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Roche Products (Ireland) Ltd

3004 Lake Drive, Citywest, Naas Road, Dublin 24,
Telephone: +353 1 469 0700
Fax: +353 1 469 0791
Medical Information e-mail: ireland.druginfo@roche.com


Summary of Product Characteristics last updated on medicines.ie: 24/07/2014
SPC Lexotan Tablets 1.5mg and 3mg



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1. NAME OF THE MEDICINAL PRODUCT

Lexotan 1.5 mg Tablets

Lexotan 3 mg Tablets


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2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Lexotan 1.5 mg Tablets:

Each tablet contains 1.5 mg bromazepam

Excipients: Also contains 96.1 mg lactose monohydrate.

Lexotan 3 mg Tablets:

Each tablet contains 3 mg bromazepam.

Excipients: Also contains 94.4 mg lactose monohydrate.

Excipient(s) with known effect:

For the full list of excipients, see section 6.1.


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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 doses.


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4. CLINICAL PARTICULARS

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4.1 Therapeutic indications

Anxiety

Benzodiazepines are only indicated when the disorder is severe, disabling or subjecting the individual to extreme distress.


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4.2 Posology and method of administration

Anxiety

Treatment should be as short as possible. The overall duration of treatment generally should not be more than 8 – 12 weeks, including tapering off process.

These amounts are general recommendations, and dosage should be individually determined. Treatment of outpatients should begin with low doses, gradually increasing to the optimum level. The patient should be reassessed regularly and the need for continued treatment should be evaluated, especially in case the patient is symptom free.

In certain cases, extension beyond the maximum treatment period may be necessary; if so, it should not take place without re-evaluation of the patient's status with special expertise.

Adults

The lowest dose which can control symptoms should be used.

The optimum dosage and frequency of administration of Lexotan should be based on the individual patient, the severity of symptoms and previous psychotropic drug history.

The usual dosage in general practice is from 3 mg to 18 mg daily in divided doses.

In exceptional circumstances, in hospitalised patients, up to the maximum daily dosage of 60 mg in divided doses, may be given.

Treatment should always be tapered off gradually. Patients who have taken benzodiazepines for a prolonged time may require a longer period during which doses are reduced. Specialist help may be appropriate.

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).

Patients with impaired hepatic and/or renal function require lower doses because of individual variations in sensitivity and pharmacokinetics.

With the elderly and patients with impaired renal and/or hepatic function, it is advisable to review treatment regularly and to discontinue use as soon as possible.

Children

Lexotan should not be used in children less than 12 years of age.


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4.3 Contraindications

Bromazepam must not be administered to patients with known hypersensitivity to the active substance or to any of the excipients listed in section 6.1, benzodiazepines, severe respiratory insufficiency, severe hepatic insufficiency (benzodiazepines are not indicated to treat patients with severe hepatic insufficiency as they may cause encephalopathy), myasthenia gravis or sleep apnea syndrome.


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4.4 Special warnings and precautions for use

Amnesia

Benzodiazepines may induce anterograde amnesia. 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 several hours. Amnestic effects may be associated with inappropriate behaviour (see also section 4.8).

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. Should this occur, use of the medicinal product should be discontinued.

They are more likely to occur in children and the elderly.

Duration of treatment

The duration of treatment should be as short as possible (see section 4.2)and should not exceed eight to twelve weeks, including a tapering off process. Extension beyond these periods should not take place without re-evaluation of the situation.

It may be useful to inform the patient when treatment is started that it will be of limited duration and to explain precisely how the dosage will be progressively decreased. Moreover it is important that the patient should be aware of the possibility of rebound phenomena, thereby minimising anxiety over such symptoms should they occur while the medicinal product is being discontinued.

When benzodiazepines with a long duration of action are being used it is important to warn against changing to a benzodiazepine with a short duration of action, as withdrawal symptoms may develop.

Concomitant use of alcohol / CNS depressants:

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

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

Tolerance

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

Specific patient groups

Benzodiazepines should not be given to children without careful assessment of the need to do so; the duration of treatment must be kept to a minimum.

Elderly should be given a reduced dose (see section 4.2).

A lower dose is also recommended for patients with chronic respiratory insufficiency due to the risk of respiratory depression.

Benzodiazepines are not indicated to treat patients with severe hepatic insufficiency as they may precipitate encephalopathy.

Benzodiazepines are not recommended for the primary treatment of psychotic illness.

Benzodiazepines should not be used alone to treat depression or anxiety associated with depression (suicide may be precipitated in such patients). Therefore, bromazepam should be used with caution and the prescription size should be limited in patients with signs and symptoms of a depressive disorder or suicidal tendencies.

Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse (see section 4.5).

Dependence

Use of benzodiazepines may lead to the development of physical and psychic dependence upon these products,. The risk of dependence increases with dose and duration of treatment; it is also greater in patients with a history of alcohol or drug abuse.

Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms. These may consist of headaches, diarrhoea, muscle pain, extreme anxiety, tension, restlessness, confusion and irritability. In severe cases the following symptoms may occur: derealisation, depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations or epileptic seizures.

Rebound insomnia and anxiety: a transient syndrome whereby the symptoms that led to treatment with a benzodiazepine recur in an enhanced form, may occur on withdrawal of treatment. It may be accompanied by other reactions including mood changes, anxiety or sleep disturbances and restlessness. Since the risk of withdrawal phenomena/rebound phenomena is greater after abrupt discontinuation of treatment, it is recommended that the dosage is decreased gradually.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsoption should not take this medicine.


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4.5 Interaction with other medicinal products and other forms of interaction

Pharmacodynamic Interaction

Benzodiazepines produce an additive effect when co-administered with alcohol or other CNS depressants. Concomitant intake with alcohol is not recommended.

Bromazepam should be used with caution when combined with other CNS depressants. Enhancement of the central depressive effect may occur in case of concomitant use with antipsychotics (neuroleptics), anxiolytics/sedatives, some antidepressant agents, opioids, anticonvulsants, sedative H1-antihistamines.

Special care should be made with drugs depressing respiratory function such as opioids (analgesics, antitussives, substitutive treatments), notably in elderly people.

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

Pharmacokinetic Interaction

Pharmacokinetic interactions can occur when bromazepam is administered along with drugs that inhibit the hepatic enzyme CYP3A4 by increasing the plasma levels of bromazepam. To a lesser degree this also applies to benzodiazepines that are metabolized only by conjugation.

The co-administration of bromazepam with strong CYP3A4 inhibitors (for example azole antifungals, protease inhibitors or some macrolides) should be made with caution and a substantial dose reduction considered. In the case of narcotic analgesics enhancement of euphoria may also occur, leading to an increase in psychic drug dependence.

Co-administration of cimetidine may prolong the elimination half-life of bromazepam.


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4.6 Fertility, pregnancy and lactation

Pregnancy

Although no specific clinical data are available for bromazepam, a large amount of data based on cohort studies indicate that first trimester exposure to benzodiazepine is not associated with an increase in the risk of major malformation. However, some early case-control epidemiological studies have found an increased risk of oral clefts. The data indicated that the risk of having an infant with an oral cleft after maternal benzodiazepine exposure is less than 2/1000 compared with an expected rate for such defects of approximately 1/1000 in the general population.

Benzodiazepine treatment at high dose, during the second and/or the third trimester of pregnancy, has revealed a decrease of foetal active movements and a variability of foetal cardiac rhythm.

When treatment has to be administered for medical reasons during the last part of pregnancy, even at low doses, floppy infant syndrome such as axial hypotonia, sucking troubles leading to a poor weight gain may be observed. These signs are reversible but they may last from 1 up to 3 weeks, according to the half-life of the product. At high doses, respiratory depression or apnea and hypothermia in newborn may appear. Moreover, neonatal withdrawal symptoms with hyperexitability, agitation and tremor may be observed a few days after birth, even if no floppy infant syndrome is observed.

Taking into account these data, the use of bromazepam during pregnancy may be considered, if therapeutic indications and posology are strictly respected.

If the product is prescribed to a woman of childbearing potential, she should be warned to contact her physician regarding discontinuance of the product if she intends to become or suspects that she is pregnant.

If bromazepam treatment is necessary during the last part of pregnancy, high doses should be avoided and withdrawal symptoms and/or floppy infant syndrome should be monitored in newborn.

Animal studies with benzodiazepines have shown minor effects on the foetus while a few studies have reported a late behavioural disturbance in offspring exposed in utero.

Breast-feeding

Since bromazepam is transferred to breast milk, breast feeding is not recommended during treatment.


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4.7 Effects on ability to drive and use machines

Sedation, amnesia, impaired concentration and impaired muscular function may adversely affect the ability to drive or to use machines. If insufficient sleep duration occurs, the likelihood of impaired alertness may be increased (see also section 4.5).This effect is increased if the patient has taken alcohol.


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4.8 Undesirable effects

Lexotan is well tolerated in therapeutic doses. :

The following undesirable effects have been reported during treatment with bromazepam with the following frequencies:

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)

MedDRA System Organ Class

Undesirable effects

Immune System Disorders

 

frequency not known

Hypersensitivity, anaphylactic shock, angioedema

Psychiatric Disorders

 

frequency not known

Confusional state*, emotional disorder*, libido disorders, drug dependence**, drug abuse**, withdrawal syndrome**

Depression

Paradoxical reactions such as restlessness, agitation, irritability, aggression, delusion, anger, nightmares, hallucinations, psychosis, inappropriate behaviour**

Anterograde amnesia**, memory impairment

Nervous System Disorders

 

frequency not known

Somnolence*, headache*, dizziness*, decreased alertness*, ataxia*

Eye Disorders

 

frequency not known

Diplopia*

Cardiac Disorders

 

frequency not known

Cardiac failure including cardiac arrest

Respiratory, Thoracic and Mediastinal Disorders

 

frequency not known

Respiratory depression

Gastrointestinal Disorders

 

frequency not known

Nausea*, vomiting*, constipation

Skin and Subcutaneous Tissue Disorders

 

frequency not known

Rash, pruritus, urticaria

Musculoskeletal and Connective Tissue Disorders

 

frequency not known

Muscle weakness*

Renal and Urinary disorders

 

frequency not known

Urinary retention

General Disorders and Administration Site Conditions

 

frequency not known

Fatigue*

Injury, Poisoning and Procedural Complications

 

frequency not known

Falls, fractures***

* These phenomena occur predominantly at the start of therapy and usually disappear with repeated administration

** see 4.4 Warnings and Precautions

*** The risk of falls and fractures is increased in those taking concomitant sedatives (including alcoholic beverages) and in the elderly.

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 to HPRA Pharmacovigilance, Earlsfort Terrace, IRL-Dublin 2. Tel: +353 1 6764971, Fax: +353 1 6762517, Website: www.hpra.ie, e-mail: medsafety@hpra.ie.


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4.9 Overdose

Symptoms

Benzodiazepines commonly cause drowsiness, ataxia, dysarthria and nystagmus. Overdose of bromazepam is seldom life-threatening if the drug is taken alone, but may lead to slurred speech areflexia, apnea, hypotension, cardiorespiratory depression and coma. Coma, if it occurs, usually lasts 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 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.


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5. PHARMACOLOGICAL PROPERTIES

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5.1 Pharmacodynamic properties

Pharmacotheapeutic group: Anxiolytic, ATC code: N05BA08.

Bromazepam is a pyridylbenzodiazepine compound with anxiolytic properties.


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5.2 Pharmacokinetic properties

Absorption

Lexotan is rapidly absorbed from the gastro-intestinal tract. Peak plasma concentrations are usually reached within 2 hours of oral administration of bromazepam. The absolute (versus i.v. solution) and relative (versus oral solution) bioavailability of the tablet is 60% and 100% respectively.

Distribution

On average, 70% of bromazepam is bound to plasma proteins. The volume of distribution is 50 litres. Steady state plasma concentrations are reached in around 5 – 9 days.

Metabolism

Bromazepam is metabolised in the liver. Quantitatively, two metabolites predominate: 3-hydroxy-bromazepam and 2-(2-amino-5-bromo-3-hydroxybenzoyl) pyridine. Metabolites of Lexotan do not contribute significantly to the effects of the drug.

Elimination

The urinary recovery of intact bromazepam and the glucuronide conjugates of 3-hydroxy-bromazepam and 2-(2-amino-5-bromo-3-hydroxybenzoyl) pyridine is 2%, 27% and 40% of the administered dose. Bromazepam has an elimination half-life of about 20 hours (between approximately 16 and 30 hours). The clearance is 40ml/min.

Pharmacokinetics in special populations

The elimination half-life may be prolonged in elderly patients (see section 4.2).


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5.3 Preclinical safety data

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).


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6. PHARMACEUTICAL PARTICULARS

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6.1 List of excipient(s)

Lexotan 1.5 mg Tablets:

Microcrystalline cellulose

Lactose monohydrate

Magnesium stearate

Talc

Lexotan 3 mg Tablets:

Microcrystalline cellulose

Lactose monohydrate

Magnesium stearate

Talc

Iron oxide red (E172)


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6.2 Incompatibilities

Not applicable.


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6.3 Shelf life

 

PVDC blister packs:

5 year shelf life.

HDPE bottles:

5 year shelf life.

PVC blister packs:

5 year shelf life.


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6.4 Special precautions for storage

Do not store above 25°C. Store in the original package in order to protect from light and moisture.


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6.5 Nature and contents of container

PVDC blister packs of 4, 10, 20, 60 or 100 tablets.

HDPE bottles of 100 tablets.

PVC blister packs of 30 tablets.

Not all pack sizes may be marketed


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6.6 Special precautions for disposal and other handling

No special requirements.


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7. MARKETING AUTHORISATION HOLDER

Roche Products Limited

6 Falcon Way, Shire Park

Welwyn Garden City

AL7 1TW

United Kingdom


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8. MARKETING AUTHORISATION NUMBER(S)

 

Lexotan 1.5 mg Tablets:

PA 50/49/1

Lexotan 3 mg Tablets:

PA 50/49/2


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9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

Date of first authorisation:

31 October 1980

Date of last renewal:

31 October 2010


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10. DATE OF REVISION OF THE TEXT

22 July 2014

Further information is available from Roche Products (Ireland) Limited, 3004 Lake Drive, City West, Naas Road, Dublin 24.

Lexotan is a registered trade mark Item code



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Active Ingredients

 
   Bromazepam