Source: Health Products Regulatory Authority (IE) Revision Year: 2018 Publisher: Roche Products (Ireland) Limited, 3004 Lake Drive, City West, Naas Road, Dublin 24, Ireland
Bromazepam is contraindicated in patients with:
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).
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.
The duration of treatment should be as short as possible (see section 4.2 Posology) and should not exceed eight to twelve weeks, including a tapering off process. Extension beyond these periods should not take place without reevaluation 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.
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 cardiovascular depression, that could result in coma or death (see section 4.5 and section 4.9).
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.
Some loss of efficacy to the effects of benzodiazepines may develop after repeated use for a few weeks.
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 Posology).
In patients with myasthenia gravis who are prescribed Lexotan, care should be taken on account of pre-existing muscle weakness.
A lower dose is also recommended for patients with chronic respiratory insufficiency due to the risk of respiratory depression.
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). Hepatic impairment Benzodiazepines may have a contributory role in precipitating episodes of hepatic encephalopathy in patients with severe hepatic impairment (see section 4.3 Contra-indications). Special caution should be exercised when administering Lexotan to patients with mild to moderate hepatic impairment.
Use of benzodiazepines may lead to the development of physical and psychological 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. Therefore, bromazepam should be used with extreme caution in patients with a history of alcohol or drug abuse. Abuse has been reported more commonly in poly-drug abusers.
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. 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 convulsions (see section 4.8 Undesirable effects).
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.
Benzodiazepines may produce enhanced side effects such as sedation and cardio-respiratory depression 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.
Warning for overdose of other central nervous system depressants, including alcohol (see section 4.9).
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 drug dependence.
Co-administration of cimetidine, a known inhibitor of many isozymes of the cytochrome P450 enzyme system (specifically CYP3A3/4, CYP2C9, CYP1A2, CYP2C18, CYP2D6) may prolong the elimination half-life of bromazepam through a substantially reduced clearance of approximately 50%.
Co-administration of propranolol prolongs the elimination half-life of bromazepam by approximately 20% and results in a non-significant increase in bromazepam clearance.
Combined administration with fluvoxamine, an inhibitor of CYP1A2, results in significantly increased bromazepam exposure (AUC, 2.4-fold) and elimination half-life (1.9-fold).
Bromazepam did not affect antipyrine metabolism, which is a surrogate marker for CYP1A2, CYP2B6, CYP2C and CYP3A activity. Furthermore bromazepam did not induce major CYP450 isozymes in vitro at the level of mRNA; also it did not activate nuclear hormone receptors. Therefore bromazepam is unlikely to cause pharmacokinetic drug-drug interactions based on CYP450 induction.
Interaction studies have only been performed in adults.
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 newborns 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 newborns.
Animal studies with benzodiazepines have shown minor effects on the foetus while a few studies have reported a late behavioral disturbance in offspring exposed in utero.
Since bromazepam is transferred to breast milk, breast feeding is not recommended during treatment.
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.
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).
Frequency not known: Hypersensitivity**, anaphylactic shock, angioedema
Frequency not known: Confusional state*, disorientation, emotional and mood disturbances*, changes in libido, drug dependence**, drug abuse**, withdrawal syndrome** Depression Paradoxical reactions such as restlessness**, agitation**, irritability**, aggressiveness**, delusion**, anger, nightmares**, hallucinations**, psychoses**, inappropriate behaviour**, nervousness, anxiety, abnormal dreams, hyperactivity Anterograde amnesia**, memory impairment
Frequency not known: Somnolence*, headache*, dizziness*, decreased alertness*, ataxia*
Frequency not known: Diplopia*
Frequency not known: Cardiac failure including cardiac arrest
Frequency not known: Respiratory depression
Frequency not known: Nausea*, vomiting*, constipation
Frequency not known: Rash, pruritus, urticaria
Frequency not known: Muscle weakness*
Frequency not known: Urinary retention
Frequency not known: Fatigue*
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 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.
Not applicable.
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