Lectopam Tab 3mg Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

LECTOPAM (bromazepam) is useful for the short-term, symptomatic relief of manifestations of excessive anxiety in patients with anxiety neurosis.

Geriatrics

Elderly and debilitated patients are especially susceptible to dose-related adverse events and a reduced dose is recommended (see WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics and DOSAGE AND ADMINISTRATION, Elderly and Debilitated Patients).

Pediatrics

LECTOPAM is not recommended for children under 18 years of age (see WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics).

CONTRAINDICATIONS

• Patients who are hypersensitive to other benzodiazepines, this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph.
• Myasthenia gravis

• Severe hepatic impairment (see WARNINGS AND PRECAUTIONS, Impaired Hepatic

  Function)

• Severe respiratory insufficiency
• Sleep apnea syndrome

• Narrow angle glaucoma

  SERIOUS WARNINGS AND PRECAUTIONS: RISKS FROM CONCOMITANT USE

  WITH OPIOIDS

  Concomitant use of LECTOPAM and opioids may result in profound sedation, respiratory depression, coma, and death (see WARNINGS AND PRECAUTIONS, Risks from concomitant use of opioids and benzodiazepines).

  • 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.

WARNINGS AND PRECAUTIONS

General

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

LECTOPAM (bromazepam) is not recommended for use in patients with depressive disorders or psychosis.

Anterograde amnesia may occur with therapeutic doses of benzodiazepines and may be associated with inappropriate behaviour, the risk increasing with higher doses, (see ADVERSE REACTIONS).

Concomitant use of alcohol / CNS depressants

The concomitant use of LECTOPAM with alcohol and/or CNS depressants should be avoided. Such concomitant use has the potential to increase the clinical effects of LECTOPAM possibly including severe sedation, clinically relevant respiratory and/or cardiovascular depression, that could result in coma or death (see DRUG INTERACTIONS and OVERDOSAGE sections).

Patients should be advised against the concurrent use of alcohol and other CNS depressant drugs.

Medical History of Alcohol or Drug Abuse

LECTOPAM should be used with extreme caution in patients with a medical history of alcohol or drug abuse. Abuse has been reported more commonly in poly-drug abusers.

Benzodiazepines have produced habituation, dependence and withdrawal symptoms similar to those noted with barbiturates and alcohol. The risk of dependence increases with dose and duration, and is greater in patients with a medical history of alcohol and drug).

Risks from concomitant use of opioids and benzodiazepines:

Concomitant use of benzodiazepines, including LECTOPAM, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone.

If a decision is made to prescribe LECTOPAM concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of LECTOPAM than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking LECTOPAM, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation (see DRUG INTERACTIONS).

Advise both patients and caregivers about the risks of respiratory depression and sedation when LECTOPAM is used with opioids.

Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the opioid have been determined.

Dependence/Tolerance

Dependence Liability and Withdrawal

With long-term LECTOPAM treatment at the therapeutic doses, development of physical and psychological dependence may occur. Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms. This may also occur following short-term use, especially at high doses, or if the daily dose is reduced rapidly or abruptly discontinued, or when switching to a benzodiazepine with a considerably shorter elimination half-life. Symptoms of withdrawal include irritability, nervousness, insomnia, agitation, tremors, convulsions, diarrhea, abdominal cramps, vomiting, sweating, memory impairment, headache, muscle pain, extreme anxiety, tension, restlessness, and confusion. In severe cases the following symptoms may occur: derealization, depersonalization, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations, or epileptic seizures. Since these symptoms are similar to those for which the patient is being treated, it may appear that he/she has suffered a relapse upon discontinuation of LECTOPAM.

Rebound anxiety

Rebound anxiety, a transient syndrome whereby the symptoms that led to treatment with LECTOPAM recur in an enhanced form, may occur on withdrawal of treatment. It may be accompanied by other reactions including mood changes, sleep disturbances and restlessness. Since the risk of withdrawal symptoms and rebound anxiety is greater after abrupt discontinuation of treatment, abrupt withdrawal of LECTOPAM should be avoided and treatment – even if only of short duration – should be terminated by gradually reducing the daily dose.

Tolerance

Some loss of response to the effects of LECTOPAM may develop after repeated use for a prolonged time.

Lactose Intolerance

Lactose monohydrate is a non-medicinal ingredient in LECTOPAM. Therefore, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Neurologic

Driving and Hazardous Activities

Since LECTOPAM has a central nervous system depressant effect, patients should be warned against driving, operating dangerous machinery, or engaging in other hazardous activities requiring mental alertness and physical coordination. Sedation, amnesia and impaired muscular function may adversely affect the ability to drive or operate machinery. This effect is increased if the patient has had alcohol (see DRUG INTERACTIONS).

Driving, operating machinery and other hazardous activities should be avoided altogether or at least during the first few days of treatment. The decision on this question rests with the patient’s physician and should be based on the patient’s response to treatment and the dosage involved. They also should be warned against the concomitant use of alcohol and other CNS depressant drugs.

Psychiatric

Mental and Emotional Disorders

It should be recognized that suicidal tendencies may be present in patients with emotional disorders and that protective measures and appropriate treatment may be necessary and should be instituted without delay.

Paradoxical reactions such as restlessness, agitation, irritability, aggressiveness, anxiety, delusion, anger, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects are known to occur when using benzodiazepines. Should this occur, the use of LECTOPAM should be discontinued. They are more likely to occur in children and in the elderly.

Since excitement and other paradoxical reactions can result from the use of anxiolytic sedatives in psychotic patients, LECTOPAM should not be used in ambulatory patients suspected of having psychotic tendencies.

As with other benzodiazepines, LECTOPAM should not be used in individuals with physiological anxiety or normal stresses of daily living, but only in the presence of disabling manifestations of an appropriate pathological anxiety disorder.

These drugs are not effective in patients with characterological and personality disorders or those with obsessive-compulsive disorders. LECTOPAM is also not recommended for management of depressive or psychotic disorders. Benzodiazepines should not be used to treat anxiety associated with depression, as suicide may be precipitated in these patients.

Respiratory

Respiratory depression may occur following administration of LECTOPAM. This effect may be aggravated by pre-existing airway obstruction or brain damage or if other medications which depress respiration have been given. As a rule, this effect can be avoided by careful adjustment of the dose to individual requirements.

LECTOPAM should be used with caution in patients with chronic respiratory diseases (see CONTRAINDICATIONS).

Falls and fractures

There have been reports of falls and fractures among benzodiazepine users. The risk is increased in those taking concomitant sedatives (including alcoholic beverages) and in the elderly.

Special Populations

Pregnant Women: The safety of use of LECTOPAM in pregnancy has not been established. Therefore, LECTOPAM should not be used during pregnancy. Several studies have suggested an increased risk of congenital malformations (e.g., congenital malformations of the heart, cleft lip and/or palate) associated with the use of the benzodiazepines chlordiazepoxide and diazepam, and meprobamate, during the first trimester of pregnancies. Since LECTOPAM is also a benzodiazepine derivative, its administration is rarely justified in women of childbearing potential. Administration of LECTOPAM during the last three months of pregnancy or during labour is allowed only in the event of a strict medical indication, when the expected benefits to the patient outweigh the possible risks to the fetus. Due to the pharmacological action of the product, effects such as irregular heartbeat in the unborn child, hypothermia, hypotonia, moderate respiratory depression, and poor feeding in the neonate can be expected. Moreover, infants born to mothers who took benzodiazepines chronically during the later stages of pregnancy may have developed physical dependence and may be at some risk for developing withdrawal symptoms in the postnatal period. If LECTOPAM is prescribed to a woman of childbearing potential, she should be warned to consult her physician regarding discontinuation of LECTOPAM if she plans to become or suspects that she is pregnant.

Nursing Women: LECTOPAM and its metabolites are probably excreted in human milk. Therefore, this drug should not be given to nursing mothers.

Pediatrics: Because of the lack of sufficient clinical experience, LECTOPAM is not recommended for use in patients less than 18 years of age.

Geriatrics: The pharmacological effects of benzodiazepines appear to be greater in elderly patients than in younger patients, even at similar plasma benzodiazepine concentrations, possibly because of age-related changes in drug-receptor interactions, post-receptor mechanisms and organ function. Elderly and debilitated patients, or those with organic brain syndrome, have been found to be prone to CNS depression after even low doses of benzodiazepines. Therefore, medication should be initiated in these patients with very low initial doses, and increments should be made gradually, depending on the response of the patient, in order to avoid over sedation or neurological impairment. A reduction in dose for patients above 50 years is recommended (see DOSAGE AND ADMINISTRATION).

There is an increased risk for falls and fractures among elderly and debilitated benzodiazepine users. The risk is increased in those taking concomitant sedatives (including alcoholic beverages).

Impaired Hepatic Function

Benzodiazepines may have a contributory role in precipitating episodes of hepatic encephalopathy in patients with severe hepatic impairment. These patients should not be treated with LECTOPAM (see CONTRAINDICATIONS). Special caution should be exercised when administering LECTOPAM to patients with mild to moderate hepatic impairment.

In patients with mild to moderate hepatic impairment, it is recommended to initiate LECTOPAM, if necessary, at a very low dose and to increase the dosage only to the extent that such an increase is compatible with the degree of residual hepatic function. Such patients should be followed closely and have periodic laboratory assessments.

Impaired Renal Function

In patients with impaired renal function, it is recommended to initiate LECTOPAM, if necessary, at a very low dose and to increase the dosage only to the extent that such an increase is compatible with the degree of residual renal function. Such patients should be followed closely and have periodic laboratory assessments.

Monitoring and Laboratory Tests

If repeated cycles of LECTOPAM should be administered, periodic blood counts and liver function tests are advisable.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Most Frequent Adverse Reactions

The most frequently reported adverse reactions with LECTOPAM (bromazepam) are related to CNS effects and include drowsiness, ataxia and dizziness. These phenomena occur predominantly when starting LECTOPAM 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, aggressiveness, 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 LECTOPAM 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 psychic drug dependence: discontinuation of LECTOPAM may result in withdrawal or rebound phenomena (see WARNINGS and PRECAUTIONS).

Abuse of benzodiazepines is more common in poly-drug abusers.

Post-Market Adverse Drug Reactions

Other side effects which can occur, listed by body systems, include the following:

Cardiovascular System: Cardiac failure including cardiac arrest; hypotension, palpitations, tachycardia.

Digestive System: Dry mouth, nausea, non-specific gastrointestinal disturbances, vomiting.

Hemic and Lymphatic System: Decreased hemoglobin and hematocrit, increased and decreased WBC.

Metabolic and Nutritional Disorders: increased and decreased blood sugar levels, elevations of alkaline phosphatase, bilirubin, SGOT, SGPT.

Musculoskeletal System: Muscle weakness, muscle spasm.

Nervous System: Drowsiness, headache, dizziness, decreased alertness, ataxia, fatigue, seizures, confusional state, disorientation, emotional and mood disturbances, nervousness, anxiety, abnormal dreams, hyperactivity, depression, euphoria, changes in libido.

Respiratory Disorders: Respiratory depression.

Skin and Subcutaneous Tissue Disorders Appendages: Pruritus, rash.

Special Senses: Diplopia, blurred vision.

Urogenital System: Incontinence.

Injury, Poisoning and Procedural Complications: 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.

DRUG INTERACTIONS

Drug-Drug Interactions

Pharmacokinetic Drug-Drug Interaction (DDI)

The specific enzymes involved in the metabolism of LECTOPAM 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 LECTOPAM through a substantially reduced clearance (with cimetidine reduction by 50%). Combined administration with fluvoxamine, an inhibitor of CYP1A2, results in significantly increased LECTOPAM exposure (2.4-fold increase in AUC) and elimination half-life (1.9-fold).

LECTOPAM 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). Furthermore, LECTOPAM did not induce major CYP450 isozymes in vitro at the level of mRNA; also it did not activate nuclear hormone receptors. Therefore, LECTOPAM is unlikely to cause pharmacokinetic drug-drug interactions based on CYP450 induction.

Pharmacodynamic Drug-Drug Interaction (DDI)

CNS-acting drugs

Enhanced side effects such as sedation and cardio-respiratory depression may also 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 (see WARNINGS AND PRECAUTIONS, Concomitant use of alcohol / CNS depressants, and OVERDOSAGE sections).

Because of the enhancement of side 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 LECTOPAM.

Opioids

Due to additive CNS depressant effect, the concomitant use of benzodiazepines, including LECTOPAM, and opioids increases the risk of profound sedation, respiratory depression, coma, and death. Enhancement of euphoria may also occur, leading to an increase in dependence. Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations of concomitant use of benzodiazepines and opioids to the minimum required. Follow patients closely for respiratory depression and sedation (see Serious Warning and Precautions box, and WARNINGS and PRECAUTIONS, Risks from concomitant use of opioids and benzodiazepines).

Drug-Lifestyle Interactions

The concomitant use of LECTOPAM with alcohol should be avoided. Such concomitant use has the potential to increase the clinical effects of LECTOPAM possibly including severe sedation, clinically relevant respiratory and/or cardiovascular depression (see WARNINGS AND PRECAUTIONS, Concomitant use of alcohol / CNS depressants, and OVERDOSAGE sections).

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 LECTOPAM (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 LECTOPAM should be provided and automatic prescription renewals should not be allowed. Subsequent prescriptions, when required, should be limited to a short course of LECTOPAM.

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 LECTOPAM is being discontinued.

Recommended Dose and Dosage Adjustment

Usual Adult Dosage

The recommended initial adult daily dosage is 6 to 18 mg 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 6 to 30 mg daily in individual patients, in divided doses. There is limited experience with higher doses up to 60 mg daily.

Geriatrics

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 (see WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics; ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions).

OVERDOSAGE

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Symptoms

Benzodiazepines commonly cause drowsiness, ataxia, dysarthria and nystagmus. Overdose is seldom life-threatening if LECTOPAM is taken alone, but may lead to 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

In managing overdosage, consider the possibility of multiple drug involvement.

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. Induction of vomiting is not generally recommended.

As in overdosage with other benzodiazepines, dialysis is of no known value in LECTOPAM overdosage.

If CNS depression is severe consider the use of flumazenil, a benzodiazepine receptor antagonist. The following should be kept in mind when flumazenil is used in the treatment of benzodiazepine overdosage:

• Flumazenil should only be administered under closely monitored conditions. In view of the short half-life (about 1 hour) and duration of action of flumazenil, and the possible need for repeat doses, the patient should be closely monitored until all possible central benzodiazepine effects (e.g., resedation) have subsided.
• Particular caution is necessary when using flumazenil in cases of multiple drug overdosage, since the toxic effects (cardiac arrhythmias and/or convulsions) of other psychotropic drugs, especially cyclic antidepressants, may increase as the effects of benzodiazepines subside. Flumazenil is contraindicated in patients who are showing signs of serious cyclic antidepressant overdose.

Warning: The benzodiazepine receptor antagonist flumazenil is not indicated in patients with epilepsy who have been treated with benzodiazepines. Antagonism of the benzodiazepine effect in such patients may provoke seizures.

Refer to the product monograph for flumazenil for further information on the correct use of this drug.

ACTION AND CLINICAL PHARMACOLOGY

Pharmacokinetics

Absorption: The absolute bioavailability of unchanged, orally administered LECTOPAM is 60%, and peak blood levels are achieved within 2 hours after administration. Steady state plasma concentrations are reached in around 5 – 9 days. Following multiple oral doses of 3 mg given three times daily, the average maximum concentration of LECTOPAM at steady-state was 120 ng/mL which is 3- to 4-fold higher than that observed after a single 3-mg dose.

Food may decrease the bioavailability of LECTOPAM, however, the clinical relevance of this has not been established.

Distribution: On average, 70% of LECTOPAM is bound to plasma proteins.

Metabolism: LECTOPAM is extensively metabolized in the liver. LECTOPAM is metabolized, at least in part, through cytochrome P450 (CYP450). 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 LECTOPAM suggest that these isozymes are not involved to a major extent. The pronounced interaction with fluvoxamine points to co-involvement of CYP1A2 (see DRUG INTERACTIONS, Drug-Drug Interactions).

Excretion: LECTOPAM has an elimination half-life of approximately 20 hours (the half-life may be longer in elderly patients). Over a 72-hour interval, 69% of a 12 mg oral dose was recovered in the urine, in the form of conjugated 3-hydroxybromazepam and conjugated 2-(2-amino-5-bromo-3-hydroxybenzoyl)-pyridine.

Special Populations and Conditions

Geriatrics: Elderly patients 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 of LECTOPAM. This indicates that steady-state concentrations of LECTOPAM at any given dosing rate will be on average nearly twice as high in an elderly subject as compared to a younger individual (see DOSAGE AND ADMINISTRATION: Recommended Dose and Dosage Adjustment, Elderly and Debilitated Patients).

Impaired Renal Function: No formal pharmacokinetic study has been conducted and no population pharmacokinetic data was collected in patients with renal impairment.

Impaired Hepatic Function: No formal pharmacokinetic study has been conducted and no population pharmacokinetic data was collected in patients with hepatic impairment.

STORAGE AND STABILITY

Keep LECTOPAM in a cool dry place stored at room temperature (15-30°C).

SPECIAL HANDLING INSTRUCTIONS

Keep this medicine out of sight and reach of children.

The release of pharmaceuticals in the environment should be minimized. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided.

DOSAGE FORMS, COMPOSITION AND PACKAGING

LECTOPAM (bromazepam) is available as 3 mg (pale red in colour, slightly speckled, cylindrical and biplane in shape, single scored on one side and engraved with ROCHE over 3 on the other side) and 6 mg (greenish-grey to greyish-green in colour, slightly speckled, cylindrical and biplane in shape, single scored on one side and engraved with ROCHE over 6 on the other side) tablets in PVC blister packs. There are 10 tablets per blister card and 10 blister cards per carton, for a total of 100 tablets per unit.

The non-medicinal ingredients are as follows:

Tablets 3 mg: iron oxide red, lactose monohydrate, magnesium stearate, microcrystalline cellulose, talc.

Tablets 6 mg: indigotine aluminum lake, iron oxide yellow, lactose monohydrate, magnesium stearate, microcrystalline cellulose, talc.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Bromazepam

Chemical name: 7-bromo-1,3-dihydro-5-(2-pyridinyl)-2H-1,4-benzodiazepine-2-one

Molecular formula and molecular mass: C₁₄H₁₀BrN₃O, 316.2

Structural formula:

DETAILED PHARMACOLOGY

Bromazepam is a benzodiazepine with CNS depressant properties. In laboratory animals, it has shown anti-anxiety, sedative, muscle relaxant and anticonvulsant properties. In a “conflict” test, bromazepam was active in restoring suppressed lever-pressing behaviour (punishment induced suppression) at a minimum effective dose (MED) of 0.16 mg/kg orally in rats. This activity was demonstrated over a dose range which did not involve either depression or stimulation of unpunished control patterns of lever-pressing behaviour. At 2.5 mg/kg, a dose 16 times greater than the MED, bromazepam produced the first decrease in unpunished lever-pressing. In rats, utilizing the Sidman continuous avoidance test, an MED of 1.7 mg/kg i.p. decreased the rate of avoidance of shock, and 5.6 mg/kg i.p. prevented the rat from turning off the shock.

A marked reduction in aggressive behaviour was observed in vicious cynomolgus monkeys after an oral dose of 1 mg/kg and a taming effect at a dose of 2.5 mg/kg p.o. In the inclined screen test in mice the ED50 for bromazepam was 30 mg/kg p.o. In cats, the minimal effective taming dose of bromazepam was 0.2 mg/kg p.o.

Doses of 0.72 to 0.94 mg/kg p.o. of bromazepam protected mice against metrazol (125 mg/kg) induced convulsions. Bromazepam administered at doses of 3.90 to 34.2 mg/kg and 65 to 133 mg/kg p.o. protected mice against maximal and minimal electroshock-induced convulsions, respectively. A single dose of bromazepam (0.25 to 0.50 mg/kg p.o.) produced sedation or ataxia and modified the sleep cycle in cats. An increase in the amplitude of the electrical patterns of the caudate nucleus was observed.

A decrease in blood pressure was observed after the intravenous administration of bromazepam to anesthetized cats (1 mg/kg) and dogs (5 mg/kg). However, in hypertensive rats, little or no antihypertensive effect was detected. Bromazepam exhibited no diuretic, anti-obesity, anti-diabetic or anti-emetic activity.

Metabolism

The metabolites of bromazepam were studied in the mouse, rat and dog using ¹⁴C labelled drug. The quantitative determination of the metabolites indicates that marked differences in the excretion patterns exist in these species. In the mouse and dog, the major metabolite is 3-hydroxybromazepam, although it is only present as a minor metabolite in the rat. Both 2-(2-amino-5-bromobenzoyl) pyridine and its 3-hydroxy derivative are found as metabolites of bromazepam in all three species. In the dog, a separate biotransformation occurs, such that the nitrogen atom, at the 4-position of the diazepam ring, is oxidized to bromazepam 4-oxide. In rats, over 80% of an administered oral dose of bromazepam is excreted in four days, whereas in the dog, excretion is much slower. In rats, biliary excretion and in dogs, urinary excretion is the predominant route of elimination.

TOXICOLOGY

Acute Toxicity

LD₅₀ (mg/kg):

Signs of toxicity included decreased motor activity, ataxia, loss of righting reflex and lacrimation.

Chronic Toxicity

Bromazepam was administered in the diet to rats for a period of 18 months at doses of 0, 5, 20 and 80 mg/kg/day. No deviations from normal were observed except for an increase in the liver weight at necropsy at the time of the interim kill (18 months). Differences were not found in animals killed at the end of the study (24 months, after 6 months recovery) except for an increase in the ratio of liver to body weight. Histopathological examination revealed centrolobular hepatocellular hypertrophy in the treated groups

Daily doses of 0, 5, 20 and 80 mg/kg were administered in the diet to dogs for a period of one year. In the high-dose group, untoward effects were slight-to-moderate sedation and ataxia, which decreased as the study progressed. Isolated brief convulsive seizures were observed and an occasional elevation in serum alkaline phosphatase, a borderline increase in SGPT and a slight increase in liver weights occurred in a few dogs in the 80 mg/kg dosage group.

Reproductive Studies

Reproductive, teratological, perinatal and postnatal studies in rats receiving bromazepam at levels of 5 and 50 mg/kg/day p.o. revealed an increase in fetal mortality in the 50 mg/kg group. However, a second reproductive study, in which rats were administered either 10 or 25 mg/kg/day, revealed an increase in the stillbirth rate and a reduction in pup survival at both doses during the first four days following delivery. In another rat study, the daily oral administration of 1 mg/kg, through two successive matings, did not affect the reproductive processes. Bromazepam, at doses of 10 mg/kg/day produced a slight decrease in the number of pregnancies and in the postpartum survival of the offsprings following the second matings. When 100 mg/kg/day was given through three successive matings, a decrease in the number of pregnancies in the parent generation and in the postpartum survivability of the offsprings was observed in all instances. Bromazepam was given to pregnant rabbits at doses of 5 and 50 mg/kg/day administered orally. The following effects were noted: a reduction in maternal weight gain, a reduction in fetal weight and an increase in the incidence of resorptions in both treated groups. In a second study in rabbits, at dose levels of 5 and 80 mg/kg/day p.o., no teratogenic effects were observed. Pregnant mice were administered bromazepam orally, by stomach tube, from day 7 through 13 or 16 of pregnancy at dose levels of 5, 10, 50 and 125 mg/kg/day. No teratogenic effects were detected.

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