Anxiolytic – Sedative

Action And Clinical Pharmacology: Bromazepam is a benzodiazepine with anxiolytic and sedative properties which are of value in the symptomatic relief of pathological anxiety in psychoneurotic patients.

The absolute bioavailability of unchanged, orally administered bromazepam is 60%, and peak blood levels are achieved within 2 hours after administration. On average, 70% of bromazepam is bound to plasma proteins. Bromazepam is metabolized in the liver, and has a elimination half-life of 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.

Indications And Clinical Uses: For the short-term, symptomatic relief of manifestations of excessive anxiety in patients with anxiety neurosis.

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

Contra-Indications: In patients with known hypersensitivity to benzodiazepines, myasthenia gravis, severe hepatic insufficiency, severe respiratory insufficiency, or sleep apnea syndrome.

Manufacturers’ Warnings In Clinical States: Bromazepam is not recommended for use in patients with depressive disorders or psychosis. Patients should be advised against the concurrent use of alcohol and other CNS depressant drugs. Patients with known or presumed dependence from alcohol or drugs should not take benzodiazepines, except in rare situations under medical supervision.

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

Occupational Hazards: Since bromazepam has a CNS depressant effect, patients should be warned against driving, operating dangerous machinery, or engaging in other hazardous activities requiring mental alertness and physical coordination, and should be cautioned that the effects of alcohol on such activities may be increased.

Pregnancy: The safety of use of bromazepam in pregnancy has not been established. Therefore, bromazepam should not be used during pregnancy. Several studies have suggested an increased risk of congenital malformations associated with the use of the benzodiazepines, such as chlordiazepoxide and diazepam, and meprobamate, during the first trimester of pregnancy. Since bromazepam is also a benzodiazepine derivative, its administration is rarely justified in women of childbearing potential. Administration of bromazepam during the last 3 months of pregnancy or during labor is allowed only in the event of a strict medical indication as, due to the pharmacological action of the product, effects on the neonate can be expected, such as hypothermia, hypotonia and moderate respiratory depression. 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 the drug is prescribed to a woman of childbearing potential, she should be warned to consult her physician regarding discontinuation of the drug if she plans to become or suspects that she is pregnant. If the drug is prescribed to a woman of childbearing potential, she should be warned to consult her physician regarding discontinuation of the drug if she plans to become or suspects that she is pregnant.

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

Precautions: Geriatrics: 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 oversedation or neurological impairment. The initial dose for the elderly or debilitated patients should not exceed 3 mg.

Dependence Liability: Bromazepam should not be administered to individuals prone to drug abuse. The risk of dependence increases with dose and duration of treatment; it is also greater in predisposed patients with a history of alcohol or drug abuse. Caution should be observed in all patients who are considered to have potential for psychological dependence.

Withdrawal symptoms similar to those occurring with other drugs of this class including alcohol, have been observed after abrupt discontinuation of the drug. These include irritability, nervousness, insomnia, agitation, tremors, convulsions, diarrhea, abdominal cramps, vomiting, 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 the drug. It is suggested that the drug should be withdrawn gradually, if the individual is suspected of being dependent, or the drug perhaps has been used in prolonged high doses.

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.

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

As with other benzodiazepines, bromazepam 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. Bromazepam is also not recommended for management of depressive or psychotic disorders.

Impaired Hepatic or Renal Function: In patients with impaired hepatic or renal function, it is recommended to initiate therapy, 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 function of these organs. Such patients should be followed closely and have periodic laboratory assessments.

Laboratory Tests: If bromazepam should be administered for repeated cycles of therapy, periodic blood counts and liver function tests are advisable.

Drug Interactions: Bromazepam may potentiate or interact with the effects of other CNS acting drugs such as alcohol, narcotics, hypnotics, sedative antihistamines, antipsychotics, anxiolytics/sedatives, anesthetics, antidepressants and anticonvulsants. Therefore, if bromazepam is to be combined with other drugs acting on the CNS, careful consideration should be given to the pharmacology of the agent involved because of possible additive or potentiation of drug effects. In the case of narcotic analgesics enhancement of euphoria may also occur, leading to an increase in psychological dependence. Patients should also be advised against the simultaneous use of other CNS depressant drugs and should be cautioned not to take alcohol during the administration of bromazepam because of the potentiation of effects that might occur.

Although not known for bromazepam, there is a possibility that compounds which inhibit certain hepatic enzymes (particularly cytochrome P450) may enhance the activity of benzodiazepines that are metabolized by these enzymes.

Cisapride may lead to a temporary increase of the effects of bromazepam due to an increased rate of absorption.

Adverse Reactions: The most frequently reported adverse reactions have been drowsiness, ataxia and dizziness. Release of hostility and other paradoxical effects such as irritability, excitability, restlessness, agitation, delusion, rages, nightmares, hallucinations, psychosis, inappropriate behavior and other adverse behavioral effects are known to occur with the use of benzodiazepines. If these occur, use of the drug should be discontinued.

Anterograde amnesia may also occur using therapeutic doses of benzodiazepines, the risk increasing with higher doses.

Other side effects less frequently reported, listed by body systems, include the following:

Neurologic: blurred or double vision, headache, seizures, slurred speech, difficulty in depth perception.

Psychiatric: mental confusion, depression, nervousness, sleep disorders, euphoria, lethargy, stupor, numbed emotions, reduced alertness.

Gastrointestinal: dry mouth, nausea, nonspecific gastrointestinal disturbances, vomiting.

Musculoskeletal: muscle spasm, muscle weakness.

Cardiovascular: hypotension, palpitations, tachycardia.

Dermatologic: pruritus, rash.

Genitourinary: incontinence, change in libido.

Hematologic: decreased hemoglobin and hematocrit, increased and decreased WBC.

Hepatic: elevations of alkaline phosphatase, bilirubin, AST, ALT.

Miscellaneous Blood Chemistry: increased and decreased blood sugar levels.

Symptoms And Treatment Of Overdose: Symptoms: Overdosage manifestations include drowsiness, somnolence, ataxia, impaired vision, depressed reflexes and finally coma. Hypotension, hypotonia and respiratory depression and very rarely death may occur with large overdoses.

Treatment: Vital signs should be monitored and general supportive measures should be employed as indicated. Special attention should be paid to respiratory and cardiac function in intensive care. Flumazenil may be useful as an antagonist.

Gastric lavage (with the airway protected) should be instituted as soon as possible. Vomiting may be included within 1 hour if the patient is fully awake. If there is no advantage in emptying the stomach, activated charcoal should be given to reduce absorption. The value of dialysis has not been determined.

As is frequently the case in intentional overdose, the probability of multiple agents having been ingested should be considered.

Dosage And Administration: The dosage of bromazepam must be individualized and carefully titrated in order to avoid excessive sedation or mental and motor impairment. Short courses 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 1 week without reassessment of the need for a limited extension. If necessary, drug dosage can be adjusted after 1 week of treatment. Initially, not more than 1 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.

Adults: Initially; 6 to 18 mg/day 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.

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 reponse of the patient.

Availability And Storage: 1.5 mg: Each white cylindrical biplane tablet with beveled edges and scored on one side, engraved ²on the other side contains: bromazepam 1.5 mg. Nonmedicinal ingredients: microcrystalline cellulose, lactose 96 mg, talc and magnesium stearate. Energy: 1.5 kJ (0.4 kcal). Gluten-, paraben-, sodium-, sulfite- and tartrazine-free. Bottles of 100 and 500.

3 mg: Each pink cylindrical biplane tablet with beveled edges and scored on one side, engraved on the other side contains: bromazepam 3 mg. Nonmedicinal ingredients: microcrystalline cellulose, lactose 94 mg, talc, magnesium stearate and erythrosine aluminum lake. Energy: 1.5 kJ (0.4 kcal). Gluten-, paraben-, sodium-, sulfite- and tartrazine-free. Bottles of 100 and 500.

6 mg: Each yellow-green cylindrical biplane tablet with beveled edges and scored on one side, engraved ºon the other side contains: bromazepam 6 mg. Nonmedicinal ingredients: microcrystalline cellulose, lactose 91 mg, talc, magnesium stearate, iron oxide and indigotine aluminum lake. Energy: 1.5 kJ (0.4 kcal). Gluten-, paraben-, sodium-, sulfite- and tartrazine-free. Bottles of 100 and 500.

Store at 15 to 30°C. (Shown in Product Recognition Section)

LECTOPAM® Roche Bromazepam Anxiolytic – Sedative

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