4.1. Therapeutic indications

Treatment of opioid dependence within a framework of medical, social and psychological treatment. Treatment is intended for use in adults and adolescents aged 16 years or over.

4.2. Posology and method of administration

Administration of Buvidal is restricted to healthcare professionals. Appropriate precautions, such as to conduct patient follow-up visits with clinical monitoring according to the patient's needs, should be taken when prescribing and dispensing buprenorphine. Take-home use or self-administration of the product by patients is not allowed.

Precautions to be taken before initiation of treatment

To avoid precipitating symptoms of withdrawal, treatment with Buvidal should be started when objective and clear signs of mild to moderate withdrawal are evident (see section 4.4). Consideration should be given to the types of opioid used (that is long- or short-acting opioid), time since last opioid use and the degree of opioid dependence.

• For patients using heroin or short-acting opioids, the initial dose of Buvidal must not be administered until at least 6 hours after the patient last used opioids.

• For patients receiving methadone, the methadone dose should be reduced to a maximum of 30 mg/day before starting treatment with Buvidal which should not be administered until at least 24 hours after the patient last received a methadone dose. Buvidal may trigger withdrawal symptoms in methadone-dependent patients.

Posology

Initiation of treatment in patients not already receiving buprenorphine

Patients not previously exposed to buprenorphine should receive a sublingual buprenorphine 4 mg dose and be observed for an hour before the first administration of weekly Buvidal to confirm tolerability to buprenorphine.

The recommended starting dose of Buvidal is 16 mg, with one or two additional 8 mg doses at least 1 day apart, to a target dose of 24 mg or 32 mg during the first treatment week. The recommended dose for the second treatment week is the total dose administered during the week of initiation.

Treatment with monthly Buvidal can be started after treatment initiation with weekly Buvidal, in accordance with the dose conversion in Table 1 and once patients have been stabilised on weekly treatment (four weeks or more, where practical).

Switching from sublingual buprenorphine products to Buvidal

Patients treated with sublingual buprenorphine may be switched directly to weekly or monthly Buvidal, starting on the day after the last daily buprenorphine sublingual treatment dose in accordance with the dosing recommendations in Table 1. Closer monitoring of patients is recommended during the dosing period after the switch.

Table 1. Conventional sublingual buprenorphine daily treatment doses and recommended corresponding doses of weekly and monthly Buvidal

Dose of daily sublingual buprenorphine

Dose of weekly Buvidal

Dose of monthly Buvidal

2-6 mg

8 mg

8-10 mg

16 mg

64 mg

12-16 mg

24 mg

96 mg

18-24 mg

32 mg

128 mg

26-32 mg

160 mg

Patients may be switched from sublingual buprenorphine 26-32 mg directly to monthly Buvidal 160 mg with close monitoring during the dosing period after the switch.

The dose of buprenorphine in mg can differ between sublingual products, which needs to be taken into consideration on a product-by-product basis. The pharmacokinetic properties of Buvidal are described in section 5.2.

Maintenance treatment and dose adjustments

Buvidal can be administered weekly or monthly. Doses may be increased or decreased and patients can be switched between weekly and monthly products according to individual patient's needs and treating physician's clinical judgement as per recommendations in Table 1. Following switching, patients may need closer monitoring. Assessment of long-term treatment is based on 48‑week data.

Supplemental dosing

A maximum of one supplemental Buvidal 8 mg dose may be administered at an unscheduled visit between regular weekly and monthly doses, based on individual patient's temporary needs.

The maximum dose per week for patients who are on weekly Buvidal treatment is 32 mg with an additional 8 mg dose. The maximum dose per month for patients who are on monthly Buvidal treatment is 160 mg.

Missed doses

To avoid missed doses, the weekly dose may be administered up to 2 days before or after the weekly time point, and the monthly dose may be administered up to 1 week before or after the monthly time point.

If a dose is missed, the next dose should be administered as soon as practically possible.

Termination of treatment

If Buvidal treatment is discontinued, its prolonged-release characteristics and any withdrawal symptoms experienced by the patient must be considered, see section 4.4. If the patient is switched to treatment with sublingual buprenorphine, this should be done one week after the last weekly dose or one month after the last monthly dose of Buvidal according to the recommendations in Table 1.

Special populations

Elderly

The efficacy and safety of buprenorphine in elderly patients > 65 years have not been established. No recommendation on posology can be made.

In general, recommended dosing for elderly patients with normal renal function is the same as for younger adult patients with normal renal function. However, because elderly patients may have diminished renal/hepatic function, dose adjustment may be necessary (see below).

Hepatic impairment

Buprenorphine should be used with caution in patients with moderate hepatic impairment (see section 5.2). In patients with severe hepatic impairment, the use of buprenorphine is contraindicated (see section 4.3).

Renal impairment

Modification of the buprenorphine dose is not required for patients with renal impairment. Caution is recommended when dosing patients with severe renal impairment (creatinine clearance < 30 ml/min) (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy buprenorphine in children and adolescents below 16 years of age have not been established (see section 4.4). No data are available.

Method of administration

Buvidal is intended for subcutaneous administration only. It should be injected slowly and completely into the subcutaneous tissue of different areas (buttock, thigh, abdomen, or upper arm), provided there is enough subcutaneous tissue. Each area can have multiple injection sites. Injection sites should be rotated for both weekly and monthly injections. A minimum of 8 weeks should be left before re-injecting a previously used injection site with the weekly dose. There is no clinical data supporting reinjection of the monthly dose into the same site. This is unlikely to be a safety concern. The decision to reinject at the same site should also be guided by the attending physicians´ clinical judgement. Administered dose should be as a single injection and not divided. The dose must not be administered intravascularly (intravenously), intramuscularly or intradermally (into the skin) (see section 4.4). See section 6.6 for administration instructions.

4.3. Contraindications

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

Severe respiratory insufficiency

Severe hepatic impairment

Acute alcoholism or delirium tremens

4.4. Special warnings and precautions for use

Administration

Care must be taken to avoid inadvertent injection of Buvidal. The dose must not be administered intravascularly (intravenously), intramuscularly or intradermally.

Intravascular such as intravenous injection would present a risk of serious harm as Buvidal forms a solid mass upon contact with body fluids, which potentially could cause blood vessel injury, occlusion, or thromboembolic events.

To minimise the risk of misuse, abuse and diversion, appropriate precautions should be taken when prescribing and dispensing buprenorphine. Healthcare professionals should administer Buvidal directly to the patient. Take-home use or self-administration of the product by patients is not allowed. Any attempts to remove the depot should be monitored throughout treatment.

Prolonged-release properties

The prolonged-release properties of the product should be considered during treatment including initiation and termination (see section 4.2). In particular, patients with concomitant medicinal products and/or co-morbidities, should be monitored for signs and symptoms of toxicity, overdose or withdrawal caused by increased or decreased levels of buprenorphine (see sections 4.5 and 5.2).

Seizures

Buprenorphine may lower the seizure threshold in patients with a history of seizure disorders.

Respiratory depression

A number of cases of death due to respiratory depression have been reported for patients being treated with buprenorphine, particularly when 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, gabapentinoids (such as pregabalin and gabapentin) (see section 4.5) or other opioids.

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-opioid dependent persons who accidentally or deliberately use it.

CNS depression

Buprenorphine may cause drowsiness particularly when taken together with alcohol or central nervous system depressants such as benzodiazepines, tranquilisers, sedatives, gabapentinoids or hypnotics (see sections 4.5 and 4.7).

Dependence

Buprenorphine is a partial agonist at the mu-opiate receptor and chronic administration can produce opioid dependence.

Serotonin syndrome

Concomitant administration of Buvidal 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.

Hepatitis and hepatic events

Baseline liver function tests and documentation of viral hepatitis status are recommended prior to starting therapy. Patients who are positive for viral hepatitis, on certain concomitant medicinal products (see section 4.5) and/or who have existing liver dysfunction are at greater risk of liver injury. Regular monitoring of the liver function is recommended.

Cases of acute hepatic injury have been reported in opioid-dependent patients both in clinical studies and in post-marketing adverse reaction reports with medicinal products containing buprenorphine. 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 medicinal products 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, further biological and aetiological evaluation is required. Depending on the findings, Buvidal may be discontinued. Monitoring beyond the weekly and monthly treatment period may be needed. If treatment is continued, hepatic function should be monitored closely.

Drug withdrawal syndrome

Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with buprenorphine.

Drug withdrawal syndrome may occur upon dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take weeks to months.

The opioid drug withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms may also develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate.

If women take this drug during pregnancy, there is a risk that their newborn infants will experience neonatal withdrawal syndrome.

Precipitation of opioid withdrawal syndrome

When initiating treatment with buprenorphine, it is important to be aware of the partial agonist profile of buprenorphine. Buprenorphine products have caused precipitated withdrawal symptoms in opioid-dependent patients when administered before the agonist effects resulting from recent opioid use or misuse have subsided. To avoid precipitated withdrawal, induction must be undertaken when objective signs and symptoms of mild to moderate withdrawal are evident (see section 4.2).

Discontinuation of treatment may result in a withdrawal syndrome that may be delayed in onset.

Hepatic impairment

Buprenorphine is extensively metabolised in the liver. Patients with moderate hepatic impairment should be monitored for signs and symptoms of precipitated opioid withdrawal, toxicity or overdose caused by increased levels of buprenorphine. Buprenorphine should be used with caution in patients with moderate hepatic impairment (see sections 4.2 and 5.2). Hepatic function should be monitored regularly whilst on treatment. The use of buprenorphine is contraindicated in patients with severe hepatic impairment (see section 4.3).

Renal impairment

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).

QT prolongation

Caution should be exercised when co-administering Buvidal with other medicinal products that prolong the QT interval and in patients with a history of long QT syndrome or other risk factors for QT prolongation.

Acute pain management

For management of acute pain during continued use of Buvidal, a combination of use of opioids with high mu-opioid receptor affinity (e.g. fentanyl), non-opioid analgesics and regional anaesthesia might be necessary. Titration of oral or intravenous short-acting opioid pain medicinal products (immediate-release morphine, oxycodone or fentanyl) to the desired analgesic effect in patients treated with Buvidal might require higher doses. Patients should be monitored during treatment and caution should be exercised due to the potential risk of overdose and/or death.

Use in children and adolescents

The safety and efficacy of buprenorphine in children below the age of 16 years have not been established (see section 4.2). Due to limited data in adolescents (aged 16 or 17 years), patients in this age group should be monitored closely 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 dose.

Class effects

Opioids may cause orthostatic hypotension.

Opioids may elevate cerebrospinal fluid pressure, which may cause seizures. Therefore, 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.

Latex

No natural rubber or latex is used in the formulation of the needle shield. Nevertheless, the presence of negligible traces cannot be excluded and there is therefore a potential risk of allergic reactions in latex-sensitive individuals which cannot be completely ruled out.

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

No interaction studies have been performed with Buvidal.

Buprenorphine should be used cautiously when co-administered with:

• naltrexone and nalmefene: These are opioid antagonists 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.

• alcoholic drinks or medicinal products containing alcohol as alcohol increases the sedative effect of buprenorphine (see section 4.7).

• benzodiazepines: This combination may result in death due to respiratory depression of central origin. Therefore, dosages must be closely monitored and this combination must be avoided in cases where there is a risk of misuse. 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 directed by their physician (see section 4.4).

• gabapentinoids: This combination may result in death due to respiratory depression. Therefore, dosages must be closely monitored and this combination must be avoided in cases where there is a risk of misuse. Patients should be cautioned to use gabapentinoids (such as pregabalin and gabapentin) concurrently with this product only as directed by their physician (see section 4.4).

• 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).

• other central nervous system depressants: Other opioid derivatives (e.g. methadone, analgesics and antitussives); certain antidepressants, sedative H1-receptor antagonists, barbiturates, anxiolytics other than benzodiazepines, antipsychotics, clonidine and related substances. These combinations increase central nervous system depression. The reduced level of alertness can make driving and using machinery hazardous (see section 4.7).

• 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).

• Buprenorphine is metabolised to norbuprenorphine primarily by CYP3A4. Interaction with co-administered inducers or inhibitors have been established in studies using transmucosal and transdermal buprenorphine. Buprenorphine is also metabolised to buprenorphine-3β-glucuronide by UGT1A1.

• CYP3A4 inhibitors may inhibit the metabolism of buprenorphine resulting in increased Cmax and AUC of buprenorphine and norbuprenorphine. Buvidal avoids first-pass effects and CYP3A4 inhibitors (e.g. protease inhibitors like ritonavir, nelfinavir or indinavir, or azole antifungals such as ketoconazole or itraconazole, or macrolide antibiotics) are expected to have less effects on buprenorphine metabolism when co-administered with Buvidal as compared to when co-administered with sublingual buprenorphine. When switching from sublingual buprenorphine to Buvidal, patients may need to be monitored to ensure plasma buprenorphine levels are adequate.

Patients already on Buvidal who start treatment with CYP3A4 inhibitors should be treated with weekly Buvidal and be monitored for signs and symptoms of overtreatment. Conversely, if a patient who is concomitantly treated with Buvidal and a CYP3A4 inhibitor stops treatment with the CYP3A4 inhibitor, the patient should be monitored for symptoms of withdrawal (see section 4.4).

• CYP3A4 inducers may induce the metabolism of buprenorphine resulting in decreased buprenorphine levels. Buvidal avoids first-pass effects and CYP3A4 inducers (e.g. phenobarbital, carbamazepine, phenytoin or rifampicin) are expected to have less effects on buprenorphine metabolism when co-administered with Buvidal as compared to when co-administered with sublingual buprenorphine. When switching from sublingual buprenorphine to Buvidal, patients may need to be monitored to ensure plasma buprenorphine levels are adequate. Patients already on Buvidal who start treatment with CYP3A4 inducers should be treated with weekly Buvidal and be monitored for signs and symptoms of withdrawal. Conversely, if a patient who is concomitantly treated with Buvidal and a CYP3A4 inducer stops treatment with the CYP3A4 inducer, the patient should be monitored for symptoms of overtreatment.

• UGT1A1 inhibitors may affect the systemic exposure of buprenorphine.

• monoamine oxidase inhibitors (MAOI): Possible exacerbation of the opioids effects, based on experience with morphine.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited data from the use of buprenorphine in pregnant women. Animal studies do not indicate reproductive toxicity (see section 5.3). 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 after birth should be considered to prevent the risk of respiratory depression or withdrawal syndrome in neonates.

Breast-feeding

Buprenorphine and its metabolites are excreted in human breast milk and Buvidal should be used with caution during breast-feeding.

Fertility

There are no or limited data on effects of buprenorphine on human fertility.

An effect of buprenorphine on fertility in animals has not been seen (see section 5.3).

4.7. Effects on ability to drive and use machines

Buprenorphine has minor to moderate influence on the ability to drive and use machines when administered to opioid-dependent patients. Buprenorphine may cause drowsiness, dizziness or impaired thinking, especially during treatment induction and dose adjustment. If used together with alcohol or central nervous system depressants, the effect is likely to be more pronounced (see sections 4.4. and 4.5).

This medicine can impair cognitive function and can affect a patient's ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

• The medicine is likely to affect your ability to drive

• Do not drive until you know how the medicine affects you

• It is an offence to drive while under the influence of this medicine

• However, you would not be committing an offence (called 'statutory defence') if:

• The medicine has been prescribed to treat a medical or dental problem and

• You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

• It was not affecting your ability to drive safely.

4.8. Undesirable effects

Summary of the safety profile

The adverse reactions most frequently reported for buprenorphine are headache, nausea, hyperhidrosis, insomnia, drug withdrawal syndrome and pain.

Tabulated list of adverse reactions

Table 2 presents adverse reactions reported for buprenorphine, including Buvidal. The following terms and frequencies are applied: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100) and frequency not known (cannot be estimated from available data).

Table 2. Adverse reactions listed by body system

System Organ Class

Very common

Common

Uncommon

Not known

Infections and infestations

Infection

Influenza

Pharyngitis

Rhinitis

Injection site cellulitis

Blood and lymphatic system disorders

Lymphadenopathy

Immune system disorders

Hypersensitivity

Metabolism and nutrition disorders

Decreased appetite

Psychiatric disorders

Insomnia

Anxiety

Agitation

Depression

Hostility

Nervousness

Thinking abnormal

Paranoia

Medical dependence

Hallucinations

Euphoric mood

Nervous system disorders

Headache

Somnolence

Dizziness

Migraine

Paraesthesia

Syncope

Tremor

Hypertonia

Speech disorders

Seizures

Eye disorders

Lacrimal disorder

Mydriasis

Miosis

Ear and labyrinth disorders

Vertigo

Cardiac disorders

Palpitations

Vascular disorders

Vasodilation

Hypotension

Respiratory, thoracic and mediastinal disorders

Cough

Dyspnoea

Yawning

Asthma

Bronchitis

Gastrointestinal disorders

Nausea

Constipation

Vomiting

Abdominal pain

Flatulence

Dyspepsia

Dry mouth

Diarrhoea

Gastrointestinal disorder

Hepatobiliary disorders

Alanine aminotransferase increased

Aspartate aminotransferase increased

Hepatic enzymes increased

Skin and subcutaneous tissue disorders

Rash

Pruritus

Urticaria

Rash macular

Erythema

Musculoskeletal and connective tissue disorders

Arthralgia

Back pain

Myalgia

Muscle spasms

Neck pain

Bone pain

Renal and urinary disorders

Urinary retention

Reproductive system and breast disorders

Dysmenorrhoea

General disorders and administration site conditions

Hyperhidrosis

Drug withdrawal syndrome

Pain

Injection site pain

Injection site pruritus

Injection site erythema

Injection site swelling

Injection site reaction

Injection site induration

Injection site mass

Oedema peripheral

Asthenia

Malaise

Pyrexia

Chills

Neonatal withdrawal syndrome

Chest pain

Injection site inflammation

Injection site bruising

Injection site urticaria

Injection site abscess

Injection site ulceration

Injection site necrosis

Investigations

Abnormal liver function tests

Injury, poisoning and procedural complications

Procedural dizziness

Description of selected adverse reactions

Injection site reactions

In the double-blind, phase 3 efficacy trial, injection site-related adverse reactions were observed in 36 (16.9%) of the 213 patients (5% of the administered injections) in the Buvidal treatment group. The most common adverse reactions were injection site pain (8.9%), injection site pruritus (6.1%) and injection site erythema (4.7%). The injection site reactions were all mild or moderate in severity and most events were transient.

Injection site-related adverse reactions of abscess, ulceration and necrosis have been reported during post-marketing use with Buvidal.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medical 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 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 buprenorphine overdose because it may lead to respiratory arrest and death. Preliminary symptoms of overdose may also include excessive sweating, 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, precautions must be taken to prevent aspiration. 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 opioids.

The long duration of action of buprenorphine and the prolonged release from Buvidal, should be taken into consideration when determining length of treatment needed to reverse the effects of an overdose, (see section 4.4). Naloxone can be cleared more rapidly than buprenorphine, allowing for a return of previously controlled buprenorphine overdose symptoms.