Leaflet SUBOXONE 2mg / 0.5mg sublingual tablets

Misuse, abuse and diversion

Buprenorphine can be misused or abused in a manner similar to other opioids, legal or illicit. Some risksof 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 intendedpatient poses the additional risk of new drug dependent individuals using buprenorphine as the primarydrug of abuse, and may occur if the medicinal product is distributed for illicit use directly by the intendedpatient or if it is not safeguarded against theft.

Suboptimal treatment with buprenorphine/naloxone may prompt misuse by the patient, leading tooverdose or treatment dropout. A patient who is underdosed with buprenorphine/naloxone may continueresponding to uncontrolled withdrawal symptoms by self-medicating with opioids, alcohol or othersedative-hypnotics such as benzodiazepines.

To minimise the risk of misuse, abuse and diversion, appropriate precautions should be taken whenprescribing and dispensing buprenorphine, such as avoiding prescribing multiple refills early intreatment, and conducting patient follow-up visits with clinical monitoring that is appropriate for thepatient's needs.

Combining buprenorphine with naloxone in Suboxone is intended to deter misuse and abuse of thebuprenorphine. Intravenous or intranasal misuse of Suboxone is expected to be less likely than withbuprenorphine alone since the naloxone in this medicinal product can precipitate withdrawal inindividual’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 whopresent with CSA, consider decreasing the total opioid dosage.

A number of cases of death due to respiratory depression have been reported, particularly whenbuprenorphine was used in combination with benzodiazepines (see section 4.5) or when buprenorphinewas not used according to the prescribing information. Deaths have also been reported in associationwith concomitant administration of buprenorphine and other depressants such as alcohol or otheropioids. If buprenorphine is administered to some non-opioid dependent individuals, who are nottolerant 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 topotential 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 theblister safely, to never open the blister in advance, to keep them out of the reach of children and otherhousehold members, and not to take this medicinal product in front of children. An emergency unitshould 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 centralnervous system depressants (such as benzodiazepines, tranquilisers, sedatives or hypnotics see sections4.5 and 4.7).

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

Concomitant use of buprenorphine/naloxone and sedative medicinal products such as benzodiazepinesor related medicinal products may result in sedation, respiratory depression, coma and death. Becauseof these risks, concomitant prescribing with these sedative medicinal products should be reserved forpatients for whom alternative treatment options are not possible. If a decision is made to prescribebuprenorphine/naloxone concomitantly with sedative medicinal products, the lowest effective dose ofthe sedative medicines should be used, and the duration of treatment should be as short as possible. Thepatients should be followed closely for signs and symptoms of respiratory depression and sedation. Inthis respect, it is strongly recommended to inform patients and their caregivers to be aware of thesesymptoms (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 ofthe 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 considereddepending on the severity of the symptoms.

Dependence

Buprenorphine is a partial agonist at the µ (mu)-opiate receptor and chronic administration producesdependence of the opioid type. Studies in animals, as well as clinical experience, have demonstratedthat 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 thatmay be delayed in onset.

Hepatitis and hepatic events

Cases of acute hepatic injury have been reported in opioid-dependent addicts both in clinical trials andin post marketing adverse reaction reports. The spectrum of abnormalities ranges from transientasymptomatic 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-existingmitochondrial impairment (genetic disease, liver enzyme abnormalities, infection with hepatitis B orhepatitis C virus, alcohol abuse, anorexia, concomitant use of other potentially hepatotoxic medicinalproduct) and ongoing injecting drug use may have a causative or contributory role. These underlyingfactors must be taken into consideration before prescribing buprenorphine/naloxone and duringtreatment. 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 preventwithdrawal symptoms and to prevent a return to illicit drug use. If the treatment is continued, hepaticfunction should be monitored closely.

Precipitation of opioid withdrawal syndrome

When initiating treatment with buprenorphine/naloxone, the physician must be aware of the partialagonist 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, orif administered less than 24 hours after the last dose of methadone. Patients should be clearly monitoredduring the switching period from buprenorphine or methadone to buprenorphine/naloxone sincewithdrawal symptoms have been reported. To avoid precipitating withdrawal, induction withbuprenorphine/naloxone should be undertaken when objective signs of withdrawal are evident (seesection 4.2).

Withdrawal symptoms may also be associated with sub-optimal dosing.

The effects of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone wereevaluated in a post-marketing study. Both buprenorphine and naloxone are extensively metabolised inthe liver, and plasma levels were found to behigher for both buprenorphine and naloxone in patientswith moderate and severe hepatic impairment compared with healthy subjects. Patients should bemonitored for signs and symptoms of precipitated opioid withdrawal, toxicity or overdose caused byincreased levels of naloxone and/or buprenorphine.

Baseline liver function tests and documentation of viral hepatitis status is recommended prior tocommencing 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. Regularmonitoring of liver function is recommended (see section 4.4).

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

Renal elimination may be prolonged since 30 % of the administered dose is eliminated by the renalroute. Metabolites of buprenorphine accumulate in patients with renal failure. Caution is recommendedwhen dosing patients with severe renal impairment (creatinine clearance <30 ml/min) (see sections 4.2and 5.2).

CYP 3A4 inhibitors

Medicinal products that inhibit the enzyme CYP3A4 may give rise to increased concentrations ofbuprenorphine. A reduction of the buprenorphine/naloxone dose may be needed. Patients already treatedwith CYP3A4 inhibitors should have their dose of buprenorphine/naloxone titrated carefully since areduced dose may be sufficient in these patients (see section 4.5).

Opioids may produce orthostatic hypotension in ambulatory patients.

Opioids may elevate cerebrospinal fluid pressure, which may cause seizures, so opioids should be usedwith caution in patients with head injury, intracranial lesions, in other circumstances wherecerebrospinal 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 urethralstenosis.

Opioid-induced miosis, changes in the level of consciousness, or changes in the perception of pain as asymptom of disease may interfere with patient evaluation or obscure the diagnosis or clinical course ofconcomitant disease.

Opioids should be used with caution in patients with myxoedema, hypothyroidism, or adrenal corticalinsufficiency (e.g., Addison's disease).

Opioids have been shown to increase intracholedochal pressure, and should be used with caution inpatients 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 theeffects of opioids, based on experience with morphine (see section 4.5).

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’.

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 closelymonitored during treatment.