Summary of Product Characteristics Updated 23-Jul-2019 | Indivior UK Limited
Excipients with known effect:Each sublingual tablet contains 168 mg lactose (as monohydrate) For the full list of excipients, see section 6.1.
Precautions to be taken before inductionPrior to treatment initiation, consideration should be given to the type 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 buprenorphine/naloxone or buprenorphine only should be undertaken when objective and clear signs of withdrawal are evident (demonstrated e.g. by a score indicating mild to moderate withdrawal on the validated Clinical Opioid Withdrawal Scale, COWS). o For patients dependent upon heroin or short-acting opioids, the first dose of buprenorphine/naloxone should be taken when signs of withdrawal appear, but not less than 6 hours after the patient last used opioids. o For patients receiving methadone, the dose of methadone should be reduced to a maximum of 30 mg/day before beginning buprenorphine/naloxone therapy. The long half life of methadone should be considered when starting buprenorphine/naloxone. The first dose of buprenorphine/naloxone should be taken only when signs of withdrawal appear, but not less than 24 hours after the patient last used methadone. Buprenorphine may precipitate symptoms of withdrawal in patients dependent upon methadone.
Initiation therapy (induction)The recommended starting dose in adults and adolescents over 15 years of age is one to two Suboxone 2 mg/0.5 mg. An additional one to two Suboxone 2 mg/0.5 mg may be administered on day one depending on the individual patient's requirement. During the initiation of treatment, daily supervision of dosing is recommended to ensure proper sublingual placement of the dose and to observe patient response to treatment as a guide to effective dose titration according to clinical effect.
Dosage adjustment and maintenance therapyFollowing treatment induction on day one, the patient should be stabilised to a maintenance dose during the next few days by progressively adjusting the dose according to the clinical effect of the individual patient. Dose titration in steps of 2-8 mg buprenorphine is guided by reassessment of the clinical and psychological status of the patient, and should not exceed a maximum single daily dose of 24 mg buprenorphine.
Less than daily dosingAfter a satisfactory stabilisation has been achieved the frequency of dosing may be decreased to dosing every other day at twice the individually titrated daily dose. For example, a patient stabilised to receive a daily dose of 8 mg buprenorphine may be given 16 mg buprenorphine on alternate days, with no dose on the intervening days. In some patients, after a satisfactory stabilisation has been achieved, the frequency of dosing may be decreased to 3 times a week (for example on Monday, Wednesday and Friday). The dose on Monday and Wednesday should be twice the individually titrated daily dose, and the dose on Friday should be three times the individually titrated daily dose, with no dose on the intervening days. However, the dose given on any one day should not exceed 24 mg buprenorphine. Patients requiring a titrated daily dose> 8 mg buprenorphine /day may not find this regimen adequate.
Medical withdrawalAfter a satisfactory stabilisation has been achieved, if the patient agrees, the dosage may be reduced gradually to a lower maintenance dose; in some favourable cases, treatment may be discontinued. The availability of doses of 2 mg/0.5 mg and 8 mg/2 mg allows for a downward titration of dosage. For patients who may require a lower buprenorphine dose, buprenorphine 0.4 mg may be used. Patients should be monitored following medical withdrawal because of the potential for relapse.
ElderlyThe safety and efficacy of buprenorphine/naloxone in elderly patients over 65 years of age have not been established. No recommendation on posology can be made.
Hepatic impairmentBaseline liver function tests and documentation of viral hepatitis status is recommended prior to commencing therapy. Patients who are positive for viral hepatitis, on concomitant medicinal products (see section 4.5) and/or have existing liver dysfunction are at risk of accelerated liver injury. Regular monitoring of liver function is recommended (see section 4.4). Both active substances of Suboxone, buprenorphine and naloxone, are extensively metabolized in the liver, and the plasma levels were found to be higher for both buprenorphine and naloxone 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 naloxone and/or buprenorphine. As buprenorphine/naloxone pharmacokinetics may be altered in patients with hepatic impairment, lower initial doses and careful dose titration in patients with mild to moderate hepatic impairment are recommended. Buprenorphine/naloxone is contraindicated in patients with severe hepatic impairment. (see section 4.3 and 5.2).
Renal impairmentModification of the buprenorphine/naloxone dose is not required in patients with renal impairment. Caution is recommended when dosing patients with severe renal impairment (creatinine clearance < 30 ml/min) (see section 4.4 and 5.2).
Paediatric populationThe safety and efficacy of buprenorphine/naloxone in children below the age of 15 years have not been established. No data are available.
Method of administrationPhysicians must warn patients that the sublingual route is the only effective and safe route of administration for this medicinal product (see section 4.4). The tablet is to be placed under the tongue until completely dissolved. Patients should not swallow or consume food or drink until the tablet is completely dissolved. The dose is made up from multiple Suboxone tablets of different strengths, which may be taken all at the same time or in two divided portions; the second portion to be taken directly after the first portion has dissolved.
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 and systemic 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 medicinal product is not safeguarded against theft. Sub-optimal treatment with buprenorphine/naloxone may prompt medicine misuse by the patient, leading to overdose or treatment dropout. A patient who is under-dosed with buprenorphine/naloxone may continue responding to uncontrolled withdrawal symptoms by self-medicating with opioids, alcohol or other sedative-hypnotics such as benzodiazepines.To minimize 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 needs. Combining buprenorphine with naloxone in Suboxone is intended to deter misuse and abuse of the buprenorphine. Intravenous or intranasal misuse of Suboxone is expected to be less likely than buprenorphine alone since the naloxone in Suboxone can precipitate withdrawal in individuals dependent on heroin, methadone, or other opioid agonists.
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.This product should be used with care in patients with asthma or respiratory insufficiency (e.g. chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, pre-existing respiratory depression or kyphoscoliosis (curvature of spine leading to potential shortness of breath)).Buprenorphine/naloxone may cause severe, possibly fatal, respiratory depression in children and non-dependent persons in case of accidental or deliberate ingestion. Patients must be warned to store the blister safely, to never open the blister in advance, to keep them out of the reach of children and other household members, and not to take this medicine in front of children. An emergency unit should be contacted immediately in case of accidental ingestion or suspicion of ingestion.
CNS depressionBuprenorphine/naloxone may cause drowsiness, particularly when taken together with alcohol or central nervous system depressants (such as tranquilisers, sedatives or hypnotics) (see section 4.5).
DependenceBuprenorphine is a partial agonist at the µ (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 e.g. morphine. 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 addicts both in clinical trials and in post marketing adverse reaction reports. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of hepatic failure, hepatic necrosis, hepatorenal syndrome, hepatic encephalopathy and death. In many cases the presence of pre-existing mitochondrial impairment (genetic disease, liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, alcohol abuse, anorexia concomitant use of other potentially hepatotoxic medicines) and ongoing injecting drug use may have a causative or contributory role. These underlying factors must be taken into consideration before prescribing buprenorphine/naloxone and during treatment. When a hepatic event is suspected, further biological and etiological evaluation is required. Depending upon the findings, the medicinal product may be discontinued cautiously so as to prevent withdrawal symptoms and to prevent a return to illicit drug use. If the treatment is continued, hepatic function should be monitored closely.
Precipitation of opioid withdrawal syndromeWhen initiating treatment with buprenorphine/naloxone, the physician must be aware of the partial agonist profile of buprenorphine and that it can precipitate withdrawal in opioid-dependent patients, particularly if administered less than 6 hours after the last use of heroin or other short-acting opioid, or if administered less than 24 hours after the last dose of methadone. Patients should be clearly monitored during the switching period from buprenorphine or methadone to buprenorphine/naloxone since withdrawal symptoms have been reported. To avoid precipitating withdrawal, induction with buprenorphine/naloxone should be undertaken when objective signs of withdrawal are evident (see section 4.2).Withdrawal symptoms may also be associated with sub-optimal dosing.
Hepatic impairmentThe effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone were evaluated in a post-marketing study. Since both buprenorphine and naloxone are extensively metabolized, plasma levels were found to be higher for both buprenorphine and naloxone in patients with moderate and severe hepatic impairment after single-dose administration. Patients should be monitored for signs and symptoms of precipitated opioid withdrawal, toxicity or overdose caused by increased levels of naloxone and/or buprenorphine. Suboxone 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/naloxone is contraindicated.
Renal impairmentRenal elimination may be prolonged since 30 % of the administered dose is eliminated by the renal route. Metabolites of buprenorphine accumulate in patients with renal failure. Caution is recommended when dosing patients with severe renal impairment (creatinine clearance <30 ml/min) (see sections 4.2 and 5.2).
Use in adolescents (Age 15-<18)Due to the lack of data in adolescents (age 15-<18), patients in this age group should be more closely monitored during treatment.
CYP 3A inhibitorsMedicines that inhibit the enzyme CYP3A4 may give rise to increased concentrations of buprenorphine. A reduction of the buprenorphine/naloxone dose may be needed. Patients already treated with CYP3A4 inhibitors should have their dose of buprenorphine/naloxone titrated carefully since a reduced dose may be sufficient in these patients (see section 4.5).
General warnings relevant to the administration of opioidsOpioids may produce 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.The concomitant use of monoamine oxidase inhibitors (MAOI) might produce an exaggeration of the effects of opioids, based on experience with morphine (see section 4.5).Suboxone contains lactose. Patients with rare hereditary problems of galactose intolerance, should not take this medicine.
PregnancyThere are no adequate data from the use of Suboxone 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 buprenorphine may induce respiratory depression in the newborn infant even after a short period of administration. Long-term administration of buprenorphine 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.Furthermore, the use of buprenorphine/naloxone during pregnancy should be assessed by the physician. Buprenorphine/naloxone should be used during pregnancy only if the potential benefit outweighs the potential risk to the foetus.
Breast-feedingIt is unknown whether naloxone is excreted in human breast milk. Buprenorphine and its metabolites are excreted in human breast milk. In rats buprenorphine has been found to inhibit lactation. Therefore, breastfeeding should be discontinued during treatment with Suboxone.
FertilityAnimal studies have shown a reduction in female fertility at high doses (systemic exposure > 2.4 times the human exposure at the maximum recommended dose of 24 mg buprenorphine, based on AUC). See section 5.3.
Summary of the safety profileThe most commonly reported treatment related adverse reactions reported during the pivotal clinical trials were constipation and symptoms commonly associated with drug withdrawal (i.e. insomnia, headache, nausea, hyperhidrosis and pain). Some reports of seizure, vomiting, diarrhoea, and elevated liver function tests were considered serious.
Tabulated list of adverse reactionsTable 1 summarises adverse reactions reported from pivotal clinical trials in which, 342 of 472 patients (72.5 %) reported adverse reactions and adverse reactions reported during post-marketing surveillance. The frequency of possible side effects listed below is defined using the following convention: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Not known (cannot be estimated from available data).
Table 1: Treatment-related adverse reactions reported in clinical trials and post-marketing surveillance of buprenorphine/naloxone
|System Organ Class||Very common||Common||Uncommon||Not Known|
|Infections and infestations||Influenza Infection Pharyngitis Rhinitis||Urinary tract infection Vaginal infection|
|Blood and lymphatic system disorders||Anaemia Leukocytosis Leukopenia Lymphadenopathy Thrombocytopenia|
|Immune system disorders||Hypersensitivity||Anaphylactic shock|
|Metabolism and nutrition disorders||Decreased appetite Hyperglycaemia Hyperlipidaemia Hypoglycaemia|
|Psychiatric disorders||Insomnia||Anxiety Depression Libido decreased Nervousness Thinking abnormal||Abnormal dreams Agitation Apathy Depersonalisation Drug dependence Euphoric mood Hostility||Hallucination|
|Nervous system disorders||Headache||Migraine Dizziness Hypertonia Paraesthesia Somnolence||Amnesia Hyperkinesia Seizure Speech disorder Tremor||Hepatic encephalopathy Syncope|
|Eye disorders||Amblyopia Lacrimal disorder||Conjunctivitis Miosis|
|Ear and labyrinth disorders||Vertigo|
|Cardiac disorders||Angina Pectoris Bradycardia Myocardial infarction Palpitations Tachycardia|
|Vascular disorders||Hypertension Vasodilatation||Hypotension||Orthostatic hypotension|
|Respiratory, thoracic and mediastinal disorders||Cough||Asthma Dyspnoea Yawning||Bronchospasm Respiratory depression|
|Gastrointestinal disorders||Constipation Nausea||Abdominal Pain Diarrhoea Dyspepsia Flatulence Vomiting||Mouth ulceration Tongue discolouration|
|Hepatobiliary disorders||Hepatitis Hepatitis acute Jaundice Hepatic necrosis Hepatorenal syndrome|
|Skin and subcutaneous tissue disorders||Hyperhidrosis||Pruritus Rash Urticaria||Acne Alopecia Dermatitis exfoliative Dry skin Skin mass||Angioedema|
|Musculoskeletal and connective tissue disorders||Back Pain Arthralgia Muscle spasms Myalgia||Arthritis|
|Renal and urinary disorders||Urine Abnormality||Albuminuria Dysuria Haematuria Nephrolithiasis Urinary retention|
|Reproductive system and breast disorders||Erectile dysfunction||Amenorrhoea Ejaculation disorder Menorrhagia Metrorrhagia|
|General disorders and administration site conditions||Drug withdrawal syndrome||Asthenia Chest Pain Chills Pyrexia Malaise Pain Oedema peripheral||Hypothermia||Drug withdrawal syndrome neonatal (see section 4.6)|
|Investigations||Liver function test abnormal Weight decreased||Blood creatinine increased||Transaminases increased|
|Injury, poisoning and procedural complications||Injury||Heat stroke|
Description of selected adverse reactionsIn cases of intravenous drug misuse, some adverse experiences are attributed to the act of misuse rather than the medicinal product and include local reactions, sometimes septic (abscess, cellulitis), and potentially serious acute hepatitis and other acute 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 drug withdrawal syndrome similar to that associated with naloxone (see sections 4.2 and 4.4).
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 national reporting system listed in Appendix V.
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. Signs of overdose may also include somnolence, amblyopia, miosis, hypotension, nausea, vomiting and/or speech disorders.
ManagementGeneral supportive measures should be instituted, including close monitoring of respiratory and cardiac status of the patient. Symptomatic treatment of respiratory depression, and standard intensive care measures, should be implemented. 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.If the patient vomits, care must be taken to prevent aspiration of the vomitus.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.If naloxone is used, the long duration of action of buprenorphine should be taken into consideration when determining the length of treatment and medical surveillance 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, so a continuing infusion may be necessary. If infusion is not possible, repeated dosing with naloxone may be required. Initial naloxone doses may range up to 2 mg and be repeated every 2-3 minutes until a satisfactory response is achieved, but should not exceed a 10 mg starting dose. Ongoing intravenous infusion rates should be titrated to patient response.
Mechanism of actionBuprenorphine is an opioid partial agonist/antagonist which binds to the μ and κ (kappa) opioid receptors of the brain. Its activity in opioid maintenance treatment is attributed to its slowly reversible properties with the μ-opioid receptors which, over a prolonged period, might minimise the need of addicted patients for drugs.Opioid agonist ceiling effects were observed during clinical pharmacology studies in opioid-dependent persons.Naloxone is an antagonist at μ-opioid receptors. When administered orally or sublingually in usual doses to patients experiencing opioid withdrawal, naloxone exhibits little or no pharmacological effect because of its almost complete first pass metabolism. However, when administered intravenously to opioid-dependent persons, the presence of naloxone in Suboxone produces marked opioid antagonist effects and opioid withdrawal, thereby deterring intravenous abuse.
Clinical efficacyEfficacy and safety data for buprenorphine/naloxone are primarily derived from a one-year clinical trial, comprising a 4-week randomised double blind comparison of buprenorphine/naloxone, buprenorphine and placebo followed by a 48 week safety study of buprenorphine/naloxone. In this trial, 326 heroin-addicted subjects were randomly assigned to either buprenorphine/naloxone 16 mg per day, 16 mg buprenorphine per day or placebo. For subjects randomized to either active treatment, dosing began with 8 mg of buprenorphine on Day 1, followed by 16 mg (two 8 mg) of buprenorphine on Day 2. On Day 3, those randomized to receive buprenorphine/naloxone were switched to the combination tablet. Subjects were seen daily in the clinic (Monday through Friday) for dosing and efficacy assessments. Take-home doses were provided for weekends. The primary study comparison was to assess the efficacy of buprenorphine and buprenorphine/naloxone individually against placebo. The percentage of thrice-weekly urine samples that were negative for non-study opioids was statistically higher for both buprenorphine/naloxone versus placebo (p < 0.0001) and buprenorphine versus placebo (p < 0.0001).In a double-blind, double-dummy, parallel-group study comparing buprenorphine ethanolic solution to a full agonist active control, 162 subjects were randomized to receive the ethanolic sublingual solution of buprenorphine at 8 mg/day (a dose which is roughly comparable to a dose of 12 mg/day of buprenorphine/naloxone), or two relatively low doses of active control, one of which was low enough to serve as an alternative to placebo, during a 3 to10 day induction phase, a 16-week maintenance phase and a 7-week detoxification phase. Buprenorphine was titrated to maintenance dose by Day 3; active control doses were titrated more gradually. Based on retention in treatment and the percentage of thrice-weekly urine samples negative for non-study opioids, buprenorphine was more effective than the low dose of the control, in keeping heroin addicts in treatment and in reducing their use of opioids while in treatment. The effectiveness of buprenorphine, 8 mg per day was similar to that of the moderate active control dose, but equivalence was not demonstrated.
AbsorptionBuprenorphine, when taken orally, undergoes first-pass metabolism with N-dealkylation and glucuroconjugation in the small intestine and the liver. The use of this medicinal product by the oral route is therefore inappropriate.Peak plasma concentrations are achieved 90 minutes after sublingual administration. Plasma levels of buprenorphine increased with the sublingual dose of buprenorphine/naloxone. Both Cmax and AUC of buprenorphine increased with the increase in dose (in the range of 4-16 mg), although the increase was less than dose-proportional.
Suboxone 4 mg
Suboxone 8 mg
Suboxone 16 mg
DistributionThe absorption of buprenorphine is followed by a rapid distribution phase (distribution half-life of 2 to 5 hours).
Biotransformation and eliminationBuprenorphine is metabolised by 14-N-dealkylation and glucuroconjugation of the parent molecule and the dealkylated metabolite. Clinical data confirm that CYP3A4 is responsible for the N-dealkylation of buprenorphine. N-dealkylbuprenorphine is a μ-opioid agonist with weak intrinsic activity.Elimination of buprenorphine is bi- or tri-exponential, and has a mean half-life from plasma of 32 hours. Buprenorphine is eliminated in the faeces by biliary excretion of the glucuroconjugated metabolites (70 %), the rest being eliminated in the urine.
Absorption and distribution:Following intravenous administration, naloxone is rapidly distributed (distribution half-life ~ 4 minutes). Following oral administration, naloxone is barely detectable in plasma; following sublingual administration of buprenorphine/naloxone, plasma naloxone concentrations are low and decline rapidly.
BiotransformationThe medicinal product is metabolized in the liver, primarily by glucuronide conjugation, and excreted in the urine. Naloxone has a mean half-life from plasma of 1.2 hours.
ElderlyNo pharmacokinetic data in elderly patients are available.
Renal impairmentRenal elimination plays a relatively small role (~30 %) in the overall clearance of buprenorphine/naloxone. No dose modification based on renal function is required but caution is recommended when dosing subjects with severe renal impairment (see Section 4.3).
Hepatic impairmentThe effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone were evaluated in a post-marketing study. Table 3 summarizes the results from a clinical trial in which the exposure after single-dose administration of Suboxone 2.0/0.5mg (buprenorphine/naloxone) sublingual tablet was determined in healthy subjects, and in subjects with hepatic impairment.
Table 3. Effect of hepatic impairment on pharmacokinetic parameters of buprenorphine and naloxone following SUBOXONE 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)
Similar to control
Similar to control
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