Bromazepam

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.

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.

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.

Patients with mild or moderate impaired hepatic and/or renal function require the lowest dose possible because of individual variations in sensitivity and pharmacokinetics.

Special care should be made with drugs depressing respiratory function such as opioids (analgesics, antitussives, substitutive treatments), notably in elderly people.

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%.

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).

Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse.

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.

A lower dose is recommended for patients with chronic respiratory insufficiency due to the risk of respiratory depression.

Co-administration of propranolol prolongs the elimination half-life of bromazepam by approximately 20% and results in a non-significant increase in bromazepam clearance.

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. This effect is increased if the patient has taken alcohol.

Bromazepam 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).

^* These phenomena occur predominantly at the start of therapy and usually disappear with repeated administration
^** The risk of falls and fractures is increased in those taking concomitant sedatives (including alcoholic beverages) and in the elderly.