Yes

Benzodiazepine

Dental: Oral medication for preoperative dental anxiety; sedative component in I.V. conscious sedation in oral surgery patients; skeletal muscle relaxant

Medical: Management of anxiety disorders; alcohol withdrawal symptoms; skeletal muscle relaxant; convulsive disorders

C-IV

D

Clinical effects on the fetus: Crosses the placenta. Oral clefts reported, however, more recent data does not support an association between drug and oral clefts; inguinal hernia, cardiac defects, spina bifida, dysmorphic facial features, skeletal defects, multiple other malformations reported; hypotonia and withdrawal symptoms reported following use near time of delivery

Breast-feeding/lactation: Crosses into breast milk

Clinical effects on the infant: Sedation; American Academy of Pediatrics reports that USE MAY BE OF CONCERN.

Hypersensitivity to this drug or any component of its formulation (cross-sensitivity with other benzodiazepines may exist); narrow angle glaucoma; pregnancy; not for use in children <6 months of age (oral) or <30 days of age (parenteral)

Diazepam has been associated with increasing the frequency of grand mal seizures. Withdrawal has also been associated with an increase in the seizure frequency. Use with caution with drugs which may decrease diazepam metabolism. Use with caution in elderly or debilitated patients, patients with hepatic disease (including alcoholics), or renal impairment. Active metabolites with extended half-lives may lead to delayed accumulation and adverse effects. Use with caution in patients with respiratory disease or impaired gag reflex.

Causes CNS depression (dose-related) resulting in sedation, dizziness, confusion, or ataxia which may impair physical and mental capabilities. Patients must be cautioned about performing tasks which require mental alertness (ie, operating machinery or driving). Use with caution in patients receiving other CNS depressants or psychoactive agents. Effects with other sedative drugs or ethanol may be potentiated. The dosage of narcotics should be reduced by approximately 1/3 when diazepam is added. Benzodiazepines have been associated with falls and traumatic injury and should be used with extreme caution in patients who are at risk of these events (especially the elderly).

Use caution in patients with depression, particularly if suicidal risk may be present. Use with caution in patients with a history of drug dependence. Benzodiazepines have been associated with dependence and acute withdrawal symptoms on discontinuation or reduction in dose. Acute withdrawal, including seizures, may be precipitated in patients after administration of flumazenil to patients receiving long-term benzodiazepine therapy.

Diazepam has been associated with anterograde amnesia. Paradoxical reactions, including hyperactive or aggressive behavior, have been reported with benzodiazepines, particularly in adolescent/pediatric or psychiatric patients. Does not have analgesic, antidepressant, or antipsychotic properties.

Cardiovascular: Hypotension

Central nervous system: Drowsiness, ataxia, amnesia, slurred speech, paradoxical excitement or rage, fatigue, insomnia, memory impairment, headache, anxiety, depression, vertigo, confusion

Dermatologic: Rash

Endocrine & metabolic: Changes in libido

Gastrointestinal: Changes in salivation, constipation, nausea

Genitourinary: Incontinence, urinary retention

Hepatic: Jaundice

Local: Phlebitis, pain with injection

Neuromuscular & skeletal: Dysarthria, tremor

Ocular: Blurred vision, diplopia

Respiratory: Decrease in respiratory rate, apnea

Symptoms of overdose include somnolence, confusion, coma, hypoactive reflexes, dyspnea, hypotension, slurred speech, impaired coordination

Treatment for benzodiazepine overdose is supportive. Rarely is mechanical ventilation required. Flumazenil has been shown to selectively block the binding of benzodiazepines to CNS receptors, resulting in a reversal of benzodiazepine-induced CNS depression, but not respiratory depression.

CYP1A2 and 2C8 enzyme substrate, CYP3A3/4 enzyme substrate (minor), and diazepam and desmethyldiazepam are CYP2C19 enzyme substrates

Cimetidine, ciprofloxacin, clarithromycin, clozapine, CNS depressants, diltiazem, disulfiram, digoxin, erythromycin, ethanol, fluconazole, fluoxetine, fluvoxamine, grapefruit juice, isoniazid, itraconazole, ketoconazole, labetalol, levodopa, loxapine, metoprolol, metronidazole, miconazole, nefazodone, omeprazole, phenytoin,protease inhibitors like amprenavir and ritonavir, rifabutin, rifampin, troleandomycin, valproic acid, verapamil may increase the serum level and/or toxicity of diazepam; monitor for altered benzodiazepine response

Protect parenteral dosage form from light; potency is retained for up to 3 months when kept at room temperature; most stable at pH 4-8, hydrolysis occurs at pH <3; do not mix I.V. product with other medications

Binds to stereospecific benzodiazepine receptors on the postsynaptic GABA neuron at several sites within the central nervous system, including the limbic system, reticular formation. Enhancement of the inhibitory effect of GABA on neuronal excitability results by increased neuronal membrane permeability to chloride ions. This shift in chloride ions results in hyperpolarization (a less excitable state) and stabilization.

I.V. for status epilepticus:

Onset of action: Almost immediate

Duration: Short, 20-30 minutes

Absorption: Oral: 85% to 100%, more reliable than I.M.

Protein binding: 98%

Metabolism: In the liver

Half-life:

Parent drug: Adults: 20-50 hours, increased half-life in neonates, elderly, and those with severe hepatic disorders

Active major metabolite (desmethyldiazepam): 50-100 hours, can be prolonged in neonates

Oral absorption is more reliable than I.M.

Conscious sedation for procedures: Oral: 0.2-0.3 mg/kg (maximum: 10 mg) 45-60 minutes prior to procedure

Sedation or muscle relaxation or anxiety:

Oral: 0.12-0.8 mg/kg/day in divided doses every 6-8 hours

I.M., I.V.: 0.04-0.3 mg/kg/dose every 2-4 hours to a maximum of 0.6 mg/kg within an 8-hour period if needed

Status epilepticus:

Infants 30 days to 5 years: I.V.: 0.05-0.3 mg/kg/dose given over 2-3 minutes, every 15-30 minutes to a maximum total dose of 5 mg; repeat in 2-4 hours as needed or 0.2-0.5 mg/dose every 2-5 minutes to a maximum total dose of 5 mg

>5 years: I.V.: 0.05-0.3 mg/kg/dose given over 2-3 minutes every 15-30 minutes to a maximum total dose of 10 mg; repeat in 2-4 hours as needed or 1 mg/dose given over 2-3 minutes, every 2-5 minutes to a maximum total dose of 10 mg

Rectal: 0.5 mg/kg, then 0.25 mg/kg in 10 minutes if needed

Adolescents: Conscious sedation for procedures:

Oral: 10 mg

I.V.: 5 mg, may repeat with 1/2 dose if needed

Adults:

Anxiety/sedation/skeletal muscle relaxation:

Oral: 2-10 mg 2-4 times/day

I.M., I.V.: 2-10 mg, may repeat in 3-4 hours if needed

Status epilepticus: I.V.: 5-10 mg every 10-20 minutes, up to 30 mg in an 8-hour period; may repeat in 2-4 hours if necessary

Rapid tranquilization of agitated patient (administer every 30-60 minutes): Oral: 5-10 mg; average total dose for tranquilization: 20-60 mg

Elderly: Oral: Initial:

Anxiety: 1-2 mg 1-2 times/day; increase gradually as needed, rarely need to use >10 mg/day

Skeletal muscle relaxant: 2-5 mg 2-4 times/day

Hemodialysis: Not dialyzable (0% to 5%); supplemental dose is not necessary

Dosing adjustment in hepatic impairment: Reduce dose by 50% in cirrhosis and avoid in severe/acute liver disease

Alcohol: Additive CNS depression has been reported with benzodiazepines; avoid or limit alcohol

Respiratory rate, heart rate, blood pressure with I.V. use

Therapeutic: Diazepam: 0.2-1.5 mg/mL (SI: 0.7-5.3 mmol/L); N-desmethyldiazepam (nordiazepam): 0.1-0.5 mg/mL (SI: 0.35-1.8 mmol/L)

False-negative urinary glucose determinations when using Clinistix® or Diastix®

No information available to require special precautions

>10% of patients experience dry mouth or changes in salivation

Take exactly as directed (do not increase dose or frequency); may cause physical and/or psychological dependence. While using this medication, do not use alcohol and other prescription or OTC medications (especially pain medications, sedatives, antihistamines, or hypnotics) without consulting prescriber. Maintain adequate hydration (2-3 L/day of fluids unless instructed to restrict fluid intake). You may experience drowsiness, dizziness, or blurred vision (use caution when driving or engaging in tasks requiring alertness until response to drug is known); nausea, vomiting, loss of appetite, or dry mouth (small frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); constipation (increased exercise, fluids, or dietary fruit and fiber may help). If medication is used to control seizures, wear identification that you are taking an antiepileptic medication. Report CNS changes (confusion, depression, increased sedation, excitation, headache, agitation, insomnia or nightmares, dizziness, fatigue, or impaired coordination) or changes in cognition; difficulty breathing or shortness of breath; changes in urinary pattern; changes in sexual activity; muscle cramping, weakness, tremors, or rigidity; ringing in ears or visual disturbances, excessive perspiration, or excessive GI symptoms (cramping, constipation, vomiting, anorexia); worsening of seizure activity, or loss of seizure control. Pregnancy/breast-feeding precautions: Do not get pregnant while taking this medication; use appropriate barrier contraceptive measures. Breast-feeding is not recommended.

Provide safety measures (ie, side rails, night light, and call button); supervise ambulation

Gel, rectal delivery system (Diastat®):

Pediatric rectal tip (4.4 cm): 5 mg/mL (2.5 mg, 5 mg, 10 mg) [twin packs]

Adult rectal tip (6 cm): 5 mg/mL (10 mg, 15 mg, 20 mg) [twin packs]

Injection: 5 mg/mL (1 mL, 2 mL, 5 mL, 10 mL)

Injection, emulsified:

Dizac®: 5 mg/mL (3 mL)

Diazemuls®: 5 mg/mL (2 mL)

Solution, oral (wintergreen-spice flavor): 5 mg/5 mL (5 mL, 10 mL, 500 mL)

Solution, oral concentrate (Diazepam Intensol®): 5 mg/mL (30 mL)

Tablet: 2 mg, 5 mg, 10 mg

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Marshall JD, Farrar HC, and Kearns GL, "Diarrhea Associated With Enteral Benzodiazepine Solutions," J Pediatr, 1995, 126(4):657-9.

Pomara N, Stanley B, Block R, et al, "Increased Sensitivity of the Elderly to the Central Depressant Effects of Diazepam," J Clin Psychiatry, 1985, 46(5):185-7.

Reidenberg MM, Levy M, Warner H, et al, "Relationship Between Diazepam Dose, Plasma Level, Age, and Central Nervous System Depression," Clin Pharmacol Ther, 1978, 23(4):371-4.

Rosman NP, Colton T, Labazzo J, et al, "A Controlled Trial of Diazepam Administered During Febrile Illnesses to Prevent Recurrence of Febrile Seizures," N Engl J Med, 1993, 329(2):79-84.

Traeger SM and Haug MT 3d, "Reduction of Diazepam Serum Half-Life and Reversal of Coma by Activated Charcoal in a Patient With Severe Liver Disease," J Toxicol Clin Toxicol, 1986, 24(4):329-37.

Votey SR, Bosse GM, Bayer MJ, et al, "Flumazenil: A New Benzodiazepine Antagonist," Ann Emerg Med, 1991, 20(2):181-8.

Zeltzer LK, Altman A, Cohen D, et al, "Report of the Subcommittee on the Management of Pain Associated With Procedures in Children With Cancer," Pediatrics, 1990, 86(5 Pt 2):826-31.