ZUBSOLV 5.7mg / 1.4mg sublingual tablets medication leaflet

Zubsolv 0.7 mg/0.18 mg sublingual tablets

Zubsolv 1.4 mg/0.36 mg sublingual tablets

Zubsolv 2.9 mg/0.71 mg sublingual tablets

Zubsolv 5.7 mg/1.4 mg sublingual tablets

Zubsolv 8.6 mg/2.1 mg sublingual tablets

Zubsolv 11.4 mg/2.9 mg sublingual tablets

Zubsolv 0.7 mg/0.18 mg sublingual tablets

Each 0.7 mg/0.18 mg sublingual tablet contains 0.7 mg buprenorphine (as hydrochloride) and0.18 mg naloxone (as hydrochloride dihydrate).

Zubsolv 1.4 mg/0.36 mg sublingual tablets

Each 1.4 mg/0.36 mg sublingual tablet contains 1.4 mg buprenorphine (as hydrochloride) and0.36 mg naloxone (as hydrochloride dihydrate).

Zubsolv 2.9 mg/0.71 mg sublingual tablets

Each 2.9 mg/0.71 mg sublingual tablet contains 2.9 mg buprenorphine (as hydrochloride) and0.71 mg naloxone (as hydrochloride dihydrate).

Zubsolv 5.7 mg/1.4 mg sublingual tablets

Each 5.7 mg/1.4 mg sublingual tablet contains 5.7 mg buprenorphine (as hydrochloride) and 1.4 mgnaloxone (as hydrochloride dihydrate).

Zubsolv 8.6 mg/2.1 mg sublingual tablets

Each 8.6 mg/2.1 mg sublingual tablet contains 8.6 mg buprenorphine (as hydrochloride) and 2.1 mgnaloxone (as hydrochloride dihydrate).

Zubsolv 11.4 mg/2.9 mg sublingual tablets

Each 11.4 mg/2.9 mg sublingual tablet contains 11.4 mg buprenorphine (as hydrochloride) and2.9 mg naloxone (as hydrochloride dihydrate).

For the full list of excipients, see section 6.1.

Sublingual tablet

Zubsolv 0.7 mg/0.18 mg sublingual tablets

A white to off-white, oval tablet, length 6.8 mm and width 4.0 mm, debossed with “.7” on one side.

Zubsolv 1.4 mg/0.36 mg sublingual tablets

A white to off-white, triangular tablet, base 7.2 mm and height 6.9 mm, debossed with “1.4” on oneside.

Zubsolv 2.9 mg/0.71 mg sublingual tablets

A white to off-white, D-shaped tablet, height 7.3 mm and width 5.65 mm, debossed with “2.9” onone side.

Zubsolv 5.7 mg/1.4 mg sublingual tablets

A white to off-white, round tablet, 7 mm in diameter, debossed with “5.7” on one side.

Zubsolv 8.6 mg/2.1 mg sublingual tablets

A white to off-white, diamond shaped tablet, length 9.5 mm and width 8.2 mm, debossed with “8.6”on one side.

Zubsolv 11.4 mg/2.9 mg sublingual tablets

A white to off-white, capsule shaped tablet, length 10.3 mm and width 8.2 mm, debossed with “11.4”on one side.

Substitution treatment for opioid drug dependence, within a framework of medical, social andpsychological treatment. The intention of the naloxone component is to deter intravenous misuse.

Zubsolv is indicated in adults and adolescents over 15 years of age who have agreed to be treated foraddiction.

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

Zubsolv is not interchangeable with other buprenorphine products, as different buprenorphineproducts have different bioavailability. Therefore, the dose in mg can differ between products. Oncethe appropriate dose has been identified for a patient with a specific buprenorphine product, thatproduct should not be exchanged with another product.

If a patient is changed between buprenorphine or buprenorphine and naloxone containingproducts, dose adjustments may be necessary due to the potential differences in bioavailability(see sections 4.4 and 5.2).

Use of multiples of the three lower dose presentations of Zubsolv to substitute for any of the threehigher dose presentations (in for example cases where the higher dose presentations aretemporarily not available) is not recommended (see section 5.2).

Precautions to be taken before induction

Prior to treatment initiation, consideration should be given to the type of opioid dependence (i.e.

long- or short-acting opioid), the time since last opioid use and the degree of opioid dependence. Toavoid precipitating withdrawal, induction with buprenorphine/naloxone or buprenorphine onlyshould be undertaken when objective and clear signs of withdrawal are evident (demonstrated e.g. bya score indicating mild to moderate withdrawal on the validated Clinical Opioid Withdrawal Scale,

COWS).

* For patients dependent upon heroin or short-acting opioids, the first dose ofbuprenorphine/naloxone must be taken when signs of withdrawal appear, but not less than 6hours after the patient last used opioids.

* For patients receiving methadone, the dose of methadone must be reduced to a maximum of 30mg/day before beginning buprenorphine/naloxone therapy. The long half-life of methadoneshould be considered when starting buprenorphine/naloxone. The first dose ofbuprenorphine/naloxone should be taken only when signs of withdrawal appear, but not lessthan 24 hours after the patient last used methadone. Buprenorphine may precipitate symptomsof withdrawal in patients dependent upon methadone.

Initiation therapy (induction)

The recommended starting dose in adults and adolescents over 15 years of age is 1.4 mg/0.36 mg or2.9 mg/0.71 mg a day. An additional Zubsolv 1.4 mg/0.36 mg or 2.9 mg/0.71 mg may beadministered on day one depending on the individual patient’s requirement.

During the initiation of treatment, daily supervision of dosing is recommended to ensure propersublingual placement of the dose and to observe patient response to treatment as a guide to effectivedose titration according to clinical effect.

Dosage stabilisation and maintenance therapy

Following treatment induction on day 1, the patient must be rapidly stabilised on an adequatemaintenance dose by titrating to achieve a dose that holds the patient in treatment and suppressesopioid withdrawal effects and is guided by reassessment of the clinical and psychological status ofthe patient. The maximum single daily dose should not exceed 17.2 mg buprenorphine (e.g. given as11.4 + 5.7 mg, 2 x 8.6 mg or 3 x 5.7 mg).

During maintenance therapy, it may be necessary to periodically restabilise the patient on a newmaintenance dose in response to changing patient needs.

The 0.7 mg/0.18 mg strength is intended to be used to fine tune the dose for patients especiallyduring tapering of treatment or in case of tolerability issues during titration.

Physicians are encouraged to prescribe a single tablet once daily regimen where possible to minimiserisk of diversion.

Less than daily dosing

After a satisfactory stabilisation has been achieved the frequency of Zubsolv dosing may bedecreased to dosing every other day at twice the individually titrated daily dose. In some patients,after a satisfactory stabilisation has been achieved, the frequency of dosing may be decreased to 3times 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 bethree times the individually titrated daily dose, with no dose on the intervening days.) However, thedose given on any one day should not exceed 17.2 mg buprenorphine. Patients requiring a titrateddaily dose > 5.7 mg buprenorphine /day may not find this regimen adequate.

Medical withdrawal

After a satisfactory stabilisation has been achieved, if the patient agrees, the dose may be reducedgradually to a lower maintenance dose; in some favourable cases, treatment may be discontinued.

The availability of six different tablet strengths supports individual dose titration and tapering.

Patients should be monitored following medical withdrawal because of the potential for relapse.

The safety and efficacy of buprenorphine/naloxone in elderly patients over 65 years of age have notbeen established. No recommendation on posology can be made.

As buprenorphine/naloxone pharmacokinetics may be altered in patients with hepatic impairment,lower initial doses and careful dose titration in patients with mild to moderate hepatic impairment arerecommended (see section 5.2). Buprenorphine/naloxone is contraindicated in patients with severehepatic impairment (see sections 4.3 and 5.2).

Modification of the buprenorphine/naloxone dose is not required in patients with renal impairment.

Caution is recommended when dosing patients with severe renal impairment (creatinine clearance <30 ml/min) (see sections 4.4 and 5.2).

The safety and efficacy of buprenorphine/naloxone in children below the age of 15 years have notbeen established. No data are available.

Physicians must warn patients that the sublingual route is the only effective and safe route ofadministration for this medicinal product (see section 4.4). The tablet is to be placed under the tongueuntil completely dissolved. Patients should not swallow or consume food or drink until the tablet iscompletely dissolved.

Zubsolv disintegrates usually within 40 seconds, however it may take 5 to 10 minutes for the patientto feel complete tablet disappearance from the mouth.

If more than one tablet is required, they may be taken all at the same time or in two divided portions;the second portion is to be taken directly after the first portion has dissolved.

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Severe respiratory insufficiency.

Acute alcoholism or delirium tremens.

Concomitant administration of opioid antagonists (naltrexone, nalmefene) for the treatment ofalcohol or opioid dependence.

Misuse, abuse and diversion

Buprenorphine can be misused or abused in a manner similar to other opioids, legal or illicit. Somerisks of misusers and abusers include overdose, spread of blood borne viral or localised and systemicinfections, respiratory depression and hepatic injury. Buprenorphine misuse by someone other thanthe intended patient poses the additional risk of new drug dependent individuals using buprenorphineas the primary drug of abuse, and may occur if the medicinal product is distributed for illicit usedirectly by the intended patient or if the medicinal product is not safeguarded against theft.

Sub-optimal treatment with buprenorphine/naloxone may prompt medicinal product misuse by thepatient, leading to overdose or treatment dropout. A patient who is under-dosed withbuprenorphine/naloxone may continue responding to uncontrolled withdrawal symptoms by self-medicating with opioids, alcohol or other sedative-hypnotics such as benzodiazepines.

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

Combining buprenorphine with naloxone in Zubsolv is intended to deter misuse and abuse of thebuprenorphine. Intravenous or intranasal misuse of Zubsolv is expected to be less likely than withbuprenorphine alone since the naloxone in Zubsolv can precipitate withdrawal in individual’sdependent on heroin, methadone, or other opioid agonists.

Sleep-related breathing disorders

Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patientswho present with CSA, consider decreasing the total opioid dosage.

A number of cases of death due to respiratory depression have been reported, particularly whenbuprenorphine was used in combination with benzodiazepines (see section 4.5) or whenbuprenorphine was not used according to the prescribing information. Deaths have also beenreported in association with concomitant administration of buprenorphine and other depressants suchas alcohol or other opioids. If buprenorphine is administered to some non-opioid dependentindividuals, who are not tolerant to the effects of opioids, potentially fatal respiratory depression mayoccur.

This medicinal product should be used with care in patients with asthma or respiratory insufficiency(e.g. chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, hypoxia,hypercapnia, pre-existing respiratory depression or kyphoscoliosis (curvature of spine leading topotential shortness of breath)).

Buprenorphine/naloxone may cause severe, possibly fatal, respiratory depression in children andnon-dependent persons in case of accidental or deliberate ingestion. Patients must be warned to storethe blister safely, to never open the blister in advance, to keep them out of the reach of children andother household members, and not to take this medicinal product in front of children. An emergencyunit should be contacted immediately in case of accidental ingestion or suspicion of ingestion.

Central Nervous System (CNS) depression

Buprenorphine/naloxone may cause drowsiness, particularly when taken together with alcohol orcentral nervous system depressants (such as benzodiazepines, tranquilisers, sedatives or hypnoticssee sections 4.5 and 4.7).

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

Concomitant use of buprenorphine/naloxone and sedative medicinal products such asbenzodiazepines or related medicinal products may result in sedation, respiratory depression, comaand death. Because of these risks, concomitant prescribing with these sedative medicinal productsshould be reserved for patients for whom alternative treatment options are not possible. If a decisionis made to prescribe buprenorphine/naloxone concomitantly with sedative medicinal products, thelowest effective dose of the sedative medicines should be used, and the duration of treatment shouldbe as short as possible. The patients should be followed closely for signs and symptoms ofrespiratory depression and sedation. In this respect, it is strongly recommended to inform patientsand their caregivers to be aware of these symptoms (see section 4.5).

Serotonin syndrome

Concomitant administration of Zubsolv and other serotonergic agents, such as MAO inhibitors,selective serotonin re-uptake inhibitors (SSRIs), serotonin norepinephrine re-uptake inhibitors(SNRIs) or tricyclic antidepressants may result in serotonin syndrome, a potentially life-threateningcondition (see section 4.5).

If concomitant treatment with other serotonergic agents is clinically warranted, careful observationof the patient is advised, particularly during treatment initiation and dose increases.

Symptoms of serotonin syndrome may include mental-status changes, autonomic instability,neuromuscular abnormalities, and/or gastrointestinal symptoms.

If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy should beconsidered depending on the severity of the symptoms.

Dependence

Buprenorphine is a partial agonist at the μ (mu)-opiate receptor and chronic administration producesdependence of the opioid type. Studies in animals, as well as clinical experience, have demonstratedthat buprenorphine may produce dependence, but at a lower level than a full agonist e.g. morphine.

Abrupt discontinuation of treatment is not recommended as it may result in a withdrawal syndromethat may be delayed in onset.

Hepatitis and hepatic events

Cases of acute hepatic injury have been reported in opioid-dependent addicts both in clinical trialsand in post marketing adverse reaction reports. The spectrum of abnormalities ranges from transientasymptomatic elevations in hepatic transaminases to case reports of hepatic failure, hepatic necrosis,hepatorenal syndrome, hepatic encephalopathy and death. In many cases the presence of pre-existingmitochondrial impairment (genetic disease, liver enzyme abnormalities, infection with hepatitis B orhepatitis C virus, alcohol abuse, anorexia, concomitant use of other potentially hepatotoxic medicinalproducts) and ongoing injecting drug use may have a causative or contributory role. Theseunderlying factors must be taken into consideration before prescribing buprenorphine/naloxone andduring treatment.

When a hepatic event is suspected, further biological and aetiological evaluation is required.

Depending upon the findings, the medicinal product may be discontinued cautiously so as to preventwithdrawal symptoms and to prevent a return to illicit drug use. If the treatment is continued, hepaticfunction should be monitored closely.

Precipitation of opioid withdrawal syndrome

When initiating treatment with buprenorphine/naloxone, the physician must be aware of the partialagonist profile of buprenorphine and that it can precipitate withdrawal in opioid-dependent patients,particularly if administered less than 6 hours after the last use of heroin or other short-acting opioid,or if administered less than 24 hours after the last dose of methadone. Patients should be clearlymonitored during the switching period from buprenorphine or methadone to buprenorphine/naloxonesince withdrawal symptoms have been reported.

To avoid precipitating withdrawal, induction with buprenorphine/naloxone should be undertakenwhen objective signs of withdrawal are evident (see section 4.2).

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

The effects of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone wereevaluated in a post-marketing study. Since both buprenorphine and naloxone are extensivelymetabolized in liver, plasma levels were found to be higher for both buprenorphine and naloxone inpatients with moderate and severe hepatic impairment compared with healthy subjects. Patientsshould be monitored for signs and symptoms of precipitated opioid withdrawal, toxicity or overdosecaused by increased levels of naloxone and/or buprenorphine.

Baseline liver function tests and documentation of viral hepatitis status is recommended prior tocommencing therapy. Patients who are positive for viral hepatitis, on concomitant medicinalproducts (see section 4.5) and/or have existing liver dysfunction are at greater risk of liver injury.

Regular monitoring of liver function is recommended (see section 4.4).

Zubsolv sublingual tablets should be used with caution in patients with moderate hepatic impairment(see sections 4.2 and 5.2). In patients with severe hepatic insufficiency the use ofbuprenorphine/naloxone is contraindicated (see section 4.3).

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

CYP 3A4 inhibitors

Medicinal products that inhibit the enzyme CYP3A4 may give rise to increased concentrations ofbuprenorphine. A reduction of the buprenorphine/naloxone dose may be needed. Patients alreadytreated with CYP3A4 inhibitors should have their dose of buprenorphine/naloxone titrated carefullysince a reduced dose may be sufficient in these patients (see section 4.5).

Opioids may produce orthostatic hypotension in ambulatory patients.

Opioids may elevate cerebrospinal fluid pressure, which may cause seizures, so opioids should be usedwith caution in patients with head injury, intracranial lesions, in other circumstances wherecerebrospinal pressure may be increased, or in patients with a history of seizure.

Opioids should be used with caution in patients with hypotension, prostatic hypertrophy or urethralstenosis.

Opioid-induced miosis, changes in the level of consciousness, or changes in the perception of pain asa symptom of disease may interfere with patient evaluation or obscure the diagnosis or clinical courseof concomitant disease.

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

Opioids have been shown to increase intracholedochal pressure, and should be used with caution inpatients with dysfunction of the biliary tract.

Opioids should be administered with caution to elderly or debilitated patients.

The concomitant use of monoamine oxidase inhibitors (MAOI) might produce an exaggeration of theeffects of opioids, based on experience with morphine (see section 4.5).

Changing between buprenorphine containing products

The dose in mg can differ between buprenorphine products and products are not directlyinterchangeable. Therefore, patients should be monitored when changing between differentbuprenorphine containing products as differences in bioavailability (see section 5.2) may benoticeable in some individual cases. Dose adjustments may therefore be necessary.

Use in adolescents (age 15 - <18 years)

Due to the lack of data in adolescents (age 15 - <18 years), patients in this age group should be moreclosely monitored during treatment.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially‘sodium-free’.

Zubsolv must not be taken together with:

Zubsolv should not be taken together with:

* Alcoholic drinks or medicinal products containing alcohol, as alcohol increases thesedative effect of buprenorphine (see section 4.7).

Zubsolv should be used cautiously when co-administered with:

* Sedatives such as benzodiazepines or related medicinal products

The concomitant use of opioids with sedative medicinal products such as benzodiazepines orrelated medicinal products increases the risk of sedation, respiratory depression, coma anddeath because of additive CNS depressant effect. The dose and duration of concomitant useof sedative medicinal products should be limited (see section 4.4). Patients should bewarned that it is extremely dangerous to self-administer non-prescribed benzodiazepineswhile taking this medicinal product and should also be cautioned to use benzodiazepinesconcurrently with this medicinal product only as directed by their physician (seesection 4.4).

* The concomitant use of Zubsolv with gabapentinoids (gabapentin and pregabalin) mayresult in respiratory depression, hypotension, profound sedation, coma or death (see section4.4).

* 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 relatedsubstances: these combinations increase central nervous system depression. The reducedlevel of alertness can make driving and using machines hazardous.

* Furthermore, adequate analgesia may be difficult to achieve when administering a full opioidagonist in patients receiving buprenorphine/naloxone. Therefore the potential to overdosewith a full agonist exists, especially when attempting to overcome buprenorphine partialagonist effects, or when buprenorphine plasma levels are declining

* Serotonergic medicinal products, such as MAO inhibitors, selective serotonin re-uptakeinhibitors (SSRIs), serotonin norepinephrine re-uptake inhibitors (SNRIs) or tricyclicantidepressants as the risk of serotonin syndrome, a potentially life-threatening condition, isincreased (see section 4.4)

* naltrexone and nalmefene are opioid antagonists that can block the pharmacological effectsof buprenorphine. Co-administration during buprenorphine/naloxone treatment iscontraindicated due to the potentially dangerous interaction that may precipitate a suddenonset of prolonged and intense opioid withdrawal symptoms (see section 4.3).

* CYP3A4 inhibitors: an interaction study of buprenorphine with ketoconazole (a potentinhibitor of CYP3A4) resulted in increased Cmax and AUC (area under the curve) ofbuprenorphine (approximately 50 % and 70 % respectively) and, to a lesser extent, ofnorbuprenorphine Patients receiving Zubsolv should be closely monitored, and may requiredose-reduction if combined with potent CYP3A4 inhibitors (e.g. protease inhibitors likeritonavir, nelfinavir or indinavir or azole antifungals such as ketoconazole or itraconazole,macrolide antibiotics).

* CYP3A4 inducers: Concomitant use of CYP3A4 inducers with buprenorphine maydecrease buprenorphine plasma concentrations, potentially resulting in sub-optimaltreatment of opioid dependence with buprenorphine. It is recommended that patientsreceiving buprenorphine/naloxone should be closely monitored if inducers (e.g.

phenobarbital, carbamazepine, phenytoin, rifampicin) are co-administered. The dose ofbuprenorphine or the CYP3A4 inducer may need to be adjusted accordingly.

* The concomitant use of monoamine oxidase inhibitors (MAOI) might produceexaggeration of the effects of opioids, based on experience with morphine.

There are no or limited amount of data from the use of buprenorphine/naloxone in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humansis unknown.

Towards the end of pregnancy buprenorphine may induce respiratory depression in the newborninfant even after a short period of administration. Long-term administration of buprenorphine duringthe last three months of pregnancy may cause a withdrawal syndrome in the neonate (e.g. hypertonia,neonatal tremor, neonatal agitation, myoclonus or convulsions). The syndrome is generally delayedfor several hours to several days after birth.

Due to the long half-life of buprenorphine, neonatal monitoring for several days should be consideredat the end of pregnancy, to prevent the risk of respiratory depression or withdrawal syndrome inneonates.

Furthermore, the use of buprenorphine/naloxone during pregnancy should be assessed by thephysician. Buprenorphine/naloxone should be used during pregnancy only if the potential benefitoutweighs the potential risk to the foetus.

It is unknown whether naloxone/metabolites are excreted in human milk. Buprenorphine and itsmetabolites are excreted in human milk. In rat’s buprenorphine has been found to inhibit lactation.

Therefore, breastfeeding should be discontinued during treatment with Zubsolv.

Animal studies have shown a reduction in female fertility at high doses (systemic exposure >2.4 times the human exposure at the maximum recommended dose of 17.2 mg buprenorphine, basedon AUC) (see section 5.3).

Buprenorphine/naloxone has minor to moderate influence on the ability to drive and use machineswhen administered to opioid dependent patients. This medicinal product may cause drowsiness,dizziness, or impaired thinking, especially during treatment induction and dose adjustment. If takentogether with alcohol or central nervous system depressants, the effect is likely to be morepronounced (see sections 4.4 and 4.5).

Patients should be cautioned about driving or operating hazardous machinery in casebuprenorphine/naloxone may adversely affect their ability to engage in such activities.

The most commonly reported treatment related adverse reactions reported during the pivotal clinicaltrials were constipation and symptoms commonly associated with drug withdrawal (i.e. insomnia,headache, nausea, hyperhidrosis and pain). Some reports of seizure, vomiting, diarrhoea, andelevated liver function tests were considered serious.

Table 1 summarises adverse reactions reported from pivotal clinical trials in which, 342 of 472patients (72.5%) reported adverse reactions and adverse reactions reported during post-marketingsurveillance.

The frequency of possible adverse reactions listed below is defined using the following convention:

Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1 000 to <1/100), Rare(≥/10 000 to <1/1 000), Very rare (<1/10 000), Not known (cannot be estimated from available data).

Table 1: Treatment-related adverse reactions reported in clinical trials and post-marketingsurveillance of buprenorphine/naloxone

System Organ Very Common Uncommon Not known

Class common

Infections and Influenza Urinary tractinfestations Infection infection

Pharyngitis Vaginal infection

Rhinitis

Blood and Anaemialymphatic Leukocytosissystem Leukopeniadisorders Lymphadenopathy

Immune system Hypersensitivity Anaphylacticdisorders shock

Metabolism and Decreased appetitenutrition Hyperglycaemiadisorders Hyperlipidaemia

Psychiatric Insomnia Anxiety Abnormal dreams Hallucinationdisorders Depression Agitation

Libido Apathydecreased Depersonalisation

Nervousness Drug dependence

Thinking Euphoric moodabnormal Hostility

Nervous system Headache Migraine Amnesia Hepaticdisorders Dizziness Hyperkinesia encephalopathy

Hypertonia Seizure Syncope

System Organ Very Common Uncommon Not known

Class common

Paraesthesia Speech disorder

Somnolence Tremor

Eye disorders Amblyopia Conjunctivitis Miosis

Lacrimaldisorder

Ear and Vertigolabyrinthdisorders

Cardiac Angina pectorisdisorders Bradycardia

Palpitations

Vascular Hypertension Hypotension Orthostaticdisorders Vasodilatation hypotension

Respiratory, Cough Asthma Dyspnoea Bronchospasmthoracic and Yawning Respiratorymediastinal depressiondisorders

Gastrointestinal Constipation Abdominal Mouth ulceration Dental cariesdisorders Nausea pain Diarrhoea Tongue

Dyspepsia discolouration

Flatulence

Hepatobiliary Hepatitisdisorders Hepatitis acute

Jaundice

Hepaticnecrosis

Hepatorenalsyndrome

Skin and Hyperhidrosis Pruritus Rash Acne Alopecia Angioedemasubcutaneous Urticaria Dermatitis exfoliativetissue disorders Dry skin

Skin mass

Musculoskeletal Back pain Arthritisand connective Arthralgiatissue disorders Muscle spasms

Myalgia

Renal and Urine Albuminuriaurinary abnormality Dysuriadisorders Haematuria

Urinary retention

Reproductive Erectile Amenorrhoeasystem and dysfunction Ejaculationbreast disorders disorder

Menorrhagia

Metrorrhagia

General Drug Asthenia Hypothermia Drugdisorders and withdrawal Chest pain withdrawaladministration syndrome Chills syndromesite conditions Pyrexia neonatal

Malaise pain

System Organ Very Common Uncommon Not known

Class common

Oedemaperipheral

Investigations Liver function Blood creatinine Transaminasestest abnormal increased increased

Weightdecreased

Injury, Injury Heat strokepoisoning andproceduralcomplications

In cases of intravenous drug misuse, some adverse reactions are attributed to the act of misuse ratherthan the medicinal product and include local reactions, sometimes septic (abscess, cellulitis), andpotentially serious acute hepatitis, and other infections such as pneumonia, endocarditis have beenreported (see section 4.4).

In patients presenting with marked drug dependence, initial administration of buprenorphine canproduce a drug withdrawal syndrome similar to that associated with naloxone (see sections 4.2 and4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Respiratory depression as a result of central nervous system depression is the primary symptomrequiring intervention in the case of overdose because it may lead to respiratory arrest and death.

Signs of overdose may also include somnolence, amblyopia, miosis, hypotension, nausea, vomitingand/or speech disorders.

General supportive measures should be initiated, including close monitoring of respiratory andcardiac status of the patient. Symptomatic treatment of respiratory depression and standard intensivecare measures should be implemented. A patent airway and assisted or controlled ventilation must beassured. The patient should be transferred to an environment within which full resuscitation facilitiesare available.

If the patient vomits, care must be taken to prevent aspiration of the vomitus.

Use of an opioid antagonist (i.e., naloxone) is recommended, despite the modest effect it may have inreversing the respiratory symptoms of buprenorphine compared with its effects on full agonist opioidagents.

If naloxone is used, the long duration of action of buprenorphine should be taken into considerationwhen determining the length of treatment and medical surveillance needed to reverse the effects of anoverdose. Naloxone can be eliminated more rapidly than buprenorphine, allowing for a return ofpreviously controlled buprenorphine overdose symptoms, so a continuing infusion may be necessary.

If infusion is not possible, repeated dosing with naloxone may be required. Ongoing intravenousinfusion rates should be titrated to patient response.

Pharmacotherapeutic group: Other nervous system drugs, drugs used in addictive disorders, ATCcode: N07BC51.

Buprenorphine is an opioid partial agonist/antagonist which binds to the μ and κ (kappa) opioidreceptors of the brain. Its activity in opioid maintenance treatment is attributed to its slowly reversibleproperties with the μ-opioid receptors which, over a prolonged period, might minimise the need ofaddicted patients for drugs.

Opioid agonist ceiling effects were observed during clinical pharmacology studies in opioid-dependent patients.

Naloxone is an antagonist at μ-opioid receptors. When administered orally or sublingually in usualdoses to patients experiencing opioid withdrawal, naloxone exhibits little or no pharmacologicaleffect because of its almost complete first pass metabolism. However, when administeredintravenously to opioid-dependent patients the presence of naloxone in Zubsolv produces markedopioid antagonist effects and opioid withdrawal, thereby deterring intravenous abuse.

Efficacy and safety data for buprenorphine/naloxone are primarily derived from a one-year clinicaltrial, comprising a 4-week randomised double blind comparison of buprenorphine/naloxone,buprenorphine and placebo followed by a 48 week safety study of buprenorphine/naloxone. In thistrial, 326 heroin-addicted subjects were randomly assigned to either buprenorphine/naloxone 16 mgper day, 16 mg buprenorphine per day or placebo. For subjects randomised to either active treatment,dosing began with 8 mg of buprenorphine on Day 1, followed by 16 mg (two 8 mg) of buprenorphineon Day 2. On Day 3, those randomised to receive buprenorphine/naloxone were switched to thecombination tablet. Subjects were seen daily in the clinic (Monday through Friday) for dosing andefficacy assessments. Take-home doses were provided for weekends. The primary study comparisonwas to assess the efficacy of buprenorphine and buprenorphine/naloxone individually againstplacebo. The percentage of thrice-weekly urine samples that were negative for non-study opioids wasstatistically higher for both buprenorphine/naloxone versus placebo (p < 0.0001) and buprenorphineversus placebo (p < 0.0001).

In a double-blind, double-dummy, parallel-group study comparing buprenorphine ethanolic solutionversus a full agonist active control, 162 subjects were randomised to receive the ethanolic sublingualsolution of buprenorphine at 8 mg/day (a dose which is roughly comparable to a dose of 12 mg/dayof buprenorphine/naloxone), or two relatively low doses of active control, one of which was lowenough to serve as an alternative to placebo, during a 3 to10 day induction phase, a 16-weekmaintenance phase and a 7-week detoxification phase. Buprenorphine was titrated to maintenancedose by Day 3; active control doses were titrated more gradually. Based on retention in treatment andthe percentage of thrice-weekly urine samples negative for non-study opioids, buprenorphine wasmore effective than the low dose of the control, in keeping heroin addicts in treatment and inreducing their use of opioids while in treatment. The effectiveness of buprenorphine, 8 mg per daywas similar to that of the moderate active control dose, but equivalence was not demonstrated.

Zubsolv disintegrates usually within 40 seconds, however it may take 5 to 10 minutes for the patientto feel complete tablet disappearance from the mouth.

Zubsolv sublingual tablets have a higher bioavailability than conventional sublingual tablets.

Therefore the dose in mg can differ between products. Zubsolv is not interchangeable with otherbuprenorphine products.

In comparative bioavailability studies Zubsolv 11.4/2.9 mg displayed equivalent buprenorphineexposure to 16/4mg (2 x 8/2mg) buprenorphine/naloxone administered as conventional sublingualtablets however Zubsolv 2 x 1.4/0.36 mg displayed 20% lower buprenorphine exposure to 2 x2/0.5 mg buprenorphine/naloxone administered as conventional sublingual tablets. Naloxoneexposure was not higher from Zubsolv at any of the tested dose levels.

Buprenorphine

Buprenorphine, when taken orally, undergoes first-pass metabolism with N-dealkylation andglucuroconjugation in the small intestine and the liver. The use of this medicinal product by the oralroute is therefore inappropriate.

There are small deviations in buprenorphine dose proportionality exposure parameters as well asdeviations from strict compositional proportionality for the three lower strengths (2.9/0.71, 1.4/0.36,and 0.7/0.18 mg) compared to the three higher dose presentations. Therefore, multiples of the threelower dose presentations of Zubsolv should not be used to substitute for any of the three higher dose

Zubsolv presentations.

Peak plasma concentrations are achieved approximately 90 minutes after sublingual administration.

Plasma levels of buprenorphine increased with increasing the sublingual dose ofbuprenorphine/naloxone. Both Cmax and AUC of buprenorphine increased with the increase in dose,although the increase was less than dose-proportional.

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

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

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

Buprenorphine is primarily metabolised through -N-dealkylation by liver microsomal CYP3A4. theparent molecule and the primary dealkylated metabolite, norbuprenorphine, undergo subsequentglucuronidation. Norbuprenorphine binds to opioid receptors in vitro; however, it is not knownwhether norbuprenorphine contributes to the overall effect of buprenorphine/naloxone.

Elimination of buprenorphine is bi- or tri-exponential, and the a mean terminal elimination half-lifefrom plasma of 32 hours.

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

Naloxone

Following sublingual administration of buprenorphine/naloxone, plasma naloxone concentrations arelow and decline rapidly. Naloxone mean peak plasma concentrations were too low to assess dose-proportionality. Naloxone has not been found to affect the pharmacokinetics of buprenorphine.

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

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

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

Naloxone is excreted in the urine, with a mean half-life of elimination from plasma ranging from 0.9to 9 hours.

No pharmacokinetic data in elderly patients are available.

Renal elimination plays a relatively small role (~30%) in the overall clearance ofbuprenorphine/naloxone. No dose modification based on renal function is required but caution isrecommended when dosing subjects with severe renal impairment (see section 4.4).

The effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone wereevaluated in a post-marketing study.

Table 2 summarizes the results from a clinical trial in which the exposure after single-doseadministration of buprenorphine/naloxone sublingual tablet was determined in healthy subjects, andin subjects with varied degree of hepatic impairment.

Table 2: Effect of hepatic impairment on pharmacokinetic parameters of buprenorphineand naloxone following administration (change relative to healthy subjects)

PK parameter Mild Moderate Severehepatic hepatic hepaticimpairment impairment impairment(Child-Pugh Class (Child-Pugh Class (Child-Pugh Class

A) (n=9) B) (n=8) C) (n=8)

Buprenorphine

Cmax 1.2-fold increase 1.1-fold increase 1.7-fold increase

AUClast Similar to control 1.6-fold increase 2.8-fold increase

Naloxone

Cmax Similar to control 2.7-fold increase 11.3-fold increase

AUClast 0.2-fold decrease 3.2-fold increase 14.0-fold increase

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

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 beenobserved. Undesirable effects were based on the known pharmacological activity of opioid agonisticand/or antagonistic substances.

The combination (4:1) of buprenorphine hydrochloride and naloxone hydrochloride was notmutagenic in a bacterial mutation assay (Ames test), and was not clastogenic in an in vitrocytogenetic 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 thatembryolethality occurred in rats in the presence of maternal toxicity at all doses. The lowest dosestudied represented exposure multiples of 1x for buprenorphine and 5 x for naloxone at the maximumhuman therapeutic dose calculated on a mg/m² basis. No developmental toxicity was observed inrabbits at maternally toxic doses. Further, no teratogenicity has been observed in either rats orrabbits. A peri-postnatal study has not been conducted with buprenorphine/naloxone; however,maternal oral administration of buprenorphine at high doses during gestation and lactation resulted indifficult parturition (possible as a result of the sedative effect of buprenorphine), high neonatalmortality and a slight delay in the development of some neurological functions (surface rightingreflex and startle response) in neonatal rats.

Dietary administration of buprenorphine/naloxone in the rat at dose levels of 500 ppm or greaterproduced a reduction in fertility demonstrated by reduced female conception rates. A dietary dose of100 ppm (estimated exposure approximately 2.4 x for buprenorphine at a human dose of 17.2 mgbuprenorphine/naloxone based on AUC, plasma levels of naloxone were below the limit of detectionin rats) had no adverse effect on fertility in females.

A carcinogenicity study with buprenorphine/naloxone was conducted in rats at doses of 7, 30 and120 mg/kg/day, with estimated exposure multiples of 3 to75 times, based on a Zubsolv equivalenthuman daily sublingual dose of 11.4 mg of buprenorphine calculated on a mg/m² basis. Statisticallysignificant increases in the incidence of benign testicular interstitial (Leydig's) cell adenomas wereobserved in all dose groups.

Mannitol (E 421)

Citric acid (E 330)

Sodium citrate (E 331)

Microcrystalline cellulose

Croscarmellose sodium

Sucralose

Levomenthol

Colloidal anhydrous silica

Sodium stearyl fumarate

Not applicable.

0.7 mg/0.18 mg2 years1.4 mg/0.36 mg4 years2.9 mg/0.71 mg3 years5.7 mg/1.4 mg4 years8.6 mg/2.1 mg4 years11.4 mg/2.9 mg4 years

Store below 25 °C.

Store in the original package in order to protect from moisture.

PVC/oPA/Alu/PVC//Alu/PET/Paper child- resistant blister cards.

Pack size of 7, 28 or 30 sublingual tablets.

Not all pack sizes may be marketed.

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

Accord Healthcare S.L.U.

World Trade Center, Moll de Barcelona, s/n

Edifici Est 6ª planta08039 Barcelona

Spain

EU/1/17/1233/001

EU/1/17/1233/002

EU/1/17/1233/003

EU/1/17/1233/004

EU/1/17/1233/005

EU/1/17/1233/006

EU/1/17/1233/007

EU/1/17/1233/008

EU/1/17/1233/009

EU/1/17/1233/010

EU/1/17/1233/011

EU/1/17/1233/012

EU/1/17/1233/013

EU/1/17/1233/014

EU/1/17/1233/015

EU/1/17/1233/016

EU/1/17/1233/017

EU/1/17/1233/018

Date of first authorisation: 10 November 2017

Date of latest renewal: 27 July 2022

Detailed information on this medicinal product is available on the website of the European

Medicines Agency http://www.ema.europa.eu.