4.1. Therapeutic indications

Substitution treatment for opioid drug dependence, within a framework of medical, social and psychological treatment.

4.2. Posology and method of administration

Posology

Treatment is intended for use in adults and adolescents aged 15 years or older who have agreed to be treated for addiction.

Induction therapy

Baseline liver function tests and documentation of viral hepatitis status is recommended prior to commencing therapy. Patients who are positive for viral hepatitis, on concomitant medication (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).

Induction

Prior to treatment induction, 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 should be undertaken when objective and clear signs of withdrawal are evident.

The initial dose is from 0.8mg to 4mg, administered as a single daily dose. 0.4mg dose strength of Buprenorphine is not available. If low dose is required, the patient should use tablets (0.4mg) of another brand.

- for opioid-dependent drug addicts who have not undergone withdrawal: one dose of buprenorphine tablet(s) administered sublingually at least 4-6 hours after the last use of the opioid, or when the first signs of craving withdrawal appear.

- for patients receiving methadone: before beginning buprenorphine therapy, the dose of methadone should be reduced to a maximum of 30mg/day. Buprenorphine may precipitate symptoms of withdrawal in patients dependent upon methadone.

Dosage adjustment and maintenance

The dosage should be individualised for each patient. The maintenance dosage will vary between individuals and should be determined by progressively increasing the dose until the minimal effective dose is identified. The mean maintenance daily dose is 8mg. The majority of patients will not require doses exceeding 16mg/day, however, the efficacy and safety of buprenorphine tablets was tested in clinical trials in doses up to 24mg per day.

The dosage is titrated according to reassessment of the clinical status and global management of the patient. Unsatisfactory stabilisation on 16mg per day may be related to potential misuse or psychiatric comorbidities. In these case alternative treatment options should be taken into account.

Daily dispensing of buprenorphine is recommended, particularly during the initiation of treatment. Then, after stabilisation, the patient may be given a supply of the product sufficient for several days of treatment. However, it is recommended that the amount of the product dispensed be limited to a maximum of 7 days or according to local requirements.

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.

Patients with hepatic impairment

The effect of hepatic impairment on the pharmacokinetics of buprenorphine is unknown. Since buprenorphine is extensively metabolized, the plasma levels will be expected to be higher in patients with moderate and severe hepatic impairment.

Patients with renal impairment

Modification of the buprenorphine dose is not required in patients with renal insufficiency. Caution is recommended when dosing patients with severe renal impairment (CLcr <30ml/min) (see section 5.2).

Paediatric population

There are no clinical data on efficacy and safety for the use of Buprenorphine in children and adolescents. Therefore, Buprenorphine should not be used in children and adolescents under the age of 16.

Method of administration

Administration is sublingual. Physicians must advise patients that the sublingual route is the only effective and safe route of administration for this medicinal product. The tablet should be kept under the tongue until dissolved, which usually occurs within 5 to 10 minutes.

The result of the treatment depends on the dosage prescribed as well as on the combined medical, psychological, social and educational measures taken in monitoring the patient.

Treatment goals and discontinuation

Before initiating treatment with Buprenorphine SUN, a treatment strategy including treatment duration and treatment goals, should be agreed together with the patient. During treatment, there should be frequent contact between the physician and the patient to evaluate the need for continued treatment, consider discontinuation and to adjust dosages if needed. When a patient no longer requires therapy with Buprenorphine SUN, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal (see section 4.4).

4.3. Contraindications

- hypersensitivity to the active substance or to any of the excipients listed in section 6.1

- children less than 15 years of age

- severe respiratory insufficiency

- severe hepatic insufficiency

- acute alcoholism or delirium tremens

- breast-feeding.

4.4. Special warnings and precautions for use

Warnings

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).

Misuse, abuse and diversion

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.

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.

Dependence

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 (e.g. morphine).Abrupt discontinuation of treatment is not recommended as it may result in a withdrawal syndrome that may be delayed in onset.

Respiratory Depression

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, spinal deviation which may lead to dyspnea). Patients with the physical and/or pharmacological risk factors described above should be monitored.

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.

Hepatitis, hepatic events

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 mitochondrial damage (genetic disease), liver enzyme abnormalities, 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 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 treatment is continued, hepatic function should be monitored closely.

All patients should have liver function tests performed at regular intervals.

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.

Tolerance and opioid use disorder (abuse and dependence)

Tolerance, physical and psychological dependence, and opioid use disorder (OUD) may develop upon repeated administration of opioids such as Buprenorphine SUN. Abuse or intentional misuse of Buprenorphine SUN may result in overdose and/or death. The risk of developing OUD is increased in patients with a personal or a family history (parents or siblings) of substance use disorders (including alcohol use disorder), in current tobacco users or in patients with a personal history of other mental health disorders (e.g. major depression, anxiety and personality disorders).

Before initiating treatment with Buprenorphine SUN and during the treatment, treatment goals and a discontinuation plan should be agreed with the patient (see section 4.2).

Patients will require monitoring for signs of drug-seeking behavior (e.g. too early requests for refills). This includes the review of concomitant opioids and psychoactive drugs (like benzodiazepines). For patients with signs and symptoms of OUD, consultation with an addiction specialist should be considered.

Precipitation of opioid withdrawal syndrome

When initiating treatment with buprenorphine, 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).

Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs:

Concomitant use of Buprenorphine 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 Buprenorphine 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).

Hepatic impairment

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 impairment

Renal elimination may be prolonged as approximately 30% of the administered dose is eliminated by the renal route. Metabolites of buprenorphine accumulate in patients with renal failure. Caution is recommended dosing patients with severe renal impairment (creatine clearance < 30 ml/min) (see section 4.2 and 5.2).

Allergic reactions: cases of acute and chronic hypersensitivity to buprenorphine have been reported both in clinical trials and in post-marketing experience. The most common signs and symptoms include skin rashes, hives, and itching.

Cases of bronchospasm, angioedema and anaphylactic shock have been reported. A positive history of hypersensitivity to buprenorphine is a contraindication to its use.

General warnings related to the administration of opioids

- opioids may cause orthostatic hypotension in ambulatory patients

- as with other opioids, caution is requested in patients using buprenorphine and having head injury, increased intracranial pressure, hypotension, prostatic hypertrophy or urethral stenosis

- 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.

- 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.

Use in adolescents

Due to lack of data in adolescents (age 16 – 18), patients in this age group should be more closely monitored during treatment.

Sleep-related breathing disorders

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.

Serotonin syndrome

Concomitant administration of Buprenorphine and other serotonergic agents, such as MAO inhibitors, 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.

Excipients

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'.

4.5. Interaction with other medicinal products and other forms of interaction

Buprenorphine should not be taken together with

- alcoholic drinks or medicinal products containing alcohol. Alcohol increases the sedative effect of buprenorphine (see Section 4.7).

Buprenorphine should be used cautiously together with:

- sedative medicines such as benzodiazepines or related drugs: 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). Patients must be closely monitored when this combination is prescribed. Patients should be warned that it is extremely dangerous to self administer non-prescribed benzodiazepines whilst taking this product, and should also be cautioned to use benzodiazepines concurrently with this product only as prescribed.

- gabapentinoids: The concomitant use of Buprenorphine SUN with gabapentinoids (gabapentin and pregabalin) may result in respiratory depression, hypotension, profound sedation, coma or death (see section 4.4).

- other central nervous system depressants; other opioid derivatives (analgesics, methadone 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. The reduced level of alertness can make driving and using machinery hazardous

- monoamine oxidase inhibitors (MAOI): Possible exaggeration of the effects of opioids, based on experience with morphine. It is recommended to avoid co-administration and the administration within the two weeks after MAO treatment discontinuation (see section 4.4).

- opioid analgesics: Adequate analgesia may be difficult to achieve when administering a full opioid agonist in patients receiving buprenorphine. The potential for overdose also exists with a full agonist, especially when attempting to overcome buprenorphine partial agonist effects, or when buprenorphine plasma levels are declining (see section 4.4)

- naltrexone: This is an opioid antagonist that can block the pharmacological effects of buprenorphine. For opioid dependent patients currently receiving buprenorphine treatment, naltrexone may precipitate a sudden onset of prolonged and intense opioid withdrawal symptoms. For patients currently receiving naltrexone treatment, the intended therapeutic effects of buprenorphine administration may be blocked by naltrexone

- Serotonergic medicinal products, such as MAO inhibitors, 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).

- Concomitant administration of buprenorphine with anticholinergics or medications with anticholinergic activity (e.g. tricyclic antidepressants, antihistamines, antipsychotics, muscle relaxants, anti-Parkinson drugs) may result in increased anticholinergic adverse effects.

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 may require dose reduction if combined with potent CYP3A4 inhibitors (e.g. HIV protease inhibitors, macrolide antibiotics and azole antifungals).

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.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of buprenorphine in pregnant women.

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.

Breast-feeding

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.

Fertility

There are no or limited data on the effects of buprenorphine on human fertility. Animal data did not indicate any impairment of fertility (see section 5.3).

4.7. Effects on ability to drive and use machines

Buprenorphine has moderate influence on the ability to drive and use machines. 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 in the event that buprenorphine affects the performance of such activities (see Section 4.5).

4.8. Undesirable effects

The onset of undesirable effects depends on the patient's tolerance threshold, which is higher in drug addicts than in the general population.

Summary of safety profile

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

System Organ Class

Frequency

Undesirable effects

Infections and infestations

Common

Bronchitis, infection, influenza, pharyngitis, rhinitis

Blood and lymphatic system disorders

Common

Lymphadenopathy

Metabolism and nutrition disorders

Common

Decreased appetite

Rare

Hypersensitivity

Psychiatric disorders

Very common

Insomnia

Common

Agitation, anxiety, depression, hostility, nervousness, paranoia, thinking abnormal

Rare

Hallucination, euphoria

Not known

Drug dependence

Nervous system disorders

Very common

Headache

Common

Dizziness, hypertonia, migraine, paraesthesia, somnolence, syncope, tremor

Eye disorders

Common

Lacrimal disorder, mydriasis, myosis

Cardiac disorders

Common

Palpitations

Vascular disorders

Common

Vasodilatation, hypertension, hypotension

Respiratory, thoracic and mediastinal disorders

Common

Cough, dyspnoea, yawning

Rare

Respiratory depression

Gastrointestinal disorders

Very common

Nausea

Common

Constipation, abdominal pain, diarrhoea, dry mouth, dyspepsia, gastrointestinal disorder, flatulence, tooth disorder, vomiting

Not known

dental caries

Skin and subcutaneous tissue disorders

Very common

Hyperhidrosis

Common

Rash

Musculoskeletal, connective tissue and bone disorders

Common

Arthralgia, back pain, bone pain, muscle spasms, myalgia, neck pain

Reproductive system and breast disorders

Common

Dysmenorrhoea

General disorders and administration site conditions

Very common

Drug withdrawal syndrome, pain

Common

Asthenia, chest pain, malaise, oedema peripheral, pyrexia

Not known

Drug withdrawal syndrome neonatal

Description of selected adverse reactions

The 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, respiratory depression, 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.

- drug dependence: Repeated use of Buprenorphine SUN can lead to drug dependence, even at therapeutic doses. The risk of drug dependence may vary depending on a patient's individual risk factors, dosage, and duration of opioid treatment (see section 4.4).

Reporting of suspected adverse reactions

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.

4.9. Overdose

Symptoms

Respiratory 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.

Treatment

General 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. If the patient vomits, care should 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.

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.