SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Prefibin 8 mg sublingual tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 8 mg of buprenorphine (as buprenorphine hydrochloride). Excipient: 292.7 mg lactose monohydrate

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Sublingual tablet.

White to off-white, oval tablet with a breaking notch on both sides (13.5 mm x 6.6 mm).

The 2 mg and 8 mg tablets can be divided into equal halves.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

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

Treatment is intended for use in adults and adolescents aged 15 years and over who have agreed to be treated for addiction.

4.2. Posology and method of administration

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

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

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. Buprenorphine binds to the p and k 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.

Initiation therapy

Baseline liver function tests 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 types of opioid dependence (i.e. long- or short- acting opioid), the time since last opioid use and the degrees 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 0.8 mg to 4 mg, administered as a single daily dose.

•    For opioid-dependent drug addicts who have not undergone withdrawal: one dose of buprenorphine tablet(s) administered sublingually at least 6 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 30 mg/day.

Buprenorphine may precipitate symptoms of withdrawal in patients dependent upon methadone, therefore buprenorphine should not be administered less than 24 hours after the last dose of methadone.

Dosage adjustment and maintenance

The dose of buprenorphine should be increased progressively according to the clinical effect of the individual patient.

The mean maintenance daily dose is 8 mg. The majority of patients will not require doses exceeding 16 mg/day, however, the efficacy and safety of buprenorphine tablets was tested in clinical trials in doses up to 24 mg per day.

The dosage is titrated according to reassessment of the clinical status and global management of the patient. Unsatisfactory stabilisation on 16 mg per day may be related to potential misuse or psychiatric comorbidities. In theses case 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 to local requirements.

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. For example, a patient stabilised to receive a daily dose of 8 mg may be given 16 mg on alternate days,with no dose on the intervening days. 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 24 mg. Patients requiring a titrated daily dose > 8 mg/day may not find this regimen adequate.

Dosage reduction and termination of treatment

After a satisfactory 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 (divisible into 2x1 mg) and 8 mg (divisible into 2x4 mg), respectively, allows for a downward titration of dosage. Patients should be monitored following termination of buprenorphine treatment because of the potential for relapse.

Patients must also be informed accordingly about the loss of opioid tolerance after discontinuation and its dangerous impact in case of relapse.

Patients with impaired hepatic function

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.

As Buprenorphine pharmacokinetics may be altered in patients with hepatic insufficiency, lower initial doses and careful dose titration in patients with mild to moderate hepatic impairment are recommended.

Patients with impaired renal function

Modification of the buprenorphine dose is not required in patients with renal impairment. Caution is recommended when dosing patients with severe renal impairment (CLcr < 30 ml/min) (see section 4.4).

4.3 Contraindications

Hypersensitivity to buprenorphine or any of the excipients Children and adolescents less than 15 years of age

Severe respiratory insufficiency Severe hepatic insufficiency Acute alcoholism or delirium tremens

4.4 Special warnings and precautions for use

Warnings

Buprenorphine sublingual tablets are recommended only for the treatment of

opioid drug dependence.

It is also recommended that treatment is prescribed by a physician who

ensures comprehensive management of drug addicts.

Special risks in substitution therapy

•    The patient must be informed on the possible deadly risk of combining centrally acting depressants like alcohol, illegal opiates, benzodiazepines, hypnotics with buprenorphine.

•    The patient must be informed on the possible risks of i.v. misuse: respiratory arrest, shock, thrombophlebitis, embolism, endocarditis, sepsis, liver damage

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

•    If high doses are used, special precaution is necessary to avoid drug diversion.

•    In case of concomitant illnesses, symptoms may be masked by analgetic effects of buprenorphine, therefore adequate surveillance is necessary.

•    Respiratory depression: some cases of death due to respiratory depression have been reported, particularly when used in combination with benzodiazepines (see section 4.5) or when buprenorphine was not used according to labelling.

•    Hepatitis, hepatic events: Serious cases of acute hepatic injury have 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. Pre-existing or acquired mitochondrial impairment (genetic diseases, viral infections particularly chronic C hepatitis, alcohol abuse, anorexia, associated mitochondrial toxins, e.g. aspirin, isoniazid, valproate, amiodarone, antiretroviral nucleoside analogues), could promote the occurrence of such hepatic injuries. These co-factors must be taken into consideration before prescribing Buprenorphine and during the treatment monitoring. When a hepatic event is suspected, further biological and etiological evaluation is required. Depending upon the findings, the medicinal product may be discontinued cautiously so as to prevent withdrawal syndrome and to prevent a return to drug addiction. If the drug treatment is continued, hepatic function should be monitored closely.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 section 4.2).

•    Discontinuation of treatment may result in a withdrawal syndrome that may be delayed

•    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 showed 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). Paediatric Use

No data are available in children less than 15 years of age; therefore, buprenorphine should not be used in children under the age of 15.

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 (30% of the administered dose is eliminated by the renal route; thus, renal elimination may be prolonged)

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

As with other opioids, caution is requested in patients using buprenorphine and having:

•    head injury and increased cranial pressure,

•    hypotension,

•    prostatic hypertrophy and urethral stenosis.

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

This medicinal product 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

Combination that is not recommended

•    Alcohol. Alcohol increases the sedative effect of buprenorphine that can be hazardous in driving vehicle or operating machinery.

Prevent taking Buprenorphine with alcoholic drinks or with medicinal products containing alcohol.

Combinations where increased caution is required

•    Combination with benzodiazepines may cause death due to respiratory depression of central origin. Therefore the lowest doses should be used and this combination should not be used in case of the risk of drug abuse (see section 4.4). An appropriate medical assessment of the benefit/risk ratio should be initiated before this combination is prescribed.

•    Other central nervous system depressants: other opioid derivatives (analgesics and antitussives); certain antidepressants, H₁-receptor antagonists with sedative effect, barbiturates, benzodiazepines, anxiolytics other than benzodiazepines, neuroleptics, clonidine and related substances: these combinations increase central nervous system depression. This can reduce a level of vigilance that can be hazardous in driving vehicle and operating machinery.

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

•    CYP3A4 inhibitors: An interaction study of buprenorphine with ketoconazole (a potent inhibitor of CYP3A4) resulted in increased C_max and AUC of buprenorphine (approximately by 70% and 50%). This influence was less marked in norbuprenorphine. Patients who receive Buprenorphine in combination with strong CYP3A4 inhibitor (e.g. protease inhibitors, such as ritonavir, nelfinavir or indinavir or azole antifungal agents such as ketoconazole or itraconazole) should be closely monitored and may require dose reduction.

•    CYP3A4 inducers: The interaction of buprenorphine and CYP3A4 inducers has not been investigated. Therefore it is recommended that patients receiving buprenorphine should be closely monitored if enzyme inducers (such as phenobarbital, carbamazepine, phenytoin, rifampicin) are co-administered.

•    Effect of buprenorphine on other medicinal products: Buprenorphine has been shown to be a CYP2D6 and CYP3A4 inhibitor in vitro. The risk of inhibition with therapeutic concentrations seems low, but cannot be excluded. When buprenorphine (predominantly at high doses) is combined with medicinal products that are CYP2D6 or CY3A4 substrates the plasma levels of these medicinal products may rise and dose dependent undesirable effects may occur. Buprenorphine does not inhibit CYP2C19 in vitro. The effect on other enzymes that metabolises medicinal products has not been investigated.

To date, no notable interaction has been observed for buprenorphine with

cocaine.

Fertility, pregnancy and lactation

Pregnancy

In humans, there is currently not sufficient data to evaluate potential malformative or foetotoxic effects of buprenorphine when administered during pregnancy.

At the end of pregnancy, high doses, even for a short duration of time, may induce respiratory depression in neonates. During the last three months of pregnancy, chronic use of buprenorphine may be responsible for a withdrawal syndrome in neonates. Consequently, the use of buprenorphine is not recommended during second and third trimester of pregnancy.

Breast-feeding

Buprenorphine and its metabolites are excreted in human milk. In rats buprenorphine has been found to inhibit lactation. Therefore, breast-feeding should be discontinued during treatment with Buprenorphine.

4.7 Effects on ability to drive and use machines

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:

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

o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and o It was not affecting your ability to drive safely.

Buprenorphine 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 section 4.5).

4.8 Undesirable effects

The evaluation of side effects is based on the following frequencies: 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)

The side effects that occurred after buprenorphine intake were observed in clinical and post-authorisation studies.

System Organ Class	Adverse Reactions
Immune system disorders Very rare	anaphylactic shock, angiooedema
Psychiatric disorders Very common Common Uncommon	insomnia anxiety, nervousness, drowsiness hallucinations
Nervous system disorders Common	dizziness, headache
Eye disorders Common	lacrimation disorders
Cardiac disorders Common	QT prolongation
Vascular disorders Common	fainting, orthostatic hypotension
Respiratory, thoracic and mediastinal disorders Common Uncommon Very rare	rhinitis respiratory depression bronchospasm
Gastrointestinal disorders Common	constipation, diarrhoea, nausea, vomiting, abdominal pain
Hepatobiliary disorders Uncommon	hepatic necrosis, hepatitis*
Skin and subcutaneous tissue disorders Common	sweating
General disorders and administration site conditions Very common common	asthenia, withdrawal syndrome back pain, chills

*In cases of intravenous misuse, local reactions, sometimes septic, and potentially serious acute hepatitis have been reported (see section 4.4).

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 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: Drugs used in opioid dependence ATC code: N07 BC01

Buprenorphine is an opioid partial agonist/antagonist which attaches itself to the p (mu) and k (kappa) receptors of the brain. Its activity in opioid maintenance treatment is attributed to its slowly reversible link with the p 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 and in the liver. The use of this medication by the oral route is therefore inappropriate.

When taken sublingually, the absolute bioavailability of buprenorphine tablets is not well known but has been estimated to be between 15 and 30%.

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 p (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 (70%), 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

Citric acid anhydrous Lactose monohydrate Mannitol Sodium citrate Sodium stearyl fumarate Pregelatinised starch (maize)

6.2 Incompatibilities

Not applicable

6.3 Shelf life

18 months

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

Nature and contents of container

PVC/PVDC-aluminium blister packs

Pack sizes 7, 10, 20, 24, 28, 30, 48 or 50 sublingual tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

Sandoz Limited Frimley Business Park,

Frimley,

Camberley,

Surrey,

GU16 7SR.

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 04416/0949

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

02/09/2011

10 DATE OF REVISION OF THE TEXT

28/08/2014