Summary of Product Characteristics Updated 23-Jul-2019 | Indivior UK Limited
PosologyTreatment with Subutex sublingual tablets is intended for use in adults and children aged 16 years or over who have agreed to be treated for opioid dependence.
Precautions to be taken before dosingPrior to treatment induction, physicians should be aware of the partial agonist profile of buprenorphine to the opiate receptors, which may precipitate a withdrawal syndrome in opioid-dependent patients and consideration should be given to the types of opioid dependence (i.e. long- or short-acting opioid), the time since last opioid use and the degree of opioid dependence. To avoid precipitating withdrawal, induction with Subutex should be undertaken when objective and clear signs of withdrawal are evident e.g. a score higher than 12 on the Clinical Opioid Withdrawal Scale (COWS).• For patients dependent on heroin or short-acting opioids: the first dose of buprenorphine should be started when objective signs of withdrawal appear, but not less than 6 hours after the patient last used opioids.• For patients receiving methadone: before beginning Subutex therapy, the dose of methadone should be reduced to a maximum of 30mg/day. Subutex may precipitate symptoms of withdrawal in patients dependent on methadone. The first dose of buprenorphine should be started only when objective signs of withdrawal appear and generally not less than 24 hours after the patient last used methadone because of the long half-life of methadone.Baseline liver function tests and documentation of viral hepatitis status is recommended prior to commencing therapy.
Induction:The initial dose is from 0.8mg to 4mg, administered as a single daily dose.
Dosage adjustment and maintenance:The dose of Subutex should be increased progressively according to the clinical effect of the individual patient and should not exceed a maximum single daily dose of 32mg. The dosage is titrated according to reassessment of the clinical and psychological status of the patient.
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 0.4mg, 2mg and 8mg, respectively, allows for a downward titration of dosage. Patients should be monitored following termination of buprenorphine treatment because of the potential for relapse.
ElderlyThe safety and efficacy of buprenorphine in elderly patients over 65 years of age has not been established.
Hepatic impairmentPatients who are positive for viral hepatitis, on concomitant medicinal products and / or have existing liver dysfunction are at risk of greater liver injury. Patients should be monitored for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine (see section 4.4). Buprenorphine should be used with caution in patients with hepatic insufficiency (see section 5.2). Buprenorphine is contraindicated in patients with severe hepatic insufficiency (see section 4.3).
Renal impairmentModification of the buprenorphine dose is not generally required for patients with renal impairment. Caution is recommended when dosing patients with severe renal impairment, which may require dose adjustment (creatinine clearance < 30 ml/min) (see section 5.2).
Paediatric populationSubutex is contraindicated in children under the age of 16 (see section 4.3).
Method of administrationAdministration is sublingual. Physicians must advise patients that the sublingual route is the only effective and safe route of administration for this drug. The tablet should be kept under the tongue until dissolved, which usually occurs within 5 to 10 minutes.
Misuse, abuse and diversionBuprenorphine 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.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.
Respiratory depressionA 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.Subutex 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.
CNS depressionBuprenorphine may cause drowsiness particularly when used with alcohol or central nervous system depressants (such as benzodiazepines, tranquillisers, sedatives or hypnotics) (see sections 4.5 and 4.7).
DependenceBuprenorphine 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.
Hepatitis and hepatic eventsCases of acute hepatic injury have been reported in opioid-dependent patients 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, genetic disease, infection with hepatitis B or hepatitis C virus, alcohol abuse, anorexia, 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 Subutex and during treatment. When a hepatic event is suspected further biological and etiological evaluation is required. Depending on the findings, Subutex may be discontinued cautiously so as to prevent withdrawal symptoms and to prevent a return to illicit drug use. If treatment is continued, hepatic function should be monitored closely.All patients should have liver function tests performed at regular intervals.
Precipitation of opioid withdrawal syndromeWhen initiating treatment with Subutex, it is important to be aware of the partial agonist profile of buprenorphine. Sublingually administered buprenorphine can precipitate withdrawal symptoms 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).
Hepatic impairmentThe 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. Subutex 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 impairmentRenal 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).
Patients with lactose intoleranceThis product contains lactose (see section 6.1). Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Use in adolescentsDue to lack of data in adolescents (age 16 18), patients in this age group should be more closely monitored during treatment.
General warnings related to the administration of opioidsOpioids may cause orthostatic hypotension in ambulatory patients.Opioids may elevate cerebrospinal fluid pressure, which may cause seizures, so opioids should be used with caution in patients with head injury, intracranial lesions, other circumstances where cerebrospinal pressure may be increased, or history of seizure.Opioids should be used with caution in patients with hypotension, prostatic hypertrophy or urethral stenosis.Opioid-induced miosis, changes in the level of consciousness or changes in the perception of pain as a symptom of disease may interfere with patient evaluation or obscure the diagnosis or clinical course of concomitant disease.Opioids should be used with caution in patients with myxoedema, hypothyroidism, or adrenal cortical insufficiency (e.g. Addison's disease).Opioids have been shown to increase intracholedochal pressure, and should be used with caution in patients with dysfunction of the biliary tract.Opioids should be administered with caution to elderly or debilitated patients.
PregnancyThere are no adequate data from the use of buprenorphine in pregnant women.Buprenorphine should be used during pregnancy only if the potential benefit outweighs the potential risk to the foetus.Towards the end of pregnancy, buprenorphine may induce respiratory depression in the newborn infant 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.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.
Breast feedingBuprenorphine and its metabolites are excreted in human breast milk. In rats, buprenorphine has been found to inhibit lactation. Therefore, breast feeding should be discontinued during treatment with Subutex (see section 4.3).
Summary of safety profileThe most commonly reported adverse drug reactions were those related to withdrawal symptoms (e.g. insomnia, headache, nausea and hyperhidrosis) and pain.
Tabulated list of adverse reactionsTable 1 summarises:• adverse reactions reported from pivotal clinical studies. The frequency of possible side effects listed below is defined using the following convention: Very common (≥1/10), common (≥1/100 to <1/10).• 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: Adverse effects observed in pivotal clinical studies and / or post marketing surveillance listed by body system
System Organ Class
Very common (≥1/10)
Common (≥1/100 to <1/10)
Frequency not known
Infections and infestations
Blood and lymphatic system disorders
Metabolism and nutrition disorders
Nervous system disorders
Respiratory, thoracic and mediastinal disorders
Skin and subcutaneous tissue disorders
Musculoskeletal, connective tissue and bone disorders
Reproductive system and breast disorders
General disorders and administration site conditions
Drug withdrawal syndrome
Drug withdrawal syndrome neonatal
Description of selected adverse reactionsThe following is a summary of other post-marketing adverse event reports that are considered serious or otherwise noteworthy:• In cases of intravenous misuse, local reactions, sometimes septic (abscess, cellulitis), and potentially serious acute hepatitis and other infections such as pneumonia, endocarditis have been reported (see section 4.4).• In patients presenting with marked drug dependence, initial administration of buprenorphine can produce a withdrawal effect similar to that associated with naloxone.• The most common signs and symptoms of hypersensitivity include rashes, urticaria, and pruritus. Cases of bronchospasm, angioedema, and anaphylactic shock have been reported (see section 4.3). • Transaminase increase, hepatitis, acute hepatitis, cytolytic hepatitis, jaundice, hepatorenal syndrome, hepatic encephalopathy, and hepatic necrosis have occurred (see section 4.4).• Neonatal drug withdrawal syndrome has been reported among newborns of women who have received buprenorphine during pregnancy. The syndrome may be milder than that seen with a full µ-opioid agonist and may be delayed in onset. The nature of the syndrome may vary depending upon the mother's drug use history (see section 4.6).• Hallucination, orthostatic hypotension, urinary retention and vertigo have been reported.
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.
SymptomsRespiratory depression, as a result of central nervous system depression, is the primary symptom requiring intervention in the case of overdose because it may lead to respiratory arrest and death. Preliminary symptoms of overdose may also include somnolence, amblyopia, miosis, hypotension, nausea, vomiting and / or speech disorders.
TreatmentGeneral supportive measures should be instituted, including close monitoring of respiratory and cardiac status of the patient. Symptomatic treatment of respiratory depression, following standard intensive care measures, should be instituted. A patent airway and assisted or controlled ventilation must be assured. The patient should be transferred to an environment within which full resuscitation facilities are available. Use of an opioid antagonist (i.e., naloxone) is recommended, despite the modest effect it may have in reversing the respiratory symptoms of buprenorphine compared with its effects on full agonist opioid agents.The long duration of action of buprenorphine should be taken into consideration when determining length of treatment needed to reverse the effects of an overdose. Naloxone can be cleared more rapidly than buprenorphine, allowing for a return of previously controlled buprenorphine overdose symptoms.
Pharmacodynamic groupDrugs used in opioid dependence ATC-code: N07BC01
Mechanism of actionBuprenorphine is an opioid partial agonist/antagonist which attaches itself to the µ (mu) k (kappa) receptors of the brain. Its activity in opioid maintenance treatment is attributed to its slowly reversible link with the µ receptors which, over a prolonged period, minimises the need of the opioid-dependent patient.
Clinical efficacy and safetyDuring clinical pharmacologic studies in opiate-dependent subjects, buprenorphine demonstrated a ceiling effect on a number of parameters, including positive mood, good effect and respiratory depression.
AbsorptionWhen taken orally, buprenorphine undergoes first-pass hepatic metabolism with N-dealkylation and glucuroconjungation in the small intestine. The use of this medication by 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.
Biotransformation and eliminationBuprenorphine is oxidatively metabolised by 14-N-dealkylation to N-desalkyl-buprenorphine (also known as norbuprenorphine) via cytochrome P450 CYP3A4 and by glucuroconjungation of the parent molecule and the dealkylated metabolite. Norbuprenorphine is µ (mu) agonist with weak intrinsic activity.Elimination of buprenorphine is bi- or tri- exponential, with long terminal elimination phase of 20-25 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 (70%), the rest being eliminated in the urine.
Hepatic ImpairmentThe effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone were evaluated in a postmarketing study. Table 2 summarizes the results from a clinical trial in which the exposure of buprenorphine was determined after administering a Suboxone 2.0/0.5mg (buprenorphine/naloxone) sublingual tablet in healthy subjects, and in subjects with varied degrees of hepatic impairment.
Table 2. Effect of hepatic impairment on pharmacokinetic parameters of buprenorphine following buprenorphine/naloxone administration (change relative to healthy subjects)
Mild Hepatic Impairment
(Child-Pugh Class A)
Moderate Hepatic Impairment
(Child-Pugh Class B)
Severe Hepatic Impairment
(Child-Pugh Class C)
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Subutex 8mg, sublingual tablets: PL 36699/0003
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