Roche Products (Ireland) Ltd

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3                 PHARMACEUTICAL FORM

Lexotan 1.5 mg Tablets:

Tablet

            Off-white to slightly yellow, cylindrical, biplane tablets scored on one side and marked Roche 1.5 on reverse.

            Lexotan 3 mg Tablets:

Tablet

Pale red, slightly speckled, cylindrical, biplane tablets scored on one side and marked Roche 3 on reverse.

The tablets can be divided into equal halves.

4.2       Posology and method of administration

The patient should be checked regularly at the start of treatment in order to minimise the dosage and/or the frequency of administration to prevent overdose due to accumulation.

Elderly and/or debilitated patients

Elderly patients require lower doses because of individual variations in sensitivity and pharmacokinetics; doses should not exceed half those normally recommended (see section 5.2 Pharmacokinetics in special populations).

4.4       Special warnings and precautions for use

General precautions

Concomitant use of alcohol / CNS depressants:

The concomitant use of Lexotan with alcohol or/and CNS depressants should be avoided. Such concomitant use has the potential to increase the clinical effects of Lexotan possibly including severe sedation, clinically relevant respiratory and/or cardio-vascular depression (see section 4.5).

Medical history of alcohol or drug abuse:

Lexotan should be used with extreme caution in patients with a medical history of alcohol or drug abuse.

Patients should be checked regularly at the start of treatment in order to minimize the dosage and/or the frequency of administration and to prevent overdose due to accumulation.

Tolerance

Some loss of efficacy to the effects of Lexotan benzodiazepines may develop after repeated use for a few weeks.

Dependence

Use of benzodiazepines and benzodiazepine-like agents may lead to the development of physical and psychic dependence upon these products, (see section 4.8).  The risk of dependence increases with dose and duration of treatment; it is also greater in patients with a medical history of alcohol and/or drug abuse.

Amnesia

It should be borne in mind that bBenzodiazepines may induce anterograde amnesia.  Anterograde amnesia may occur using higher therapeutic dosages (documented at 6mg), the risk increasing at higher dosages.  Amnestic effects may be associated with inappropriate behaviour.  The condition occurs most often several hours after ingesting the product and therefore to reduce the risk patients should ensure that they will be able to have an uninterrupted sleep of 7 – 8 hours (see section 4.8).

Benzodiazepines should not be used alone to treat depression or anxiety associated with depression (suicide may be precipitated in such patients).    Patients with known or presumed dependence on alcohol, medicines or drugs should not take benzodiazepines, except in rare situations under medical supervision.

4.5       Interaction with other medicinal products and other forms of interaction

Pharmacokinetic Drug-Drug Interaction (DDI)

Not recommended:     Concomitant intake with alcohol.

The sedative effect may be enhanced when the product is used in combination with alcohol.  This affects the ability to drive or use machines.

Take into account:     Combinations with CNS depressants

Enhancement of the central depressive effect may occur in cases of concomitant use with antipsychotics (neuroleptics), hypnotics, anxiolytics/sedatives, antidepressant agents, narcotic analgesics, anti-epileptic drugs, anaesthetics and sedative antihistamines.

In the case of narcotic analgesics, enhancement of the euphoria may also occur leading to an increase in psychic dependence.

Pharmacodynamic Drug-Drug Interaction (DDI)

Enhanced effects on sedation, respiration and hemodynamics may occur when Lexotan is co-administered with any centrally acting depressants including alcohol.

Alcohol should be avoided in patients receiving Lexotan (see section 4.4).

(See section 4.9) Overdose for warnings of other central nervous system depressants, including alcohol.

In the case of narcotic analgesics, enhancement of the euphoria may also occur leading to an increase in psychic drug dependence.

4.8       Undesirable effects

Drowsiness (when the product is used as a hypnotic it should be stated explicitly, drowsiness during the day), numbed emotions, reduced alertness, confusion, fatigue, headache, dizziness, muscle weakness, ataxia or double vision.  These phenomena occur predominantly at the start of therapy and usually disappear with repeated administration.

Other side-effects like gastrointestinal disturbances, changes in libido or skin reactions have been reported occasionally.

Amnesia

Anterograde amnesia may occur using therapeutic dosages, the risk increasing at higher dosages.  Amnestic effects may be associated with inappropriate behaviour (see section 4.4 Special warnings and special precautions for use).

Depression

Pre-existing depression may be unmasked during benzodiazepine use.

Psychiatric and “paradoxical” reactions

Reactions like restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects are known to occur when using benzodiazepines or benzodiazepine-like agents, see section 4.4 Special warnings and special precautions for use.  They may be quite severe with this product.  Should this occur, the use of the drug should be discontinued.  They are more likely to occur in children and the elderly than in other patients.

Dependence

Use (even at therapeutic doses) may lead to the development of physical dependence:  discontinuation of the therapy may result in withdrawal or rebound phenomena (see section 4.4 Special warnings and special precautions for use).  Psychic dependence may occur.  Abuse of benzodiazepines has been reported.

Lexotan is well tolerated in therapeutic doses.  The following undesirable effects may occur:

Psychiatric Disorders:

Confusional state, emotional disorder.  These phenomena occur predominantly at the start of therapy and usually disappear with repeated administration. Libido disorders have been reported occasionally.

Depression: Pre-existing depression may be unmasked during benzodiazepine use.

Paradoxical reactions such as restlessness, agitation, irritability, aggression, delusion, anger, nightmares, hallucinations, psychosis, inappropriate behaviour and other adverse behavioural effects are known to occur with benzodiazepines or benzodiazepine-like agents (see section 4.4).  Should this occur, the use of the drug should be discontinued.  They are more likely to occur in children and elderly patients than in other patients.

Dependence: Chronic use (even therapeutic doses) may lead to the development of physical and psychic drug dependence: discontinuation of therapy may result in withdrawal or rebound phenomena (see section 4.4)

Abuse of benzodiazepines has been reported.

Nervous System Disorder: Drowsiness, headache, dizziness, decreased alertness, ataxia.  These phenomena occur predominantly at the start of therapy and usually disappear with repeated administration.  Anterograde amnesia may occur using therapeutic dosages, the risk increasing at higher dosages.  Amnestic effects may be associated with inappropriate behaviour.

Eye Disorders: Diplopia, this phenomenon occurs predominantly at the start of therapy and usually disappears with repeated administration.

Gastrointestinal Disorders: Gastrointestinal disorders have been reported occasionally.

Skin and Subcutaneous Tissue Disorders: Skin reactions have been reported occasionally.

Musculoskeletal and Connective Tissue Disorders: Muscle weakness, this phenomenon occurs predominantly at the start of therapy and usually disappears with repeated administration.

General Disorders and Administration Site Conditions: Fatigue, this phenomenon occurs predominantly at the start of therapy and usually disappears with repeated administration.

Injury, Poisoning and Procedural Complications: An increased risk for falls and fractures has been reported in elderly benzodiazepine users.

Respiratory Disorders: Respiratory depression.

Cardiac Disorders: Cardiac failure including cardiac arrest.

4.9       Overdose

Symptoms

Benzodiazepines commonly cause drowsiness, ataxia, dysarthria and nystagmus. Coma, hypotension and respiratory depression occasionally occur but are seldom serious if these drugs are taken alone. Overdose of Lexotan is seldom life-threatening if the drug is taken alone, but may lead to areflexia, apnea, hypotension, cardiorespiratory depression and coma.  Coma, if it occurs, usually lasts only a few hours but it may be more protracted and cyclical, particularly in elderly patients. Benzodiazepine respiratory depressant effects are more serious in patients with respiratory disease.

If CNS depression is severe consider the use of flumazenil (Anexate^®), a benzodiazepine antagonist. This should only be administered under closely monitored conditions. It has a short half-life (about an hour), therefore patients administered flumazenil will require monitoring after its effects have worn off. Flumazenil is contraindicated to be used with extreme caution in the presence of drugs that reduce seizure threshold (e.g. tricyclic antidepressants). Refer to the prescribing information for flumazenil (Anexate^®), for further information on the correct use of this drug.

10.       DATE OF  REVISION OF THE TEXT

April 2007November 2009

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QUALITATIVE AND QUANTITATIVE COMPOSITION

Lexotan 1.5mg Tablets:

Each tablet contains 1.5mg bromazepam

            Excipients: Also contains 96.1mg lactose monohydrate

Lexotan 3mg Tablets:

Each tablet contains 3mg bromazepam

Excipients: Also contains 94.3mg lactose monohydrate

For a full list of excipients, see section 6.1.

Overdose

As with other benzodiazepines, overdose should not present a threat to life unless combined with other CNS depressants (including alcohol).

In the management of overdose with any medicinal product, it should be borne in mind that multiple agents have been taken.

Following overdose with any medicinal product, vomiting should be induced (within one hour) if the patient is conscious or gastric lavage undertaken with the airway protected if the patient is unconscious.  If there is no advantage in emptying the stomach, activated charcoal should be given to reduce absorption.  Special attention should be paid to respiratory and cardiovascular functions in intensive care.

Overdose of benzodiazepines is usually manifested by degrees of central nervous system depression ranging from drowsiness to coma.  In mild cases, symptoms include drowsiness, mental confusion and lethargy.  In most cases it is sufficient to monitor the vital functions and await recovery.  Higher doses, especially in combination with other centrally acting drugs, can result in ataxia, hypotonia, hypotension, respiratory depression, rarely coma and very rarely death.

Flumazenil may be useful as an antidote.  Patients requiring such intervention should be monitored closely in hospital (see separate prescribing information). Flumazenil is not recommended in patients with epilepsy who have been treated with benzodiazepines.  Antagonism in such patients may produce seizures.

Symptoms

Benzodiazepines commonly cause drowsiness, ataxia, dysarthria and nystagmus. Coma, hypotension and respiratory depression occasionally occur but are seldom serious if these drugs are taken alone. Coma, if it occurs, usually lasts only a few hours but it may be more protracted and cyclical, particularly in elderly patients. Benzodiazepine respiratory depressant effects are more serious in patients with respiratory disease.

Benzodiazepines increase the effects of other central nervous system depressants, including alcohol.

Treatment

Monitor the patient’s vital signs and institute supportive measures as indicated by the patient’s clinical state. In particular, patients may require symptomatic treatment for cardiorespiratory effects or central nervous system effects.

Further absorption should be prevented using an appropriate method e.g. treatment within 1-2 hours with activated charcoal. If activated charcoal is used airway protection is imperative for drowsy patients. In case of mixed ingestion gastric lavage may be considered, however not as a routine measure

If CNS depression is severe consider the use of flumazenil (Anexate^®), a benzodiazepine antagonist. This should only be administered under closely monitored conditions. It has a short half-life (about an hour), therefore patients administered flumazenil will require monitoring after its effects have worn off. Flumazenil is contraindicated in the presence of drugs that reduce seizure threshold (e.g. tricyclic antidepressants). Refer to the prescribing information for flumazenil (Anexate^®), for further information on the correct use of this drug.

Preclinical safety data

There is no further information from the preclinical testing which could be of relevance to the prescriber which has not been included in other sections of the Summary of Product Characteristics.

Carcinogenicity

Carcinogenicity studies conducted in rats did not reveal any evidence of a carcinogenic potential for bromazepam.

Mutagenicity

Bromazepam was not genotoxic in in-vitro and in-vivo tests.

Impairment of Fertility

Daily oral administration of bromazepam did not have any affect on the fertility and general reproductive performance of rats.

Teratogenicity

Increases in foetal mortality, an increase in the stillbirth rate and a reduction in pup survival have been observed when bromazepam was given to pregnant rats. In studies on embryotoxicity/teratogenicity no teratogenic effect was detected up to a dosage of 125 mg/kg/day.

Following per os administration with doses of up to 50 mg/kg/day to pregnant rabbits a reduction in maternal weight gain, a reduction in foetal weight and an increase in the incidence of resorptions have been observed.

Other

Chronic toxicity

No deviations from normal were observed in long-term toxicology studies except for an increase in liver weight. Histopathological examination revealed centrolobular hepatocellular hypertrophy which was considered to be indicative of enzyme induction by bromazepam. Adverse effects observed after high doses were slight to moderate sedation, ataxia, isolated brief convulsive seizures, occasional elevation in serum alkaline phosphatase and a borderline increase in SGPT (ALT).

List of excipients

Lexotan 1.5mg Tablets:

Microcrystalline cellulose

Lactose monohydrate

Magnesium stearate

Talc

Lexotan 3mg Tablets:

Microcrystalline cellulose

Lactose monohydrate

Magnesium stearate

Talc

Erythrosine aluminium lake (E127).

DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

Date of first authorisation:          31 October 1980/

Date of last renewal:                 31 October 2005

DATE OF (PARTIAL) REVISION OF THE TEXT

March 2006April 2007