Read this leaflet carefully before you start taking this medicine. (DOWNLOAD)
CALMNOX® 3 TABLETS
Bromazepam USP 3 mg
Description
Calmnox is a lipophilic, long-acting benzodiazepine and with sedative, hypnotic, anxiolytic and skeletal muscle relaxant properties. It is used variously to aid sleep, as a muscle relaxant, or in the treatment of some symptoms associated with anxiety. Its structural formula is:
C14H10BrN3O 316.2
Metabolism/pharmacokinetics
Absorption
It is rapidly absorbed from the gastro-intestinal tract and reaches peak plasma concentration within 2 hours of oral administration. The absolute bioavailability of the bromazepam tablet is 60%.
During multiple dosing of bromazepam the extent of absorption remains constant; predictable steady-state concentrations are observed and confirm linear kinetics for the drug. Steady state plasma concentrations are reached in around 5 – 9 days. When given three times daily, 3-4 fold higher concentrations are observed at steady state than after a single dose.
Distribution
After absorption, bromazepam is rapidly distributed in the body. On the average, 70% of bromazepam is bound by hydrophobic interaction to plasma proteins; binding partners are albumin and α1-acid glycoprotein. The volume of distribution is around 50 liters.
Bromazepam is extensively metabolised in the liver. No metabolites with a half-life longer than that of the parent drug are formed. Quantitatively, two metabolites dominate, 3-hydroxy-bromazepam (less active than bromazepam) and 2-(2-amino-5-bromo-3-hydroxybenzoyl) pyridine (inactive). Metabolites of bromazepam do not contribute significantly to the effects of the drug.
Bromazepam is metabolized, at least in part, through cytochrome p450 (CYP 450). However, the specific CYP isozymes involved have not been identified. Nevertheless, the observations that a strong CYP3a4 inhibitor (itraconazole) and a moderate CYP2c9 inhibitor (fluconazole) had no effect on the pharmacokinetics of bromazepam suggest that these isozymes are not involved to a major extent. The pronounced interaction with fluvoxamine points to co-involvement of CYP1a2.
Elimination
Calmnox has an elimination half-life of about 20 hours and an elimination clearance of around 40ml/min.
Metabolism is the key elimination pathway for the drug. The urinary recovery of intact bromazepam is only 2% and of the glucuronide conjugates of 3-hydroxy-bromazepam and 2-(2-amino-5-bromo-3-hydroxybenzoyl) pyridine are 27% and 40% of the administered dose respectively.
Pharmacokinetics in special populations
Older people may have significantly higher peak concentrations, a smaller volume of distribution, increased serum free fraction, lower clearance and hence also a prolonged elimination half-life. This indicates that steady-state concentrations of bromazepam at any given dosing rate will be on average nearly twice as high in an elderly subject as compared to a younger individual
Indication
Calmnox is used for the treatment of anxiety. Also used as a premedicant prior to minor surgery.
Anxiety: Treatment should be as short as possible. The overall duration of treatment generally should not be more than 8 – 12 weeks, including a 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 a re-evaluation of the patient’s status with special expertise.
Posology
Adults
The lowest dose which can control symptoms should be used.
The optimum dosage and frequency of administration of bromazepam 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 the those normally recommended.
Patients with hepatic impairment
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
It should not be used in children less than 12 years of age. The safety and efficacy in children less than 12 years have not been established
Contraindication
Calmnox must not be administered to patients with known hypersensitivity to the active substance, 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.
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 behavior.
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 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 minimizing 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 cardiovascular depression.
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.
The elderly should be given a reduced dose.
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.
Dependence
Use of benzodiazepines may lead to the development of physical and psychological dependence on 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
Usage in Pregnancy/Breast-feeding
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 a 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 discontinuation 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.
Breast-feeding
Since bromazepam is transferred to breast milk, breast feeding is not recommended during treatment.
Side effects
Bromazepam is similar in side effects to other benzodiazepines. The most common side effects reported are drowsiness, sedation, ataxia, memory impairment and dizziness. Impairments to memory functions are common with bromazepam and include a reduced working memory and reduced ability to process environmental information. Various studies report impaired memory, visual information processing and sensory data and impaired psychomotor performance; deterioration of cognition including attention capacity and impaired coordinative skills, impaired reactive and attention performance, which can impair driving skills; drowsiness and decrease in libido. Unsteadiness after taking bromazepam is, however, less pronounced than other benzodiazepines such as lorazepam.
On some occasions, benzodiazepines can induce extreme alterations in memory such as anterograde amnesia and amnesic automatism, which may have medico-legal consequences. Such reactions occur usually only at the higher dose end of the prescribing spectrum
Very rarely, dystonia can develop up to 30% of patients treated on a long-term basis develop a form of dependence, i.e. these patients cannot stop the medication without experiencing physical and/or psychological withdrawal symptoms.
Leukopenia and liver-damage of the cholestatic type with or without jaundice (icterus) have additionally been seen; the original manufacturer, regular laboratory examinations is to be performed routinely.
Ambulatory patients should be warned that bromazepam may impair the ability to drive vehicles and to operate machinery. The impairment is worsened by consumption of alcohol, because both act as central nervous system depressants. During therapy, tolerance to the sedative effect usually develops.
Adverse reactions
Most frequent adverse reactions
The most frequently reported adverse reactions with bromazepam are related to CNS effects and include drowsiness, ataxia and dizziness. These phenomena occur predominantly at the start of therapy and usually disappear with repeated administration.
Serious and important adverse reactions
There have been reports of falls and fractures in benzodiazepine users. The risk is increased in those taking concomitant sedatives (including alcoholic beverages) and in the elderly.
Allergic reactions and a very few cases of anaphylaxis have been reported to occur with benzodiazepines.
Release of hostility and other paradoxical reactions such as irritability, excitability, restlessness, agitation, aggression, delusion, anger, nightmares, hallucinations, psychosis, inappropriate behaviour and other adverse behavioural effects are known to occur with the use of benzodiazepines. They are more likely to occur in children and elderly patients than in other patients. If these occur, use of the drug should be discontinued.
Anterograde amnesia may occur using therapeutic doses of benzodiazepines, the risk increasing with higher doses. Effects of anterograde amnesia may be associated with inappropriate behaviour.
Chronic use (even at therapeutic doses) may lead to the development of physical and psychological drug dependence: discontinuation of therapy may result in withdrawal or rebound phenomena.
Symptoms of Overdose/treatment
Symptoms
Benzodiazepines commonly cause drowsiness, ataxia, dysarthria and nystagmus. Overdose of Somnox is seldom life-threatening if the drug is taken alone, but may lead to slurred speech, apnea, hypotension, cardio-respiratory 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. Patients may require symptomatic treatment for cardio-respiratory 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, 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).
Possible drug interactions
Pharmacokinetic drug-drug interaction (DDI)
The specific enzymes involved in the metabolism of bromazepam have not been fully elucidated. There is a possibility that compounds which inhibit key oxidative hepatic enzymes may enhance the activity of benzodiazepines. Co-administration of cimetidine, a multi-CYP inhibitor, and possibly propranolol may prolong the elimination half-life of bromazepam through a substantially reduced clearance (with cimetidine reduction by 50%). Combined administration with fluvoxamine, an inhibitor of CYP1a2, results in significantly increased bromazepam exposure (2.4-fold increase in AUC) and elimination half-life (1.9-fold).
Bromazepam at therapeutic doses does not change the pharmacokinetics of co-administered antipyrine, a substrate of several CYP enzymes (CYP1a2, CYP2b6, CYP2c8, CYP2c9, CYP2c18, and CYP3a4).
Pharmacodynamic drug-drug interaction (DDI)
CNS-acting drugs
Enhanced effects on sedation, respiration and hemodynamics may occur when lectopam is co-administered with any centrally acting depressants including alcohol, narcotics, narcotic analgesics, barbiturates, non-barbiturate hypnotics, antihistamines, phenothiazines, thioxanthenes, butyrophenones classes of antipsychotics, anxiolytics/sedatives, anesthetics, monoamine oxidase inhibitors, tricyclic antidepressants and anticonvulsants.
In the case of narcotic analgesics enhancement of euphoria may also occur, leading to an increase in psychological dependence. Because of the enhancement of effects that might occur, patients should be advised against the simultaneous use of other CNS depressant drugs and should be cautioned not to take alcohol during the administration of bromazepam.
Drug-lifestyle interactions
The concomitant use of bromazepam with alcohol 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.
Dosage and administration
Dosing considerations
Patients should be evaluated carefully at the start of treatment in order to minimize the dosage and/or the frequency of administration and to prevent overdose due to accumulation.
The dosage of bromazepam must be individualized and carefully titrated in order to avoid excessive sedation or mental and motor impairment. Short course of treatment should usually be the rule for the symptomatic relief of excessive anxiety and the initial course of treatment should not last longer than one week without reassessment of the need for a limited extension. If necessary, drug dosage can be adjusted after one week of treatment. Initially, not more than one week’s supply of the drug should be provided, and automatic prescription renewals should not be allowed. Subsequent prescriptions, when required, should be limited to a short course of therapy.
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. It is important that the patient should be aware of the possibility of rebound phenomena that may occur while the drug is being discontinued.
Recommended dose and dosage adjustment
Usual adult dosage
The recommended initial adult daily dosage is 6mg to 18mg in equally divided doses, depending on the severity of symptoms and response of the patient. Treatment should be initiated by lower doses and adjusted as necessary. The optimal dosage may range from 6mg to 30mg daily in individual patients, in divided doses. There is limited experience with higher doses up to 60 mg daily.
Elderly and debilitated patients
The initial daily dose in these patients should not exceed 3 mg in divided doses. This dosage can be carefully adjusted, depending on tolerance and response of the patient.
Presentation
3×10 tablets
Storage
Store below 30°C. Protect from direct sunlight.
Keep all medicines out of reach of children.
