higher for buprenorphine in patients with moderate and severe hepatic impairment. Patients should be monitored for signs and symptoms of precipitated opioid withdrawal, toxicity or overdose caused by increased levels of buprenorphine. Buprenorphine sublingual tablets should be used with caution in patients with moderate hepatic impairment (see section 4.3 and 5.2). In patients with severe hepatic insufficiency the use of buprenorphine is contraindicated.
Renal elimination plays a relatively small role (approximately 30%) in the overall clearance of buprenorphine; therefore, no dose modification based on renal function is generally required. Metabolites of buprenorphine accumulate in patients with renal failure. Caution is recommended dosing patients with severe renal impairment (creatinine clearance < 30 ml/min) (see section 5.2).
This product should be used with care in patients with:
Opioids should be administered with caution to elderly or debilitated patients.
Due to lack of data in adolescents (age 16–18), patients in this age group should be more closely monitored during treatment.
This medicinal product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
This medicinal product contains butylhydroxyanisole (E320), which may cause local skin reactions (e.g. contact dermatitis), or irritation to the eyes and mucous membranes.
This medicinal product contains less than 1 mmol sodium (23 mg) per maximum daily dose, that is to say ‘sodium- free’.
Buprenorphine should not be taken together with
Buprenorphine should be used cautiously together with:
A suspected interaction between buprenorphine injection and phenprocoumon, resulting in purpura, has been reported.
An interaction study of buprenorphine with ketoconazole (a potent inhibitor of CYP3A4) resulted in increased Cmax and AUC of buprenorphine (approximately 70% and 50% respectively) and, to a lesser extent, of the metabolite, norbuprenorphine. Patients receiving buprenorphine should be closely monitored and the dose of buprenorphine should be halved when starting treatment with ketoconazole.
Further titration of buprenorphine should be made as clinically indicated. Although no data from clinical trials are available, the use of other inhibitors of CYP3A4 (e.g. gestodene, troleandoymycin, the HIV protease inhibitors ritonavir, indinavir and saquinavir) may also increase exposure levels to buprenorphine and norbuprenorphine and a similar dose-reduction should be considered when initiating treatment.
Concomitant use of CYP3A4 inducers with buprenorphine may decrease buprenorphine plasma concentrations, potentially in sub-optimal treatment of opioid dependence with buprenorphine. It is recommended that patients receiving buprenorphine should be closely monitored if inducers (e.g. phenobarbital, carbamazepine, phenytoin or rifampicin) are co-administered. The dose of either buprenorphine or the CYP3A4 inducer may need to be adjusted accordingly.
Interaction studies have only been performed in adults.
There are no adequate data from the use of buprenorphine in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.
At the end of pregnancy, high doses may induce respiratory depression in new-born infants even after a short period of administration. Long-term administration during the last three months of pregnancy may cause a withdrawal syndrome in the neonate (e.g. hypertonia, neonatal tremor, neonatal agitation, myoclonus or convulsions). The syndrome is generally delayed from several hours to several days after birth. Buprenorphine should only be used during pregnancy in case the potential benefits outweigh the risks.
Due to the long half-life of buprenorphine, neonatal monitoring for several days should be considered at the end of pregnancy to prevent the risk of respiratory depression or withdrawal syndrome in neonates.
Buprenorphine is excreted in human breast milk. In rats, buprenorphine has the potential to inhibit lactation or milk production. Therefore buprenorphine should not be used during breast-feeding.
No human data on the effects of buprenorphine on fertility are available. In rats, there was no effect on mating or fertility with buprenorphine (see section 5.3).
Buprenorphine has minor to moderate influence on the ability to drive and use machine. Buprenorphine may cause drowsiness, dizziness or impaired thinking especially during treatment induction and dose adjustment. If taken together with alcohol or central nervous system depressants, the effect is likely to be more pronounced (see section 4.4. and 4.5). Therefore, patients should be warned against driving or operating machinery (see Section 4.5).
The onset of undesirable effects depends on the patient’s tolerance threshold, which is higher in drug addicts than in the general population.
The most commonly reported adverse drug reactions were those related to withdrawal symptoms (e.g. insomnia, headache, nausea and hyperhidrosis) and pain.
Adverse reactions are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 1 summarises the most commonly reported adverse drug reactions during post-marketing surveillance. Events occurring in at least 1% of reports by healthcare professionals and considered expected are included. Frequency of events not reported in pivotal studies cannot be estimated and is given as not known.
Table 1. Undesirable effects observed in pivotal clinical studies and/or post marketing surveillance listed by body system:
Common: Bronchitis, infection, influenza, pharyngitis, rhinitis
Common: Lymphadenopathy
Common: Decreased appetite
Very common: Insomnia
Common: Agitation, anxiety, depression, hostility, nervousness, paranoia, thinking abnormal
Not known: Drug dependence
Very common: Headache
Common: Dizziness, hypertonia, migraine, paraesthesia, somnolence, syncope, tremor
Common: Lacrimal disorder, mydriasis
Common: Palpitations
Common: Vasodilatation
Common: Cough, dyspnoea, yawning
Uncommon: Respiratory depression
Very common: Nausea
Common: Constipation, abdominal pain, diarrhoea, dry mouth, dyspepsia, gastrointestinal disorder, flatulence, tooth disorder, vomiting
Very common: Hyperhidrosis
Common: Rash
Common: Arthralgia, back pain, bone pain, muscle spasms, myalgia, neck pain
Common: Dysmenorrhoea
Very common: Drug withdrawal syndrome, pain
Common: Asthenia, chest pain, chills, malaise, oedema peripheral, pyrexia
Not known: Drug withdrawal syndrome neonatal
The following is a summary of other post-marketing adverse event reports that are considered serious or otherwise noteworthy:
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 or search for MHRA Yellow Card in the Google Play or Apple App Store.
Not applicable.
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