SUBOXONE 2 MG / 0.5 MG SUBLINGUAL FILM - summary of medicine characteristics

Suboxone 2 mg/0.5 mg sublingual film

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Suboxone 2 mg/0.5 mg sublingual film

Each film contains 2 mg buprenorphine (as hydrochloride) and 0.5 mg naloxone (as hydrochloride dihydrate).

Excipients with known effect

Each film contains 5.87 mg maltitol liquid and 0.01 mg sunset yellow (E 110).

For the full list of excipients, see section 6.1.

Sublingual film

Suboxone 2 mg/0.5 mg sublingual film

2 mg/0.5 mg orange rectangular film of nominal dimensions 22.0 mm x

12.8 mm, with ‘N2’ imprinted in white ink.

4.1 Therapeutic indications

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.

4.2 Posology and method of administration

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

Prior to starting treatment with opioids, a discussion should be held with patients to put in place a strategy for ending treatment with buprenorphine in order to minimise the risk of addiction and drug withdrawal syndrome (see section 4.4). The decision to maintain a patient on a long-term opioid prescription should be an active decision agreed between the clinician and patient with review at regular intervals (usually at least three-monthly, depending on clinical progress).

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 two Suboxone 2 mg/0.5 mg sublingual films or one Suboxone 4 mg/1 mg sublingual film. This may be achieved using two Suboxone 2 mg/0.5 mg sublingual films as a single dose or one Suboxone 4 mg/1 mg sublingual film, which can be repeated up to twice 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.D 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. □ DThis may be taken all at the same time or in two divided portions. □ DThe 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.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

Drug dependence, tolerance, potential for abuse and diversion

Prolonged use of this product may lead to drug dependence (addiction), even at therapeutic doses. The risks are increased in individuals with current or past history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g., major depression). Overuse or misuse may result in overdose and/or death. It is important that patients only use medicines that are prescribed for them at the dose they have been prescribed and do not give this medicine to anyone else. Patients should be closely monitored for signs of misuse, abuse, or addiction. The clinical need for continuing opioid substitution therapy should be reviewed regularly.

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.

Seizures

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

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 reuptake 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 li (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.

Drug withdrawal syndrome

Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with buprenorphine The decision to maintain a patient on a long-term opioid prescription should be an active decision agreed between the clinician and patient with review at regular intervals (usually at least three-monthly, depending on clinical progress).

Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal.

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

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

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.

4.5 Interaction with other medicinal products and other forms of interaction

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).

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 reuptake 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.

4.6 Fertility, pregnancy and lactation

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).

4.7 Effects on ability to drive and use machines

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.

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

The medicine is likely to affect your ability to drive

Do not drive until you know how the medicine affects you

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

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

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

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

o It was not affecting your ability to drive safely

4.8 Undesirable effects

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 postmarketing surveillance of buprenorphine/na­loxone

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 Yellow Card Scheme website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

5   PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic 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 li and k (kappa) opioid receptors of the brain. Its activity in opioid maintenance treatment is attributed to its slowly reversible properties with the l-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 l-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 solution of buprenorphine at 8 mg/day (a dose which is roughly comparable to a dose of 12 mg/day of buprenorphine/na­loxone), or two relatively low doses of active control, one of which was low enough to serve as an alternative to placebo, during a 3 to10 day induction phase, a 16-week maintenance phase and a 7-week detoxification phase. Buprenorphine was titrated to maintenance dose by Day 3; active control doses were titrated more gradually. Based on retention in treatment and the percentage of thrice-weekly urine samples negative for nonstudy opioids, buprenorphine was more effective than the low dose of the control in keeping heroin addicts in treatment and in reducing their use of opioids while in treatment. The effectiveness of buprenorphine, 8 mg per day was similar to that of the moderate active control dose, but equivalence was not demonstrated.

In a multicentre RCT study, 92 patients received either Suboxone film or Suboxone sublingual tablets following a 7-day run-in period with Suboxone sublingual tablets. It took 4 minutes on average for the sublingual tablets to visibly dissolve and 3 minutes on average for the sublingual film to dissolve. As concerns removability of sublingually applied films it was demonstrated that after 30 seconds of the application of a single film, none of the study participants could remove some or all the film. However, when 2 or more films were administered the participants were more likely to be able to remove some or all the film after 30 seconds. No more than 2 films should be administered at the same time (see section 4.2).

5.2 Pharmacokinetic properties

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

*There are no data for the 4 mg/1 mg strength film; it is compositionally proportional to 2 mg/0.5 mg strength film and has the same size of 2 × 2 mg/0.5 mg film strength.

Table 3. Changes in pharmacokinetic parameters for Suboxone film administered sublingually or buccally in comparison to Suboxone sublingual tablet

Note 1. ‘- ‘represents no change when the 90 % confidence intervals for the geometric mean ratios of the Cmax and AUC0-last values are within the 80 % to 125 % limit.

Note 2. There are no data for the 4 mg/1 mg strength film; it is compositionally proportional to the 2 mg/0.5 mg strength film and has the same size as the 2 × 2 mg/0.5 mg film strength.

Distribution

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

Buprenorphine is highly lipophilic, which leads to rapid penetration of the blood-brain barrier.

Buprenorphine is approximately 96 % protein bound, primarily to alpha and beta globulin.

Biotransformation

Buprenorphine is primarily metabolised through N-dealkylation by liver microsomal CYP3A4. The parent molecule and the primary dealkylated metabolite, norbuprenorphine, undergo subsequent glucuronidation.

Norbuprenorphine binds to opioid receptors in vitro; however, it is not known whether norbuprenorphine contributes to the overall effect of buprenorphine/na­loxone.

Elimination

Elimination of buprenorphine is bi- or tri-exponential, and the mean terminal elimination half-life from plasma is reported in Table 2.

Buprenorphine is excreted in the faeces (~70 %) by biliary excretion of the glucuroconjugated metabolites, the rest (~30 %) being excreted in the urine.

Linearity/non-linearity

Buprenorphine Cmax and AUC increased in a linear fashion with the increasing dose (in the range of 4 to 16 mg), although the increase was not directly doseproportional.

Naloxone

Absorption

Naloxone mean peak plasma concentrations were too low to assess doseproportio­nality, and in seven of eight subjects tested who had naloxone plasma levels above the limit of quantification (0.05 ng/mL), naloxone was not detected beyond 2 hours post-dose.

Naloxone has not been found to affect the pharmacokinetics of buprenorphine, and both buprenorphine sublingual tablets and buprenorphine/na­loxone sublingual film deliver similar plasma concentrations of buprenorphine.

Distribution

Naloxone is approximately 45 % protein bound, primarily to albumin.

Biotransformation

Naloxone is metabolized in the liver, primarily by glucuronide conjugation, and excreted in the urine.

Naloxone undergoes direct glucuronidation to naloxone 3-glucuronide, as well as N-dealkylation and reduction of the 6-oxo group.

Elimination

Naloxone is excreted in the urine, with a mean half-life of elimination from plasma ranging from 2 to 12 hours.

Special populations

Elderly

No pharmacokinetic data in elderly patients are available.

Renal impairment

Renal elimination plays a relatively small role (~30 %) in the overall clearance of buprenorphine/na­loxone. No dose modification based on renal function is required but caution is recommended when dosing subjects with severe renal impairment (see section 4.3).

Hepatic impairment

The effect of hepatic impairment on the pharmacokinetics of buprenorphine were evaluated in a post-marketing study. Table 4 summarises the results from a clinical trial in which the exposure of buprenorphine and naloxone was determined after administering a buprenorphine/na­loxone 2.0/0.5 mg sublingual tablet in healthy subjects, and in subjects with varied degrees of hepatic impairment.

Table 4. Effect of hepatic impairment on pharmacokinetic parameters of buprenorphine and naloxone following Suboxone administration (change relative to healthy subjects)

Overall, buprenorphine plasma exposure increased approximately 3-fold in patients with severely impaired hepatic function, while naloxone plasma exposure increased 14-fold with severely impaired hepatic function.

5.3 Preclinical safety data

The combination of buprenorphine and naloxone has been investigated in acute and repeated dose (up to 90 days in rats) toxicity studies in animals. No synergistic enhancement of toxicity has been observed. Undesirable effects were based on the known pharmacological activity of opioid agonist and/or antagonistic substances.

The combination (4:1) of buprenorphine hydrochloride and naloxone hydrochloride was not mutagenic in a bacterial mutation assay (Ames test) and was not clastogenic in an in vitro cytogenetic assay in human lymphocytes or in an intravenous micronucleus test in the rat.

Reproduction studies by oral administration of buprenorphine: naloxone (ratio 1:1) indicated that embryolethality occurred in rats in the presence of maternal toxicity at all doses. The lowest dose studied represented exposure multiples of 1 x for buprenorphine and 5 x for naloxone at the maximum human therapeutic dose calculated on a mg/m2 basis. No developmental toxicity was observed in rabbits at maternally toxic doses. Further, no teratogenicity has been observed in either rats or rabbits. A peri-postnatal study has not been conducted with buprenorphine/na­loxone; however, maternal oral

administration of buprenorphine at high doses during gestation and lactation resulted in difficult parturition (possible as a result of the sedative effect of buprenorphine), high neonatal mortality and a slight delay in the development of some neurological functions (surface righting reflex and startle response) in neonatal rats.

Dietary administration of buprenorphine/na­loxone in the rat at dose levels of 500 ppm or greater produced a reduction in fertility demonstrated by reduced female conception rates. A dietary dose of 100 ppm (estimated exposure approximately 2.4 x for buprenorphine at a human dose of 24 mg buprenorphine/na­loxone based on AUC, plasma levels of naloxone were below the limit of detection in rats) had no adverse effect on fertility in females.

A carcinogenicity study with buprenorphine/na­loxone was conducted in rats at doses of 7 mg/kg/day, 30 mg/kg/day and 120 mg/kg/day, with estimated exposure multiples of 3 times to 75 times, based on a human daily sublingual dose of 16 mg calculated on a mg/m2 basis. Statistically significant increases in the incidence of benign testicular interstitial (Leydig's) cell adenomas were observed in all dosage groups.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Macrogol

Maltitol liquid

Natural lime flavour

Hypromellose

Citric acid

Acesulfame potassium

Sodium citrate

Sunset yellow (E 110)

Printing ink

Propylene Glycol (E1520)

6.2 Incompatibilities

Not applicable

6.3 Shelf life

2 years

6.4 Special precautions for storage

Store below 25 °C.

6.5 Nature and contents of container

The films are packed in child-resistant individual sachets consisting of four composite layers of polyethylene terephthalate (PET), Low Density Polyethylene (LDPE), aluminium foil and Low-Density Polyethylene (LDPE), which are heat sealed at the edges.

Pack sizes: 7 × 1, 14 × 1 and 28 × 1 sublingual films.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.