Suboxone · 4.4 Special warnings and precautions for use · 2

HOS-094376 · has-adverse-reaction-information · PDF-Seite 10

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 Very common Common Uncommon Not known Class Infections and Influenza Urinary tract infestations Infection infection Pharyngitis Vaginal infection Rhinitis Blood and Anaemia lymphatic system Leukocytosis disorders Leukopenia Lymphadenopathy Thrombocytopenia Immune system Hypersensitivity Anaphylactic disorders shock Metabolism and Decreased appetite nutrition Hyperglycaemia disorders Hyperlipidaemia Hypoglycaemia Psychiatric Insomnia Anxiety Abnormal dreams Hallucination disorders Depression Agitation Libido decreased Apathy Nervousness Depersonalisation Thinking Drug

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HOS-094382 · has-adverse-reaction-information · PDF-Seite 28

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 Very common Common Uncommon Not Known Class Infections and Influenza, Urinary tract infestations Infection, infection, Pharyngitis, Vaginal infection Rhinitis Blood and Anaemia, lymphatic system Leukocytosis, disorders Leukopenia, Lymphadenopathy , Thrombocytopenia Immune system Hypersensitivity Anaphylactic disorders shock Metabolism and Decreased nutrition appetite, disorders Hyperglycaemia,

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HOS-094378 · has-contraindication-information · PDF-Seite 22

• 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

HOS-094372 · has-contraindication-information · PDF-Seite 5

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.

HOS-094377 · has-indication-information · PDF-Seite 20

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.

HOS-094371 · has-indication-information · PDF-Seite 2

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. 2

HOS-094380 · has-interaction-information · PDF-Seite 26

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 durin

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HOS-094374 · has-interaction-information · PDF-Seite 8

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 bupren

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HOS-094381 · has-pregnancy-information · PDF-Seite 27

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).

HOS-094375 · has-pregnancy-information · PDF-Seite 9

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).

HOS-094379 · has-warning-information · PDF-Seite 22

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. 22 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

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HOS-094373 · has-warning-information · PDF-Seite 5

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 depressi

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