Buprenorphine 2mg Sublingual Tablets

Document: spc-doc_PL 30306-0327 change

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each sublingual tablet contains 2 mg of buprenorphine (as buprenorphine hydrochloride). Excipients with known effect: Each tablet contains 43.9 mg of lactose monohydrate and 0.19 mg of sunset yellow (E110).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Sublingual tablet.

Uncoated, light orange, 5x8 mm oval, biconvex tablets with “B” 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 must be under the supervision of a physician experienced in the management of opiate dependence/addiction.

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

When initiating buprenorphine treatment, the physician should be aware of the partial agonist profile of buprenorphine and that it can precipitate withdrawal symptoms in opioid-dependent patients. Buprenorphine binds to the p (mu) and k (kappa) opiate receptors.

Adults:

Baseline liver function tests and documentation of viral hepatitis status is recommended prior to commencing therapy. Patients who are positive for viral hepatitis, on concomitant medicinal products (see section 4.5) and/or have existing liver dysfunction are at 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.

Posology Initiation therapy

The recommended starting dose is from 0.8 mg to 4 mg of buprenorphine as a single daily dose. An additional dose of 2 to 4 mg buprenorphine can be given on day one depending on the individual patient’s need.

For opioid-dependent drug addicts who have not undergone withdrawal When treatment starts, the first dose of buprenorphine should be taken when signs of withdrawal appear, but not less than 6 hours after the patient last used opioids (e.g. heroin; short acting opioids).

For patients receiving methadone

Before beginning buprenorphine therapy, the dose of methadone must be reduced to a maximum of 30 mg/day. The first dose of buprenorphine should be taken when signs of withdrawal appear, but not less than 24 hours after the patient last used methadone. Buprenorphine may precipitate symptoms of withdrawal in patients dependent upon methadone.

Dosage adjustment and maintenance

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

During the initiation of treatment, daily dispensing of buprenorphine is recommended. After stabilisation, a reliable patient may be given a supply of buprenorphine sufficient for several days of treatment. It is recommended that the amount of buprenorphine be limited to 7 days or according to local requirements.

Less than daily dosing:

After a satisfactory stabilisation has been achieved the frequency of buprenorphine 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. However, the dose given on any one day should not exceed 24 mg. In some patients, after a satisfactory stabilisation has been achieved, the frequency of buprenorphine 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 stabilisation has been achieved, if the patient agrees, the dosage may be reduced gradually to a lower maintenance dose; in some favourable cases, treatment may be discontinued. The availability of the sublingual tablet in doses of 0.4 mg, 2 mg and 8 mg allows for a downward titration of dosage. Patients should be monitored following termination of treatment because of the potential for relapse.

Elderly

No data is available on elderly patients.

Paediatric population

Buprenorphine is not recommended for use in children and adolescents below the age of 15 years due to lack of data on safety and efficacy.

Patients with impaired hepatic function

The effect of hepatic impairment on the pharmacokinetics of buprenorphine is unknown.

Since the active substance is extensively metabolised, 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 (see section 5.2).

Patients with impaired renal function

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

Method of administration

Administration is sublingual. Physicians must warn patients that the sublingual route is the only effective and safe route of administration for this medicinal product (see section 4.4). Buprenorphine sublingual tablets are to be placed under the tongue until dissolved.

The tablet should not be swallowed, crushed or chewed.

4.3 Contraindications

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

- 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.

Due to the lack of data in adolescents (age 15-<18), buprenorphine should be used only with caution in this age group.

Patients should be closely monitored during the switching period from methadone to buprenorphine since withdrawal symptoms have been reported.

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

Diversion:

Diversion refers to the introduction of 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 buprenorphine as the primary drug of abuse with the risk of overdose, spread of blood borne viral infections, respiratory depression and hepatic injury. The physician should consider the risk of diversion of buprenorphine into the illicit market before prescribing buprenorphine.

The risk of serious adverse events such as overdose or treatment dropout is greater if the patient is under treated with buprenorphine and continues to self medicate withdrawal symptoms with opioids, alcohol or other sedatives and hypnotics (in particular benzodiazepines).

Buprenorphine is a partial agonist at the p opiate receptor and chronic administration produces dependence of the opioid type.

Precipitated withdrawal:

When initiating treatment with buprenorphine the physician must be aware of the partial agonist profile of buprenorphine and that it can precipitate withdrawal in opioid-dependent patients particularly if administered less than 6 hours after the last use of heroin or other short-acting opioid, or if administered less than 24 hours after the last dose of methadone (see section 4.2). Conversely, withdrawal symptoms may also be associated with suboptimal dosing.

Buprenorphine can cause drowsiness, which may be exacerbated by other centrally acting agents such as alcohol, tranquilisers, sedatives and hypnotics (see section 4.5).

Animal studies, as well as clinical experience, have demonstrated that buprenorphine may cause dependence but at a lower level than morphine.

Discontinuation of treatment may result in a withdrawal syndrome that may be delayed. Buprenorphine can cause orthostatic hypotension.

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

Buprenorphine is an opioid and may mask pain as a disease symptom.

Medicinal products that inhibit the enzyme CYP3A4 may cause increased concentrations of buprenorphine. A reduction of the buprenorphine dose may be necessary. In patients who are already treated with CYP3A4 inhibitors the dose of buprenorphine should be titrated carefully since a reduced dose may be sufficient in these patients (see section 4.5).

Concomitant use of monoamine oxidase inhibitors (MAOI) can increase the efficacy of opioids based on experience with morphine.

Respiratory depression:

Some 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. Cases of death have been reported in connection with concomitant administration of buprenorphine and other medicinal products that causes central nervous system depression such as alcohol or other opioids..

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 hepatic failure, hepatic necrosis, hepatorenal syndrome and hepatic encephalopathy. 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 medicines, 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, further biological and etiological evaluation is required. Depending upon the findings, the medicinal product may be discontinued cautiously so as to prevent withdrawal symptoms and to prevent a return to illicit drug use. If the treatment is continued, hepatic function should be monitored closely.

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 product should be used with caution in patients with:

- asthma or respiratory insufficiency (cases of respiratory depression have been reported with buprenorphine, see section 4.3);

- 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, see section 4.3);

- head injuries;

- increased intracranial pressure;

- hypotension;

- prostatic hypertrophy;

- urethral stenosis.

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.

Buprenorphine 2 mg sublingual tablets_also contain the azo colouring agent sunset yellow (E110), which may cause allergic reactions.

4.5 Interaction with other medicinal products and other forms of interaction

Buprenorphine should not be taken together with alcoholic drinks or medications containing

alcohol. Alcohol increases the sedative effect of buprenorphine (see section 4.7).

The effect of other medicinal products on buprenorphine Buprenorphine is metabolised by CYP3A4. An interaction study with buprenorphine and ketoconazole (a potent inhibitor of CYP3A4) resulted in increased C_max and AUC (area under the curve) of buprenorphine (approximately 70% and 50% respectively) and to a lesser extent, of norbuprenorphine. Concomitant administration of buprenorphine and potent CYP3A4 inhibitors (e.g. azole antifungals such as ketoconazole or itraconazole, erythromycin, gestodene, troleandomycin, HIV protease inhibitors like ritonavir, indinavir, nelfinavir and saquinavir) can lead to markedly increased plasma concentrations of buprenorphine and norbuprenorphine. The combination should be avoided or monitored closely since a dose reduction may be required.

The interaction between buprenorphine and CYP3A4 inducers has not been investigated. It is therefore recommended that patients that are treated with buprenorphine are monitored closely if enzyme inducers such as phenobarbital, carbamazepine, phenytoin and rifampicine are given concomitantly.

The effect of buprenorphine on other medicinal products Buprenorphine has been shown to be a CYP2D6 and CYP3A4 inhibitor in vitro. The risk of inhibition at therapeutic concentrations in vivo seems low but can not be excluded. When buprenorphine is combined with other medicinal products that are CYP2D6 or CYP3A4 substrates the plasma concentrations of these medicinal products may be increased and the risk of dose dependent adverse reactions may occur. Buprenorphine does not inhibit the enzyme CYP2C19 in vitro. The effect on other enzymes that metabolise medicinal products has not been investigated.

Buprenorphine should be used with caution in combination with:

- Benzodiazepines: This combination may result in death due to respiratory depression of central origin. Therefore, dosages must be individually titrated and the patient monitored carefully. The risk of drug abuse should also be considered (see section 4.4).

- Other central nervous system depressants: other opioid derivatives (analgesics and antitussives (such as methadone, dextropropoxyphene, codeine, dextromethorphan and noscapine)), certain antidepressants, sedative H1-receptor antagonists, barbiturates, anxiolytics other than benzodiazepines, neuroleptics, clonidine and related substances. These combinations increase central nervous system depression and may also affect the ability to drive and operate machines.

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

To date, no notable interaction has been observed with cocaine.

4.6 Fertility, pregnancy and lactation

Pregnancy

In humans there is currently not sufficient data to evaluate the safety of buprenorphine when administered during pregnancy. Neonatal withdrawal symptoms and respiratory suppression have been reported in newborns after treatment of the mothers in the last part of the pregnancy. Animal studies have shown reproduction toxic effects (see section 5.3). Buprenorphine should only be used in pregnancy if the benefits outweigh the possible risk. At the end of pregnancy, if high doses have to be given occasionally, or if continuously use is necessary, neonatal monitoring should be considered.

Breast-feeding

Buprenorphine and its metabolites are excreted in human breast 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

In general buprenorphine has minor to moderate influence on the ability to move safely in traffic, use machines, or perform other hazardous activities. Buprenorphine may cause drowsiness, dizziness, or impaired thinking, particularly when taken together with alcohol or central nervous system depressants. Therefore, caution is advised when performing the above mentioned activities (see sections 4.4 and 4.5).

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 following frequency convention is used in the evaluation of undesirable effects: 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 form the available data).

System organ class

Frequency

Side effects

Immune system disorder

Very rare:

Anaphylactic shock,

angioneurotic oedema (Quincke-oedema), bronchospasm.

Psychiatric disorders	Common:	Anxiety, Nervousness.
	Uncommon:	Hallucinations.
Nervous system disorders	Very Common:	Insomnia.
	Common	Dizziness, drowsiness, headache.
Eye disorders	Common:	Lacrimation disorder.
Cardiac disorders	Common:	ECG abnormalities (QT prolongation).
Vascular disorders	Common:	Syncope, orthostatic hypotension.
Respiratory, thoracic and	Common:	Rhinorrhoea.
mediastinal disorders	Uncommon:	Respiratory depression.
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	Very common:	Asthenia,
administration site		withdrawal syndrome.
conditions	Common:	Back pain, Chills.

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

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

There have been reports of neonatal withdrawal syndrome in neonates where the mothers have been treated with buprenorphine during pregnancy. The syndrome may be milder and of longer duration than that which is caused by short acting full p opioid agonists. The nature of the syndrome may vary depending upon the mother’s drug use history (see section 4.6).

There have been reports of cases with spontaneous abortions associated with the use of buprenorphine. It is not possible to establish a causal relationship, since cases typically involve other drug use or risk factors for spontaneous abortion.

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; website: www.mhra.gov.uk/yellowcard

4.9 Overdose

In the event of 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, and standard intensive care measures, should be implemented. 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 the length of treatment and medical surveillance needed to reverse the effects of an overdose.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in opioid dependence, ATC code: N07BC01

Mechanism of action:

Buprenorphine is an opioid partial agonist/antagonist which binds to the p (mu) and k (kappa) receptors of the brain. Its activity in opioid maintenance treatment is attributed to its slowly reversible properties with the p receptors which, over a prolonged period, might minimise the need of addicted patients for drugs.

Opioid agonist ceiling effects were observed during clinical pharmacology studies in opioid dependent persons.

Buprenorphine has a wide therapeutic index as a consequence of its partial agonist/antagonist which limits its suppressive effects on especially cardiac and respiratory function.

5.2 Pharmacokinetic properties

Absorption

When taken orally, buprenorphine undergoes first-pass metabolism with N-dealkylation and glucuroconjugation in the small intestine and the liver. The use of this medicinal product by the oral route is therefore inappropriate.

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 (distribution halflife of 2 to 5 hours).

Biotransformation

Buprenorphine is metabolised by 14-N-dealkylation and glucuroconjugation of the parent molecule and the dealkylated metabolite. Clinical data confirm that CYP3A4 is responsible for the N-dealkylation of buprenorphine. N-dealkylbuprenorphine is a p (mu)-opioid agonist with weak intrinsic activity.

Elimination

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

Special populations :

Elderly: No pharmacokinetic data in elderly patients are available.

Renal impairment: Renal elimination plays a relatively small role (~30 %) in the overall clearance of buprenorphine. No dose modification based on renal function is required but caution is recommended when dosing subjects with severe renal impairment.

Hepatic impairment: Hepatic elimination plays a relatively large role (~70 %) in the overall clearance of buprenorphine and the action of buprenorphine may be prolonged in subjects with impaired hepatic clearance. Lower initial buprenorphine doses and cautious titration of dosage may be required in patients with mild to moderate hepatic dysfunction. Buprenorphine is contraindicated in patients with severe hepatic dysfunction (see section 4.3).

5.3 Preclinical safety data

Toxicologic studies does not show any risk for humans with regards to pharmacological effects, toxicity with repeat dosage, genotoxicity or carcinogenicity.

Buprenorphine was not teratogenic in animal studies. Intramuscular doses of 0.05 mg/kg/day and higher caused foetal growth retardation in rats. High doses (1 mg/kg/day and higher) resulted in increased perinatal mortality in rats.

A peri-postnatal study with maternal oral administration of buprenorphine at high doses (80 mg/kg/day) during gestation and lactation resulted in difficult parturition (possible as a result of the sedative effect of buprenorphine), high neonatal mortality and a slight delay in the development of some neurological functions (surface righting reflex and startle response) in neonatal rats.

6.1 List of excipients

Magnesium stearate

Sodium citrate Povidone

Citric acid, anhydrous Starch, pregelatinised (maize) Lactose monohydrate Sunset yellow (E110) Crospovidone Mannitol

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Blister packs (Al/Al and Al/ PVC/PVDC): 2 years Blister packs (Al/PVC/PVDC Perlalux Tristar Ultra): 1 year Tablet containers: 2 years

6.4 Special precautions for storage

Blister packs: Do not store above 25°C. Store in the original package in order to protect from moisture.

Tablet containers: Do not store above 30°C. Keep the container tightly closed in order to protect from moisture.

6.5 Nature and contents of container

Tablet containers (HDPE) with a plastic cap (LDPE) and a desiccant.

Blister packs (Al/Al, Al/PVC/PVDC or Al/PVC/PVDC Perlalux Tristar Ultra). Child resistant blister packs (Al/Al).

Pack sizes:

1, 7, 20, 24, 28, 48 and 50 sublingual tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Medicines no longer required should not be disposed of via wastewater or the municipal sewage system. Patients should be instructed to return them to a pharmacy or to ask their pharmacist how to dispose of them in accordance with the national regulations. These measures will help to protect the environment.

Instructions for use of child resistant blisters:

1. Do not push the tablet directly out of the pocket

2. Separate one blister cell from the strip at the perforations

3. Carefully peel off the backing at the arrow

4. Push the tablet through the foil

5. Put the tablet under your tounge

7 MARKETING AUTHORISATION HOLDER

Actavis Group PTC ehf.

Reykjavikurvegi 76-78 220 Hafnarfjorour Iceland

8 MARKETING AUTHORISATION NUMBER(S)

PL 30306/0327

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

07/09/2011

10 DATE OF REVISION OF THE TEXT

07/12/2015