Document: spc-doc_PL 20117-0119 change

• spc-doc_PL 00240-0354
• spc-doc_PL 20117-0119
• spc-doc_PL 30306-0327

---

NAME OF THE MEDICINAL PRODUCT

Buprenorphine 2 mg Sublingual Tablets Natzon 2 mg Sublingual Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 2 mg of buprenorphine (as buprenorphine hydrochloride). Excipient: Each tablet contains 20 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Sublingual tablet.

Off-white to brownish, oval, biplane tablets marked with “B2” 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 adolescents aged 16 years or over 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 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 takes 5 to 10 minutes.

Adults

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 medication (see section 4.5 Interaction with other medicinal products and other forms of interaction) and/or have existing liver dysfunction are at risk of accelerated liver injury. Regular monitoring of liver function is recommended (see section 4.4 Special warnings and precautions for use).

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 tablet(s) 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.

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 32 mg. The dosage is titrated according to reassessment of the clinical and psychological status of the patient.

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 of the excipients

-    Children and adolescents 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. It is also recommended that that treatment is prescribed by a physician who ensures comprehensive management of the drug addicted patient(s)

-    The clinician 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.

Precipitated withdrawal

-    When initiating treatment with buprenorphine the physicians 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 opioids, or if administered less than 24 hours after the last dose of methadone. Conversely, withdrawal symptoms may also be associated with suboptimal dosing.

-    The risk of serious adverse events such as overdose or treatment dropout is greater if a patient is under treated with Buprenorphine and continues to self medicate withdrawal symptoms with opioids, alcohol or other sedative-hypnotics in particular benzodiazepines.

-    Dependence: Buprenorphine is a partial agonist at the mu-opiate receptor and chronic administration produces dependence of the opioid type. Discontinuation of treatment may result in a withdrawal that may be delayed

-    Respiratory Depression: some cases of death due to respiratory depression have been reported, particularly when used in combination with benzodiazepines (see Section 4.5 Interaction with other medicinal products 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 opioid-dependent addicts both in clinical trials and in post-marketing adverse event reports especially by intravenous route. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of hepatic failure. In many cases, these hepatic injuries have mainly been observed at the high doses and may be promoted by presence of pre-existing liver enzyme abnormalities, infection with hepatitis B, viral infections particularly chronic C hepatitis, alcohol abuse, anorexia, the concurrent use of other potentially hepatotoxic drugs and ongoing injecting drug use may have a causative or contributory role. These underlying factors must be taken into consideration before prescribing Buprenorphine and during treatment.

-    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 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 Section

4.5 Interaction with other medicinal products and other forms of interaction).

-    This product can cause orthostatic hypotension.

-    Studies in animals, as well as clinical experience, have demonstrated that buprenorphine may produce a low level of dependence.

-    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 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).

Excipient:

Patient with lactose intolerance: 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

Buprenorphine should not be taken together with alcoholic drinks or medications containing alcohol. Alcohol increases the sedative effect of buprenorphine (see Section 4.7 Effects on ability to drive and use machines).

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 C_max and AUC of buprenorphine (approximately 70% and 50% respectively) and, to a lesser extent, of the metabolite, norbuprenorphine. Patients receiving buprenorphine should be closely monitored and the dose of buprenorphine should be halved when starting treatment with ketoconazole.

Further titration of buprenorphine should be made as clinically indicated. Although no data from clinical trials are available, the use of other inhibitors of CYP3A4 (e.g. gestodene, troleandomycin, 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 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 Pregnancy and lactation

Pregnancy

Studies in rats and rabbits have evidenced foetotoxicity including post-implantation loss. In addition, maternal oral administration at high doses during gestation and lactation resulted in a slight delay in the development of some neurological functions (surface righting reflex and startle response) in neonatal rats.

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 pregnancy.

Breast-feeding

As evidenced in rats, buprenorphine has the potential to inhibit lactation or milk production. In addition, because buprenorphine passes into the mother's milk, breastfeeding is contra-indicated.

4.7 Effects on ability to drive and use machines

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 Interaction with other medicinal products 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:

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

4.8 Undesirable effects

Summary of safety profile

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

Tabulated list of adverse reactions

•    adverse reactions reported from pivotal clinical studies. The frequency of possible side effects listed below is defined using the following convention: Very common (>1/10), common (>1/100 to <1/10).

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

Adverse effects observed in pivotal clinical studies and / or post marketing surveillance listed by body system
System Organ Class	Very common (>1/10)	Common (>1/100 to <1/10)	Frequency not known
Infections and infestations		Bronchitis Infection Influenza Pharyngitis

		Rhinitis
Blood and lymphatic system disorders		Lymphadenopathy
Metabolism and nutrition disorders		Decreased appetite
Psychiatric disorders	Insomnia	Agitation Anxiety Depression Hostility Nervousness Paranoia Thinking abnormal	Drug dependence
Nervous system disorders	Headache	Dizziness Hypertonia Migraine Paraesthesia Somnolence Syncope Tremor
Eye disorders		Lacrimal disorder Mydriasis
Cardiac disorders		Palpitations
Vascular disorders		Vasodilatation
Respiratory, thoracic and mediastinal disorders		Cough Dyspnoea Yawning
Gastrointestinal disorders	Nausea	Abdominal pain Constipation Diarrhoea Dry mouth Dyspepsia Gastrointestinal disorder Flatulence Tooth disorder Vomiting
Skin and	Hyperhidrosis	Rash

subcutaneous tissue disorders
Musculoskeletal, connective tissue and bone disorders		Arthralgia Back pain Bone pain Muscle spasms Myalgia Neck pain
Reproductive system and breast disorders		Dysmenorrhoea
General disorders and administration site conditions	Drug withdrawal syndrome Pain	Asthenia Chest pain Chills Malaise Oedema peripheral Pyrexia	Drug withdrawal syndrome neonatal

Description of selected adverse reactions

The following is a summary of other post-marketing adverse event reports that are

considered serious or otherwise noteworthy:

•    In cases of intravenous misuse, local reactions, sometimes septic (abscess, cellulitis), and potentially serious acute hepatitis and other infections such as pneumonia, endocarditis have been reported (see section 4.4).

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

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

•    Transaminase increase, hepatitis, acute hepatitis, cytolytic hepatitis, jaundice, hepatorenal syndrome, hepatic encephalopathy, and hepatic necrosis have occurred (see section 4.4).

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

•    Hallucination, orthostatic hypotension, urinary retention and vertigo have been reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system using the Yellow Card Scheme, Website: www.mhra.gov.uk/vellowcard.

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. 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 halflife 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 (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 (E421)

Maize starch

Citric acid, anhydrous

Sodium citrate

Povidone (Pasdone K29/32)

Magnesium stearate

Ascorbic acid

Edetic acid (EDTA)

6.2 Incompatibilities

Not applicable.

6.3. Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 30

Store in original package to protect from moisture.

6.5 Nature and contents of container

White opaque PVC/PVDC/Aluminium foil blisters with 7 tablets per blister. Pack sizes: 7, 14, or 28 tablets per carton.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.