ZUBSOLV 1.4 MG / 0.36 MG SUBLINGUAL TABLETS - summary of medicine characteristics

Zubsolv 1.4 mg / 0.36 mg sublingual tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

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

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Sublingual tablet

White, triangular tablets, base 7.2 mm and height 6.9 mm, debossed with “1.4” on one 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 opioid dependence/ad­diction.

Prior to starting treatment with opioids, a discussion should be held with patients to put in place a strategy for ending treatment with buprenorphine in order to minimise the risk of addiction and drug withdrawal syndrome (see section 4.4). The decision to maintain a patient on a long-term opioid prescription should be an active decision agreed between the clinician and patient with review at regular intervals (usually at least three-monthly, depending on clinical progress).

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

If a patient is changed between buprenorphine or buprenorphine and naloxone containing products, 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 three higher dose presentations (in for example cases where the higher dose presentations are temporarily not available) is not recommended (see section5.2).

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. To avoid precipitating withdrawal, induction with buprenorphine/na­loxone or buprenorphine only should be undertaken when objective and clear signs of withdrawal are evident (demonstrated e.g. by ascore 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 of buprenorphine/na­loxone should be taken when signs of withdrawal appear, but not less than 6 hours after the patient last used opioids.

For patients receiving methadone, the dose of methadone should be reduced to a maximum of 30 mg/day before beginning buprenorphine/na­loxone therapy. The long half-life of methadone should be considered when starting buprenorphine/na­loxone. The first dose of buprenorphine/na­loxone should be taken only 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.

Posology

Initiation therapy

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

Induction

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

Dosage adjustment and maintenance therapy

Following treatment induction on day one, the patient should be stabilised to a maintenance dose during the next few days by progressively adjusting the dose according to the clinical effect on the individual patient. Patients should be monitored during dose titration. For steps of 1.4–5.7 mg buprenorphine this titration is guided by reassessment of the clinical and psychological status of the patient, and should not exceed a maximum single daily dose of 17.2 mg buprenorphine (e.g. given as 11.4 + 5.7 mg, 2 × 8.6 mg or 3 × 5.7 mg).

The 0.7mg / 0.18mg strength is intended to be used to fine tune the dose for patients especially during 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 minimise risk of diversion.

Less than daily dosing

After a satisfactory stabilisation has been achieved the frequency of dosing may be decreased 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 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 17.2 mg buprenorphine. Patients requiring a titrated daily 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 dosage may be reduced gradually 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.

Switching between buprenorphine and buprenorphine/na­loxone

When used sublingually, buprenorphine/na­loxone and buprenorphine have similar clinical effects and are interchangeable; however, before switching between buprenorphine/na­loxone and buprenorphine, the prescriber and patient should agree to the change, and the patient should be monitored in case a need to readjust the dose occurs.

Special populations

Elderly

The safety and efficacy of buprenorphine/na­loxone in elderly patients over 65 years of age have not been established. No recommendation on posology can be made.

Hepatic impairment

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 are recommended (see section 5.2).

Buprenorphine/na­loxone is contraindicated in patients with severe hepatic impairment (see sections 4.3 and 5.2).

Renal impairment

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).

Paediatric population

The safety and efficacy of buprenorphine/na­loxone in children below the age of 15years have not been established. No data are available.

Method of administration

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). The tablet is to be placed under the tongue until completely dissolved.

Patients should not swallow or consume food or drink until the tablet is completely dissolved.

Zubsolv disintegrates usually within 40 seconds, however it may take 5 to 10 minutes for the patient to 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.

4.3 Contraindications

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

Severe respiratory insufficiency.

Severe hepatic impairment.

Acute alcoholism or delirium tremens.

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

4.4 Special warnings and precautions for use

Drug dependence, tolerance and potential for abuse

Prolonged use of this product may lead to drug dependence (addiction), even at therapeutic doses. The risks are increased in individuals with current or past history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g. major depression). Overuse or misuse may result in overdose and/or death. It is important that patients only use medicines that are prescribed for them at the dose they have been prescribed and do not give this medicine to anyone else. Patients should be closely monitored for signs of misuse, abuse, or addiction. The clinical need for continuing opioid substitution therapy should be reviewed regularly.

Buprenorphine can be misused or abused in a manner similar to other opioids, legal or illicit. Some risks of misuse and abuse include overdose, spread of bloodborne viral or localised and systemic infections, respiratory depression and hepatic injury. Buprenorphine misuse by someone other than the intended patient poses the additional risk of new drug dependent individuals using buprenorphine as the primarydrug of abuse, and may occur if the medicinal product is distributed for illicit use directly by the intended patient or if it is not safeguarded against theft.

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

To minimize the risk of misuse, abuse and diversion, appropriate precautions should be taken when prescribing and dispensing buprenorphine, such as avoiding prescribing multiple refills early in treatment, and conducting patient follow-upvisits with clinical monitoring that is appropriate for the patient's needs.

Combining buprenorphine with naloxone in Zubsolv is intended to deter

misuse and abuse of the buprenorphine. Intravenous or intranasal misuse of Zubsolv is expected to be less likely than with buprenorphine alone since the naloxone in this medicinal product can precipitate withdrawal in individuals dependent on heroin, methadone, or other opioidagonists.

Seizures

Buprenorphine may lower the seizure threshold in patients with a history of seizure disorder.

Respiratory depression

A number of cases of death due to respiratory depression have been reported, particularly when buprenorphine was used in combination with benzodiazepines (seesection 4.5) or when buprenorphine was not used according to the prescribing information. Deaths have also been reported in association with concomitant administration of buprenorphine and other depressants such as alcohol or other opioids.

If buprenorphine is administered to some non-opioid dependent individuals, who arenot tolerant to the effects of opioids, potentially fatal respiratory depression may occur.

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

Buprenorphine/na­loxone may cause severe, possibly fatal, respiratory depression inchildren and non-dependent persons in case of accidental or deliberate ingestion.

Patients must be warned to store the blister safely, to never open the blister in advance, to keep them out of the sight and reach of children and other householdmembers, and not to take this medicinal product in front of children. An emergency unit should be contacted immediately in case of accidental ingestion or suspicion of ingestion.

CNS depression

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

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

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

Serotonin syndrome

Concomitant administration of Zubsolv and other serotonergic agents, such as MAOinhibitors, selective serotonin re-uptake inhibitors (SSRIs), serotonin norepinephrinere-uptake inhibitors (SNRIs) or tricyclic antidepressants may result in serotonin

syndrome, a potentially life-threatening condition (see section 4.5). If concomitant treatment with other serotonergic agents is clinically warranted, careful observation of the patient is advised, particularly during treatment initiationand dose increases.

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

If serotonin syndrome is suspected, a dose reduction or discontinuation of therapyshould be considered depending on the severity of the symptoms.

Dependence

Buprenorphine is a partial agonist at the g (mu)-opiate receptor and chronic administration produces dependence of the opioid type. Studies in animals, as well asclinical experience, have demonstrated that 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 withdrawal syndrome that may be delayed in onset.

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 reaction reports. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminasesto case reports of hepatic failure, hepatic necrosis, hepatorenal syndrome, hepatic encephalopathy and death. In many cases the presence of pre-existing mitochondrial impairment (genetic disease, liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, alcohol abuse, anorexia, concomitant use of other potentially hepatotoxic medicinal products) and ongoing injecting drug use may have a causative or contributory role.These underlying factors must be taken into consideration before prescribing buprenorphine/na­loxone and during 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 prevent withdrawal symptoms and to prevent a return to illicit druguse. If the treatment is continued, hepatic function should be monitored closely.

Drug withdrawal syndrome

Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with buprenorphine. The decision to maintain a patient on a long-term opioid prescription should be an active decision agreed between the clinician and patient with review at regular intervals (usually at least three-monthly, depending on clinical progress).

Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal.

The opioid drug withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms may also develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate.

If women take this drug during pregnancy, there is a risk that their new-born infants will experience neonatal withdrawal syndrome.

Precipitation of opioid withdrawal syndrome

When initiating treatment with buprenorphine/na­loxone, the physician must be aware of the partial agonist profile of buprenorphine and that it can precipitate withdrawal inopioid-dependent patients, particularly if administered less than 6 hours after the last use of heroin or other shortacting opioid, or if administered less than 24 hours after the last dose of methadone. Patients should be closely monitored during the switching period from buprenorphine or methadone to buprenorphine/na­loxone since withdrawal symptoms have been reported. To avoid precipitating withdrawal, induction with buprenorphine/na­loxone should be undertaken when objective signs of withdrawal are evident (see section 4.2).

Hepatic impairment

The effects of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone were evaluated in a post-marketing study. Both buprenorphine and naloxone are extensively metabolized in the liver, and plasma levels were found to be higherfor both buprenorphine and naloxone in patients with moderate and severe hepatic impairment compared with healthy subjects. Patients should be monitored for signs and symptoms of precipitated opioid withdrawal, toxicity or overdose caused by increased levelsof naloxone and/or buprenorphine. 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 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 of buprenorphine/na­loxone is contraindicated.

Renal impairment

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

Paediatric population

Use in adolescents (Age 15 – <18 years)

Due to the lack of data in adolescents (age 15 – <18 years), patients in this age groupshould be more closely monitored during treatment.

CYP 3A4 inhibitors

Medicinal products that inhibit the enzyme CYP3A4 may give rise to increased concentrationsof buprenorphine. A reduction of the buprenorphine/na­loxone dose may be needed.

Patients already treated with CYP3A4 inhibitors should have their dose of buprenorphine/na­loxone titrated carefully since a reduced dose may be sufficient inthese patients (see section 4.5).

General warnings relevant to the administration of opioids

Opioids may produce orthostatic hypotension in ambulatory patients.

Opioids may elevate cerebrospinal fluid pressure, which may cause seizures, soopioids should be used with caution in patients with head injury, intracranial lesions, in other circumstances where cerebrospinal 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 urethral stenosis.

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

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

Opioids have been shown to increase intracholedochal pressure, and should be usedwith caution in patients 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 the effects of opioids, based on experience with morphine (see section 4.5).

Sleep-related breathing disorders

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

Excipients

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is essentially “sodium-free”.

4.5 Interaction with other medicinal products and other forms of interaction

Zubsolv should not be taken together with:

alcoholic drinks or medicinal products containing alcohol, as alcohol increases the sedative effect of buprenorphine (see section 4.7)

Zubsolv should be used cautiously when co-administered with:

sedatives such as benzodiazepines or related medicinal products: The concomitant use of opioids with sedative medicinal products such as benzodiazepines or related medicinal products increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use of sedative medicinal products should be limited (see section 4.4). Patients should be warned that it is extremely dangerous to self-administer non-prescribed benzodiazepines while taking this medicinal product, and should also becautioned to use benzodiazepines concurrently with this medicinal product only as directed by their physician (see section 4.4)

other central nervous system depressants, other opioid derivatives (e.g. methadone, analgesics and antitussives), certain antidepressants, sedative H1-receptor antagonists, barbiturates, anxiolytics other than benzodiazepines, neuroleptics, clonidine and related substances: these combinations increase central nervous system depression. The reduced level of alertness can make driving and using machines hazardous

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

serotonergic medicinal products, such as MAO inhibitors, selective serotonin re-uptake inhibitors (SSRIs), serotonin norepinephrine re-uptake inhibitors (SNRIs) or tricyclic antidepressants as the risk of serotonin syndrome, a potentially life-threatening condition, is increased (see section4.4)

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

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 50 % and 70 % respectively) and, to a lesser extent, of norbuprenorphine. Patients receiving Zubsolv 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, or macrolide antibiotics)

CYP3A4 inducers: Concomitant use of CYP3A4 inducers with buprenorphine may decrease buprenorphine plasma concentrations, potentially resulting in sub-optimal treatment of opioid dependence with buprenorphine. It is recommended that patients receiving buprenorphine/na­loxone should be closely monitored if inducers (e.g. phenobarbital, carbamazepine, phenytoin, rifampicin) are co-administered. The dose of buprenorphine or the CYP3A4 inducer may need to be adjusted accordingly

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

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of buprenorphine/na­loxone in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

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

Due to the long half-life of buprenorphine, neonatal monitoring for several days should be considered at the end of pregnancy, to prevent the risk of respiratory

depression or withdrawal syndrome in neonates.

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

Breast-feeding

In rats buprenorphine has been found to inhibit lactation. Buprenorphine and its metabolites are excreted in human milk. It is unknown whether naloxone/meta­bolites are excreted in human milk. Therefore, breastfeeding should be discontinued during treatment with Zubsolv.

Fertility

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

4.7 Effects on ability to drive and use machines

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

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

This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

The medicine is likely to affect your ability to drive

Do not drive until you know how the medicine affects you

It is an offence to drive while under the influence of this medicine

However, you would not be committing an offence (called ‘statutory defence’) if:

– The medicine has been prescribed to treat a medical or dental problem and

– You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

– It was not affecting your ability to drive safely.

4.8 Undesirable effects

Summary of the safety profile

The most commonly reported treatment related adverse reactions reported during the pivotal clinical trials were constipation and symptoms commonly associated with drugwithdrawal (i.e. insomnia, headache, nausea, hyperhidrosis and pain). Some reports ofseizure, vomiting, diarrhoea, and elevated liver function tests were considered serious.

Tabulated list of adverse reactions

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

The frequency of possible side effects listed below is defined using the followingconven­tion:

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 beestimated from available data).

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

Description of selected adverse reactions

In cases of intravenous drug misuse, some adverse reactions are attributed to the act of misuse rather than the medicinal product. These include local reactions, sometimesseptic (abscess, cellulitis), potentially serious acute hepatitis, and other acute infections such as pneumonia, endocarditis (see section 4.4).

In patients with marked drug dependence, initial administration of buprenorphine canproduce a drug withdrawal syndrome similar to that associated with naloxone (see sections 4.2 and 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product isimportant. It allows continued monitoring of the benefit/risk balance of the medicinalproduct. Healthcare professionals are asked to report any suspected adverse reactionsvia the Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Patients should be informed of the signs and symptoms of overdose and to ensure that family and friends are also aware of these signs and to seek immediate medical help if they occur.

Symptoms

Respiratory depression as a result of central nervous system depression is the primarysymptom requiring 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, vomiting and/or speech disorders.

Management

General supportive measures should be initiated, including close monitoring of respiratory and cardiac status of the patient. 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 betransferred to an environment where full resuscitation facilities are 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 in reversing the respiratory symptoms of buprenorphine comparedwith its effects on full agonist opioid agents.

If naloxone is used, the long duration of action of buprenorphine should be taken intoconsideration when determining the length of treatment and medical surveillance needed to reverse the effects of an overdose. Naloxone can be eliminated more rapidly than buprenorphine, allowing for a return of previously controlled buprenorphine overdose symptoms, so a continuing infusion may be necessary. If infusion is not possible, repeated dosing with naloxone may be required. Initial naloxone doses may range up to 2 mg and be repeated every 2–3 minutes. Ongoing intravenous infusion rates should be titrated to patient response. The diagnosis of opioid-related toxicity should be reconsidered if there is still failure to respond after atotal of 10 mg of naloxone has been administered.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

Mechanism of action

Buprenorphine is an opioid partial agonist/antagonist which binds to the p and k (kappa) opioid receptors of the brain. Its activity in opioid maintenance treatment is attributed to its slowly reversible properties with the g-opioid 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 patients.

Naloxone is an antagonist at g-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 patients the presence of naloxone in Zubsolv produces marked opioid antagonist effects, thereby deterring intravenous abuse.

Clinical efficacy

Efficacy and safety data for buprenorphine/na­loxone are primarily derived from a one-year clinical trial, 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 this trial, 326 heroin-addicted subjects were randomly assigned to either buprenorphine/na­loxone 16 mg per 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 buprenorphine on Day 2. On Day 3, those randomised to receive buprenorphine/na­loxone 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 buprenorphine/na­loxone individually against placebo. The percentage of thrice-weekly urine samples that were negative for non-study opioids was statistically higher for both buprenorphine/na­loxone 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 randomised 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 buprenorphine/na­loxone), 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 7-week 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 thrice-weekly 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

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

Zubsolv sublingual tablets have a higher bioavailability than conventional sublingualtablets. Therefore the dose in mg can differ between products. Zubsolv is not interchangeable with other buprenorphine products.

In comparative bioavailability studies Zubsolv 11.4/2.9 mg displayed equivalent buprenorphine exposure to 16/4mg (2 × 8/2mg) buprenorphine/na­loxone administeredas conventional sublingual tablets however Zubsolv 2 × 1.4/0.36 mg displayed 20% lower buprenorphine exposure to 2 × 2/0.5 mg buprenorphine/na­loxone administered as conventional sublingual tablets.

Naloxone exposure was not higher from Zubsolv at any of the tested dose levels.

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.

There are small deviations in buprenorphine dose proportionality exposure parameters as well as deviations 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 three lower dose presentationsof Zubsolv should not be used to substitute for any of the three higher dose Zubsolv presentations.

Peak plasma concentrations are achieved 90 minutes after sublingual administration. Plasma levels of buprenorphine increased with increasing sublingual dose of buprenorphine/na­loxone.

Distribution

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

Biotransformation

Buprenorphine is primarily metabolised through N-dealkylation by liver microsomal CYP3A4. The parent molecule and the primary dealkylated metabolite, norbuprenorphine, undergo subsequent glucuronidation.

Norbuprenorphine binds to opioid receptors in vitro; however, it is not known whether norbuprenorphine contributes to the overall effect of buprenorphine/na­loxone.

Elimination

Elimination of buprenorphine is bi- or tri-exponential, and has a mean half-life from plasma of 32 hours.

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

Linearity/ non-linearity

Buprenorphine Cmax and AUC increased in a linear fashion with the increasing dose, although the increase was not directly dose-proportional.

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 buprenorphine/na­loxone, plasma naloxone concentrations are low and decline rapidly. Naloxone mean peak plasma concentrations were too low to assess dose-proportionality.

Distribution

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

Biotransformation

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 and reduction of the 6-oxo group.

Elimination

Naloxone is excreted in the urine, with a mean half-life of elimination from plasma ranging from 0.9 to 9 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 buprenorphine/na­loxone. No dose modification based on renal function is required but caution is recommended when dosing subjects with severe renal impairment (seesection 4.4).

Hepatic impairment

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

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

Table 2: Effect of hepatic impairment on pharmacokinetic parameters of buprenorphine and naloxone following administration (change relative tohealthy subjects)

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

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 1× for buprenorphine and 5 x 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 buprenorphine/na­loxone; 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.

Dietary administration of buprenorphine 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 2.4 x for buprenorphine at a human dose of 17.2 mg buprenorphine/na­loxone 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 buprenorphine/na­loxone was conducted in rats at doses of 7, 30 and 120 mg/kg/day, with estimated dose multiples of 3 to75 times, based on a Zubsolv equivalent human daily sublingual dose of 11.4 mg of buprenorphine 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

Mannitol

Citric acid Sodium citrate

Microcrystalline cellulose

Croscarmellose sodium Sucralose

Levomenthol

Colloidal anhydrous silica Sodium stearyl fumarate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

4 years

6.4 Special precautions for storage

Store in the original package below 25°C in order to protect from moisture.

6.5 Nature and contents of container

PVC/OPA/Al/PVC // Al/PET/Paper child resistant blister cards.

Pack-size of 7 (1 × 7) tablets.

Pack-size of 28 (4 × 7) tablets.

Pack-size of 30 (3 × 10) tablets.

Not all pack-sizes may be marketed.

6.6 Special precautions for disposal

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

Accord Healthcare Limited

Sage House

319 Pinner Road

North Harrow

Middlesex

HA1 4HF

United Kingdom