Schering-Plough Ltd

SUBUTEX 0.4 mg, 2 mg and 8 mg sublingual tablets.

Buprenorphine hydrochloride equivalent to buprenorphine base 0.4 mg, 2 mg or 8 mg.

Excipients: Lactose monohydrate 29.262mg/tablet (0.4 mg), 47.94mg/tablet (2 mg) or 191.76mg/tablet (8 mg).

For full list of excipients, see section 6.1

Sublingual tablet

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

Treatment with SUBUTEX sublingual tablets is intended for use in adults and children over 15 years of age who have agreed to be treated for addiction.

Treatment with SUBUTEX sublingual tablets must be by physicians who have specialist training in its use and all treated patients must be on a central register according to Drug Misuse Programme guidelines. These physicians can be consultants, and/or Level I or Level II GPs who have received special training. All patients will be reviewed and reassessed regularly.

Administration is sublingual. Physicians must advise patients that the sublingual route is the only effective and safe route of administration for this drug. The tablet should be kept under the tongue until dissolved, which usually occurs within 5 to 10 minutes.

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) 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 Subutex should be undertaken when objective and clear signs of withdrawal are evident.

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

. for opioid-dependent drug addicts who have not undergone withdrawal: one dose of SUBUTEX tablet(s) administered sublingually at least 6 hours after the last use of the opioid, or when the first signs of craving appear (see 4.4).

. for patients receiving methadone: before beginning SUBUTEX therapy, the dose of methadone should be reduced to a maximum of 30 mg/day.

SUBUTEX may precipitate symptoms of withdrawal in patients dependent upon opioids or methadone.

Dosage adjustment and maintenance: the dose of SUBUTEX 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; this caution should be followed especially in patients being transferred from methadone to SUBUTEX.

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.

Renal insufficiency: 20% of the administered dose is eliminated by the renal route; thus, renal elimination may be prolonged. In these patients titration of SUBUTEX should be slower to allow for stabilisation.

Hepatic insufficiency: Hepatic metabolism of buprenorphine may be altered. In these patients titration of SUBUTEX should be slower to allow for stabilisation.

- Paediatric use: No data are available in children under 15 years of age; therefore, SUBUTEX should not be used in children under the age of 15.

- Hypersensitivity to buprenorphine or any other component of the product

Severe respiratory insufficiency

Severe hepatic insufficiency

- Acute alcoholism or delirium tremens

- Use during acute asthma attack

- Head injury and increased intracranial pressure

- Lactation (see 4.6)

oWarnings

SUBUTEX sublingual tablets are recommended only for the treatment of major 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 Subutex 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 Subutex 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 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 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 Subutex 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 4.5 Interaction with other medicaments and other forms of interaction) or when buprenorphine was not used according to labelling.

Concomitant use of benzodiazepines with Subutex: Combination with benzodiazepines increases central nervous system depression. Coma, heart block and death due to respiratory depression of central origin resulting from the concomitant use of Subutex and benzodiazepines have occurred in post-marketing experience. The risk of central nervous system depression is greatly increased when Subutex is abused by deliberate overdose, inhalation or intravenous administration. Patients who are taking Subutex should inform their physician before any elective anaesthesia procedures which may require the use of benzodiazepines.

Therefore, the concomitant prescription of benzodiazepines with buprenorphine in the treatment of opiate dependence should be avoided unless medically necessary in the context of the comprehensive medical, social and psychological management strategy; the benefits outweigh the risks associated with concomitant use and patients are aware of the associated risks (see 4.5).

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. 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 drugs and ongoing injecting drug use may have a causative or contributory role. These underlying factors must be taken into consideration before prescribing Subutex and during treatment. When a hepatic event is suspected and the causality is unknown, further evaluation is required. If SUBUTEX is suspected to be the cause of hepatic necrosis or jaundice, it must be discontinued as rapidly as the patient's clinical condition permits. If the drug treatment is continued, hepatic function should be monitored.

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

As buprenorphine is an opioid, pain as a symptom of a disease may be attenuated.

This product can cause drowsiness, which may be exacerbated by other centrally acting agents, such as: alcohol, tranquillisers, sedatives, hypnotics. (See 4.5 Interactions with other medicaments 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. Therefore, Subutex is a drug of addiction.

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

- It is important to follow recommendations for initiating treatment, dosage adjustment and monitoring of the patient (see 4.2).

o 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).

Patients with lactose intolerance: This product contains lactose (see section 6.1). Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

SUBUTEX should not be taken together with alcoholic drinks or medications containing alcohol. Alcohol increases the sedative effect of buprenorphine, which can make driving vehicles and operating machinery hazardous.

SUBUTEX should be used cautiously together with:

- Benzodiazepines: This combination may potentiate respiratory depression of central origin, with risk of death; therefore, the concomitant prescription of benzodiazepines with buprenorphine in the treatment of opiate dependence should be avoided unless medically necessary in the context of the comprehensive medical, social and psychological management strategy; the benefits outweigh the risks associated with concomitant use and patients are aware of the associated risks. 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 H₁receptor antagonists, barbiturates, anxiolytics other than benzodiazepines, neuroleptics, clonidine and related substances. This combination increases central nervous system depression and can make driving vehicles and operating machinery hazardous.

- 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 multidrug 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 resulted in increases in buprenorphine and norbuprenorphine concentrations. Subjects receiving Subutex should be closely monitored and may require dose-reduction if inhibitors of CYP3A4 (e.g. ketoconazole, gestodene, troleandoymycin, the HIV protease inhibitors ritonavir, indinavir and saquinavir) are co-administered.

The interaction of buprenorphine with CYP3A4 inducers has not been investigated, therefore it is recommended that patients receiving Subutex should be closely monitored if enzyme inducers (e.g. phenobarbital, carbamazepine, phenytoin, rifampicin) are co-administered.

Pregnancy

In humans, there is currently no sufficient relevant data to evaluate a potential malformative or foetotoxic effect of buprenorphine when administered during pregnancy. At the end of pregnancy, high doses, even for a short treatment, may induce respiratory depression in neonates.

During the last three months of pregnancy, chronic use of buprenorphine by the mother, whatever the dose taken, may be responsible of a withdrawal syndrome in neonates. Consequently, the use of buprenorphine is not recommended during the 2nd and the 3rd trimester of pregnancy.

At the end of pregnancy, in case of occasional high doses, or in case of chronic use a neonatal survey must be considered, in order to prevent any respiratory depression risk or any withdrawal syndrome in children.

- Lactation

In animals buprenorphine passes into the mother's milk. Breast-feeding is therefore contraindicated for use in female addicted patients.

SUBUTEX may cause drowsiness, particularly when taken together with alcohol or central nervous system depressants. Therefore, caution is advised when driving motor vehicles or operating machinery. (See 4.5 Interaction with other medicaments and other forms of interaction.)

The onset of side effects depends on the patient's tolerance threshold, which is higher in drug addicts than in the general population.

The symptoms most frequently observed with buprenorphine administration are:

constipation

headaches

insomnia

asthenia

drowsiness

nausea and vomiting

fainting and dizziness

orthostatic hypotension

sweating

Other side effects that have been reported are:

respiratory depression (See 4.4 Special warnings and special precautions for use, and 4.5 Interaction with other medicaments and other forms of interaction)

hepatic necrosis and hepatitis (see 4.4 Special warnings and special precautions for use)

hallucinations.

Hypersensitivity reactions such as rash, urticaria, pruritus, bronchospasm, angioneurotic oedema, anaphylactic shock have been reported very rarely during the post-marketing period.

In case of IV misuse, local reactions have been reported, sometimes septic and potentially serious acute hepatitis have been reported (see 4.4 “Special warnings and special precautions for use”).

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

Buprenorphine appears to have a wide margin of safety because of its partial opioid agonist/antagonist properties.

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: NALOXONE MAY NOT BE EFFECTIVE IN REVERSING THE RESPIRATORY DEPRESSION PRODUCED BY BUPRENORPHINE. THEREFORE, THE PRIMARY MANAGEMENT OF OVERDOSE SHOULD BE THE RE-ESTABLISHMENT OF ADEQUATE VENTILATION WITH MECHANICAL ASSISTANCE OR RESPIRATION, IF REQUIRED.

Symptomatic treatment of respiratory depression, and 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.

The long duration of action of SUBUTEX should be taken into consideration when determining length of treatment needed to reverse the effects of an overdose.

Use of an opioid antagonist (i.e., naloxone at a dosage not exceeding 10 mg) 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. DOSES OF NALOXONE HYDROCHLORIDE HIGHER THAN 10MG MAY BE OF LIMITED VALUE AND ARE NOT RECOMMENDED IN THE MANAGEMENT OF BUPRENORPHINE OVERDOSE. Since most of overdose cases reported with buprenorphine were associated with concomitant abuse of other CNS depressants (e.g. benzodiazepines, certain anti-depressants, barbiturates, neuroleptics), measures appropriate for the overdose of any concomitant medications should be taken.

OPIOID ANALGESIC

(N: central nervous system)

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 (mu) receptors which, over a prolonged period, minimises the need of the addicted patient for drugs of addiction.

Buprenorphine has a wide margin of safety due to its partial agonist/antagonist activity, which limits its depressant effects, particularly on cardiac and respiratory functions.

Absorption

When taken orally, buprenorphine undergoes first-pass hepatic metabolism with Ndealkylation 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 metabolised by 14Ndealkylation and glucuroconjugation of the parent molecule and the dealkylated metabolite. The Ndealkybuprenorphine is a µ (mu) agonist with weak intrinsic activity.

Elimination of buprenorphine is bi or triexponential, 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.

Chronic toxicity studied in four species (rodents and non rodents) by four different administration routes has not showed any clinically pertinent element. In one oral study of one year in dogs, a hepatic toxicity has been observed at very high dose (75 mg/kg).

Teratology studies conducted in rats and rabbits allow to conclude that buprenorphine is not embryotoxic nor teratogenic. No undesirable effect on fertility has been reported in rats, however a high peri- and post- natal mortality has been observed in this species by IM and oral administration routes, due to difficult parturition and impairment of maternal lactation.

In a standard series of tests, none-proof of genotoxic potential has been evidenced.

Carcinogenicity studies in mice and rats show that there is no difference in the incidences of different tumour types between control and buprenorphine treated animals. However, in a study conducted with pharmacological doses in mice, an atrophy and a tubular mineralisation of testis have been evidenced in treated animals.

Monohydrated lactose, approx. 28 mg (0.4 mg), approx. 45 mg (2 mg), approx. 182 mg (8 mg)

Mannitol

Maize starch

Povidone excipient K30

Citric acid

Sodium citrate

Magnesium stearate

None known

1 year

Subutex 0.4 mg Sublingual Tablets :

Do not store above 25°C. Store in the original package.

Subutex 2 mg & 8 mg Sublingual Tablets :

Do not store above 30°C. Store in the original package.

7 or 28 tablets in blister packs PVC/PVdC/Aluminium.

Not applicable

Schering-Plough Ltd

Shire Park

Welwyn Garden City

Hertfordshire

AL7 1TW

UK

Subutex 0.4mg, sublingual tablets : PA 277/78/1

Subutex 2mg, sublingual tablets : PA 277/78/2

Subutex 8mg, sublingual tablets : PA 277/78/3

16^th August 2002

July 2007

Prescription Only Medicine

Subutex/IRL/07-07/6