This information is intended for use by health professionals

1. Name of the medicinal product

Buprenorphine 2 mg sublingual tablets

2. Qualitative and quantitative composition

Buprenorphine 2mg: each tablet contains 2.16mg buprenorphine hydrochloride equivalent to 2mg buprenorphine.

Excipients with known effect:

Each tablet contains 29.85mg of lactose monohydrate and 0.25mg of butylhydroxyanisole (E320).

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Sublingual tablet

2 mg tablet: White to off-white, round, biconvex uncoated sublingual tablet debossed with “2” on one side and plain on the other side.

4. Clinical particulars
4.1 Therapeutic indications

Substitution treatment for opioid drug dependence, within a framework of medical, social and psychological treatment.

4.2 Posology and method of administration

Posology

Treatment is intended for use in adults and adolescents aged 16 years or older who have agreed to be treated for addiction.

Induction therapy

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 medication (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

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 Buprenorphine should be undertaken when objective and clear signs of withdrawal are evident.

The initial dose is from 0.8mg to 4mg, administered as a single daily dose. 0.4mg dose strength of Buprenorphine is not available. If low dose is required, the patient should use tablets (0.4mg) of another brand.

- for opioid-dependent drug addicts who have not undergone withdrawal: one dose of buprenorphine tablet(s) administered sublingually at least 4-6 hours after the last use of the opioid, or when the first signs of craving withdrawal appear.

- for patients receiving methadone: before beginning buprenorphine therapy, the dose of methadone should be reduced to a maximum of 30mg/day. Buprenorphine may precipitate symptoms of withdrawal in patients dependent upon methadone.

Dosage adjustment and maintenance

The dosage should be individualised for each patient. The maintenance dosage will vary between individuals and should be determined by progressively increasing the dose until the minimal effective dose is identified. The mean maintenance daily dose is 8mg. The majority of patients will not require doses exceeding 16mg/day, however, the efficacy and safety of buprenorphine tablets was tested in clinical trials in doses up to 24mg per day.

The dosage is titrated according to reassessment of the clinical status and global management of the patient. Unsatisfactory stabilisation on 16mg per day may be related to potential misuse or psychiatric comorbidities. In these cases alternative treatment options should be taken into account.

Daily dispensing of buprenorphine is recommended, particularly during the initiation of treatment. Then, after stabilisation, the patient may be given a supply of the product sufficient for several days of treatment. However, it is recommended that the amount of the product dispensed be limited to a maximum of 7 days or according to local requirements.

Dosage reduction and termination of treatment

After a satisfactory period of stabilisation has been achieved, the dosage may be reduced gradually to a lower maintenance dose; when deemed appropriate treatment may be discontinued in some patients. The availability of the sublingual tablet in doses of 0.4mg, 2mg and 8mg, respectively, allows for a downward titration of dosage. Patients should be monitored following termination of buprenorphine treatment because of the potential for relapse.

Patients with hepatic impairment

The effect of hepatic impairment on the pharmacokinetics of buprenorphine is unknown. Since buprenorphine is extensively metabolized, the plasma levels will be expected to be higher in patients with moderate and severe hepatic impairment.

Patients with renal impairment

Modification of the buprenorphine dose is not required in patients with renal insufficiency. Caution is recommended when dosing patients with severe renal impairment (CLcr <30ml/min) (see section 5.2).

Paediatric population

There are no clinical data on efficacy and safety for the use of Buprenorphine in children and adolescents. Therefore, Buprenorphine should not be used in children and adolescents under the age of 16.

Method of administration

Administration is sublingual. Physicians must advise patients that the sublingual route is the only effective and safe route of administration for this medicinal product. The tablet should be kept under the tongue until dissolved, which usually occurs within 5 to 10 minutes.

The result of the treatment depends on the dosage prescribed as well as on the combined medical, psychological, social and educational measures taken in monitoring the patient.

4.3 Contraindications

- hypersensitivity to the active substance or to any of the excipients listed in section 6.1

- children less than 16 years of age

- severe respiratory insufficiency

- severe hepatic insufficiency

- acute alcoholism or delirium tremens

- breast-feeding.

4.4 Special warnings and precautions for use

Due to lack of data in adolescents (age 16-18), buprenorphine should be used only with caution in this age group.

Warnings

Buprenorphine sublingual tablets are indicated only for the treatment of opioid drug dependence. It is also recommended that treatment is prescribed by a physician who ensures comprehensive management of the drug addicted patient(s).

Precipitation of opioid withdrawal syndrome

When initiating buprenorphine treatment, the physician should be aware of the partial agonist profile of buprenorphine and that it can precipitate withdrawal in opioid-dependent patients. If administered before the agonist effects resulting from recent opioid use or misuse have subsided. To avoid precipitated withdrawal, induction should be undertaken when objective signs and symptoms of moderate withdrawal are evident (see section 4.2). Buprenorphine binds to the μ and κ opiate receptors.

Due to misuse risk, especially by intravenous route, and posology adaptation, prescription duration should be brief particularly at the beginning of the treatment. If possible, a controlled or partial dispensing should be implemented in order to favour also treatment compliance. Discontinuation of treatment may result in a withdrawal syndrome that may be delayed.

Misuse, abuse and diversion

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

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

Diversion: diversion refers to the introduction of sublingual 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 sublingual buprenorphine as the primary drug of abuse with the risk of overdose, spread of blood borne viral infections, respiratory depression and hepatic injury.

To minimise the risk of misuse, abuse and diversion, physicians should take appropriate precautions when prescribing and dispensing buprenorphine, such as to avoid prescribing multiple refills early in treatment and to conduct patient follow-up visits with clinical monitoring that is appropriate to the patient's level of stability.

Dependence

Buprenorphine is a partial agonist at the mu-opiate receptor and chronic administration produces dependence of the opioid type. Studies in animals, as well as clinical experience, have demonstrated that buprenorphine may produce dependence, but at a lower level than a full agonist.

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

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 also been reported in association with concomitant administration of buprenorphine and other depressants such as alcohol or other opioids. If buprenorphine is administered to some non-opioid dependent individuals who are not tolerant to the effects of opioids, potentially fatal respiratory depression may occur.

Buprenorphine should be used with care in patients with respiratory insufficiency (e.g. chronic obstructive pulmonary disease, asthma, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, pre-existing respiratory depression or kyphoscoliosis).

Buprenorphine may cause severe, possibly fatal, respiratory depression in children and non-dependent persons who accidentally or deliberately ingest it. Protect children and non-dependent persons against exposure.

Hepatitis, 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 cytolytic hepatitis, hepatic failure, hepatic necrosis, hepatorenal syndrome, hepatic encephalopathy and death. 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 drugs and ongoing injecting drug use may have a causative or contributory role. These underlying factors must be taken into consideration before prescribing buprenorphine and during treatment. When a hepatic event is suspected and the causality is unknown, further evaluation is required.

Depending on the findings, buprenorphine may be discontinued cautiously so as to prevent withdrawal symptoms and to prevent a return to illicit drug use.

If buprenorphine is suspected to be the cause of hepatic necrosis or jaundice, it must be discontinued as rapidly as the patient's clinical condition permits. All patients should have liver function tests performed at regular intervals. Serious cases of acute hepatic injury have also been reported in a context of misuse, especially by intravenous route. These hepatic injuries have mainly been observed at the high doses and could be due to a mitochondrial toxicity (genetic diseases, viral infections particularly chronic C hepatitis, alcohol abuse, anorexia, associated mitochondrial toxins, e.g. aspirin, isoniazid, valproate, amiodarone, antiretroviral nucleoside analogues, and the concurrent use of other potentially hepatotoxic medicinal products).

Because CYP3A4 inhibitors (see section 4.5) may increase concentrations of buprenorphine, patients already treated with CYP3A4 inhibitors should have their dose of buprenorphine titrated carefully since a reduced dosing may be sufficient in these patients.

Buprenorphine can precipitate withdrawal symptoms in opioid-dependent patients particularly if administered less than 4-6 hours after the last use of heroin or other short-acting opioids, or if administered less than 24 hours after the last dose of methadone.

CNS depression

This product can cause drowsiness, which may be exacerbated by other centrally acting agents, such as: alcohol, tranquillisers, sedatives, hypnotics (see Section 4.5).

This product can cause orthostatic hypotension.

Studies in animals, as well as clinical experience, have shown that buprenorphine may produce dependence but at a lower level than morphine. Consequently, it is important to follow the recommendations for initiating treatment, dosage adjustment and monitoring of the patient (see section 4.2).

Athletes should be aware that this medicinal product may cause a positive reaction to “anti-doping tests.”

Hepatic impairment

The effects of hepatic impairment on the pharmacokinetics of buprenorphine were evaluated in a post marketing study. Buprenorphine is extensively metabolized in the liver, plasma levels were found to be higher for buprenorphine in patients with moderate and severe hepatic impairment. Patients should be monitored for signs and symptoms of precipitated opioid withdrawal, toxicity or overdose caused by increased levels of buprenorphine. Buprenorphine sublingual tablets should be used with caution in patients with moderate hepatic impairment (see section 4.3 and 5.2). In patients with severe hepatic insufficiency the use of buprenorphine is contraindicated.

Renal impairment

Renal elimination plays a relatively small role (approximately 30%) in the overall clearance of buprenorphine; therefore, no dose modification based on renal function is generally required. Metabolites of buprenorphine accumulate in patients with renal failure. Caution is recommended dosing patients with severe renal impairment (creatinine clearance < 30 ml/min) (see section 5.2).

Precautions for use

This product should be used with care in patients with:

- asthma or respiratory insufficiency (cases of respiratory depression have been reported with buprenorphine)

- hepatic insufficiency (hepatic metabolism of buprenorphine may be altered)

- as with other opioids, caution is requested in patients using buprenorphine and having head injury, increased intracranial pressure, hypotension, prostatic hypertrophy or urethral stenosis

- as buprenorphine is an opioid, pain as a symptom of a disease may be attenuated

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

- 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, or adrenal cortical insufficiency (e.g. Addison's disease)

- opioids have been shown to increase intracholedochal pressure, and should be used with caution in patients with dysfunction of the biliary tract.

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

Use in adolescents

Due to lack of data in adolescents (age 16 – 18), patients in this age group should be more closely monitored during treatment.

Excipients

This medicinal product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains butylhydroxyanisole (E320), which may cause local skin reactions (e.g. contact dermatitis), or irritation to the eyes and mucous membranes.

This medicinal product contains less than 1 mmol sodium (23 mg) per maximum daily dose, that is to say 'sodium- free'.

4.5 Interaction with other medicinal products and other forms of interaction

Buprenorphine should not be taken together with

- alcoholic drinks or medicinal products containing alcohol. Alcohol increases the sedative effect of buprenorphine (see Section 4.7).

Buprenorphine should be used cautiously together with:

- benzodiazepines: This combination may potentiate respiratory depression of central origin, with risk of death; therefore patients must be closely monitored and this combination should be avoided in cases where there is risk of misuse. Patients should be warned that it is extremely dangerous to self administer non-prescribed benzodiazepines whilst taking this product, and should also be cautioned to use benzodiazepines concurrently with this product only as prescribed. The risk of drug abuse should also be considered (see section 4.4)

- other central nervous system depressants; other opioid derivatives (analgesics, methadone and antitussives); certain antidepressants, sedative H1-receptor antagonists, barbiturates, anxiolytics other than benzodiazepines, neuroleptics, clonidine and related substances. This combination increases central nervous system depression. The reduced level of alertness can make driving and using machinery hazardous

- monoamine oxidase inhibitors (MAOI): Possible exaggeration of the effects of opioids, based on experience with morphine. Buprenorphine should not be administered concomitantly or until two weeks after the end of treatment with MAOI.

- naltrexone: This is an opioid antagonist that can block the pharmacological effects of buprenorphine. For opioid dependent patients currently receiving buprenorphine treatment, naltrexone may precipitate a sudden onset of prolonged and intense opioid withdrawal symptoms. For patients currently receiving naltrexone treatment, the intended therapeutic effects of buprenorphine administration may be blocked by naltrexone

- opioid analgesics: Adequate analgesia may be difficult to achieve when administering a full opioid agonist in patients receiving buprenorphine. The potential for overdose also exists with a full agonist, especially when attempting to overcome buprenorphine partial agonist effects, or when buprenorphine plasma levels are declining

- to date, no notable interaction has been observed with cocaine, the agent most frequently used by multi-drug abusers in association with opioids.

A suspected interaction between buprenorphine injection and phenprocoumon, resulting in purpura, has been reported.

An interaction study of buprenorphine with ketoconazole (a potent inhibitor of CYP3A4) resulted in increased Cmax and AUC of buprenorphine (approximately 70% and 50% respectively) and, to a lesser extent, of the metabolite, norbuprenorphine. Patients receiving buprenorphine should be closely monitored and the dose of buprenorphine should be halved when starting treatment with ketoconazole.

Further titration of buprenorphine should be made as clinically indicated. Although no data from clinical trials are available, the use of other inhibitors of CYP3A4 (e.g. gestodene, troleandoymycin, the HIV protease inhibitors ritonavir, indinavir and saquinavir) may also increase exposure levels to buprenorphine and norbuprenorphine and a similar dose-reduction should be considered when initiating treatment.

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

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy

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

At the end of pregnancy, high doses may induce respiratory depression in new-born infants even after a short period of administration. Long-term administration during the last three months of pregnancy may cause a withdrawal syndrome in the neonate (e.g. hypertonia, neonatal tremor, neonatal agitation, myoclonus or convulsions). The syndrome is generally delayed from several hours to several days after birth. Buprenorphine should only be used during pregnancy in case the potential benefits outweigh the risks.

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.

Breast-feeding

Buprenorphine is excreted in human breast milk. In rats, buprenorphine has the potential to inhibit lactation or milk production. Therefore buprenorphine should not be used during breast-feeding.

Fertility

No human data on the effects of buprenorphine on fertility are available. In rats, there was no effect on mating or fertility with buprenorphine (see section 5.3).

4.7 Effects on ability to drive and use machines

Buprenorphine has minor to moderate influence on the ability to drive and use machine. Buprenorphine 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 section 4.4. and 4.5). Therefore, patients should be warned against driving or operating machinery (see Section 4.5).

4.8 Undesirable effects

The onset of undesirable effects depends on the patient's tolerance threshold, which is higher in drug addicts than in the general population.

Summary of safety profile

The most commonly reported adverse drug reactions were those related to withdrawal symptoms (e.g. insomnia, headache, nausea and hyperhidrosis) and pain.

Adverse reactions are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1 summarises the most commonly reported adverse drug reactions during post-marketing surveillance. Events occurring in at least 1% of reports by healthcare professionals and considered expected are included. Frequency of events not reported in pivotal studies cannot be estimated and is given as not known.

Table 1 Undesirable effects observed in pivotal clinical studies and / or post marketing surveillance listed by body system

System Organ Class

Frequency

Undesirable effects

Infections and infestations

Common

Bronchitis, infection, influenza, pharyngitis, rhinitis

Blood and lymphatic system disorders

Common

Lymphadenopathy

Metabolism and nutrition disorders

Common

Decreased appetite

Psychiatric disorders

Very common

Insomnia

Common

Agitation, anxiety, depression, hostility, nervousness, paranoia, thinking abnormal

Not known

Drug dependence

Nervous system disorders

Very common

Headache

Common

Dizziness, hypertonia, migraine, paraesthesia, somnolence, syncope, tremor

Eye disorders

Common

Lacrimal disorder, mydriasis

Cardiac disorders

Common

Palpitations

Vascular disorders

Common

Vasodilatation

Respiratory, thoracic and mediastinal disorders

Common

Cough, dyspnoea, yawning

Uncommon

Respiratory depression

Gastrointestinal disorders

Very common

Nausea

Common

Constipation, abdominal pain, diarrhoea, dry mouth, dyspepsia, gastrointestinal disorder, flatulence, tooth disorder, vomiting

Skin and subcutaneous tissue disorders

Very common

Hyperhidrosis

Common

Rash

Musculoskeletal, connective tissue and bone disorders

Common

Arthralgia, back pain, bone pain, muscle spasms, myalgia, neck pain

Reproductive system and breast disorders

Common

Dysmenorrhoea

General disorders and administration site conditions

Very common

Drug withdrawal syndrome, pain

Common

Asthenia, chest pain, chills, malaise, oedema peripheral, pyrexia

Not known

Drug withdrawal syndrome neonatal

Description of selected adverse reactions

The following is a summary of other post-marketing adverse event reports that are considered serious or otherwise noteworthy:

- in cases of intravenous misuse, local reactions, sometimes septic (abscess, cellulitis), and potentially serious acute hepatitis and other infections such as pneumonia, endocarditis 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

- the most common signs and symptoms of hypersensitivity include rashes, urticaria, and pruritus. Cases of bronchospasm, angioedema, and anaphylactic shock have been reported (see section 4.3)

- transaminase increase, hepatitis, acute hepatitis, cytolytic hepatitis, jaundice, hepatorenal syndrome, hepatic encephalopathy, and hepatic necrosis have occurred (see section 4.4)

- neonatal drug withdrawal syndrome has been reported among newborns of women who have received buprenorphine during pregnancy. The syndrome may be milder than that seen with a full μ-opioid agonist and may be delayed in onset. The nature of the syndrome may vary depending upon the mother's drug use history (see section 4.6)

- hallucination, orthostatic hypotension, urinary retention and vertigo have been reported.

Reporting of suspected adverse reactions

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

4.9 Overdose

Symptoms

Preliminary symptoms of overdose may also include somnolence, amblyopia, miosis, hypotension, nausea, vomiting and / or speech disorders.

In the event of accidental 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, following standard intensive care measures, should be instituted. 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 buprenorphine should be taken into consideration when determining length of treatment needed to reverse the effects of an overdose.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group

Other nervous system drugs; drugs used in addictive disorders; drugs used in opioid dependence.

ATC code: N07 BC01

Mechanism of action

Buprenorphine is an opioid partial agonist/antagonist which attaches itself to the μ (mu) and κ (kappa) receptors of the brain. Its activity in opioid maintenance treatment is attributed to its slowly reversible link with the μ receptors which, over a prolonged period, minimises the need of the addicted patient for drugs.

Clinical efficacy and safety

During clinical pharmacologic studies in opiate-dependent subjects, buprenorphine demonstrated a ceiling effect on a number of parameters, including positive mood, “good effect” and respiratory depression.

5.2 Pharmacokinetic properties

Absorption

When taken orally, buprenorphine undergoes first-pass hepatic metabolism with N-dealkylation and glucuroconjugation in the small intestine. N-dealkylation and glucuroconjugation also take place in 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 and the maximal dose-concentration relationship is linear, between 2mg and 16mg.

Distribution

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

Biotransformation

Buprenorphine is oxidatively metabolised by 14-N-dealkylation to N-desalkyl-buprenorphine (also known as norbuprenorphine) via cytochrome P450 CYP3A4 and by glucuroconjugation of the parent molecule and the dealkylated metabolite. Norbuprenorphine is a μ (mu) agonist with weak intrinsic activity.

Elimination

Elimination of buprenorphine is bi- or tri- exponential, with a long terminal elimination phase of 20 to 25 hours, due in part to reabsorption of buprenorphine after intestinal hydrolysis of the conjugated derivative, and in part to the highly lipophilic nature of the molecule.

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

Hepatic Impairment

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

Table 2 summarizes the results from a clinical trial in which the exposure of buprenorphine was determined after administering a 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 following buprenorphine/naloxone administration (change relative to healthy subjects)

PK Parameter

Mild Hepatic Impairment

(Child-Pugh Class A)

(n=9)

Moderate Hepatic Impairment

(Child-Pugh Class B)

(n=8)

Severe Hepatic Impairment

(Child-Pugh Class 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

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

5.3 Preclinical safety data

Acute toxicity of buprenorphine was determined in the mouse and rat following oral and parenteral administration. The median lethal doses (LD50) in the mouse were 26, 94 and 261 mg/kg for intravenous, intraperitoneal and oral administration, respectively. The LD50 values in a rat were 35, 243 and 600 mg/kg for intravenous, intraperitoneal and oral administration, respectively.

When beagles were dosed continuously subcutaneously for one month, rhesus monkeys orally for one month and rats and baboons intramuscularly for six months, buprenorphine showed remarkably low tissue and biochemical toxicities.

From teratology studies in rats and rabbits, it was concluded that buprenorphine is not embryotoxic or teratogenic, and it does not have any marked effects on weaning potential. There were no adverse effects on fertility or general reproductive function in rats, although at the highest intramuscular dose (5mg/kg/day) the mothers experienced some difficulty in parturition and there was a high neonatal mortality.

Minimal to moderate hyperplasia of the bile duct with associated peribiliary fibrosis occurred in dogs following 52 weeks of oral dosing of 75mg/kg/day.

6. Pharmaceutical particulars
6.1 List of excipients

Lactose monohydrate

Mannitol

Citric acid anhydrous

Sodium citrate dihydrate

Povidone K30

Butylhydroxyanisole (E320)

Maize starch

Maize starch pregelatinised

Magnesium stearate.

6.2 Incompatibilities

Not applicable

6.3 Shelf life

30 months

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Blister consists of PVC, PVDC, aluminium and heat seal lacquer lidding foil.

Pack size: 7 and 28 sublingual tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

Sun Pharmaceutical Industries Europe B.V.

Polarisavenue 87

2132 JH Hoofddorp

The Netherlands

8. Marketing authorisation number(s)

PL 31750/0043

9. Date of first authorisation/renewal of the authorisation

30/03/2015

10. Date of revision of the text

12/03/2019