This information is intended for use by health professionals

1. Name of the medicinal product

Prefibin, 2 mg, sublingual tablets

2. Qualitative and quantitative composition

Each tablet contains 2 mg of buprenorphine (as buprenorphine hydrochloride).

Excipient(s) with known effect:

Each 2 mg sublingual tablet contains 69,5 mg lactose (as monohydrate).

For the 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 (9.4 x 4.0 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.

Prefibin is indicated in adults and adolescents aged 15 years and over who have agreed to be treated for addiction.

4.2 Posology and method of administration

Posology

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 dose 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 µ and κ opiate receptors.

Initiation 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 medicinal product (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)

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 degree of opioid dependence. To avoid precipitating withdrawal, induction with buprenorphine should be undertaken when objective and clear signs of withdrawal are evident.

- 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.

Induction

The initial dose is from 0.8 mg to 4 mg, administered as a single daily dose.

Dose 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 sublingual tablets was tested in clinical trials in doses up to 24 mg per day.

The dose 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 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 medicinal product sufficient for several days of treatment. However, it is recommended that the amount of the medicinal 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.

Dose reduction and termination of treatment

After a satisfactory period of stabilisation has been achieved, the dose 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 dose. 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.

Special populations

Elderly

The safety and efficacy of buprenorphine in elderly patients over 65 years of age has not been established.

Paediatric population

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.

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.

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.

Renal impairment

Modification of the buprenorphine dose is not generally required for patients with renal impairment. Caution is recommended when dosing patients with severe renal impairment, which may require dose adjustment (creatinine clearance < 30 ml/min) (see section 5.2).

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 sublingual tablet should be kept under the tongue until dissolved, which usually occurs within 5 to 10 minutes.

4.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

• Children and adolescents less than 15 years of age

• Severe respiratory insufficiency

• Severe hepatic insufficiency

• Acute alcoholism or delirium tremens

• Breast-feeding (see section 4.6)

4.4 Special warnings and precautions for use

Prefibin is 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 intravenous misuse: respiratory arrest, shock, thrombophlebitis, embolism, endocarditis, sepsis, liver damage.

• The clinician should consider the risk of abuse and misuse (e.g. intravenous 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.

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

Concomitant use of buprenorphine 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 concomitantly with sedative medicinal products the lowest effective dose 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).

• 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. acetylsalicylic acid, 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 medicinal 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 medicinal product can cause drowsiness, which may be exacerbated by other centrally acting agents, such as: alcohol, tranquillisers, sedatives, hypnotics (see section 4.5).

• This medicinal 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, dose adjustment and monitoring of the patient (see section 4.2).

Paediatric population

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 medicinal 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 medicinal product may cause a positive reaction to sports doping control tests.

Excipients

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 medicinal product.

4.5 Interaction with other medicinal products and other forms of interaction

Combination that is not recommended

Naltrexone: risk of withdrawal syndrome evoking

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

Sedative medicinal products 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 should be limited (see section 4.4).

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 Cmax 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 CYP3A4 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.

4.6 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 is contra-indicated and must be discontinued during treatment with Prefibin (see section 4.3).

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 has moderate influence on the ability to use machines when administered to opioid dependent patients. 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

Summary of the safety profile

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

Tabulated list of adverse reactions

The evaluation of side effects is based on the following MedDRA frequency 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)

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

System Organ Class

Very common

Common

Uncommon

Very rare

Immune system disorders

Anaphylactic shock,

angioedema

Psychiatric disorders

Insomnia

Anxiety,

nervousness,

drowsiness

Hallucination

Nervous system disorders

Dizziness,

headache

Eye disorders

Lacrimation disorders

Cardiac disorders

QT prolongation

Vascular disorders

Fainting,

orthostatic hypotension

Respiratory, thoracic and mediastinal disorders

Rhinitis

Respiratory depression

Bronchospasm

Gastrointestinal disorders

Constipation,

diarrhoea,

nausea,

vomiting,

abdominal pain

Hepatobiliary disorders

Hepatic necrosis,

hepatitis*

Skin and subcutaneous tissue disorders

Sweating

General disorders and administration site conditions

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).

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: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in Google play or Apple App store.

4.9 Overdose

Symptoms

The major symptom requiring intervention is respiratory depression, which could lead to respiratory arrest and death.

Treatment

In the event of accidental overdose, general supportive measures should be instituted, including close monitoring of respiratory and cardiac status of the patient.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.

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

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 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.

Pharmacodynamic effects

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 medicinal product 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.

Biotransformation 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 (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 (5 mg/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 75 mg/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.

6.5 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 and other handling

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 04416/0948

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 02 August 2011

Date of latest renewal:

10. Date of revision of the text

26/04/2019