This information is intended for use by health professionals

1. Name of the medicinal product

Buprenorphine 8mg Sublingual Tablets

2. Qualitative and quantitative composition

Each tablet contains buprenorphine hydrochloride 8.64mg equivalent to buprenorphine 8mg.

Excipient 191.36mg of lactose monohydrate per tablet.

For a full list of excipients see section 6.1.

3. Pharmaceutical form

Sublingual tablet

White, oval shaped, biconvex uncoated tablets with '8' embossed 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.

4.2 Posology and method of administration

Treatment with Buprenorphine Sublingual Tablets is intended for use in adults and children age 16 years or over who have agreed to be treated for addiction.

When initiating treatment the physician should be aware of the partial agonist profile of buprenorphine and that it can precipitate withdrawal in opioid dependent patients. Buprenorphine binds to the µ and κ opiate receptors.

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

Induction therapy: the initial dose is from 0.8mg to 4mg, administered as a single daily dose.

. for opioid-dependent drug addicts who have not undergone withdrawal: one dose of Buprenorphine Tablets administered sublingually at least 4 hours after the last use of the opioid, or when the first signs of craving 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.

Titration to a maintenance dose:

The dosage should be individually titrated to each patient. The maintenance dosage varies from individual to individual and should be titrated by gradually increasing the dose until the minimum effective dose is reached.

- Dosage adjustment and maintenance: the dose of Buprenorphine should be increased progressively according to the clinical effect of the individual patient and should not exceed a maximum single daily dose of 16mg. The dosage is titrated according to reassessment of the clinical and psychological status of the patient.

Daily dispensing of buprenorphine is recommended, especially during the treatment initiation period. Subsequently, following stabilisation, the patient can be issued with quantities of the medication to last for several days of treatment. It is recommended, however, that the amount of the medication issued should be limited to enough for a maximum of 7 days.

- 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 0.4 mg, 2 mg and 8 mg, respectively, allows for a downward titration of dosage. Patients should be monitored following termination of buprenorphine treatment because of the potential for relapse.

4.3 Contraindications

Hypersensitivity to buprenorphine or any other component of the tablet

- 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

Warnings

Buprenorphine sublingual tablets are recommended only for the treatment of opioid drug dependence.

- The clinician should consider the risk of abuse and misuse (e.g. IV administration), particularly at the beginning of the treatment.

- Respiratory Depression: some cases of death due to respiratory depression have been reported, particularly when used in combination with benzodiazepines (see 4.5 Interaction with other medicaments and other forms of interaction) or when buprenorphine was not used according to labelling.

Hepatitis, hepatic events: hepatic necrosis and hepatitis with jaundice, which generally have resolved favourably, have been reported in patients who use buprenorphine. Causality has not been clearly established. When a hepatic event is suspected and the causality is unknown, further evaluation is required. 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 may be promoted by viral infections particularly chronic C hepatitis, alcohol abuse, anorexia, and the concurrent use of other potentially hepatotoxic drugs.

These co-factors should be investigated before prescribing Buprenorphine and when monitoring treatment. If hepatic injury is suspected, biological and etiological evaluation must be performed.

Depending on the case, the doctor may either discontinue treatment under the right conditions, in order to prevent withdrawal symptoms and a return to drug abuse, or introduce close monitoring of hepatic function.

- This product can cause opioid withdrawal symptoms if administered to an addicted patient less than 4 hours after the last use of the drug (see 4.2 Posology and method of administration.)

- This product can cause drowsiness, which may be exacerbated by other centrally acting agents, such as: alcohol, tranquillisers, sedatives, hypnotics (see 4.5 Interactions with other medicaments and other forms of interaction.)

- This product can cause orthostatic hypotension.

Buprenorphine is an opioid and can therefore alleviate the painful symptoms of certain conditions.

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

Paediatric Use

No data are available in children less than 16 years of age; therefore, Buprenorphine Tablets should not be used in children under the age of 16.

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);

- renal insufficiency (20% of the administered dose is eliminated by the renal route; thus, renal elimination may be prolonged);

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

Because of the risks of misuse, primarily by intravenous injection, and because of the need for dosage titration, especially in the early stages of treatment, short term prescription is required and if possible staggered or controlled dispensing so as to promote treatment adherence.

Animal studies and clinical experience have shown that buprenorphine itself carries the risk of dependence, but less than morphine. It is therefore important to adhere to the treatment initiation and monitoring criteria and the titration schedule (see section 4.2).

As with other opioids, caution is advised in patients on buprenorphine in the event of:

- Head trauma and intracranial hypertension

- Hypotension

- Prostatic hypertrophy and urethral stenosis;

Titration of buprenorphine must be performed with care in patients treated with CYP3A4 inhibitors, which may increase buprenorphine concentrations, meaning that a lower dose is sufficient (see section 4.5).

Contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Contraindicated combinations

Methadone – Decrease in the effect of methadone through competitive receptor inhibition, with the risk of withdrawal symptoms.

Step III Analgesics – Decrease in the analgesic effect of the opioid through competitive receptor inhibition, with the risk of withdrawal symptoms.

Inadvisable combinations

Alcohol - Buprenorphine Sublingual Tablets should not be taken together with alcoholic drinks or medicines containing alcohol. Alcohol increases the sedative effect of buprenorphine (see 4.7. Effects on the ability to drive vehicles or operate machinery.)

Naltrexone – risk of withdrawal symptoms.

Buprenorphine should be used cautiously together with:

- Benzodiazepines: This combination may potentiate respiratory depression of central origin, with risk of death; therefore, dosages must be individually titrated and the patient monitored carefully. The risk of drug abuse should also be considered (see 4.4 Special warnings and special precautions for use).

- Other central nervous system depressants; other opioid derivatives (analgesics 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.

- Monoamine oxidase inhibitors (MAOI): Possible exaggeration of the effects of opioids, based on experience with morphine.

- 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 Tablets should be closely monitored and the dose of buprenorphine should be halved when starting treatment with ketoconazole.

Further titration of Buprenorphine Tablets 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.

The interaction of buprenorphine with CYP 3A4 inducers has not been investigated, therefore it is recommended that patients receiving Buprenorphine Tablets should be closely monitored if enzyme inducers (e.g. phenobarbital, carbamazepine, phenytoin, rifampicin) are co-administered. Use of these medications may increase the metabolism of buprenorphine and the dose of buprenorphine should be increased appropriately if patients complain of decreased benefit from buprenorphine or if there is re-emergence of craving for illicit drugs.

4.6 Fertility, pregnancy and lactation

There are no adequate data from the use of buprenorphine in pregnant women..

Buprenorphine should be used during pregnancy only if the potential benefit outweighs the potential risk to the foetus.

Towards the end of pregnancy, buprenorphine may induce respiratory depression in the newborn infant 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.

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 and its metabolites are excreted in human breast milk. In rates, buprenorphine has been found to inhibit lactation. Therefore, breast feeding should be discontinued during treatment with buprenorphine tablets (see section 4.3).

4.7 Effects on ability to drive and use machines

Buprenorphine Tablets may cause drowsiness, particularly when taken together with alcohol or central nervous system depressants. Therefore, patients should be warned against driving or operating machinery (see 4.5 Interaction with other medicaments and other forms of interaction.)

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

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

The table below presents the undesirable effects reported in clinical studies.

Undesirable effects reported associated with treatment, according to organ system

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)

(CIOMS III)

Psychiatric disorders

Rare

Hallucinations

Nervous System disorders

Common

Insomnia, headache, fainting, dizziness

Vascular disorders

Common

Orthostatic hypotension

Respiratory, thoracic and mediastinal disorders

Rare

Respiratory depression

Gastrointestinal disorders

Common

Constipation, nausea, vomiting

General disorders and administration site conditions

Common

Asthaenia, drowsiness, sweating

Other undesirable effects reported since marketing authorisation

Immune System Disorders

Hypersensitivity reactions such as rash, urticaria, pruritus, bronchospasm, angioneurotic oedema, angio-oedema and anaphylactic shock

Hepatobiliary Disorders

Hepatic necrosis

Under normal conditions of use: rare cases of elevation of transaminase levels and hepatitis with jaundice with a generally favourable outcome.

In the event of intravenous misuse: potentially serious acute hepatitis

Skin and subcutaneous tissue disorders

In the event of intravenous misuse: local reactions, sometimes septic

In patients presenting with marked drug dependence, initial administration of buprenorphine can produce a withdrawal effect similar to that associated with naloxone.

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.

4.9 Overdose

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 Tablets 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

DRUGS USED IN OPIOID DEPENDENCE

(N: central nervous system)

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.

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. The use of this medication 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 2 mg and 16 mg.

Distribution

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

Metabolism and elimination

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 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 (80%), the rest being eliminated in the urine.

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 the 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

maize starch

povidone K30

citric acid anhydrous

sodium citrate

magnesium stearate

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions

6.5 Nature and contents of container

Aluminium coupled with polyamide + polyvinylchloride/Aluminium/PET peelable strip. Each strip contains 7 tablets.

The strips are constructed of Aluminium/PA/PVC laminate film (130 µm thickness) and Aluminium + PET lidding foil (20 + 23 µm thickness).

6.6 Special precautions for disposal and other handling

No special requirements

7. Marketing authorisation holder

Thornton & Ross Ltd

Linthwaite

Huddersfield

West Yorkshire

HD7 5QH

UK

8. Marketing authorisation number(s)

PL 00240/0355

9. Date of first authorisation/renewal of the authorisation

16/08/2010

10. Date of revision of the text

25/02/2016