SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Tephine 200 microgram Sublingual Tablets

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each tablet contains 200 microgram of buprenorphine (as buprenorphine hydrochloride).

Excipient: 45.0 mg lactose (as lactose monohydrate).

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Sublingual tablet.

White, round tablet.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Tephine is used as astrong analgesic for the relief of severe pain, e.g. following surgery or injuries, myocardial infarction and in cancer.

Use of Tephine is NOT indicated in the treatment of headache, toothache, migraine or other conditions involving pain which can be treated using peripherally active analgesics and/or spasmolytics.

4.2 Posology and method of administration

Dosage

The dosage of Tephine should generally be adjusted to the intensity of the pain and the individual sensitivity of the patient.

The recommended single dose in patients with a bodyweight greater than 45 kg is 1 - 2 sublingual tablets Tephine 200 microgram

The onset of effects generally occurs within 30 minutes after sublingual administration.

The average duration of effects is 6 - 8 hours.

If necessary, 1-2 sublingual tablets Tephine 200 microgram may be administered every 6 - 8 hours.

In severe chronic pain, the dose of Tephine should be adjusted to the intensity of the pain and administered regularly in accordance with a fixed schedule corresponding to the duration of effects.

Patients with a bodyweight of 35 - 45 kg should be given a single dose of 1 sublingual tablet Tephine 200 microgram, if necessary, every 6 - 8 hours. This is equivalent to an average single dose of 5 micrograms/kg bodyweight.

Patients with a bodyweight of 16 - 35 kg should be given a single dose of 100 microgram of buprenorphine, if necessary, every 6 - 8 hours. Tephine 200 microgram sublingual tablets are not divisible. Other buprenorphine containing products covering the 100 microgram dosage are available.

Buprenorphine should not be used in children less than 2 years of age or in children weighing less than 16 kg.

Patients with hepatic insufficiency:

Buprenorphine is metabolised in the liver. The degree and duration of its effects in patients with impaired hepatic function may therefore be altered. It is thus advisable to appropriately adjust the dose of Tephine in this patient group.

Method of administration

The sublingual tablets are placed under the tongue, where they will dissolve within 5 - 10 minutes. In the presence of very dry oral mucosa, a few drops of liquid will accelerate the dissolution process.

The sublingual tablets must not be sucked, chewed or swallowed.

At the beginning of treatment, ambulatory patients should rest during and for 1 - 2 hours after administration of Tephine.

Duration of use

Tephine should not be used for longer than is absolutely necessary. If longer term pain management is required, it is advisable to reassess at regular and

frequent intervals (with administration pauses, if applicable) whether and at what dosage Tephine should continue to be administered.

There is currently insufficient clinical experience of longer term use of buprenorphine in children.

4.3 Contraindications

Hypersensitivity to buprenorphine, centrally active analgesics or to any of the excipients of the medicinal product (see section 6.1)

Opioid-dependent patients and for drug-substitution treatment Severe respiratory insufficiency Severe hepatic insufficiency

Patients treated concurrently with MAO inhibitors or who have used these in the previous 2 weeks (see section 4.5)

4.4 Special warnings and precautions for use

Buprenorphine should be used only under close monitoring and with particular

caution:

•    in case of impaired respiratory function (e.g. in acute asthma, obstructive pulmonary disorders, cor pulmonale, hypoxia, hypercapnia or pre-existing respiratory depression)

•    in patients with head injuries, cerebral damage or pre-existing elevated intracranial pressure. In common with other potent analgesics, buprenorphine can cause elevation of cerebrospinal pressure. In combination with the depressant effect on respiration, this effect can be significantly increased in the presence of head injuries. As buprenorphine can also cause miosis and influence the degree of consciousness, the clinical course of patients with head injuries may be masked and the evaluation of their condition more difficult.

Buprenorphine should be used only with particular caution:

•    in elderly and debilitated patients

•    in the presence of impaired renal function or renal insufficiency (e.g. Addison’s disease)

•    in patients with myxoedema or hypothyroidism

•    in toxic psychosis, central nervous depression or coma

•    in acute alcoholism or delirium tremens

•    in kyphoscoliosis with restrictive disturbances of the airways

•    in patients who have recently been treated with narcoanalgesics.

It has been demonstrated in controlled studies in humans and animals that buprenorphine has a lower dependency potential than pure opioid agonists. Minor euphoric effects of buprenorphine have been observed in humans. This could result in abuse of the substance to some extent. Caution should therefore be exercised if buprenorphine is prescribed for patients with a known or suspected history of drug abuse.

In addition, buprenorphine should be used with particular caution and at a reduced dose in prostatic hypertrophy, constriction of the urinary tract and biliary tract disorders.

As is the case with all opioids, chronic use of buprenorphine can result in development of physical dependence. Withdrawal symptoms (abstinence syndrome) - should they occur at all - tend to be mild, commence after 2 days and may persist for up to 2 weeks. Withdrawal symptoms include excitation, anxiety states, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal complaints.

Use of Tephine can lead to positive results in doping tests. Abuse of the medicinal product Tephine for doping purposes can endanger health.

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.

Diversion of buprenorphine has been reported. 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 risks of overdose, spread of blood borne viral infections and respiratory depression.

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).

A reduction of hepatic perfusion induced when certain general anaesthetics, such as halothane, and other medicinal products are used may reduce the rate of hepatic elimination of buprenorphine.

Buprenorphine should be used cautiously together with:

•    Benzodiazepines: This combination may potentiate respiratory depression of central origin, with risk of death.

•    Other central nervous system depressants; other opioid derivatives (analgesics and antitussives); certain antidepressants, sedative Hl-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 (see section 4.3).

•    CYP3A4 inhibitors and inducers: in a study of the interactions of buprenorphine with ketoconazole, elevated concentrations of buprenorphine and norbuprenorphine were measured. Patients treated with CYP3A4 inhibitors (e.g. ketoconazole, gestodene, triacetyloleandomycin, the HIV protease inhibitors ritronavir, indinavir, saquinavir and atazanavir) should therefore be closely monitored and may require a lower dose of buprenorphine.

The interaction of buprenorphine with CYP3A4 inducers has not been investigated to date. It is therefore recommended that patients treated with CYP3A4 inducers (e.g. phenobarbital, carbamazepine, phenytoin, rifampicin) be closely monitored if buprenorphine is administered concomitantly.

A suspected interaction between buprenorphine injection and phenprocoumon, resulting in purpura, has been reported.

To date, no notable interaction has been observed with cocaine, the agent most frequently used by multi-drug abusers in association with opioids.

4.6 Fertility, pregnancy and lactation

There are insufficient data on the use of buprenorphine during pregnancy and the lactation period. Animal studies have demonstrated reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

The administration of high doses of buprenorphine towards the end of pregnancy, even if only over the short term, may induce respiratory depression in the neonate. Chronic use of buprenorphine during the final trimester of pregnancy may be responsible for withdrawal symptoms in neonates. Tephine is not recommended for use during pregnancy.

Buprenorphine may be used during pregnancy only if this appears to be absolutely necessary after careful weighing of the potential risks against the expected benefits. In this case, close monitoring of the pregnant women, the foetus and the neonate by the physician are essential.

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 Tephine.

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.

Even when used as recommended, buprenorphine can influence reactions to such an extent that, for example, driving or operating machines is not recommended during treatment with buprenorphine.

This is particularly the case if there is concurrent use of centrally active substances, including alcohol, tranquillizers, sedatives and hypnotics. The treating physician should provide recommendations in each individual case.

4.8 Undesirable effects

The evaluation of undesirable effects is based on the following frequency conventions:

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 most commonly reported undesirable effect of buprenorphine is tiredness. Sleep, from which the patient can be easily wakened, occurs most frequently during use in the postoperative phase.

Table 1. Undesirable effects associated with the treatment:

General disorders and administration site conditions
Common:	flushing
Immune system disorders
Uncommon: Very rare:	Generalised (systemic) hypersensitivity reactions Anaphylactic shock

Psychiatric disorders
Uncommon:	Confusion, disorientation, nervousness, depression, psychosis, hallucinations, depersonalisation, euphoria, dysphoria, agitation (restlessness)
Nervous system disorders
Very common:	Tiredness, sleep disturbances, drowsiness
Common:	Dizziness, headache
Uncommon:	Exhaustion, dry mouth, slurred speech, coma, tremor (shaking), seizures, lack of muscle coordination
Eye disorders
Common:	Miosis
Uncommon:	Double vision, visual disturbances, conjunctivitis
Ear and labyrinth disorders
Uncommon:	Tinnitus
Cardiac disorders
Uncommon:	Tachycardia, bradycardia, cyanosis, AV block
Vascular disorders
Common:	Orthostatic hypotension
Uncommon:	Hypertension
Respiratory, thoracic and mediastinal disorders
Common: Uncommon: Very rare:	Respiratory depression Dyspnoea (respiratory distress), apnoea (respiratory arrest) Bronchospasm
Gastrointestinal disorders
Common: Uncommon:	Nausea, vomiting Constipation, dyspepsia, loss of appetite, diarrhoea
Skin and subcutaneous tissue c	isorders
Common: Uncommon: Very rare:	Sweating Paraesthesia, pruritus (itching), skin rash, pallor, urticaria Angioneurotic oedema (Quincke’s oedema)
Renal and urinary disorders
Uncommon:	Micturition disorders, urinary retention

The following undesirable effects have also been reported during use of buprenorphine in drug-substitution treatment: Nervous system: insomnia, sleepiness, Cardiovascular system: fainting, fall in blood pressure, Respiratory tract: respiratory depression, Liver: hepatic necrosis and hepatitis.

Circulatory dysregulation may occur on initial use of buprenorphine.

Local irritation of the oral mucosa (in some cases with development of mouth ulcers and haemorrhagic diathesis) can occur after use of buprenorphine.

In opioid-dependent patients, first administration of buprenorphine may induce withdrawal symptoms comparable to those seen after use of naloxone.

The safety profile of buprenorphine in children is comparable with that in adults.

Even doses in the therapeutic range may cause serious poisoning (intoxications) in subjects who are hypersensitive (particularly children). The symptoms of excessive effects of buprenorphine are characterised by signs such as “feeling strange”, poor ability to concentrate, sleepiness and (possibly) a sensation of dizziness when standing. Other symptoms of overdose are respiratory depression, (reduced respiratory rate and/or respiratory volume, Cheyne-Stokes respiration, cyanosis), extreme sleepiness, disturbance of consciousness with coma in extreme cases, miosis, flaccidity of the skeletal muscles, moist-cold skin, bradycardia and hypotension.

Massive intoxication can induce respiratory arrest, circulatory failure, cardiac arrest and result in death.

Treatment:

In case of overdose, the cardiac and respiratory status of the patient must be closely monitored and appropriate supportive measures should be initiated. A specific opioid antagonist, such as naloxone, can counteract the effects of buprenorphine. Higher doses are generally required for this purpose than with other opioids. It must be borne in mind that the duration of effects of opioids can exceed that of naloxone, so that there is a risk of recurrence of respiratory depression.

Gastric lavage should be considered if larger doses of Tephine have been ingested.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Potent analgesic, partial opioid receptor agonist ATC code: N02A E01

Buprenorphine is a potent, centrally active analgesic with opioid-agonistic and opioid-antagonistic properties. The analgesic effect is attributable to interaction with specific opioid receptors (mainly p-receptors) in the central nervous system. The long duration of effects (6 - 8 hours) is attributed to the slow rate of dissociation of buprenorphine from receptors and the limited extent to which the effects are counteracted by morphine antagonists because of the high affinity of buprenorphine for the receptor.

Buprenorphine can induce a fall (or rarely, also an increase) in heart rate and blood pressure and also has antitussive and respiratory depressive effects.

If buprenorphine is administered after pure opioid agonists, its antagonistic effects may be manifested dependent on the dose administered, i.e. the effects of the agonists, such as morphine, may be attenuated or abolished.

5.2 Pharmacokinetic properties

Absorption

The absorption of buprenorphine after sublingual administration is good. The onset of analgesic effects commences approximately 30 minutes after sublingual administration. The effects peak after 60 - 120 minutes and persist for 6 - 8 hours.

Peak plasma concentrations are reached within approximately 200 minutes after sublingual administration. Following intravenous injection of buprenorphine, plasma concentrations fall rapidly in the initial phase with a half-life of 2 - 5 minutes (distribution phase). Terminal half-life is approximately 3 hours. The concentrations of the active substance 10 minutes after i.m. injection are equivalent to those after i.v. injection. Terminal halflife after i.m. administration is also 3 hours. Because of the persistent receptor binding, pharmacodynamic effects do not correlate with blood concentrations or the elimination half-life of buprenorphine.

In human plasma, 96% of a buprenorphine dose is bound to plasma proteins, mainly to a- and P-globulins. An influence on the protein binding of anticoagulants (bound to albumin) is therefore unlikely.

Metabolism and elimination

Buprenorphine is metabolised in the liver. It is subject to a phase 1 (N-dealkylation) and a phase 2 (O- and/or N-glucuronidation) metabolism. Unchanged buprenorphine and its metabolites are also excreted by the biliary route.

Elimination occurs within 7 days, mainly via the faeces but 27% of a dose is eliminated in the urine.

While predominantly unchanged buprenorphine has been detected in faeces, glucuronide derivatives of buprenorphine and N-dealkylbuprenorphine are mainly found in the urine. The slow rate of faecal excretion indicates the presence of an enterohepatic circulation.

Passage into cerebrospinal fluid

Buprenorphine crosses the blood-brain barrier and is detectable in all sections of the brain. The concentration is highest in the pituitary gland and lower in the cerebellum and spinal marrow.

Placental _ passage

Studies conducted in gestating rats have shown that buprenorphine crosses the placental barrier. The concentrations of buprenorphine in foetal tissue in the early phase of pregnancy are equivalent to maternal plasma levels. With progression of the pregnancy, buprenorphine can also be detected in the gastrointestinal tract of the foetus in some cases.

Only immediately prior to birth is the foetal liver capable of metabolising buprenorphine and the substance is then found in the form of derivatives in the gastrointestinal tract of the foetus.

Passage into breast milk

Studies conducted in rats have demonstrated that buprenorphine passes into breast milk.

5.3 Preclinical safety data

No undesirable effects on fertility or general reproductive potential have been observed in rats. However, evidence of fetotoxic effects and an increased rate of postimplantation losses have been reported from studies in the rat and rabbit.

Studies in rats have demonstrated a reduced rate of intrauterine growth, delayed development of certain neurological functions and a high rate of peri-and postnatal mortality of offspring after treatment of the maternal animals during the gestation/lactation period. There is evidence that problems relating to parturition and reduced milk production contributed to these effects. There were no signs of embryotoxic or teratogenic effects in the rat or rabbit.

No clinically relevant effects are reported from in vitro and in vivo studies of the mutagenic potential of buprenorphine.

No evidence of a carcinogenic potential relevant to humans has been identified in long-term studies in the rat and mouse.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

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

Not applicable

6.3 Shelf life

18 months

6.4 Special precautions for storage

6.5 Nature and contents of container

PVC/PVDC-aluminium blister packs

Pack sizes 7, 10, 20, 24, 28, 30, 48, 50 or 70 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 04416/0956

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

02/09/2011

10    DATE OF REVISION OF THE TEXT

15/08/2014