- buprenorphine hydrochloride
POM: Prescription only medicine
This information is intended for use by health professionals
Titration to a maintenance dose:The dosage should be individually titrated to each patient. The maintenance dosage varies from individual to individual and should be titrated by gradually increasing the dose until the minimum effective dose is reached. - Dosage adjustment and maintenance: the dose of Buprenorphine should be increased progressively according to the clinical effect of the individual patient and should not exceed a maximum single daily dose of 16mg. The dosage is titrated according to reassessment of the clinical and psychological status of the patient. Daily dispensing of buprenorphine is recommended, especially during the treatment initiation period. Subsequently, following stabilisation, the patient can be issued with quantities of the medication to last for several days of treatment. It is recommended, however, that the amount of the medication issued should be limited to enough for a maximum of 7 days.- Dosage reduction and termination of treatment: after a satisfactory period of stabilisation has been achieved, the dosage may be reduced gradually to a lower maintenance dose; when deemed appropriate, treatment may be discontinued in some patients. The availability of the sublingual tablet in doses of 0.4 mg, 2 mg and 8 mg, respectively, allows for a downward titration of dosage. Patients should be monitored following termination of buprenorphine treatment because of the potential for relapse.
WarningsBuprenorphine sublingual tablets are recommended only for the treatment of opioid drug dependence.- The clinician should consider the risk of abuse and misuse (e.g. IV administration), particularly at the beginning of the treatment.- Respiratory Depression: some cases of death due to respiratory depression have been reported, particularly when used in combination with benzodiazepines (see 4.5 Interaction with other medicaments and other forms of interaction) or when buprenorphine was not used according to labelling.Hepatitis, hepatic events: hepatic necrosis and hepatitis with jaundice, which generally have resolved favourably, have been reported in patients who use buprenorphine. Causality has not been clearly established. When a hepatic event is suspected and the causality is unknown, further evaluation is required. 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 may be promoted by viral infections particularly chronic C hepatitis, alcohol abuse, anorexia, and the concurrent use of other potentially hepatotoxic drugs.These co-factors should be investigated before prescribing Buprenorphine and when monitoring treatment. If hepatic injury is suspected, biological and etiological evaluation must be performed.Depending on the case, the doctor may either discontinue treatment under the right conditions, in order to prevent withdrawal symptoms and a return to drug abuse, or introduce close monitoring of hepatic function.- This product can cause opioid withdrawal symptoms if administered to an addicted patient less than 4 hours after the last use of the drug (see 4.2 Posology and method of administration.)- This product can cause drowsiness, which may be exacerbated by other centrally acting agents, such as: alcohol, tranquillisers, sedatives, hypnotics (see 4.5 Interactions with other medicaments and other forms of interaction.)- This product can cause orthostatic hypotension.Buprenorphine is an opioid and can therefore alleviate the painful symptoms of certain conditions.Athletes should be aware that this medicine may cause a positive reaction to anti-doping tests.
Paediatric UseNo data are available in children less than 16 years of age; therefore, Buprenorphine Tablets should not be used in children under the age of 16.
Precautions for useThis product should be used with care in patients with:- asthma or respiratory insufficiency (cases of respiratory depression have been reported with buprenorphine);- renal insufficiency (20% of the administered dose is eliminated by the renal route; thus, renal elimination may be prolonged);- hepatic insufficiency (hepatic metabolism of buprenorphine may be altered).Because of the risks of misuse, primarily by intravenous injection, and because of the need for dosage titration, especially in the early stages of treatment, short term prescription is required and if possible staggered or controlled dispensing so as to promote treatment adherence.Animal studies and clinical experience have shown that buprenorphine itself carries the risk of dependence, but less than morphine. It is therefore important to adhere to the treatment initiation and monitoring criteria and the titration schedule (see section 4.2). As with other opioids, caution is advised in patients on buprenorphine in the event of:- Head trauma and intracranial hypertension- Hypotension- Prostatic hypertrophy and urethral stenosis;Titration of buprenorphine must be performed with care in patients treated with CYP3A4 inhibitors, which may increase buprenorphine concentrations, meaning that a lower dose is sufficient (see section 4.5).Contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Contraindicated combinationsMethadone Decrease in the effect of methadone through competitive receptor inhibition, with the risk of withdrawal symptoms.Step III Analgesics Decrease in the analgesic effect of the opioid through competitive receptor inhibition, with the risk of withdrawal symptoms.
Inadvisable combinationsAlcohol - Buprenorphine Sublingual Tablets should not be taken together with alcoholic drinks or medicines containing alcohol. Alcohol increases the sedative effect of buprenorphine (see 4.7. Effects on the ability to drive vehicles or operate machinery.)Naltrexone risk of withdrawal symptoms.Buprenorphine should be used cautiously together with:- Benzodiazepines: This combination may potentiate respiratory depression of central origin, with risk of death; therefore, dosages must be individually titrated and the patient monitored carefully. The risk of drug abuse should also be considered (see 4.4 Special warnings and special precautions for use).- Other central nervous system depressants; other opioid derivatives (analgesics and antitussives); certain antidepressants, sedative H1-receptor antagonists, barbiturates, anxiolytics other than benzodiazepines, neuroleptics, clonidine and related substances. This combination increases central nervous system depression. - Monoamine oxidase inhibitors (MAOI): Possible exaggeration of the effects of opioids, based on experience with morphine.- To date, no notable interaction has been observed with cocaine, the agent most frequently used by multi-drug abusers in association with opioids.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 Tablets should be closely monitored and the dose of buprenorphine should be halved when starting treatment with ketoconazole. Further titration of Buprenorphine Tablets 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.The interaction of buprenorphine with CYP 3A4 inducers has not been investigated, therefore it is recommended that patients receiving Buprenorphine Tablets should be closely monitored if enzyme inducers (e.g. phenobarbital, carbamazepine, phenytoin, rifampicin) are co-administered. Use of these medications may increase the metabolism of buprenorphine and the dose of buprenorphine should be increased appropriately if patients complain of decreased benefit from buprenorphine or if there is re-emergence of craving for illicit drugs.
Breast-feedingBuprenorphine and its metabolites are excreted in human breast milk. In rates, buprenorphine has been found to inhibit lactation. Therefore, breast feeding should be discontinued during treatment with buprenorphine tablets (see section 4.3).
|Undesirable effects reported associated with treatment, according to organ system 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) (CIOMS III)|
|Psychiatric disorders Rare||Hallucinations|
|Nervous System disorders Common||Insomnia, headache, fainting, dizziness|
|Vascular disorders Common||Orthostatic hypotension|
|Respiratory, thoracic and mediastinal disorders Rare||Respiratory depression|
|Gastrointestinal disorders Common||Constipation, nausea, vomiting|
|General disorders and administration site conditions Common||Asthaenia, drowsiness, sweating|
|Immune System Disorders||Hypersensitivity reactions such as rash, urticaria, pruritus, bronchospasm, angioneurotic oedema, angio-oedema and anaphylactic shock|
|Hepatobiliary Disorders||Hepatic necrosis Under normal conditions of use: rare cases of elevation of transaminase levels and hepatitis with jaundice with a generally favourable outcome. In the event of intravenous misuse: potentially serious acute hepatitis|
|Skin and subcutaneous tissue disorders||In the event of intravenous misuse: local reactions, sometimes septic|
Reporting of suspected adverse reactionsReporting 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.
AbsorptionWhen taken orally, buprenorphine undergoes first-pass hepatic metabolism with N-dealkylation and glucuroconjugation in the small intestine. The use of this medication by the oral route is therefore inappropriate.Peak plasma concentrations are achieved 90 minutes after sublingual administration and the maximal dose-concentration relationship is linear, between 2 mg and 16 mg.
DistributionThe absorption of buprenorphine is followed by a rapid distribution phase and a half-life of 2 to 5 hours.
Metabolism and eliminationBuprenorphine is oxidatively metabolised by 14-N-dealkylation to N-desalkyl-buprenorphine (also known as norbuprenorphine) via cytochrome P450 CYP3A4 and by glucuroconjugation of the parent molecule and the dealkylated metabolite. Norbuprenorphine is a μ (mu) agonist with weak intrinsic activity.Elimination of buprenorphine is bi- or tri- exponential, with a long terminal elimination phase of 20 to 25 hours, due in part to reabsorption of buprenorphine after intestinal hydrolysis of the conjugated derivative, and in part to the highly lipophilic nature of the molecule.Buprenorphine is essentially eliminated in the faeces by biliary excretion of the glucuroconjugated metabolites (80%), the rest being eliminated in the urine.