Zubsolv · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-098223 · has-adverse-reaction-information · PDF-Seite 11

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 Very Common Uncommon Not known Class common Infections and Influenza Urinary tract infestations Infection infection Pharyngitis Vaginal infection Rhinitis Blood and Anaemia lymphatic Leukocytosis system Leukopenia disorders 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 Apathy

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HOS-098219 · 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-098218 · has-indication-information · PDF-Seite 3

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.

HOS-098221 · has-interaction-information · PDF-Seite 9

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 bupreno

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HOS-098222 · has-pregnancy-information · PDF-Seite 10

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).

HOS-098220 · 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 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- 5 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 individua

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