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10 X 0.25 mg
20 X 0.25 mg
Unless otherwise prescribed, the usual dose is ½ – 1 tablet a day (equivalent to 0.125 – 0.25 mg brotizolam).
Treatment should be started with ½ a tablet a day (equivalent to 0.125 mg brotizolam). Depending on individual response, ½ a tablet a day (equivalent to 0.125 mg brotizolam) may be sufficient. The maximum dose of 1 tablet a day (equivalent to 0.25 mg brotizolam) should not be exceeded because of
the increased risk of adverse CNS effects.
In isolated cases (e.g. pre-operative sleep disturbances) the dose may be increased to 2 tablets.
Special populations: A reduction in dosage to ½ a tablet a day should be considered in the following populations:
– patients with impaired liver function.
– elderly and debilitated patients.
– patients with chronic respiratory insufficiency with hypercapnia due to the risk of respiratory depression, especially at night.
The tablets can be divided into equal halves for this purpose.
No dosage adjustment is normally necessary in patients with impaired renal function.
Paediatric population: Bondormin is contraindicated in children aged up to 18 years.
Method of administration: Bondormin should be taken with a little liquid just before going to bed. To avoid affecting the onset and duration of action, Bondormin should not be taken on a full stomach.
Alternatively, the tablet may be allowed to dissolve under the tongue.
Sufficient time for sleep must be guaranteed to reduce the risk of affecting reactions (and hence the ability to drive) the following morning. Patients should therefore ensure that they will be able to sleep for 7 – 8 hours after taking a tablet.
Duration of treatment: Treatment should be as short as possible. Generally, the duration of treatment varies from a few days to a maximum of two weeks. Treatment should be discontinued by gradual tapering, which should be tailored to the individual. It should be borne in mind that discontinuation may initially
cause rebound insomnia and that, in rare cases, restlessness, anxiety and tension may also occur.
In certain cases, extension beyond the maximum two-week treatment period may be necessary; if so, it should not take place without re-evaluation of the patient’s status.
Treatment of Insomnia.
– Patients with known hypersensitivity to brotizolam or other benzodiazepines or to any of the excipients.
– Patients with myasthenia gravis.
– Patients with severe respiratory insufficiency.
– Patients with sleep apnoea syndrome.
– Patients with severe hepatic insufficiency.
– Patients with a history of dependence on alcohol, medicines or other drugs.
– Patients acutely intoxicated with alcohol, hypnotics, opiate-type analgesics or psychotropics (antipsychotics, antidepressants, lithium).
– Pregnant women.
– Breast-feeding women.
– Children and adolescents up to 18 years of age, as safety and efficacy have not been investigated in this age group.
– Patients with any rare hereditary intolerance to any of the ingredients of the product.
WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS
Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression,coma, and death.
Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
Limit dosages and durations to the minimum required.
Follow patients for signs and symptoms of respiratory depression and sedation.
Psychiatric conditions: Benzodiazepines should not be used alone for the treatment of psychotic illness.
Benzodiazepines alone are not suitable for the treatment of severe depression and should not be used alone for the treatment of anxiety associated with severe depression (suicide may be precipitated in such patients). Appropriate precautions must be taken when using benzodiazepines in severely depressed and suicidal patients. Pre-existing depression may be unmasked.
Psychiatric and paradoxical reactions can occur during benzodiazepine treatment, particularly in the elderly. These reactions include restlessness, agitation, irritability, rages, nightmares, increased insomnia, hallucinations, psychoses, inappropriate behaviour, delirium and other adverse behavioural
effects. Should this occur, use of the medicinal product should be discontinued.
Dependence: Chronic use of benzodiazepines may lead to the development of physical and psychic dependence.
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, muscle pain, extreme anxiety, tension, insomnia, restlessness, confusion and irritability. In severe cases, the following symptoms may occur: derealisation, depersonalisation, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations or epileptic seizures.
Withdrawal symptoms may occur several days after discontinuation of treatment.
Use with alcohol: Concurrent use of brotizolam and alcohol can result in sedation, drowsiness and impaired concentration.
Tolerance: Some loss of efficacy to the hypnotic effect may develop after repeated use for a few weeks.
Rebound anxiety and tension: Withdrawal of brotizolam treatment can lead to the development of a transient syndrome whereby the symptoms that led to treatment with a benzodiazepine recur in an enhanced form. The syndrome may
be accompanied by mood changes, sleep disturbances and restlessness. Since the risk of withdrawal phenomena / rebound phenomena is greater after sudden dose reduction or abrupt discontinuation of treatment, it is recommended that the dosage is decreased gradually.
Duration of treatment: The duration of treatment should be as short as possible. Extension beyond the recommended maximum treatment period 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.
Abrupt withdrawal of benzodiazepines can lead to the occurrence of paraesthesias, perceptual disturbances and depersonalisation, which may last for a week or more. Convulsions have been reported in a small number of cases.
Amnesia: In common with other benzodiazepines, brotizolam may induce anterograde amnesia. The condition occurs most often several hours after ingesting the product.
Specific patient groups: Benzodiazepines have a muscle relaxant effect, which increases the risk of falls. Brotizolam should therefore be used with caution in the elderly.
Benzodiazepines are not indicated to treat patients with severe hepatic insufficiency as they may precipitate encephalopathy.
Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse.
Lactose: Bondormin tablets contain 82.75 mg lactose monohydrate per tablet. Patients with the rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take Bondormin.
Most of the undesirable effects observed to date are related to the product’s pharmacological activity. They occur predominantly at the start of therapy and usually decrease with continued administration.
The risk of dependence (in the form of e.g. a rebound effect, altered mood, anxiety and restlessness) increases with the duration of Bondormin treatment, which should not exceed two weeks.
Common undesirable effects: Light-headedness, headache, Gastrointestinal disturbances.
Brotizolam has a muscle relaxant effect and should therefore be used with caution in the elderly because of the risk of falls.
Abuse of benzodiazepine has been reported.
Withdrawal symptoms: Withdrawal and rebound phenomena may indicate development of dependence.
Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms such as headaches, muscle pain, extreme anxiety, tension, restlessness, confusion and irritability.
In severe cases, derealisation, depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations or epileptic seizures may occur.
Psychiatric and paradoxical reactions: Reactions such as restlessness, agitation, irritability, aggressiveness, delusion, rages, vivid nightmares,
hallucinations, psychoses and behavioural changes are known to occur when using benzodiazepines and benzodiazepine-like agents. They are more likely to occur in children and the elderly.
Should this occur, use of the medicinal product should be discontinued.
See prescribing information for full details.
Alcohol should be avoided during treatment with brotizolam as it modifies and increases the effects of brotizolam in an unpredictable manner.
Concurrent use of brotizolam and alcohol can result in sedation, drowsiness and impaired concentration.
Co-administration of brotizolam with other CNS depressants (antipsychotics (neuroleptics), antidepressants, hypnotics, anxiolytics/sedatives, narcotic analgesics, anaesthetics, anti-epileptics and sedative antihistamines) can lead to mutual enhancement of the CNS depressant effect and therefore requires very careful consideration.
Co-administration of brotizolam with narcotic analgesics can lead to enhancement of the euphoria and accelerate the development of dependence.
The nature and extent of interactions between brotizolam and other medicinal products (antidiabetics, antihypertensives, cardiac glycosides and hormones) varies unpredictably between individuals and caution is therefore required when giving Bondormin to patients taking these products.
Co-administration of brotizolam with muscle relaxants can increase the muscle relaxant effect.
Brotizolam is metabolised chiefly by the cytochrome P450 isoenzyme CYP 3A4 in the liver. Agents that compete with brotizolam for CYP 3A4 (competitive inhibition) and agents that inhibit CYP 3A4 can therefore increase the effect of brotizolam.
Known substrates for CYP 3A4 include astemizole, azole antifungals (such as itraconazole and ketoconazole), immunosuppressants (such as ciclosporin A, sirolimus and tacrolimus), calcium antagonists, macrolide antibiotics (such as clarithromycin and erythromycin), antimalarials (such as halofantrine and mefloquine), midazolam, pimozide, protease inhibitors (such as indinavir, nelfinavir and ritonavir), sildenafil, statins (such as atorvastatin, lovastatin and simvastatin), steroids (such as ethinyl-estradiol), tamoxifen and terfenadine.
Inhibitors of CYP 3A4, which can increase the toxicity of brotizolam, include azole antifungals, cimetidine, grapefruit juice, macrolide antibiotics and protease inhibitors.
Inducers of CYP 3A4, which increase enzyme activity and can reduce the effect of brotizolam, include carbamazepine, efavirenz, St. John’s wort, nevirapine, phenobarbital, phenytoin, primidone, rifabutin and rifampicin.
Pregnancy and Lactation
Pregnancy: Brotizolam should not be used during pregnancy or lactation.
Infants born to mothers who took benzodiazepines chronically during pregnancy may have developed physical dependence and may be at some risk of developing withdrawal symptoms in the postnatal period.
If brotizolam is prescribed to a woman of child-bearing potential, she should be warned to contact her physician immediately if she intends to become or suspects that she is pregnant.
Lactation: Brotizolam and its metabolites are excreted in breast milk. There is therefore a risk of accumulation in the breast-feeding child. Accordingly, breast-feeding should be discontinued or interrupted on repeated administration of brotizolam to the mother.
See prescribing information for full details.
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 may have been taken.
Symptoms: Overdose of benzodiazepines is usually manifested by various degrees of CNS depression. In mild cases, symptoms include drowsiness, mental confusion and lethargy. In more serious cases, symptoms may include ataxia, hypotonia, hypotension, respiratory depression, rarely coma and very rarely death.
Management: Symptomatic measures are the mainstay of treatment.
Following overdose with oral benzodiazepines, 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 an intensive care setting where appropriate.
If necessary, the specific benzodiazepine antagonist flumazenil may be used as an antidote. The Summary of Product Characteristics for flumazenil should be consulted prior to use.
Forced diuresis and haemodialysis are likely to be of limited value in pure brotizolam poisoning in view of the large volume of distribution of the substance and the fact that it is extensively bound to plasma proteins.