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ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1/48 1. NAME OF THE MEDICINAL PRODUCT Suboxone 2 mg/0.5 mg sublingual tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains 2 mg buprenorphine (as buprenorphine hydrochloride) and 0.5 mg naloxone (as naloxone hydrochloride dihydrate). Excipients: lactose 42 mg For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Sublingual tablet White hexagonal biconvex tablets, embossed with a sword logo on one side and “N2” on the reverse side. 4. CLINICAL PARTICULARS 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. Treatment is intended for use 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. Each Suboxone sublingual tablet contains buprenorphine and naloxone. Suboxone containing 2 mg buprenorphine and 0.5 mg naloxone is referred to as the "2 mg" tablets. 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). Suboxone sublingual tablets are to be placed under the tongue until dissolved, which usually requires 5 to 10 minutes. The dose is made up from Suboxone 2 mg/0.5 mg and Suboxone 8 mg/2 mg sublingual tablets, 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. Adults: 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 risk of accelerated liver injury. Regular monitoring of liver function is recommended (see section 4.4). Induction: 2/48 Prior to treatment induction, 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 Suboxone or buprenorphine only tablets should be undertaken when objective and clear signs of withdrawal are evident. Initiation therapy: The recommended starting dose is one to two tablets of Suboxone 2 mg/0.5 mg sublingual tablets. An additional one to two tablets of the Suboxone 2 mg/0.5 mg may be administered on day one depending on the individual patient’s requirement. Opioid-dependent drug addicts who have not undergone withdrawal: When treatment starts, the first dose of Suboxone should be taken when signs of withdrawal appear, but not less than 6 hours after the patient last used opioids (eg. heroin; short acting opioids). Patients receiving methadone: Before beginning Suboxone therapy, the dose of methadone must be reduced to a maximum of 30 mg/day. The first dose of Suboxone should be taken 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. Dosage adjustment and maintenance: The dose of Suboxone should be increased progressively according to the clinical effect of the individual patient and should not exceed a maximum single daily dose of 24 mg. The dosage is titrated according to reassessment of the clinical and psychological status of the patient and should be made in steps of 2-8 mg. During the initiation of treatment, daily dispensing of buprenorphine is recommended. After stabilisation, a reliable patient may be given a supply of Suboxone sufficient for several days of treatment. It is recommended that the amount of Suboxone be limited to 7 days or according to local requirements. 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 may be given 16 mg on alternate days, with no dose on the intervening days. However, the dose given on any one day should not exceed 24 mg. 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. Dosage reduction and termination of treatment: After a satisfactory stabilisation has been achieved, if the patient agrees, the dosage 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 and 8 mg allows for a downward titration of dosage. For patients who may require a lower buprenorphine dose, buprenorphine 0.4 mg sublingual tablets may be used. Patients should be monitored following termination of treatment because of the potential for relapse. Elderly: No data is available on elderly patients. Paediatrics: Suboxone is not recommended for use in children below age 15 years due to lack of data on safety and efficacy. Patients with impaired hepatic function: 3/48 The effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone is unknown. Since both active substances are extensively metabolized, the plasma levels will be expected to be higher in patients with moderate and severe hepatic impairment. It is not known whether both active substances are affected to the same extent. As Suboxone pharmacokinetics may be altered in patients with hepatic insufficiency, lower initial doses and careful dose titration in patients with mild to moderate hepatic impairment are recommended (see section 5.2). Patients with impaired renal function: Modification of the Suboxone dose is not required in patients with renal insufficiency. Caution is recommended when dosing patients with severe renal impairment (CLcr < 30 ml/min) (see section 5.2). 4.3 Contraindications Suboxone is contraindicated in the following instances: • hypersensitivity to buprenorphine, to naloxone, or to any of the excipients, • severe respiratory insufficiency, • severe hepatic insufficiency, • acute alcoholism or delirium tremens. 4.4 Special warnings and precautions for use Due to the lack of data in adolescents (age 15-<18), Suboxone should be used only with caution in this age group. Patients should be closely monitored during the switching period from buprenorphine or methadone to Suboxone since withdrawal symptoms have been reported. Diversion: Diversion refers to the introduction of buprenorphine into the illicit market either by patients or by individuals who obtain the medicinal product through theft from patients or pharmacies. This diversion may lead to new addicts using buprenorphine as the primary drug of abuse, with the risks of overdose, spread of blood borne viral infections, respiratory depression and hepatic injury. Because the naloxone in the combination tablet precipitated withdrawal in individuals dependent on heroin, methadone, or other full agonists, Suboxone is expected to be less likely to be diverted for intravenous use. Precipitated withdrawal: When initiating treatment with buprenorphine, 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 (see section 4.2). Conversely, withdrawal symptoms may also be associated with suboptimal dosing. The risk of serious undesirable effects such as overdose or treatment dropout is greater if a patient is under dosed with Suboxone and continues to self medicate withdrawal symptoms with opioids, alcohol or other sedative-hypnotics in particular benzodiazepines. Dependence: Buprenorphine is a partial agonist at the mu-opiate receptor and chronic administration produces dependence of the opioid type. Discontinuation of treatment may result in a withdrawal syndrome that may be delayed. 4/48 Suboxone may cause drowsiness, particularly when taken together with alcohol or central nervous system depressants (such as tranquilisers, sedatives or hypnotics) (see section 4.5). Studies in animals, as well as clinical experience, have demonstrated that buprenorphine may produce dependence but at a lower level than morphine. 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 prescribing information. Deaths have been reported in association with concomitant administration of buprenorphine and other depressants such as alcohol or other opioids. 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 event reports. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of hepatic failure, hepatic necrosis, hepatorenal syndrome and hepatic encephalopathy. In many cases the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant use of other potentially hepatotoxic medicines, and ongoing injecting drug use may have a causative or contributory role. These underlying factors must be taken into consideration before prescribing Suboxone and during treatment. When a hepatic event is suspected, further biological and etiological 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. As buprenorphine is an opioid, pain as a symptom of a disease may be attenuated. Athletes must be aware that this medicine may cause a positive reaction to ‘anti-doping’ tests. As with other opioids, caution is requested in patients using buprenorphine and having head injury, increased intracranial pressure, hypotension, prostatic hypertrophy or urethral stenosis. This product should be used with care in patients with: asthma or respiratory insufficiency (cases of respiratory depression have been reported with buprenorphine); renal insufficiency (30 % of the administered dose is eliminated by the renal route; thus, renal elimination may be prolonged); hepatic insufficiency (hepatic metabolism of buprenorphine may be altered) (see section 4.3). Medicines that inhibit the enzyme CYP3A4 may give rise to increased concentrations of buprenorphine. A reduction of the Suboxone dose may be needed. Patients already treated with CYP3A4 inhibitors should have their dose of Suboxone titrated carefully since a reduced dose may be sufficient in these patients (see section 4.5). The concomitant use of monoamine oxidase inhibitors (MAOI) might produce exaggeration of the effects of opioids, based on experience with morphine. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose malabsorption should not take this medicine. 4.5 Interaction with other medicinal products and other forms of interaction Suboxone should not be taken together with: • alcoholic drinks or medications containing alcohol, as alcohol increases the sedative effect of buprenorphine (see section 4.7). Suboxone should be used cautiously when co-administered with: 5/48 • benzodiazepines: This combination may result in death due to respiratory depression of central origin. Therefore, dosages must be limited and this combination must be avoided in cases where there is a risk of misuse (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. • 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 70 % and 50 % 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). • CYP3A4 inducers: the interaction of buprenorphine with CYP3A4 inducers has not been investigated. Therefore it is recommended that patients receiving Suboxone should be closely monitored if inducers (e.g. phenobarbital, carbamazepine, phenytoin, rifampicin) are coadministered. To date, no notable interaction has been observed with cocaine, the agent most frequently used by multi-drug abusers in association with opioids. 4.6 Pregnancy and lactation Pregnancy: There is very limited experience with 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 high doses of buprenorphine may induce respiratory depression in the neonate 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. Suboxone should not be used during pregnancy. If it is the prescriber’s opinion that therapy in pregnancy is required, the use of buprenorphine may be considered according to the local buprenorphine labeling. In case pregnancy occurs while on Suboxone treatment, the mother and the unborn child should be closely monitored and switched to buprenorphine if further treatment is required. Breast-feeding: It is unknown whether naloxone is excreted in human breast milk. Buprenorphine and its metabolites are excreted in human breast milk. In rats buprenorphine has been found to inhibit lactation. Therefore, breast-feeding should be discontinued during treatment with Suboxone. 4.7 Effects on ability to drive and use machines In general Suboxone has minor to moderate influence on the ability to move safely in traffic, use machines, or perform other hazardous activities. Suboxone may cause drowsiness, dizziness, or impaired thinking, particularly when taken together with alcohol or central nervous system depressants. Therefore caution is advised when performing the above mentioned activities (see sections 4.4 and 4.5). 4.8 Undesirable effects 6/48 The most common-treatment related undesirable effects reported during clinical trials with Suboxone were those related to withdrawal symptoms (e.g. abdominal pain, diarrhoea, muscle aches, anxiety, sweating). In the pivotal clinical study of Suboxone, 342 of 472 patients (72.5 %) reported treatment related adverse reactions. These reactions are listed in Table 1 by system organ class and frequency (very common (> 1/10), common (> 1/100, < 1/10), uncommon (> 1/1,000 to ≤ 1/100)). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Table 1: Treatment-related undesirable effects reported in the pivotal clinical study of Suboxone (≥ 0.1% of Suboxone-treated patients) Infections and infestations Common: Infection Uncommon: Vaginitis Blood and lymphatic system disorders Uncommon: Anaemia, thrombocytopenia, leucopenia, lymphadenopathy, leukocytosis Immune system disorders Uncommon: Allergic reaction Metabolism and nutrition disorders Common: Peripheral oedema, weight decreased Uncommon: Hyperglycaemia, hyperlipemia, hypoglycemia Psychiatric disorders Common: Anxiety, nervousness, depression, libido decreased, thinking abnormal Uncommon: Drug dependence, amnesia, hostility, speech disorder, depersonalization, abnormal dream, apathy, euphoria Nervous system disorders Very Common: Insomnia Common: Somnolence, dizziness, paresthesia, hypertonia Uncommon: Convulsion, agitation, tremor, hyperkinesia Eye disorders Common: Lacrimation disorder, amblyopia Uncommon: Miosis, conjunctivitis Cardiac disorders Uncommon: Myocardial infarction, angina pectoris, palpitation, tachycardia, bradycardia 7/48 Vascular disorders Common: Vasodilation, hypertension, migraine Uncommon: Hypotension, heat stroke Respiratory, thoracic and mediastinal disorders Common: Rhinitis, pharyngitis, cough increased Uncommon: Dyspnoea, asthma, yawn Gastrointestinal disorders Very Common: Constipation, nausea Common: Vomiting, dyspepsia, diarrhoea, anorexia, flatulence Uncommon: Ulcerative stomatitis, tongue discolouration Hepatobiliary disorders Common: Liver function abnormal Skin and subcutaneous tissue disorders Very Common: Sweating Common: Rash, pruritus, urticaria Uncommon: Exfoliative dermatitis, acne, skin nodule, alopecia, dry skin Musculoskeletal, connective tissue and bone disorders Common: Arthralgia, myalgia, leg cramps Uncommon: Arthritis Renal and urinary disorders Common: Albuminuria, urine abnormality Uncommon: Haematuria, kidney calculus, increased creatinine, urinary tract infection, dysuria, urinary retention Reproductive system and breast disorders Uncommon: Impotence, amenorrhoea, abnormal ejaculation, menorrhagia, metrorrhagia General disorders Very Common: Withdrawal syndrome, headache Common: Asthenia, fever, flu syndrome, malaise, accidental injury, chills, chest pain, abdominal pain, back pain, pain Injury, poisoning and procedural complications Uncommon: Hypothermia Buprenorphine used alone for treatment of opioid dependency has been associated with the following symptoms (> 1 %): constipation, headache, insomnia, asthenia, drowsiness, nausea and vomiting, fainting and dizziness, orthostatic hypotension, and sweating. Other undesirable effects (< 0.1 %) have been reported in association with buprenorphine alone. These are: • respiratory depression (see sections 4.4 and 4.5), • hepatic necrosis and hepatitis (see section 4.4), • hallucinations, 8/48 • cases of bronchospasm, angioneurotic oedema and anaphylactic shock. In cases of intravenous misuse, local reactions, sometimes septic, and potentially serious acute hepatitis have been reported (see section 4.4). In patients presenting with marked drug dependence, initial administration of buprenorphine can produce a withdrawal effect similar to that associated with naloxone. Spontaneous abortion has been reported with both buprenorphine and buprenorphine-naloxone. It is not possible to establish a causal relationship, since cases typically involve other drug use or risk factors for spontaneous abortion (see section 4.6). A neonatal abstinence syndrome has been reported among newborns of women who have received buprenorphine during pregnancy. The syndrome may be milder and more protracted than that from short acting full µ-opioid agonists. The nature of the syndrome may vary depending upon the mother’s drug use history (see section 4.6). 4.9 Overdose In the event of overdose, general supportive measures should be instituted, including close monitoring of respiratory and cardiac status of the patient. The major symptom requiring intervention is respiratory depression, which could lead to respiratory arrest and death. If the patient vomits, care must be taken to prevent aspiration of the vomitus. Treatment: 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. 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. The long duration of action of Suboxone should be taken into consideration when determining the length of treatment and medical surveillance needed to reverse the effects of an overdose. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Drugs used in opioid dependence, ATC code: N07B C51. Mechanism of action: Buprenorphine is an opioid partial agonist/antagonist which binds to the µ (mu) and κ (kappa) receptors of the brain. Its activity in opioid maintenance treatment is attributed to its slowly reversible properties with the µ 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 (mu)-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. 9/48 Clinical efficacy: Efficacy and safety data for Suboxone are primarily derived from a one-year clinical trial, comprising a 4-week randomised double blind comparison of Suboxone, buprenorphine and placebo tablets followed by a 48 week safety study of Suboxone. In this trial, 326 heroin-addicted subjects were randomly assigned to either Suboxone 16 mg per day, 16 mg buprenorphine per day or placebo tablets. For subjects randomized to either active treatment, dosing began with one 8 mg tablet of buprenorphine on Day 1, followed by 16 mg (two 8 mg tablets) of buprenorphine on Day 2. On Day 3, those randomized to receive Suboxone 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 Suboxone individually against placebo. The percentage of thrice-weekly urine samples that were negative for non-study opioids was statistically higher for both Suboxone 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 to 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 Suboxone), 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 7week 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 thriceweekly urine samples negative for non-study 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. 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. Peak plasma concentrations are achieved 90 minutes after sublingual administration. Plasma levels of buprenorphine increased with the sublingual dose of Suboxone. 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. Suboxone 4 mg Suboxone 8 mg Suboxone 16 mg Cmax · ng/ml 1.84 (39) 3.0 (51) 5.95 (38) AUC0-48 hour · ng/ml 12.52 (35) 20.22 (43) 34.89 (33) Pharmacokinetic Parameter Distribution: The absorption of buprenorphine is followed by a rapid distribution phase (distribution half-life of 2 to 5 hours). Metabolism and elimination: Buprenorphine is metabolised by 14-N-dealkylation and glucuroconjugation of the parent molecule and the dealkylated metabolite. Clinical data confirm that CYP3A4 is responsible for the N- 10/48 dealkylation of buprenorphine. N-dealkylbuprenorphine is a µ (mu)-opioid agonist with weak intrinsic activity. Elimination of buprenorphine is bi- or tri-exponential, and has a mean half-life from plasma of 32 hours. Buprenorphine is eliminated in the faeces by biliary excretion of the glucuroconjugated metabolites (70 %), the rest being eliminated in the urine. Naloxone Absorption and distribution: Following intravenous administration, naloxone is rapidly distributed (distribution half-life ~ 4 minutes). Following oral administration, naloxone is barely detectable in plasma; following sublingual administration of Suboxone, plasma naloxone concentrations are low and decline rapidly. Metabolism and elimination: The medicinal product is metabolized in the liver, primarily by glucuronide conjugation, and excreted in the urine. Naloxone has a mean half-life from plasma of 1.2 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 Suboxone. No dose modification based on renal function is required but caution is recommended when dosing subjects with severe renal impairment. Hepatic impairment: Hepatic elimination plays a relatively large role (~70 %) in the overall clearance of Suboxone and the action of buprenorphine may be prolonged in subjects with impaired hepatic clearance. Lower initial Suboxone doses and cautious titration of dosage may be required in patients with mild to moderate hepatic dysfunction. Suboxone is contraindicated in patients with severe hepatic dysfunction (see section 4.3). 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 agonistic 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 1x for buprenorphine and 5x 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 Suboxone; 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. 11/48 Dietary administration of Suboxone 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 2.4x for buprenorphine at a human dose of 24 mg Suboxone 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 Suboxone was conducted in rats at doses of 7, 30 and 120 mg/kg/day, with estimated exposure multiples of 3 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 Lactose monohydrate, Mannitol, Maize starch, Povidone K 30, Citric acid anhydrous, Sodium citrate, Magnesium stearate, Acesulfame potassium, Natural lemon and lime flavour. 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container 7 tablets in blister packs Nylon/Aluminum/PVC. 28 tablets in blister packs Nylon/Aluminum/PVC. Not all pack sizes may be marketed. 6.6 Special precautions for disposal Medicines no longer required should not be disposed of via wastewater or the municipal sewage system. Patients should be instructed to return them to a pharmacy or to ask their pharmacist how to dispose of them in accordance with the national regulations. These measures will help to protect the environment. 7. MARKETING AUTHORISATION HOLDER 12/48 SP Europe Rue de Stalle, 73 B-1180 Bruxelles Belgium 8. MARKETING AUTHORISATION NUMBER(S) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 10. DATE OF REVISION OF THE TEXT Detailed information on this product is available on the web-site of the European Medicines Agency (EMEA) http://www.emea.eu.int/ 13/48 1. NAME OF THE MEDICINAL PRODUCT Suboxone 8 mg/2 mg sublingual tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains 8 mg buprenorphine (as buprenorphine hydrochloride) and 2 mg naloxone (as naloxone hydrochloride dihydrate). Excipients: lactose 168 mg For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Sublingual tablet White hexagonal biconvex tablets, embossed with a sword logo on one side and “N8” on the reverse side. 4. CLINICAL PARTICULARS 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. Treatment is intended for use 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. Each Suboxone sublingual tablet contains buprenorphine and naloxone. Suboxone containing 8 mg buprenorphine and 2 mg naloxone is referred to as the "8 mg" tablets. 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). Suboxone sublingual tablets are to be placed under the tongue until dissolved, which usually requires 5 to 10 minutes. The dose is made up from Suboxone 2 mg/0.5 mg and Suboxone 8 mg/2 mg sublingual tablets, 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. Adults: 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 risk of accelerated liver injury. Regular monitoring of liver function is recommended (see section 4.4). Induction: 14/48 Prior to treatment induction, 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 Suboxone or buprenorphine only tablets should be undertaken when objective and clear signs of withdrawal are evident. Initiation therapy: The recommended starting dose is one to two tablets of Suboxone 2 mg/0.5 mg sublingual tablets. An additional one to two tablets of the Suboxone 2 mg/0.5 mg may be administered on day one depending on the individual patient’s requirement. Opioid-dependent drug addicts who have not undergone withdrawal: When treatment starts, the first dose of Suboxone should be taken when signs of withdrawal appear, but not less than 6 hours after the patient last used opioids (eg. heroin; short acting opioids). Patients receiving methadone: Before beginning Suboxone therapy, the dose of methadone must be reduced to a maximum of 30 mg/day. The first dose of Suboxone should be taken 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. Dosage adjustment and maintenance: The dose of Suboxone should be increased progressively according to the clinical effect of the individual patient and should not exceed a maximum single daily dose of 24 mg. The dosage is titrated according to reassessment of the clinical and psychological status of the patient and should be made in steps of 2-8 mg. During the initiation of treatment, daily dispensing of buprenorphine is recommended. After stabilisation, a reliable patient may be given a supply of Suboxone sufficient for several days of treatment. It is recommended that the amount of Suboxone be limited to 7 days or according to local requirements. 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 may be given 16 mg on alternate days, with no dose on the intervening days. However, the dose given on any one day should not exceed 24 mg. 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. Dosage reduction and termination of treatment: After a satisfactory stabilisation has been achieved, if the patient agrees, the dosage 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 and 8 mg allows for a downward titration of dosage. For patients who may require a lower buprenorphine dose, buprenorphine 0.4 mg sublingual tablets may be used. Patients should be monitored following termination of treatment because of the potential for relapse. Elderly: No data is available on elderly patients. Paediatrics: Suboxone is not recommended for use in children below age 15 years due to lack of data on safety and efficacy. Patients with impaired hepatic function: 15/48 The effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone is unknown. Since both active substances are extensively metabolized, the plasma levels will be expected to be higher in patients with moderate and severe hepatic impairment. It is not known whether both active substances are affected to the same extent. As Suboxone pharmacokinetics may be altered in patients with hepatic insufficiency, lower initial doses and careful dose titration in patients with mild to moderate hepatic impairment are recommended (see section 5.2). Patients with impaired renal function: Modification of the Suboxone dose is not required in patients with renal insufficiency. Caution is recommended when dosing patients with severe renal impairment (CLcr < 30 ml/min) (see section 5.2). 4.3 Contraindications Suboxone is contraindicated in the following instances: • hypersensitivity to buprenorphine, to naloxone, or to any of the excipients, • severe respiratory insufficiency, • severe hepatic insufficiency, • acute alcoholism or delirium tremens. 4.4 Special warnings and precautions for use Due to the lack of data in adolescents (age 15-<18), Suboxone should be used only with caution in this age group. Patients should be closely monitored during the switching period from buprenorphine or methadone to Suboxone since withdrawal symptoms have been reported. Diversion: Diversion refers to the introduction of buprenorphine into the illicit market either by patients or by individuals who obtain the medicinal product through theft from patients or pharmacies. This diversion may lead to new addicts using buprenorphine as the primary drug of abuse, with the risks of overdose, spread of blood borne viral infections, respiratory depression and hepatic injury. Because the naloxone in the combination tablet precipitated withdrawal in individuals dependent on heroin, methadone, or other full agonists, Suboxone is expected to be less likely to be diverted for intravenous use. Precipitated withdrawal: When initiating treatment with buprenorphine, 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 (see section 4.2). Conversely, withdrawal symptoms may also be associated with suboptimal dosing. The risk of serious undesirable effects such as overdose or treatment dropout is greater if a patient is under dosed with Suboxone and continues to self medicate withdrawal symptoms with opioids, alcohol or other sedative-hypnotics in particular benzodiazepines. Dependence: Buprenorphine is a partial agonist at the mu-opiate receptor and chronic administration produces dependence of the opioid type. Discontinuation of treatment may result in a withdrawal syndrome that may be delayed. 16/48 Suboxone may cause drowsiness, particularly when taken together with alcohol or central nervous system depressants (such as tranquilisers, sedatives or hypnotics) (see section 4.5). Studies in animals, as well as clinical experience, have demonstrated that buprenorphine may produce dependence but at a lower level than morphine. 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 prescribing information. Deaths have been reported in association with concomitant administration of buprenorphine and other depressants such as alcohol or other opioids. 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 event reports. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of hepatic failure, hepatic necrosis, hepatorenal syndrome and hepatic encephalopathy. In many cases the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant use of other potentially hepatotoxic medicines, and ongoing injecting drug use may have a causative or contributory role. These underlying factors must be taken into consideration before prescribing Suboxone and during treatment. When a hepatic event is suspected, further biological and etiological 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. As buprenorphine is an opioid, pain as a symptom of a disease may be attenuated. Athletes must be aware that this medicine may cause a positive reaction to ‘anti-doping’ tests. As with other opioids, caution is requested in patients using buprenorphine and having head injury, increased intracranial pressure, hypotension, prostatic hypertrophy or urethral stenosis. This product should be used with care in patients with: asthma or respiratory insufficiency (cases of respiratory depression have been reported with buprenorphine); renal insufficiency (30 % of the administered dose is eliminated by the renal route; thus, renal elimination may be prolonged); hepatic insufficiency (hepatic metabolism of buprenorphine may be altered) (see section 4.3). Medicines that inhibit the enzyme CYP3A4 may give rise to increased concentrations of buprenorphine. A reduction of the Suboxone dose may be needed. Patients already treated with CYP3A4 inhibitors should have their dose of Suboxone titrated carefully since a reduced dose may be sufficient in these patients (see section 4.5). The concomitant use of monoamine oxidase inhibitors (MAOI) might produce exaggeration of the effects of opioids, based on experience with morphine. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose malabsorption should not take this medicine. 4.5 Interaction with other medicinal products and other forms of interaction Suboxone should not be taken together with: • alcoholic drinks or medications containing alcohol, as alcohol increases the sedative effect of buprenorphine (see section 4.7). Suboxone should be used cautiously when co-administered with: 17/48 • benzodiazepines: This combination may result in death due to respiratory depression of central origin. Therefore, dosages must be limited and this combination must be avoided in cases where there is a risk of misuse (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. • 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 70 % and 50 % 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). • CYP3A4 inducers: the interaction of buprenorphine with CYP3A4 inducers has not been investigated. Therefore it is recommended that patients receiving Suboxone should be closely monitored if inducers (e.g. phenobarbital, carbamazepine, phenytoin, rifampicin) are coadministered. To date, no notable interaction has been observed with cocaine, the agent most frequently used by multi-drug abusers in association with opioids. 4.6 Pregnancy and lactation Pregnancy: There is very limited experience with 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 high doses of buprenorphine may induce respiratory depression in the neonate 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. Suboxone should not be used during pregnancy. If it is the prescriber’s opinion that therapy in pregnancy is required, the use of buprenorphine may be considered according to the local buprenorphine labeling. In case pregnancy occurs while on Suboxone treatment, the mother and the unborn child should be closely monitored and switched to buprenorphine if further treatment is required. Breast-feeding: It is unknown whether naloxone is excreted in human breast milk. Buprenorphine and its metabolites are excreted in human breast milk. In rats buprenorphine has been found to inhibit lactation. Therefore, breast-feeding should be discontinued during treatment with Suboxone. 4.7 Effects on ability to drive and use machines In general Suboxone has minor to moderate influence on the ability to move safely in traffic, use machines, or perform other hazardous activities. Suboxone may cause drowsiness, dizziness, or impaired thinking, particularly when taken together with alcohol or central nervous system depressants. Therefore caution is advised when performing the above mentioned activities (see sections 4.4 and 4.5). 4.8 Undesirable effects 18/48 The most common-treatment related undesirable effects reported during clinical trials with Suboxone were those related to withdrawal symptoms (e.g. abdominal pain, diarrhoea, muscle aches, anxiety, sweating). In the pivotal clinical study of Suboxone, 342 of 472 patients (72.5 %) reported treatment related adverse reactions. These reactions are listed in Table 1 by system organ class and frequency (very common (> 1/10), common (> 1/100, < 1/10), uncommon (> 1/1,000 to ≤ 1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Table 1: Treatment-related undesirable effects reported in the pivotal clinical study of Suboxone (≥ 0.1 % of Suboxone-treated patients) Infections and infestations Common: Infection Uncommon: Vaginitis Blood and lymphatic system disorders Uncommon: Anaemia, thrombocytopenia, leucopenia, lymphadenopathy, leukocytosis Immune system disorders Uncommon: Allergic reaction Metabolism and nutrition disorders Common: Peripheral oedema, weight decreased Uncommon: Hyperglycaemia, hyperlipemia, hypoglycemia Psychiatric disorders Common: Anxiety, nervousness, depression, libido decreased, thinking abnormal Uncommon: Drug dependence, amnesia, hostility, speech disorder, depersonalization, abnormal dream, apathy, euphoria Nervous system disorders Very Common: Insomnia Common: Somnolence, dizziness, paresthesia, hypertonia Uncommon: Convulsion, agitation, tremor, hyperkinesia Eye disorders Common: Lacrimation disorder, amblyopia Uncommon: Miosis, conjunctivitis Cardiac disorders Uncommon: Myocardial infarction, angina pectoris, palpitation, tachycardia, bradycardia 19/48 Vascular disorders Common: Vasodilation, hypertension, migraine Uncommon: Hypotension, heat stroke Respiratory, thoracic and mediastinal disorders Common: Rhinitis, pharyngitis, cough increased Uncommon: Dyspnoea, asthma, yawn Gastrointestinal disorders Very Common: Constipation, nausea Common: Vomiting, dyspepsia, diarrhoea, anorexia, flatulence Uncommon: Ulcerative stomatitis, tongue discolouration Hepatobiliary disorders Common: Liver function abnormal Skin and subcutaneous tissue disorders Very Common: Sweating Common: Rash, pruritus, urticaria Uncommon: Exfoliative dermatitis, acne, skin nodule, alopecia, dry skin Musculoskeletal, connective tissue and bone disorders Common: Arthralgia, myalgia, leg cramps Uncommon: Arthritis Renal and urinary disorders Common: Albuminuria, urine abnormality Uncommon: Haematuria, kidney calculus, increased creatinine, urinary tract infection, dysuria, urinary retention Reproductive system and breast disorders Uncommon: Impotence, amenorrhoea, abnormal ejaculation, menorrhagia, metrorrhagia General disorders Very Common: Withdrawal syndrome, headache Common: Asthenia, fever, flu syndrome, malaise, accidental injury, chills, chest pain, abdominal pain, back pain, pain Injury, poisoning and procedural complications Uncommon: Hypothermia Buprenorphine used alone for treatment of opioid dependency has been associated with the following symptoms (> 1 %): constipation, headache, insomnia, asthenia, drowsiness, nausea and vomiting, fainting and dizziness, orthostatic hypotension, and sweating. Other undesirable effects (< 0.1 %) have been reported in association with buprenorphine alone. These are: • respiratory depression (see sections 4.4 and 4.5), • hepatic necrosis and hepatitis (see section 4.4), • hallucinations, 20/48 • cases of bronchospasm, angioneurotic oedema and anaphylactic shock. In cases of intravenous misuse, local reactions, sometimes septic, and potentially serious acute hepatitis have been reported (see section 4.4). In patients presenting with marked drug dependence, initial administration of buprenorphine can produce a withdrawal effect similar to that associated with naloxone. Spontaneous abortion has been reported with both buprenorphine and buprenorphine-naloxone. It is not possible to establish a causal relationship, since cases typically involve other drug use or risk factors for spontaneous abortion (see section 4.6). A neonatal abstinence syndrome has been reported among newborns of women who have received buprenorphine during pregnancy. The syndrome may be milder and more protracted than that from short acting full µ-opioid agonists. The nature of the syndrome may vary depending upon the mother’s drug use history (see section 4.6). 4.9 Overdose In the event of overdose, general supportive measures should be instituted, including close monitoring of respiratory and cardiac status of the patient. The major symptom requiring intervention is respiratory depression, which could lead to respiratory arrest and death. If the patient vomits, care must be taken to prevent aspiration of the vomitus. Treatment: 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. 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. The long duration of action of Suboxone should be taken into consideration when determining the length of treatment and medical surveillance needed to reverse the effects of an overdose. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Drugs used in opioid dependence, ATC code: N07B C51. Mechanism of action: Buprenorphine is an opioid partial agonist/antagonist which binds to the µ (mu) and κ (kappa) receptors of the brain. Its activity in opioid maintenance treatment is attributed to its slowly reversible properties with the µ 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 (mu)-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. 21/48 Clinical efficacy: Efficacy and safety data for Suboxone are primarily derived from a one-year clinical trial, comprising a 4-week randomised double blind comparison of Suboxone, buprenorphine and placebo tablets followed by a 48 week safety study of Suboxone. In this trial, 326 heroin-addicted subjects were randomly assigned to either Suboxone 16 mg per day, 16 mg buprenorphine per day or placebo tablets. For subjects randomized to either active treatment, dosing began with one 8 mg tablet of buprenorphine on Day 1, followed by 16 mg (two 8 mg tablets) of buprenorphine on Day 2. On Day 3, those randomized to receive Suboxone 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 Suboxone individually against placebo. The percentage of thrice-weekly urine samples that were negative for non-study opioids was statistically higher for both Suboxone 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 to 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 Suboxone), 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 7week 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 thriceweekly urine samples negative for non-study 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. 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. Peak plasma concentrations are achieved 90 minutes after sublingual administration. Plasma levels of buprenorphine increased with the sublingual dose of Suboxone. 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. Suboxone 4 mg Suboxone 8 mg Suboxone 16 mg Cmax · ng/ml 1.84 (39) 3.0 (51) 5.95 (38) AUC0-48 hour · ng/ml 12.52 (35) 20.22 (43) 34.89 (33) Pharmacokinetic Parameter Distribution: The absorption of buprenorphine is followed by a rapid distribution phase (distribution half-life of 2 to 5 hours). Metabolism and elimination: Buprenorphine is metabolised by 14-N-dealkylation and glucuroconjugation of the parent molecule and the dealkylated metabolite. Clinical data confirm that CYP3A4 is responsible for the N- 22/48 dealkylation of buprenorphine. N-dealkylbuprenorphine is a µ (mu)-opioid agonist with weak intrinsic activity. Elimination of buprenorphine is bi- or tri-exponential, and has a mean half-life from plasma of 32 hours. Buprenorphine is eliminated in the faeces by biliary excretion of the glucuroconjugated metabolites (70 %), the rest being eliminated in the urine. Naloxone Absorption and distribution: Following intravenous administration, naloxone is rapidly distributed (distribution half-life ~ 4 minutes). Following oral administration, naloxone is barely detectable in plasma; following sublingual administration of Suboxone, plasma naloxone concentrations are low and decline rapidly. Metabolism and elimination: The medicinal product is metabolized in the liver, primarily by glucuronide conjugation, and excreted in the urine. Naloxone has a mean half-life from plasma of 1.2 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 Suboxone. No dose modification based on renal function is required but caution is recommended when dosing subjects with severe renal impairment. Hepatic impairment: Hepatic elimination plays a relatively large role (~70 %) in the overall clearance of Suboxone and the action of buprenorphine may be prolonged in subjects with impaired hepatic clearance. Lower initial Suboxone doses and cautious titration of dosage may be required in patients with mild to moderate hepatic dysfunction. Suboxone is contraindicated in patients with severe hepatic dysfunction (see section 4.3). 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 agonistic 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 1x for buprenorphine and 5x 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 Suboxone; 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. 23/48 Dietary administration of Suboxone 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 2.4x for buprenorphine at a human dose of 24 mg Suboxone 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 Suboxone was conducted in rats at doses of 7, 30 and 120 mg/kg/day, with estimated exposure multiples of 3 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 Lactose monohydrate, Mannitol, Maize starch, Povidone K 30, Citric acid anhydrous, Sodium citrate, Magnesium stearate, Acesulfame potassium, Natural lemon and lime flavour. 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container 7 tablets in blister packs Nylon/Aluminum/PVC. 28 tablets in blister packs Nylon/Aluminum/PVC. Not all pack sizes may be marketed. 6.6 Special precautions for disposal Medicines no longer required should not be disposed of via wastewater or the municipal sewage system. Patients should be instructed to return them to a pharmacy or to ask their pharmacist how to dispose of them in accordance with the national regulations. These measures will help to protect the environment. 7. MARKETING AUTHORISATION HOLDER 24/48 SP Europe Rue de Stalle, 73 B-1180 Bruxelles Belgium 8. MARKETING AUTHORISATION NUMBER(S) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 10. DATE OF REVISION OF THE TEXT Detailed information on this product is available on the web-site of the European Medicines Agency (EMEA) http://www.emea.eu.int/ 25/48 ANNEX II A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OF THE MARKETING AUTHORISATION 26/48 A. MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturers responsible for batch release Reckitt Benckiser Healthcare (UK) Ltd Dansom Lane Hull, East Yorkshire HU8 7DS United Kingdom B. CONDITIONS OF THE MARKETING AUTHORISATION • CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON THE MARKETING AUTHORISATION HOLDER Medicinal product subject to special and restricted medical prescription (See Annex I: Summary of Product Characteristics, section 4.2). Substitution treatment for opioid drug dependence is intended for use in adults and adolescents over 15 years of age who have agreed to be treated for addiction, within a framework of medical, social and psychological treatment, by physicians experienced in the treatment of opiate dependence/addiction. • CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT Not applicable. • OTHER CONDITIONS The MAH must ensure that the system of pharmacovigilance is in place and functioning before the product is placed on the market and for as long as the marketed product remains in use. The MAH commits to performing the studies and additional pharmacovigilance activities detailed in the Pharmacovigilance Plan. An updated Risk Management Plan should be provided as per the CHMP Guideline on Risk Management Systems for medicinal products for human use. 27/48 ANNEX III LABELLING AND PACKAGE LEAFLET 28/48 A. LABELLING 29/48 PARTICULARS TO APPEAR ON THE OUTER PACKAGING PACK OF 7 and 28 TABLETS 2 MG STRENGTH 1. NAME OF THE MEDICINAL PRODUCT Suboxone 2 mg/0.5 mg sublingual tablets buprenorphine / naloxone 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each sublingual tablet contains 2 mg buprenorphine as buprenorphine hydrochloride and 0.5 mg naloxone as naloxone hydrochloride dihydrate. 3. LIST OF EXCIPIENTS Includes lactose monohydrate. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS 7 sublingual tablets 28 sublingual tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Sublingual use Do not swallow. Keep the tablet under your tongue until it dissolves. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 30/48 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER SP Europe Rue de Stalle 73 B-1180 Bruxelles, Belgium 12. MARKETING AUTHORISATION NUMBER(S) EU/0/00/000/000 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Suboxone 2 mg/0.5 mg 31/48 PARTICULARS TO APPEAR ON THE OUTER PACKAGING PACK OF 7 and 28 TABLETS 8 MG STRENGTH 1. NAME OF THE MEDICINAL PRODUCT Suboxone 8 mg/2 mg sublingual tablets buprenorphine / naloxone 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each sublingual tablet contains 8 mg buprenorphine as buprenorphine hydrochloride and 2 mg naloxone as naloxone hydrochloride dihydrate. 3. LIST OF EXCIPIENTS Includes lactose monohydrate. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS 7 sublingual tablets 28 sublingual tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Sublingual use Do not swallow. Keep the tablet under your tongue until it dissolves. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 32/48 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER SP Europe Rue de Stalle 73 B-1180 Bruxelles, Belgium 12. MARKETING AUTHORISATION NUMBER(S) EU/0/00/000/000 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Suboxone 8 mg/2 mg 33/48 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS PACK OF 7 and 28 TABLETS 2 MG STRENGTH 1. NAME OF THE MEDICINAL PRODUCT Suboxone 2 mg/0.5 mg sublingual tablets buprenorphine / naloxone 2. NAME OF THE MARKETING AUTHORISATION HOLDER SP Europe 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 34/48 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS PACK OF 7 and 28 TABLETS 8 MG STRENGTH 1. NAME OF THE MEDICINAL PRODUCT Suboxone 8 mg/2 mg sublingual tablets buprenorphine / naloxone 2. NAME OF THE MARKETING AUTHORISATION HOLDER SP Europe 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER 35/48 B. PACKAGE LEAFLET 36/48 PACKAGE LEAFLET: INFORMATION FOR THE USER Suboxone 2 mg/0.5 mg sublingual tablets buprenorphine / naloxone Read all of this leaflet carefully before you start taking this medicine. Keep this leaflet. You may need to read it again. If you have any further questions, ask your doctor or pharmacist. This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. In this leaflet: 1. What Suboxone is and what it is used for 2. Before you take Suboxone 3. How to take Suboxone 4. Possible side effects 5 How to store Suboxone 6. Further information 1. WHAT SUBOXONE IS AND WHAT IT IS USED FOR Medicinal product used in opioid dependence. Suboxone is part of a medical, social and psychological treatment program for patients addicted to opiate (narcotic) drugs. Treatment is prescribed and monitored by physicians who are specialists in the treatment of drug dependence. Treatment with Suboxone sublingual tablets is intended for use in adults and adolescents over 15 years of age. 2. BEFORE YOU TAKE SUBOXONE Do not take Suboxone if you are allergic (hypersensitive) to buprenorphine, naloxone or any of the other ingredients of Suboxone, if you have serious breathing problems, if you have serious problems with your liver, if you are intoxicated due to alcohol or have delirium tremens. Take special care with Suboxone Some people have died from respiratory failure (inability to breathe) because they misused buprenorphine or took it while in combination with other Central Nervous System depressants, such as alcohol, benzodiazepines (tranquilisers), or other opioids. Cases of acute hepatic injury (liver problems) have been reported in a context of misuse, especially by intravenous route and at a high dose. These injuries could be due to special conditions as viral infections (chronic C hepatitis), alcohol abuse, anorexia, or medicines association (for example: antiretroviral nucleoside analogues, acetylsalicylic acid (aspirin), amiodarone, isoniazid, valproate). If you have symptoms of severe fatigue, itching, or if your skin or eyes look yellow, tell your doctor immediately, so that you can receive the proper treatment. 37/48 This product can cause withdrawal symptoms if you take it less than six hours after you use a narcotic (e.g. morphine, heroin) or less than 24 hours after you use methadone. This product can cause sleepiness which may be increased by alcohol or anti-anxiety medicines. Advise your physician in case of: recent head injury or brain disease, decrease of blood pressure, in men: urinary disorders (especially linked to enlarged prostate). This medicinal product may mask pain reflecting some diseases. Do not forget to advise your physician if you take this medicine. This product may cause your blood pressure to drop suddenly, causing you to feel dizzy if you get up too quickly from sitting or lying down. This product can cause dependence. Athletes should be aware that this medicine, due to its active substance, may cause a positive reaction to “anti-doping tests”. Advise your physician in case of: asthma or other breathing problems, kidney disease, liver disease. Using other medicines Using other medicines may increase the undesirable effects of buprenorphine and use of these medicines must be carefully monitored: • tranquilizers • anti-anxiety medicines • anti-depressants • benzodiazepines • some medicines used to treat high blood pressure. If your physician prescribes benzodiazepines, you must not take more than the prescribed dose. Taking this product with benzodiazepines (medicines used to treat anxiety or sleep disorders) may cause death due to respiratory failure. The following medicines may increase the buprenorphine blood concentrations, so concomitant use of these medicines together with Suboxone should be closely monitored and could require in some cases a dose reduction by your doctor: • anti-retrovirals (ritonavir, nelfinavir, indinavir) • ketoconazole • itraconazole Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. Using Suboxone with food and drink Do not take Suboxone together with alcoholic beverages as alcohol may possibly increase drowsiness induced by Suboxone. Pregnancy and breast-feeding Ask your doctor or pharmacist for advice before taking any medicine. 38/48 You should not use Suboxone during pregnancy. Tell your doctor if you are pregnant or intend to become pregnant. He will decide if your treatment should be continued with an alternative medication. Since this product will pass into your milk and may adversely affect the breast-fed child, you should discontinue breast-feeding while taking Suboxone. Driving and using machines Suboxone may cause drowsiness. If you feel tired, do not drive a motor vehicle or operate machinery. Important information about some of the ingredients of Suboxone Suboxone contains lactose. If you have been told by your doctor that you have intolerance to some sugars, contact your doctor before taking this medicinal product. 3. HOW TO TAKE SUBOXONE Sublingual route is the only efficacious administration route for this product. Do not swallow the tablets. Keep the tablet dose under your tongue until it dissolves. This may take 5-10 minutes. Take the dose once a day. Your doctor will determine the best dose for you. During your treatment, the doctor may adjust the dose, depending upon your response. To get the greatest benefit from taking Suboxone, you must tell your doctor about all the medicines you are taking, including alcohol, medicines containing alcohol, street drugs, and any prescription medicine you are taking that had not been prescribed to you by your doctor. Treatment duration The length of treatment will be determined individually by your doctor. After a time of successful treatment, the doctor may reduce the dose gradually to a lower maintenance dose. Depending on your condition, the Suboxone dose may continue to be reduced under careful medical supervision, until eventually it may be stopped. Do not change the treatment in any way or stop treatment without the agreement of the doctor who is treating you. The effectiveness of this treatment depends: on the dose, in combination with the associated medical, psychological and social treatment. If you have the impression that the effect of Suboxone is too strong or too weak, talk to your doctor or pharmacist. If you use more Suboxone than you should In case of overdose of buprenorphine, you must go or be taken immediately to an emergency centre or hospital for treatment. Advise immediately your doctor or your pharmacist. If you forget to use Suboxone Contact your doctor. If you stop using Suboxone Stopping treatment suddenly may cause withdrawal symptoms. If you have any further questions on the use of this product, ask your doctor or pharmacist. 39/48 4. POSSIBLE SIDE EFFECTS Like all medicines, Suboxone can cause side effects, although not everybody gets them. After the first dose of Suboxone, you may have some opiate withdrawal symptoms. Very common side effects (occurring in at least 1 in 10 patients) that may occur with Suboxone are: insomnia, constipation, nausea, sweating, headache, withdrawal syndrome. Common side effects (occurring in at least 1 in 100 patients) that may occur during treatment with Suboxone are: weight loss, swelling (hands and feet), tiredness, drowsiness, anxiety, nervousness, tingling, depression, decreased sexual drive, muscle spasms, abnormal thinking, tearing disorder, blurred vision, flushing, increased blood pressure, migraines, runny nose, sore throat and painful swallowing, increased cough, upset stomach, diarrhoea, abnormal liver function, loss of appetite, flatulence, vomiting, rash, itching, hives, pain, joint pain, muscle pain, leg cramps, impotence, urine abnormality, abdominal pain, back pain, weakness, infection, chills, chest pain, fever, flu syndrome, feeling of general discomfort, accidental injury, faintness and dizziness, drop in blood pressure on changing position from sitting or lying down to standing. Uncommon side effects (occurring in at least 1 in 1,000 patients) with Suboxone are: swollen glands (lymph nodes), agitation, tremor, abnormal dream, excessive muscle activity, depersonalization (not feeling like yourself), medicine dependence, amnesia (memory disturbance), loss of interest, exaggerated feeling of well being, convulsion (fits), speech disorder, small pupil size, problems with urination, conjunctivitis, rapid or slow heart beat, low blood pressure, palpitations, myocardial infarction (heart attack), shortness of breath, asthma, yawning, pain and sores in mouth, tongue discolouration, acne, skin nodule, hair loss, dry or scaling skin, inflammation of joints, urinary tract infection, blood in urine, abnormal ejaculation, menstrual or vaginal problems, kidney stone, sensitivity to heat or cold, allergic reaction, feelings of hostility. Rarely (occurring in at least 1 in 10,000 patients), the following have occurred with buprenorphine alone: respiratory depression (severe difficulty in breathing) - see “Take special care with Suboxone”, liver problems with or without jaundice- see “Take special care with Suboxone”, hallucinations. Misusing this medicine by injecting it can cause withdrawal symptoms, infections, other skin reactions and potentially serious liver problems - see “Take special care with Suboxone”. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. 5. HOW TO STORE SUBOXONE Keep out of the reach and sight of children. Do not use Suboxone after the expiry date which is stated on the carton. The expiry date refers to the last day of that month. This medicinal product does not require any special storage conditions. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. 40/48 6. FURTHER INFORMATION What Suboxone contains - The active substance is buprenorphine and naloxone. Each tablet contains 2 mg buprenorphine as buprenorphine hydrochloride and 0.5 mg naloxone as naloxone hydrochloride dihydrate. The other ingredients are lactose monohydrate, mannitol, maize starch, povidone K30, citric acid anhydrous, sodium citrate, magnesium stearate, acesulfame potassium and natural lemon and lime flavour. What Suboxone looks like and contents of the pack Sublingual tablets, white hexagonal biconvex tablets, embossed with a sword logo on one side and “N2” on the reverse side, packed in packs of 7 and 28 tablets. Not all pack sizes may be marketed. Marketing Authorisation Holder and Manufacturer Marketing Authorisation Holder: SP Europe, Rue de Stalle 73, B-1180 Bruxelles, Belgium. Manufacturer: Reckitt Benckiser Healthcare (UK) Ltd, Dansom Lane, Hull, East Yorkshire HU8 7DS, United Kingdom. For any information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien Rue de Stalle/Stallestraat 73 B-1180 Bruxelles/Brussel/Brüssel Tél/Tel: + 32-(0)2 370 92 11 Luxembourg/Luxemburg Rue de Stalle 73 B-1180 Bruxelles/Brüssel Belgique/Belgien Tél/Tel: + 32-(0)2 370 92 11 Česká republika Na Příkopě 25 CZ-110 00 Praha 1 Tel: + 420 221771250 Magyarország Alkotás u. 53. H-1123 Budapest Tel.: + 36 1 457-8500 Danmark Hvedemarken 12 DK-3520 Farum Tlf: + 45-44 39 50 00 Malta 168 Christopher Street MT-VLT02 Valletta Tel: + 356-21 23 21 75 Deutschland Thomas-Dehler-Straße 27 D-81737 München Tel: + 49-(0)89 627 31-0 Nederland Maarssenbroeksedijk 4 NL-3542 DN Utrecht Tel: + 31-(0)30 240 88 88 Eesti Järvevana tee 9 EE-11314 Tallinn Tel: + 372 654 96 86 Norge Ankerveien 209 N-1359 Eiksmarka Tlf: + 47 67 16 64 50 Ελλάδα Αγίου ∆ηµητρίου 63 GR-174 55 Άλιµος Österreich Badener Strasse 23 A-2514 Traiskirchen 41/48 Tηλ: + 30-210 98 97 300 Tel: + 43-(0)2252 502-0 España Km. 36, Ctra. Nacional I E-28750 San Agustín de Guadalix – Madrid Tel: + 34-91 848 85 00 Polska Al. Jerozolimskie 195a PL-02-222 Warszawa Tel.: + 48-(0)22 478 41 50 France 92 rue Baudin F-92300 Levallois-Perret Tél: + 33-(0)1 41 06 35 00 Portugal Rua Agualva dos Açores 16 P-2735-557 Agualva-Cacém Tel: + 351-21 433 93 00 Ireland Shire Park Welwyn Garden City Hertfordshire AL7 1TW Tel: + 44-(0)1 707 363 636 Slovenija Dunajska 22 SI-1000 Ljubljana Tel: + 386 01 3001070 Ísland Hörgatún 2 IS-210 Garðabær Sími: + 354 535 70 00 Slovenská republika Strakova 5 SK-811 01 Bratislava Tel: + 421 (2) 5920 2712 Italia Centro Direzionale Milano Due Palazzo Borromini I-20090 Segrate (Milano) Tel: + 39-02 21018.1 Suomi/Finland PL 3/PB 3 FIN-02201 Espoo/Esbo Puh/Tel: + 358-(0)20 7570 300 Κύπρος Οδός Αγίου Νικολάου, 8 CY-1055 Λευκωσία Τηλ: + 357-22 757188 Sverige Box 27190 S-102 52 Stockholm Tel: + 46-(0)8 522 21 500 Latvija Vāgnera iela 13 Rīga LV-1050 Tel: + 371-7 21 38 25 United Kingdom Shire Park Welwyn Garden City Hertfordshire AL7 1TW - UK Tel: + 44-(0)1 707 363 636 Lietuva Kęstučio g. 65/40 LT-08124 Vilnius Tel. + 370 52 638 446 This leaflet was last approved on Detailed information on this product is available on the web-site of the European Medicines Agency (EMEA) http://www.emea.eu.int/ 42/48 PACKAGE LEAFLET: INFORMATION FOR THE USER Suboxone 8 mg/2 mg sublingual tablets buprenorphine / naloxone Read all of this leaflet carefully before you start taking this medicine. Keep this leaflet. You may need to read it again. If you have any further questions, ask your doctor or pharmacist. This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. In this leaflet: 1. What Suboxone is and what it is used for 2. Before you take Suboxone 3. How to take Suboxone 4. Possible side effects 5 How to store Suboxone 6. Further information 1. WHAT SUBOXONE IS AND WHAT IT IS USED FOR Medicinal product used in opioid dependence. Suboxone is part of a medical, social and psychological treatment program for patients addicted to opiate (narcotic) drugs. Treatment is prescribed and monitored by physicians who are specialists in the treatment of drug dependence. Treatment with Suboxone sublingual tablets is intended for use in adults and adolescents over 15 years of age. 2. BEFORE YOU TAKE SUBOXONE Do not take Suboxone if you are allergic (hypersensitive) to buprenorphine, naloxone or any of the other ingredients of Suboxone, if you have serious breathing problems, if you have serious problems with your liver, if you are intoxicated due to alcohol or have delirium tremens. Take special care with Suboxone Some people have died from respiratory failure (inability to breathe) because they misused buprenorphine or took it while in combination with other Central Nervous System depressants, such as alcohol, benzodiazepines (tranquilisers), or other opioids. Cases of acute hepatic injury (liver problems) have been reported in a context of misuse, especially by intravenous route and at a high dose. These injuries could be due to special conditions as viral infections (chronic C hepatitis), alcohol abuse, anorexia, or medicines association (for example: antiretroviral nucleoside analogues, acetylsalicylic acid (aspirin), amiodarone, isoniazid, valproate). If you have symptoms of severe fatigue, itching, or if your skin or eyes look yellow, tell your doctor immediately, so that you can receive the proper treatment. 43/48 This product can cause withdrawal symptoms if you take it less than six hours after you use a narcotic (e.g. morphine, heroin) or less than 24 hours after you use methadone. This product can cause sleepiness which may be increased by alcohol or anti-anxiety medicines. Advise your physician in case of: recent head injury or brain disease, decrease of blood pressure, in men: urinary disorders (especially linked to enlarged prostate). This medicinal product may mask pain reflecting some diseases. Do not forget to advise your physician if you take this medicine. This product may cause your blood pressure to drop suddenly, causing you to feel dizzy if you get up too quickly from sitting or lying down. This product can cause dependence. Athletes should be aware that this medicine, due to its active substance, may cause a positive reaction to “anti-doping tests”. Advise your physician in case of: asthma or other breathing problems, kidney disease, liver disease. Using other medicines Using other medicines may increase the undesirable effects of buprenorphine and use of these medicines must be carefully monitored: • tranquilizers • anti-anxiety medicines • anti-depressants • benzodiazepines • some medicines used to treat high blood pressure. If your physician prescribes benzodiazepines, you must not take more than the prescribed dose. Taking this product with benzodiazepines (medicines used to treat anxiety or sleep disorders) may cause death due to respiratory failure. The following medicines may increase the buprenorphine blood concentrations, so concomitant use of these medicines together with Suboxone should be closely monitored and could require in some cases a dose reduction by your doctor: • anti-retrovirals (ritonavir, nelfinavir, indinavir) • ketoconazole • itraconazole Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. Using Suboxone with food and drink Do not take Suboxone together with alcoholic beverages as alcohol may possibly increase drowsiness induced by Suboxone. Pregnancy and breast-feeding Ask your doctor or pharmacist for advice before taking any medicine. 44/48 You should not use Suboxone during pregnancy. Tell your doctor if you are pregnant or intend to become pregnant. He will decide if your treatment should be continued with an alternative medication. Since this product will pass into your milk and may adversely affect the breast-fed child, you should discontinue breast-feeding while taking Suboxone. Driving and using machines Suboxone may cause drowsiness. If you feel tired, do not drive a motor vehicle or operate machinery. Important information about some of the ingredients of Suboxone Suboxone contains lactose. If you have been told by your doctor that you have intolerance to some sugars, contact your doctor before taking this medicinal product. 3. HOW TO TAKE SUBOXONE Sublingual route is the only efficacious administration route for this product. Do not swallow the tablets. Keep the tablet dose under your tongue until it dissolves. This may take 5-10 minutes. Take the dose once a day. Your doctor will determine the best dose for you. During your treatment, the doctor may adjust the dose, depending upon your response. To get the greatest benefit from taking Suboxone, you must tell your doctor about all the medicines you are taking, including alcohol, medicines containing alcohol, street drugs, and any prescription medicine you are taking that had not been prescribed to you by your doctor. Treatment duration The length of treatment will be determined individually by your doctor. After a time of successful treatment, the doctor may reduce the dose gradually to a lower maintenance dose. Depending on your condition, the Suboxone dose may continue to be reduced under careful medical supervision, until eventually it may be stopped. Do not change the treatment in any way or stop treatment without the agreement of the doctor who is treating you. The effectiveness of this treatment depends: on the dose, in combination with the associated medical, psychological and social treatment. If you have the impression that the effect of Suboxone is too strong or too weak, talk to your doctor or pharmacist. If you use more Suboxone than you should In case of overdose of buprenorphine, you must go or be taken immediately to an emergency centre or hospital for treatment. Advise immediately your doctor or your pharmacist. If you forget to use Suboxone Contact your doctor. If you stop using Suboxone Stopping treatment suddenly may cause withdrawal symptoms. If you have any further questions on the use of this product, ask your doctor or pharmacist. 45/48 4. POSSIBLE SIDE EFFECTS Like all medicines, Suboxone can cause side effects, although not everybody gets them. After the first dose of Suboxone, you may have some opiate withdrawal symptoms. Very common side effects (occurring in at least 1 in 10 patients) that may occur with Suboxone are: insomnia, constipation, nausea, sweating, headache, withdrawal syndrome. Common side effects (occurring in at least 1 in 100 patients) that may occur during treatment with Suboxone are: weight loss, swelling (hands and feet), tiredness, drowsiness, anxiety, nervousness, tingling, depression, decreased sexual drive, muscle spasms, abnormal thinking, tearing disorder, blurred vision, flushing, increased blood pressure, migraines, runny nose, sore throat and painful swallowing, increased cough, upset stomach, diarrhoea, abnormal liver function, loss of appetite, flatulence, vomiting, rash, itching, hives, pain, joint pain, muscle pain, leg cramps, impotence, urine abnormality, abdominal pain, back pain, weakness, infection, chills, chest pain, fever, flu syndrome, feeling of general discomfort, accidental injury, faintness and dizziness, drop in blood pressure on changing position from sitting or lying down to standing. Uncommon side effects (occurring in at least 1 in 1,000 patients) with Suboxone are: swollen glands (lymph nodes), agitation, tremor, abnormal dream, excessive muscle activity, depersonalization (not feeling like yourself), medicine dependence, amnesia (memory disturbance), loss of interest, exaggerated feeling of well being, convulsion (fits), speech disorder, small pupil size, problems with urination, conjunctivitis, rapid or slow heart beat, low blood pressure, palpitations, myocardial infarction (heart attack), shortness of breath, asthma, yawning, pain and sores in mouth, tongue discolouration, acne, skin nodule, hair loss, dry or scaling skin, inflammation of joints, urinary tract infection, blood in urine, abnormal ejaculation, menstrual or vaginal problems, kidney stone, sensitivity to heat or cold, allergic reaction, feelings of hostility. Rarely (occurring in at least 1 in 10,000 patients), the following have occurred with buprenorphine alone: respiratory depression (severe difficulty in breathing) - see “Take special care with Suboxone”, liver problems with or without jaundice- see “Take special care with Suboxone”, hallucinations. Misusing this medicine by injecting it can cause withdrawal symptoms, infections, other skin reactions and potentially serious liver problems - see “Take special care with Suboxone”. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. 5. HOW TO STORE SUBOXONE Keep out of the reach and sight of children. Do not use Suboxone after the expiry date which is stated on the carton. The expiry date refers to the last day of that month. This medicinal product does not require any special storage conditions. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. 46/48 6. FURTHER INFORMATION What Suboxone contains - The active substance is buprenorphine and naloxone. Each tablet contains 8 mg buprenorphine as buprenorphine hydrochloride and 2 mg naloxone as naloxone hydrochloride dihydrate. The other ingredients are lactose monohydrate, mannitol, maize starch, povidone K30, citric acid anhydrous, sodium citrate, magnesium stearate, acesulfame potassium and natural lemon and lime flavour. What Suboxone looks like and contents of the pack Sublingual tablets, white hexagonal biconvex tablets, embossed with a sword logo on one side and “N8” on the reverse side, packed in packs of 7 and 28 tablets. Not all pack sizes may be marketed. Marketing Authorisation Holder and Manufacturer Marketing Authorisation Holder: SP Europe, Rue de Stalle 73, B-1180 Bruxelles, Belgium. Manufacturer: Reckitt Benckiser Healthcare (UK) Ltd, Dansom Lane, Hull, East Yorkshire HU8 7DS, United Kingdom. For any information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien Rue de Stalle/Stallestraat 73 B-1180 Bruxelles/Brussel/Brüssel Tél/Tel: + 32-(0)2 370 92 11 Luxembourg/Luxemburg Rue de Stalle 73 B-1180 Bruxelles/Brüssel Belgique/Belgien Tél/Tel: + 32-(0)2 370 92 11 Česká republika Na Příkopě 25 CZ-110 00 Praha 1 Tel: + 420 221771250 Magyarország Alkotás u. 53. H-1123 Budapest Tel.: + 36 1 457-8500 Danmark Hvedemarken 12 DK-3520 Farum Tlf: + 45-44 39 50 00 Malta 168 Christopher Street MT-VLT02 Valletta Tel: + 356-21 23 21 75 Deutschland Thomas-Dehler-Straße 27 D-81737 München Tel: + 49-(0)89 627 31-0 Nederland Maarssenbroeksedijk 4 NL-3542 DN Utrecht Tel: + 31-(0)30 240 88 88 Eesti Järvevana tee 9 EE-11314 Tallinn Tel: + 372 654 96 86 Norge Ankerveien 209 N-1359 Eiksmarka Tlf: + 47 67 16 64 50 Ελλάδα Αγίου ∆ηµητρίου 63 GR-174 55 Άλιµος Tηλ: + 30-210 98 97 300 Österreich Badener Strasse 23 A-2514 Traiskirchen Tel: + 43-(0)2252 502-0 47/48 España Km. 36, Ctra. Nacional I E-28750 San Agustín de Guadalix – Madrid Tel: + 34-91 848 85 00 Polska Al. Jerozolimskie 195a PL-02-222 Warszawa Tel.: + 48-(0)22 478 41 50 France 92 rue Baudin F-92300 Levallois-Perret Tél: + 33-(0)1 41 06 35 00 Portugal Rua Agualva dos Açores 16 P-2735-557 Agualva-Cacém Tel: + 351-21 433 93 00 Ireland Shire Park Welwyn Garden City Hertfordshire AL7 1TW Tel: + 44-(0)1 707 363 636 Slovenija Dunajska 22 SI-1000 Ljubljana Tel: + 386 01 3001070 Ísland Hörgatún 2 IS-210 Garðabær Sími: + 354 535 70 00 Slovenská republika Strakova 5 SK-811 01 Bratislava Tel: + 421 (2) 5920 2712 Italia Centro Direzionale Milano Due Palazzo Borromini I-20090 Segrate (Milano) Tel: + 39-02 21018.1 Suomi/Finland PL 3/PB 3 FIN-02201 Espoo/Esbo Puh/Tel: + 358-(0)20 7570 300 Κύπρος Οδός Αγίου Νικολάου, 8 CY-1055 Λευκωσία Τηλ: + 357-22 757188 Sverige Box 27190 S-102 52 Stockholm Tel: + 46-(0)8 522 21 500 Latvija Vāgnera iela 13 Rīga LV-1050 Tel: + 371-7 21 38 25 United Kingdom Shire Park Welwyn Garden City Hertfordshire AL7 1TW - UK Tel: + 44-(0)1 707 363 636 Lietuva Kęstučio g. 65/40 LT-08124 Vilnius Tel. + 370 52 638 446 This leaflet was last approved on Detailed information on this product is available on the web-site of the European Medicines Agency (EMEA) http://www.emea.eu.int/ 48/48