Diazepam

DIAZEPAM- diazepam gel
Bryant Ranch Prepack

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WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS

  • Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for 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 (see WARNINGS and PRECAUTIONS).
  • The use of benzodiazepines, including diazepam rectal gel, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. 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. Before prescribing diazepam rectal gel and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (see WARNINGS).
  • The continued use of benzodiazepines may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Although diazepam rectal gel 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 diazepam rectal gel may precipitate acute withdrawal reactions, which can be life-threatening. For patients using diazepam rectal gel more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue diazepam rectal gel (see WARNINGS).

DESCRIPTION

Diazepam rectal gel rectal delivery system is a non-sterile diazepam gel provided in a prefilled, unit-dose, rectal delivery system. Diazepam rectal gel contains 5 mg/mL diazepam, benzoic acid, benzyl alcohol (1.5%), ethyl alcohol (10%), hydroxypropyl methylcellulose, propylene glycol, purified water, and sodium benzoate. Diazepam rectal gel is clear to slightly yellow and has a pH between 6.5-7.5.

Diazepam, the active ingredient of diazepam rectal gel, is a benzodiazepine anticonvulsant with the chemical name 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2 H -1,4-benzodiazepin-2-one. The structural formula is as follows:

chemstructure
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CLINICAL PHARMACOLOGY

Mechanism of Action

Although the precise mechanism by which diazepam exerts its antiseizure effects is unknown, animal and in vitro studies suggest that diazepam acts to suppress seizures through an interaction with γ-aminobutyric acid (GABA) receptors of the A-type (GABA A ). GABA, the major inhibitory neurotransmitter in the central nervous system (CNS), acts at this receptor to open the membrane channel allowing chloride ions to flow into neurons. Entry of chloride ions causes an inhibitory potential that reduces the ability of neurons to depolarize to the threshold potential necessary to produce action potentials. Excessive depolarization of neurons is implicated in the generation and spread of seizures. It is believed that diazepam enhances the actions of GABA by causing GABA to bind more tightly to the
GABA A receptor.

Pharmacokinetics

Pharmacokinetic information of diazepam following rectal administration was obtained from studies conducted in healthy adult subjects. No pharmacokinetic studies were conducted in pediatric patients. Therefore, information from the literature is used to define pharmacokinetic labeling in the pediatric population.

Diazepam rectal gel is well absorbed following rectal administration, reaching peak plasma concentrations in 1.5 hours. The absolute bioavailability of diazepam rectal gel relative to Valium injectable is 90%. The volume of distribution of diazepam rectal gel is calculated to be approximately 1 L/kg. The mean elimination half-life of diazepam and desmethyldiazepam following administration of a 15 mg dose of diazepam rectal gel was found to be about 46 hours (CV=43%) and 71 hours (CV=37%), respectively. Both diazepam and its major active metabolite desmethyldiazepam bind extensively to plasma proteins (95-98%).

FIGURE 1: Plasma Concentrations of Diazepam and Desmethyldiazepam Following Diazepam Rectal Gel or IV Diazepam

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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. At therapeutic doses, desmethyldiazepam is found in plasma at concentrations equivalent to those of diazepam while oxazepam and temazepam are not usually detectable. The metabolism of diazepam is primarily hepatic and involves demethylation (involving primarily CYP2C19 and CYP3A4) and 3-hydroxylation (involving primarily CYP3A4), followed by glucuronidation. 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. 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.

Special Populations

Hepatic Impairment:

No pharmacokinetic studies were conducted with diazepam rectal gel in hepatically impaired subjects. Literature review indicates that following administration of 0.1 to 0.15 mg/kg of diazepam intravenously, the half-life of diazepam was prolonged by two to five-fold in subjects with alcoholic cirrhosis (n=24) compared to age-matched control subjects (n=37) with a corresponding decrease in clearance by half: however, the exact degree of hepatic impairment in these subjects was not characterized in this literature (see PRECAUTIONS).

Renal Impairment:

The pharmacokinetics of diazepam have not been studied in renally impaired subjects (see PRECAUTIONS).

Pediatrics:

No pharmacokinetic studies were conducted with diazepam rectal gel in the pediatric population. However, literature review indicates that following IV administration (0.33 mg/kg), diazepam has a longer half-life in neonates (birth up to one month; approximately 50-95 hours) and infants (one month up to two years; about 40-50 hours), whereas it has a shorter half-life in children (two to 12 years; approximately 15-21 hours) and adolescents (12 to 16 years; about 18-20 hours) (see PRECAUTIONS).

Elderly:

A study of single dose IV administration of diazepam (0.1 mg/kg) indicates that the elimination half-life of diazepam increases linearly with age, ranging from about 15 hours at 18 years (healthy young adults) to about 100 hours at 95 years (healthy elderly) with a corresponding decrease in clearance of free diazepam (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

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