![]() ![]() The first dose was given at the onset of an identified episode. The effectiveness of diazepam rectal gel has been established in two adequate and well controlled clinical studies in children and adults exhibiting the seizure pattern described below under INDICATIONS AND USAGE.Ī randomized, double-blind study compared sequential doses of diazepam rectal gel and placebo in 91 patients (47 children, 44 adults) exhibiting the appropriate seizure profile. No inhibition was demonstrated in the presence of inhibitors selective for CYP2A6, CYP2C9, CYP2D6, CYP2E1, or CYP1A2, indicating that these enzymes are not significantly involved in metabolism of diazepam. The marked inter-individual variability in the clearance of diazepam reported in the literature is probably attributable to variability of CYP2C19 (which is known to exhibit genetic polymorphism about 3-5% of Caucasians have little or no activity and are “poor metabolizers”) and CYP3A4. The metabolism of diazepam is primarily hepatic and involves demethylation (involving primarily CYP2C19 and CYP3A4) and 3-hydroxylation (involving primarily CYP3A4), followed by glucuronidation. At therapeutic doses, desmethyldiazepam is found in plasma at concentrations equivalent to those of diazepam while oxazepam and temazepam are not usually detectable. Metabolism and Elimination: It has been reported in the literature that diazepam is extensively metabolized to one major active metabolite (desmethyldiazepam) and two minor active metabolites, 3-hydroxydiazepam (temazepam) and 3-hydroxy-N-diazepam (oxazepam) in plasma. For patients using DIASTAT more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue DIASTAT (see WARNINGS). Although DIASTAT is indicated only for intermittent use (see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION), if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction of DIASTAT may precipitate acute withdrawal reactions, which can be life-threatening. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. The continued use of benzodiazepines may lead to clinically significant physical dependence.Before prescribing DIASTAT and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (see WARNINGS). Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. The use of benzodiazepines, including DIASTAT, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death.Follow patients for signs and symptoms of respiratory depression and sedation (see WARNINGS and PRECAUTIONS). Limit dosages and durations to the minimum required. Reserve concomitant prescribing of these drugs for patients for whom alternative treatment options are inadequate. ![]() Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death.WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS ABUSE, MISUSE, AND ADDICTION and DEPENDENCE AND WITHDRAWAL REACTIONS ![]()
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