buprenorphine/naloxone: prescribing information – dosing, contraindications, interactions, side effects

Substitution treatment for opioid drug dependence, within a framework of medical, social and psychological treatment. The intention of the naloxone component is to deter intravenous misuse.
Suboxone is indicated in adults and adolescents over 15 years of age who have agreed to be treated for addiction.

Treatment must be under the supervision of a physician experienced in the management of opiate dependence/addiction.

Precautions to be taken before induction
Prior 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 must 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 must 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.

Posology

Initiation therapy (induction)
The recommended starting dose in adults and adolescents over 15 years of age is 4 mg/1 mg and can be repeated up to a maximum dose of 12 mg/ 3 mg on day 1 to minimise undue withdrawal symptoms and retain the patient in treatment.
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 stabilisation and maintenance therapy
Following treatment induction on day 1, the patient must be rapidly stabilised on an adequate maintenance dose by titrating to achieve a dose that holds the patient in treatment and suppresses opioid withdrawal effects and is guided by reassessment of the clinical and psychological status of the patient.
The maximum single daily dose should not exceed 24 mg buprenorphine.

During maintenance therapy, it may be necessary to periodically restabilise the patient on a new maintenance dose in response to changing patient needs.

Less than daily dosing
After a satisfactory stabilisation has been achieved the frequency of Suboxone 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/2 mg may be given 16 mg/4 mg on alternate days, with no dose on the intervening days. In some patients, after a satisfactory stabilisation has been achieved, the frequency of Suboxone 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 . Patients requiring a titrated daily dose> 8 mg /day may not find this regimen adequate.

Medical withdrawal
After a satisfactory stabilisation has been achieved, if the patient agrees, the dose may be reduced gradually to a lower maintenance dose; in some favourable cases, treatment may be discontinued. The availability of the sublingual tablet in doses of 2 mg/0.5 mg and 8 mg/2 mg allows for a downward

titration of dose. For patients who may require a lower buprenorphine dose, buprenorphine 0.4 mg sublingual tablet may be used. Patients should be monitored following medical withdrawal because of the potential for relapse.

Switching between buprenorphine and buprenorphine/naloxone
When used sublingually, buprenorphine/naloxone and buprenorphine have similar clinical effects and are interchangeable; however, before switching between buprenorphine/naloxone and buprenorphine, the prescriber and patient should agree to the change, and the patient should be monitored in case a need to readjust the dose occurs.

Switching between sublingual tablet and film (where applicable)
Patients being switched between Suboxone sublingual tablets and Suboxone film should be started on the same dose as the previously administered medicinal product. However, dose adjustments may be necessary when switching between medicinal products. Due to the potentially greater relative bioavailability of Suboxone film compared to Suboxone sublingual tablets, patients switching from sublingual tablets to film should be monitored for overdose. Those switching from film to sublingual tablets should be monitored for withdrawal or other indications of underdosing. In clinical studies, the pharmacokinetics of Suboxone film were not consistently shown to be similar to the respective dosage strengths of Suboxone sublingual tablets, as well as to the combinations (see section 5.2). If switching between Suboxone film and Suboxone sublingual tablets, the patient should be monitored in case a need to readjust the dose occurs. Combining different formulations or alternating between film and sublingual tablet formulations is not advised.

Special populations

Elderly
The 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 impairment
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 sections 4.3 and 5.2).

Renal impairment
Modification 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 sections 4.4 and 5.2).

Paediatric population
The safety and efficacy of buprenorphine/naloxone in children below the age of 15 years have not been established. No data are available.

Method of administration

Physicians 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 can be 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.

Treatment must be under the supervision of a physician experienced in the management of opiate dependence/addiction.

Precautions to be taken before induction
Prior 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 by a score indicating mild to moderate withdrawal on the validated Clinical Opioid Withdrawal Scale, COWS).
- For patients dependent upon heroin or short-acting opioids, the first dose of buprenorphine/naloxone must be taken when signs of withdrawal appear, but not less than 6 hours after the patient last used opioids.
- For patients receiving methadone, the dose of methadone must 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.

Posology

Initiation therapy (induction)
The recommended starting dose in adults and adolescents over 15 years of age is 4 mg/1 mg and can be repeated up to a maximum dose of 12 mg/ 3 mg on day 1 to minimise undue withdrawal symptoms and retain the patient in treatment.

Due to naloxone exposure being somewhat higher following buccal administration than sublingual administration, it is recommended that the sublingual site of administration be used during induction to minimise naloxone exposure and to reduce the risk of precipitated withdrawal.

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 stabilisation and maintenance therapy
Following treatment induction on day 1, the patient must be rapidly stabilised on an adequate maintenance dose by titrating to achieve a dose that holds the patient in treatment and suppresses opioid withdrawal effects and is guided by reassessment of the clinical and psychological status of the patient.
The maximum single daily dose should not exceed 24 mg buprenorphine.

During maintenance therapy, it may be necessary to periodically restabilise the patient on a new maintenance dose in response to changing patient needs.

Less than daily dosing
After a satisfactory stabilisation has been achieved the frequency of Suboxone 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/2 mg may be given 16 mg/4 mg on alternate days, with no dose on the intervening days. In some patients, after a satisfactory stabilisation has been achieved, the frequency of Suboxone 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. Patients requiring a titrated daily dose > 8 mg/day may not find this regimen adequate.

Medical withdrawal
After a satisfactory stabilisation has been achieved, if the patient agrees, the dose may be reduced gradually to a lower maintenance dose, in some favourable cases, treatment may be discontinued. The availability of the sublingual film in doses of 2 mg/0.5 mg, 4 mg/1 mg and 8 mg/2 mg allows for a downward titration of dose. For patients who may require a lower buprenorphine dose, buprenorphine 0.4 mg sublingual tablets may be used. Patients should be monitored following medical withdrawal because of the potential for relapse.

Switching between sublingual and buccal sites of administration
The systemic exposure of buprenorphine between buccal and sublingual administration of Suboxone film is approximately similar (see section 5.2). Therefore, once induction is complete, patients can switch between buccal and sublingual administration without significant risk of under- or overdosing.

Switching between buprenorphine and buprenorphine/naloxone
When used sublingually, buprenorphine/naloxone and buprenorphine have similar clinical effects and are interchangeable; however, before switching between buprenorphine/naloxone and buprenorphine, the prescriber and patient should agree to the change, and the patient should be monitored in case a need to readjust the dose occurs.

Switching between sublingual tablet and film (where applicable)
Patients being switched between Suboxone sublingual tablets and Suboxone film should be started on the same dose as the previously administered medicinal product. However, dose adjustments may be necessary when switching between medicinal products. Due to the potentially greater relative bioavailability of Suboxone film compared to Suboxone sublingual tablets, patients switching from sublingual tablets to film should be monitored for overdose. Those switching from film to sublingual tablets should be monitored for withdrawal or other indications of underdosing. In clinical studies, the pharmacokinetics of Suboxone film were not consistently shown to be similar to the respective dosage strengths of Suboxone sublingual tablets, as well as to the combinations (see section 5.2). If switching between Suboxone film and Suboxone sublingual tablets, the patient should be monitored in case a need to readjust the dose occurs. Combining different formulations or alternating between film and sublingual tablet formulations is not advised.

Special populations

Elderly
The safety and efficacy of buprenorphine/naloxone in elderly patients over 65 years of age has not been established. No recommendation on posology can be made.

Hepatic impairment
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 sections 4.3 and 5.2).

Renal impairment
Modification 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 sections 4.4 and 5.2).

Paediatric population
The safety and efficacy of buprenorphine/naloxone in children below the age of 15 years have not been established. No data are available.

Method of administration

Sublingual use and/or buccal use only.

For induction buprenorphine/naloxone should be administered sublingually. For maintenance therapy, Suboxone film may be administered buccally and/or sublingually.

The film is not to be swallowed. The film is to be placed under the tongue or inside either cheek until completely dissolved. It is advised that patients moisten their mouths prior to dosing. Patients should not swallow or consume food or drink until the film is completely dissolved. The film should not be moved after placement, and proper administration technique should be demonstrated to the patient.

For buccal use one film should be placed on the inside of the right or left cheek. If an additional film is necessary to achieve the prescribed dose, an additional film should be placed on the opposite side.  The film must be kept on the inside of the cheek until completely dissolved. If a third film is necessary to achieve the prescribed dose, it should be placed on the inside of the right or left cheek after the first two films have dissolved.

For sublingual use one film should be placed under the tongue. If an additional film is necessary to achieve the prescribed dose, an additional film should be placed under the tongue on the opposite side.
The film must be kept under the tongue until completely dissolved. If a third film is necessary to achieve the prescribed dose, it should be placed under the tongue after the first two films have dissolved.

A daily dose can be made up from multiple Suboxone films of different strengths.  This may be taken all at the same time or in two divided portions.  The second portion should be placed sublingually and/or buccally directly after the first portion has dissolved.

No more than two films should be administered at the same time. It should be ensured that the films do not overlap.

The film is not designed to be split or subdivided into smaller doses.

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
Severe respiratory insufficiency
Severe hepatic impairment
Acute alcoholism or delirium tremens.
Concomitant administration of opioid antagonists (naltrexone, nalmefene) for the treatment of alcohol or opioid dependence.

• Hypersensitivity to the active substances or to any of the excipients listed in section 6.1
• Severe respiratory insufficiency
• Severe hepatic impairment
• Acute alcoholism or delirium tremens
• Concomitant administration of opioid antagonists (naltrexone, nalmefene) for the treatment of alcohol or opioid dependence

Summary of the safety profile
The most commonly reported treatment related adverse reactions reported during the pivotal clinical studies 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 reactions
Table 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 undesirable 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

System
Organ
Class
Very common
Common
Uncommon
Not known
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
Dental caries
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

System
Organ
Class
Very common
Common
Uncommon
Not known
Investigations

Liver function test abnormal
Weight decreased
Blood creatinine increased
Transaminases increased
Injury, poisoning and procedural complications

Injury
Heat stroke

Description of selected adverse reactions
In cases of intravenous drug misuse, some adverse reactions 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 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 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 national reporting system listed in Appendix V.*

Summary of the safety profile

The most commonly reported treatment-related adverse reactions reported during the pivotal clinical studies 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.

The most commonly reported treatment-related adverse reactions associated with the sublingual or buccal administration of buprenorphine/naloxone were oral hypoesthesia and oral mucosal erythema, respectively. Other treatment-related adverse reactions reported by more than one patient were constipation, glossodynia and vomiting.

Tabulated list of adverse reactions

Adverse reactions reported during post-marketing surveillance are also included.

The frequency of possible undesirable 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 the 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,
Abnormal dreams,
Agitation,
Apathy,
Depersonalisation,
Drug dependence,
Hallucination

System
Organ
Class
Very common

Common

Uncommon

Not Known
Thinking abnormal
Euphoric mood,
Hostility
Nervous system disorders
Headache
Migraine,
Dizziness,
Hypertonia,
Paraesthesia,
Somnolence
Amnesia,
Disturbance in attention,
Hyperkinesia,
Seizure,
Speech disorder,
Tremor
Hepatic encephalopathy,
Syncope
Eye disorders

Amblyopia,
Lacrimal disorder
Conjunctivitis,
Miosis,
Vision blurred

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,
Oral mucosal erythema,
Vomiting
Hypoaesthesia oral,
Glossodynia,
Mouth ulceration,
Oedema mouth,
Oral pain,
Paraesthesia oral,
Tongue discolouration
Glossitis,
Stomatitis,
Dental caries
Hepatobiliary disorders

Hepatic function abnormal

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,

System
Organ
Class
Very common

Common

Uncommon

Not Known
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
Investigations

Liver function test abnormal,
Weight decreased
Blood creatinine increased
Transaminases increased
Injury, poisoning and procedural complications

Injury
Heat stroke,
Poisoning
(Intoxication)

Description of selected adverse reactions

In cases of intravenous drug misuse, some adverse reactions 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 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 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 national reporting system listed in Appendix V.*

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 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 medicinal product is distributed for illicit use directly by the intended patient or if it is not safeguarded against theft.

Suboptimal treatment with buprenorphine/naloxone may prompt misuse by the patient, leading to overdose or treatment dropout. A patient who is underdosed with buprenorphine/naloxone 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, appropriate precautions should be taken when prescribing and dispensing buprenorphine, such as avoiding prescribing multiple refills early in treatment, and conducting patient follow-up visits with clinical monitoring that is appropriate for 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 with buprenorphine alone since the naloxone in this medicinal product can precipitate withdrawal in individual’s dependent on heroin, methadone, or other opioid agonists.

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.

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 the 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 medicinal 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 medicinal product in front of children. An emergency unit should be contacted immediately in case of accidental ingestion or suspicion of ingestion.

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

Risk from concomitant use of sedative medicinal products such as benzodiazepines or related medicinal products Concomitant use of buprenorphine/naloxone and sedative medicinal products such as benzodiazepines or related medicinal products may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicinal products should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe buprenorphine/naloxone concomitantly with sedative medicinal products, the lowest effective dose of the sedative medicines 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).

Serotonin syndrome
Concomitant administration of Suboxone 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.

Dependence
Buprenorphine 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 events
Cases 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 medicinal product) 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 aetiological 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 syndrome
When 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 impairment
The effects of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone were evaluated in a post-marketing study. Both buprenorphine and naloxone are extensively metabolised in the liver, and plasma levels were found to behigher for both buprenorphine and naloxone in patients with moderate and severe hepatic impairment compared with healthy subjects. Patients should be monitored for signs and symptoms of precipitated opioid withdrawal, toxicity or overdose caused by increased levels of naloxone and/or buprenorphine.

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 medicinal products (see section 4.5) and/or have existing liver dysfunction are at greater risk of liver injury. Regular monitoring of liver function is recommended (see section 4.4).

Buprenorphine/naloxone should be used with caution in patients with moderate hepatic impairment (see sections 4.3 and 5.2). In patients with severe hepatic insufficiency the use of buprenorphine/naloxone is contraindicated.

Renal impairment
Renal 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).

CYP 3A4 inhibitors
Medicinal products 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).

Class effects
Opioids 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, in other circumstances where cerebrospinal pressure may be increased, or in patients with a 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).

Excipients
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Paediatric population
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.

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 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 medicinal product is distributed for illicit use directly by the intended patient or if it is not safeguarded against theft.

Suboptimal treatment with buprenorphine/naloxone may prompt misuse by the patient, leading to overdose or treatment dropout. A patient who is underdosed with buprenorphine/naloxone 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, appropriate precautions should be taken when prescribing and dispensing buprenorphine, such as avoiding prescribing multiple refills early in treatment, and conducting patient follow-up visits with clinical monitoring that is appropriate for 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 with buprenorphine alone since the naloxone in this medicinal product can precipitate withdrawal in individual’s dependent on heroin, methadone, or other opioid agonists.

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.

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 the 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 medicinal 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 sachet safely, to never open the sachet in advance, to keep them out of the reach of children and other household members, and not to use this medicinal product in front of children. An emergency unit should be contacted immediately in case of accidental ingestion or suspicion of ingestion.

CNS depression

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

Risk from concomitant use of sedative medicinal products such as benzodiazepines or related medicinal products

Concomitant use of buprenorphine/naloxone and sedative medicinal products such as benzodiazepines or related medicinal products may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicinal products should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe buprenorphine/naloxone concomitantly with sedative medicinal products, the lowest effective dose of the sedative medicines 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).

Serotonin syndrome

Concomitant administration of Suboxone 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.

Dependence

Buprenorphine 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 events

Cases 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 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/naloxone and during treatment. When a hepatic event is suspected, further biological and aetiological 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 syndrome

When 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 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 impairment

The effects of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone were evaluated in a post-marketing study. Both buprenorphine and naloxone are extensively metabolised in the liver, and plasma levels were found to be higher for both buprenorphine and naloxone in patients with moderate and severe hepatic impairment compared with healthy subjects. Patients should be monitored for signs and symptoms of precipitated opioid withdrawal, toxicity or overdose caused by increased levels of naloxone and/or buprenorphine.

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 medicinal products (see section 4.5) and/or have existing liver dysfunction are at greater risk of liver injury. Regular monitoring of liver function is recommended (see section 4.4).

Buprenorphine/naloxone should be used with caution in patients with moderate hepatic impairment (see sections 4.3 and 5.2). In patients with severe hepatic insufficiency the use of buprenorphine/naloxone is contraindicated.

Renal impairment

Renal 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).

CYP3 A4 inhibitors

Medicinal products 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).

Class effects

Opioids 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, in other circumstances where cerebrospinal pressure may be increased, or in patients with a 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).

Excipients

This medicinal product contains maltitol liquid. Patients with rare hereditary problems of fructose intolerance should not take this medicinal product.
This medicinal product contains sunset yellow (E 110). Sunset yellow may cause allergic reactions.
This medicinal product contains less than 1 mmol sodium (23 mg) per film i.e. essentially “sodium free”.

Paediatric population

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.

Buprenorphine/naloxone should not be taken together with:

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

Suboxone should be used cautiously when co-administered with:

- Sedatives such as benzodiazepines or related medicinal products
The concomitant use of opioids with sedative medicinal products such as benzodiazepines or related medicinal products increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use of sedative medicinal products should be limited (see section 4.4). Patients should be warned that it is extremely dangerous to self-administer non-prescribed benzodiazepines while taking this medicinal product and should also be cautioned to use benzodiazepines concurrently with this medicinal product only as directed by their physician (see section 4.4).

• The concomitant use of Suboxone 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 (e.g. methadone, analgesics and antitussives), certain antidepressants, sedative H1-receptor antagonists, barbiturates, anxiolytics other than benzodiazepines, neuroleptics, clonidine and related substances: these combinations increase central nervous system depression. The reduced level of alertness can make driving and using machines hazardous.

• Furthermore, adequate analgesia may be difficult to achieve when administering a full opioid agonist in patients receiving buprenorphine/naloxone. Therefore the potential to overdose with a full agonist exists, especially when attempting to overcome buprenorphine partial agonist effects, or when buprenorphine plasma levels are declining.

• Serotonergic medicinal products, such as MAO inhibitors, selective serotonin re-uptake inhibitors (SSRIs), serotonin norepinephrine re-uptake inhibitor (SNRIs) or tricyclic antidepressants as the risk of serotonin syndrome, a potentially life-threatening condition, is increased (see section 4.4).

• Naltrexone and nalmefene are opioid antagonists that can block the pharmacological effects of buprenorphine. Co-administration during buprenorphine/naloxone treatment is contraindicated due

to the potentially dangerous interaction that may precipitate a sudden onset of prolonged and intense opioid withdrawal symptoms (see section 4.3).

• CYP3A4 inhibitors: an interaction study of buprenorphine with ketoconazole (a potent inhibitor of CYP3A4) resulted in increased Cmax and AUC (area under the curve) of buprenorphine (approximately 50 % and 70 % respectively) and, to a lesser extent, of norbuprenorphine. Patients receiving Suboxone should be closely monitored, and may require dose-reduction if combined with potent CYP3A4 inhibitors (e.g. protease inhibitors like ritonavir, nelfinavir or indinavir or azole antifungals such as ketoconazole or itraconazole, macrolide antibiotics).

• CYP3A4 inducers: Concomitant use of CYP3A4 inducers with buprenorphine may decrease buprenorphine plasma concentrations, potentially resulting in sub-optimal treatment of opioid dependence with buprenorphine. It is recommended that patients receiving buprenorphine/naloxone should be closely monitored if inducers (e.g. phenobarbital, carbamazepine, phenytoin, rifampicin) are co-administered. The dose of buprenorphine or the CYP3A4 inducer may need to be adjusted accordingly.

• The concomitant use of monoamine oxidase inhibitors (MAOI) might produce exaggeration of the effects of opioids, based on experience with morphine.

Buprenorphine/naloxone should not be taken together with:

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

Buprenorphine/naloxone should be used cautiously when co-administered with:

- Sedatives such as benzodiazepines or related medicinal products
The concomitant use of opioids with sedative medicinal products such as benzodiazepines or related medicinal products increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use of sedative medicinal products should be limited (see section 4.4). Patients should be warned that it is extremely dangerous to self-administer non-prescribed benzodiazepines while taking this medicinal product and should also be cautioned to use benzodiazepines concurrently with this medicinal product only as directed by their physician (see section 4.4).

• The concomitant use of Suboxone 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 (e.g. methadone, analgesics and antitussives), certain antidepressants, sedative H1-receptor antagonists, barbiturates, anxiolytics other than benzodiazepines, neuroleptics, clonidine and related substances: these combinations increase central nervous system depression. The reduced level of alertness can make driving and using machines hazardous.

• Furthermore, adequate analgesia may be difficult to achieve when administering a full opioid agonist in patients receiving buprenorphine/naloxone. Therefore, the potential to overdose with a full agonist exists, especially when attempting to overcome buprenorphine partial agonist effects, or when buprenorphine plasma levels are declining.

• Serotonergic medicinal products, such as MAO inhibitors, selective serotonin re-uptake inhibitors (SSRIs), serotonin norepinephrine re-uptake inhibitor (SNRIs) or tricyclic antidepressants as the risk of serotonin syndrome, a potentially life-threatening condition, is increased (see section 4.4).

• Naltrexone and nalmefene are opioid antagonists that can block the pharmacological effects of buprenorphine. Co-administration during buprenorphine/naloxone treatment is contraindicated due to the potentially dangerous interaction that may precipitate a sudden onset of prolonged and intense opioid withdrawal symptoms (see section 4.3).

• CYP3A4 inhibitors: an interaction study of buprenorphine with ketoconazole (a potent inhibitor of CYP3A4) resulted in increased Cmax and AUC (area under the curve) of buprenorphine (approximately 50 % and 70 % respectively) and, to a lesser extent, of norbuprenorphine. Patients receiving Suboxone should be closely monitored and may require dose reduction if combined with potent CYP3A4 inhibitors (e.g. protease inhibitors like ritonavir, nelfinavir or indinavir or azole antifungals such as ketoconazole or itraconazole, macrolide antibiotics).

- CYP3A4 inducers: Concomitant use of CYP3A4 inducers with buprenorphine may decrease buprenorphine plasma concentrations, potentially resulting in sub-optimal treatment of opioid dependence with buprenorphine.
It is recommended that patients receiving buprenorphine/naloxone should be closely monitored if inducers (e.g. phenobarbital, carbamazepine, phenytoin, rifampicin) are co-administered. The dose of buprenorphine or the CYP3A4 inducer may need to be adjusted accordingly.

• The concomitant use of MAOI might produce exaggeration of the effects of opioids, based on experience with morphine.

Pregnancy
There are no or limited amount of data from the use of buprenorphine/naloxone 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 for 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 fetus.

Breast-feeding
It is unknown whether naloxone is excreted in human milk. Buprenorphine and its metabolites are excreted in human milk. In rat’s buprenorphine has been found to inhibit lactation. Therefore, breastfeeding should be discontinued during treatment with Suboxone.

Fertility
Animal 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).

Pregnancy

There are no or limited amount of data from the use of buprenorphine/naloxone 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 fetus.

Breast-feeding

It is unknown whether naloxone is excreted in human milk. Buprenorphine and its metabolites are excreted in human milk. In rat’s buprenorphine has been found to inhibit lactation. Therefore, breastfeeding should be discontinued during treatment with Suboxone.

Fertility

Animal 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).

Buprenorphine/naloxone has minor to moderate influence on the ability to drive and use machines when administered to opioid dependent patients. This medicinal product 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 sections 4.4 and 4.5).

Patients should be cautioned about driving or operating hazardous machinery in case buprenorphine/naloxone may adversely affect their ability to engage in such activities.

Buprenorphine/naloxone has minor to moderate influence on the ability to drive and use machines when administered to opioid-dependent patients. This medicinal product 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 sections 4.4 and 4.5).

Patients should be cautioned about driving or operating hazardous machinery in case buprenorphine/naloxone may adversely affect their ability to engage in such activities.

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. Signs of overdose may also include somnolence, amblyopia, miosis, hypotension, nausea, vomiting and/or speech disorders.

Management
General 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. Ongoing intravenous infusion rates should be titrated to patient response.

5.
PHARMACOLOGICAL PROPERTIES

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. Signs of overdose may also include somnolence, amblyopia, miosis, hypotension, nausea, vomiting and/or speech disorders.

Management

General 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. Ongoing intravenous infusion rates should be titrated to patient response.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Other nervous system drugs, drugs used in addictive disorders, ATC code:
N07BC51.

Mechanism of action
Buprenorphine 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 efficacy and safety
Efficacy 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).

Pharmacotherapeutic group: Other nervous system drugs, drugs used in addictive disorders, ATC code:
N07BC51.

Mechanism of action

Buprenorphine 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 efficacy and safety

Efficacy 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 versus a full agonist active control, 162 subjects were randomized to receive the ethanolic sublingual

Buprenorphine

Absorption
Buprenorphine, 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 increasing 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.

Table 2: Buprenorphine Mean Pharmacokinetic Parameters

Pharmacokinetic Parameter

Suboxone 4 mg
Suboxone 8 mg
Suboxone 16 mg
Cmax ng/ml

Buprenorphine

Absorption
Buprenorphine, 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.

Plasma levels of buprenorphine increased with increasing sublingual dose of buprenorphine/naloxone.
There was wide inter-patient variability in buprenorphine plasma levels, but within subjects the variability was low.

Table 2. Pharmacokinetic parameters (Mean ± SD) of buprenorphine and naloxone following sublingual administration of Suboxone film

PK Parameter
Suboxone film dose (mg)
2 mg/0.5 mg
4 mg / 1 mg*
8 mg / 2 mg
12 mg / 3 mg
Buprenorphine
Cmax (ng/mL)
0.947 ± 0.374

Substitution treatment for opioid drug dependence, within a framework of medical, social and psychological treatment. The intention of the naloxone component is to deter intravenous misuse.
Zubsolv is indicated in adults and adolescents over 15 years of age who have agreed to be treated for addiction.

Treatment must be under the supervision of a physician experienced in the management of opioid dependence/addiction.

Zubsolv is not interchangeable with other buprenorphine products, as different buprenorphine products have different bioavailability. Therefore, the dose in mg can differ between products. Once the appropriate dose has been identified for a patient with a specific buprenorphine product, that product should not be exchanged with another product.

If a patient is changed between buprenorphine or buprenorphine and naloxone containing products, dose adjustments may be necessary due to the potential differences in bioavailability (see sections 4.4 and 5.2).

Use of multiples of the three lower dose presentations of Zubsolv to substitute for any of the three higher dose presentations (in for example cases where the higher dose presentations are temporarily not available) is not recommended (see section 5.2).

Precautions to be taken before induction

Prior 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).
- For patients dependent upon heroin or short-acting opioids, the first dose of buprenorphine/naloxone must be taken when signs of withdrawal appear, but not less than 6 hours after the patient last used opioids.
- For patients receiving methadone, the dose of methadone must 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.

Posology

Initiation therapy (induction)
The recommended starting dose in adults and adolescents over 15 years of age is 1.4 mg/0.36 mg or 2.9 mg/0.71 mg a day. An additional Zubsolv 1.4 mg/0.36 mg or 2.9 mg/0.71 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 stabilisation and maintenance therapy
Following treatment induction on day 1, the patient must be rapidly stabilised on an adequate maintenance dose by titrating to achieve a dose that holds the patient in treatment and suppresses opioid withdrawal effects and is guided by reassessment of the clinical and psychological status of the patient. The maximum single daily dose should not exceed 17.2 mg buprenorphine (e.g. given as 11.4 + 5.7 mg, 2 x 8.6 mg or 3 x 5.7 mg).

During maintenance therapy, it may be necessary to periodically restabilise the patient on a new maintenance dose in response to changing patient needs.

The 0.7 mg/0.18 mg strength is intended to be used to fine tune the dose for patients especially during tapering of treatment or in case of tolerability issues during titration.

Physicians are encouraged to prescribe a single tablet once daily regimen where possible to minimise risk of diversion.

Less than daily dosing
After a satisfactory stabilisation has been achieved the frequency of Zubsolv dosing may be decreased to dosing every other day at twice the individually titrated daily dose. 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 17.2 mg buprenorphine. Patients requiring a titrated daily dose > 5.7 mg buprenorphine /day may not find this regimen adequate.

Medical withdrawal
After a satisfactory stabilisation has been achieved, if the patient agrees, the dose may be reduced gradually to a lower maintenance dose; in some favourable cases, treatment may be discontinued.
The availability of six different tablet strengths supports individual dose titration and tapering.
Patients should be monitored following medical withdrawal because of the potential for relapse.

Special populations

Elderly
The 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 impairment
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 (see section 5.2). Buprenorphine/naloxone is contraindicated in patients with severe hepatic impairment (see sections 4.3 and 5.2).

Renal impairment
Modification 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 sections 4.4 and 5.2).

Paediatric population
The safety and efficacy of buprenorphine/naloxone in children below the age of 15 years have not been established. No data are available.

Method of administration

Physicians 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.

Zubsolv disintegrates usually within 40 seconds, however it may take 5 to 10 minutes for the patient to feel complete tablet disappearance from the mouth.

If more than one tablet is required, they may be taken all at the same time or in two divided portions;
the second portion is to be taken directly after the first portion has dissolved.

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
Severe respiratory insufficiency.
Severe hepatic impairment.
Acute alcoholism or delirium tremens.
Concomitant administration of opioid antagonists (naltrexone, nalmefene) for the treatment of alcohol or opioid dependence.

Summary of the safety profile

The 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 reactions

Table 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 adverse reactions 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), Rare (≥/10 000 to <1/1 000), Very rare (<1/10 000), 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
Amnesia
Hyperkinesia
Seizure
Hepatic encephalopathy
Syncope

System Organ
Class
Very common
Common
Uncommon
Not known
Paraesthesia
Somnolence
Speech disorder
Tremor
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
Dental caries
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
Hypothermia
Drug withdrawal syndrome neonatal

System Organ
Class
Very common
Common
Uncommon
Not known
Oedema peripheral
Investigations

Liver function test abnormal
Weight decreased
Blood creatinine increased
Transaminases increased
Injury, poisoning and procedural complications

Injury
Heat stroke

Description of selected adverse reactions

In cases of intravenous drug misuse, some adverse reactions 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 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 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 national reporting system listed in Appendix V.

Misuse, abuse and diversion

Buprenorphine can be misused or abused in a manner similar to other opioids, legal or illicit. Some risks of misusers and abusers 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 medicinal product 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 medicinal product 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, appropriate precautions should be taken when prescribing and dispensing buprenorphine, such as to avoiding prescribing multiple refills early in treatment, and to conducting patient follow-up visits with clinical monitoring that is appropriate to the patient's needs.

Combining buprenorphine with naloxone in Zubsolv is intended to deter misuse and abuse of the buprenorphine. Intravenous or intranasal misuse of Zubsolv is expected to be less likely than with buprenorphine alone since the naloxone in Zubsolv can precipitate withdrawal in individual’s dependent on heroin, methadone, or other opioid agonists.

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.

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 the 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 medicinal 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 medicinal product in front of children. An emergency unit should be contacted immediately in case of accidental ingestion or suspicion of ingestion.

Central Nervous System (CNS) depression

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

Risk from concomitant use of sedative medicinal products such as benzodiazepines or related medicinal products

Concomitant use of buprenorphine/naloxone and sedative medicinal products such as benzodiazepines or related medicinal products may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicinal products should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe buprenorphine/naloxone concomitantly with sedative medicinal products, the lowest effective dose of the sedative medicines 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).

Serotonin syndrome

Concomitant administration of Zubsolv 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.

Dependence

Buprenorphine 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 events

Cases 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 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/naloxone and during treatment.

When a hepatic event is suspected, further biological and aetiological 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 syndrome

When 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 impairment

The effects 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 in liver, plasma levels were found to be higher for both buprenorphine and naloxone in patients with moderate and severe hepatic impairment compared with healthy subjects. Patients should be monitored for signs and symptoms of precipitated opioid withdrawal, toxicity or overdose caused by increased levels of naloxone and/or buprenorphine.

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 medicinal products (see section 4.5) and/or have existing liver dysfunction are at greater risk of liver injury.
Regular monitoring of liver function is recommended (see section 4.4).

Zubsolv sublingual tablets should be used with caution in patients with moderate hepatic impairment (see sections 4.2 and 5.2). In patients with severe hepatic insufficiency the use of buprenorphine/naloxone is contraindicated (see section 4.3).

Renal impairment

Renal 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).

CYP 3A4 inhibitors

Medicinal products 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).

Class effects
Opioids 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, in other circumstances where cerebrospinal pressure may be increased, or in patients with a 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).

Changing between buprenorphine containing products

The dose in mg can differ between buprenorphine products and products are not directly interchangeable. Therefore, patients should be monitored when changing between different buprenorphine containing products as differences in bioavailability (see section 5.2) may be noticeable in some individual cases. Dose adjustments may therefore be necessary.

Paediatric population

Use in adolescents (age 15 - <18 years)

Due to the lack of data in adolescents (age 15 - <18 years), patients in this age group should be more closely monitored during treatment.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

Zubsolv must not be taken together with:

Zubsolv should not be taken together with:
- Alcoholic drinks or medicinal products containing alcohol, as alcohol increases the sedative effect of buprenorphine (see section 4.7).

Zubsolv should be used cautiously when co-administered with:
- Sedatives such as benzodiazepines or related medicinal products
The concomitant use of opioids with sedative medicinal products such as benzodiazepines or related medicinal products increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use of sedative medicinal products should be limited (see section 4.4). Patients should be warned that it is extremely dangerous to self-administer non-prescribed benzodiazepines while taking this medicinal product and should also be cautioned to use benzodiazepines concurrently with this medicinal product only as directed by their physician (see section 4.4).
- The concomitant use of Zubsolv 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 (e.g. methadone, analgesics and antitussives), certain antidepressants, sedative H1-receptor antagonists, barbiturates, anxiolytics other than benzodiazepines, neuroleptics, clonidine and related substances: these combinations increase central nervous system depression. The reduced level of alertness can make driving and using machines hazardous.
- Furthermore, adequate analgesia may be difficult to achieve when administering a full opioid agonist in patients receiving buprenorphine/naloxone. Therefore the potential to overdose with a full agonist exists, especially when attempting to overcome buprenorphine partial agonist effects, or when buprenorphine plasma levels are declining
- 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)
- naltrexone and nalmefene are opioid antagonists that can block the pharmacological effects of buprenorphine. Co-administration during buprenorphine/naloxone treatment is

contraindicated due to the potentially dangerous interaction that may precipitate a sudden onset of prolonged and intense opioid withdrawal symptoms (see section 4.3).
- CYP3A4 inhibitors: an interaction study of buprenorphine with ketoconazole (a potent inhibitor of CYP3A4) resulted in increased Cmax and AUC (area under the curve) of buprenorphine (approximately 50 % and 70 % respectively) and, to a lesser extent, of norbuprenorphine Patients receiving Zubsolv should be closely monitored, and may require dose-reduction if combined with potent CYP3A4 inhibitors (e.g. protease inhibitors like ritonavir, nelfinavir or indinavir or azole antifungals such as ketoconazole or itraconazole, macrolide antibiotics).
- CYP3A4 inducers: Concomitant use of CYP3A4 inducers with buprenorphine may decrease buprenorphine plasma concentrations, potentially resulting in sub-optimal treatment of opioid dependence with buprenorphine. It is recommended that patients receiving buprenorphine/naloxone should be closely monitored if inducers (e.g.
phenobarbital, carbamazepine, phenytoin, rifampicin) are co-administered. The dose of buprenorphine or the CYP3A4 inducer may need to be adjusted accordingly.
- The concomitant use of monoamine oxidase inhibitors (MAOI) might produce exaggeration of the effects of opioids, based on experience with morphine.

Pregnancy

There are no or limited amount of data from the use of buprenorphine/naloxone 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 for 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-feeding

It is unknown whether naloxone/metabolites are excreted in human milk. Buprenorphine and its metabolites are excreted in human milk. In rat’s buprenorphine has been found to inhibit lactation.
Therefore, breastfeeding should be discontinued during treatment with Zubsolv.

Fertility

Animal 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 17.2 mg buprenorphine, based on AUC) (see section 5.3).

Buprenorphine/naloxone has minor to moderate influence on the ability to drive and use machines when administered to opioid dependent patients. This medicinal product 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 sections 4.4 and 4.5).

Patients should be cautioned about driving or operating hazardous machinery in case buprenorphine/naloxone may adversely affect their ability to engage in such activities.

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.
Signs of overdose may also include somnolence, amblyopia, miosis, hypotension, nausea, vomiting and/or speech disorders.

Management

General supportive measures should be initiated, 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 eliminated 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. Ongoing intravenous infusion rates should be titrated to patient response.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Other nervous system drugs, drugs used in addictive disorders, ATC code: N07BC51.

Mechanism of action

Buprenorphine 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 patients.

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 patients the presence of naloxone in Zubsolv produces marked opioid antagonist effects and opioid withdrawal, thereby deterring intravenous abuse.

Clinical efficacy and safety

Efficacy 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 randomised 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 randomised 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).

Zubsolv disintegrates usually within 40 seconds, however it may take 5 to 10 minutes for the patient to feel complete tablet disappearance from the mouth.

Zubsolv sublingual tablets have a higher bioavailability than conventional sublingual tablets.
Therefore the dose in mg can differ between products. Zubsolv is not interchangeable with other buprenorphine products.

In comparative bioavailability studies Zubsolv 11.4/2.9 mg displayed equivalent buprenorphine exposure to 16/4mg (2 x 8/2mg) buprenorphine/naloxone administered as conventional sublingual tablets however Zubsolv 2 x 1.4/0.36 mg displayed 20% lower buprenorphine exposure to 2 x 2/0.5 mg buprenorphine/naloxone administered as conventional sublingual tablets. Naloxone exposure was not higher from Zubsolv at any of the tested dose levels.

Buprenorphine

Absorption
Buprenorphine, 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.

There are small deviations in buprenorphine dose proportionality exposure parameters as well as deviations from strict compositional proportionality for the three lower strengths (2.9/0.71, 1.4/0.36, and 0.7/0.18 mg) compared to the three higher dose presentations. Therefore, multiples of the three lower dose presentations of Zubsolv should not be used to substitute for any of the three higher dose Zubsolv presentations.

Peak plasma concentrations are achieved approximately 90 minutes after sublingual administration.
Plasma levels of buprenorphine increased with increasing the sublingual dose of buprenorphine/naloxone. Both Cmax and AUC of buprenorphine increased with the increase in dose, although the increase was less than dose-proportional.

Distribution
The absorption of buprenorphine is followed by a rapid distribution phase (distribution half-life of 2 to 5 hours).