Yes

Benzodiazepine

Management of anxiety disorder or for the short-term relief of symptoms of anxiety; withdrawal symptoms of acute alcoholism; and preoperative apprehension and anxiety

C-IV

D

Hypersensitivity to this drug or any component of its formulation (cross-sensitivity with other benzodiazepines may exist); narrow angle glaucoma (not in product labeling: however, benzodiazepines are contraindicated); pregnancy

Active metabolites with extended half-lives may lead to delayed accumulation and adverse effects. Use with caution in elderly or debilitated patients, pediatric patients, patients with hepatic disease (including alcoholics) or renal impairment. Use with caution in patients with respiratory disease or impaired gag reflex. Use with caution in patients with porphyria.

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 (lithium, phenothiazines). Effects with other sedative drugs or ethanol may be potentiated. 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.

Benzodiazepines have 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.

>10%:

Central nervous system: Drowsiness, fatigue, ataxia, lightheadedness, memory impairment, dysarthria, irritability

Dermatologic: Rash

Endocrine & metabolic: Decreased libido, menstrual disorders

Gastrointestinal: Xerostomia, decreased salivation, increased or decreased appetite, weight gain or loss

Genitourinary: Micturition difficulties

1% to 10%:

Cardiovascular: Hypotension

Central nervous system: Confusion, dizziness, disinhibition, akathisia, increased libido

Dermatologic: Dermatitis

Gastrointestinal: Increased salivation

Genitourinary: Sexual dysfunction, incontinence

Neuromuscular & skeletal: Rigidity, tremor, muscle cramps

Otic: Tinnitus

Respiratory: Nasal congestion

Symptoms of overdose include hypotension, respiratory depression, coma, hypothermia, cardiac arrhythmias

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. Respiratory depression may not be reversed.

CYP3A3/4 enzyme substrate

Increased toxicity: 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, rifabutin, rifampin, troleandomycin, valproic acid, verapamil may increase the serum level and/or toxicity of alprazolam; monitor for altered benzodiazepine response

Refrigerate injection; protect from light; incompatible when mixed with Ringer's solution, normal saline, ascorbic acid, benzquinamide, heparin, phenytoin, promethazine, secobarbital

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.

Duration: 48 hours to 1 week

Distribution: V_d: 3.3 L/kg; crosses the placenta; appears in breast milk

Protein binding: 90% to 98%

Metabolism: Extensive in the liver to desmethyldiazepam (active and long-acting)

Half-life: 6.6-25 hours; End-stage renal disease: 5-30 hours; Cirrhosis: 30-63 hours

Time to peak serum concentration: Oral: Within 2 hours; I.M.: Results in lower peak plasma levels than oral

Elimination: Very little excretion in urine as unchanged drug

Children:

<6 years: Not recommended

>6 years: Anxiety: Oral, I.M.: 0.5 mg/kg/24 hours divided every 6-8 hours

Adults:

Anxiety:

Oral: 15-100 mg divided 3-4 times/day

I.M., I.V.: Initial: 50-100 mg followed by 25-50 mg 3-4 times/day as needed

Preoperative anxiety: I.M.: 50-100 mg prior to surgery

Alcohol withdrawal symptoms: Oral, I.V.: 50-100 mg to start, dose may be repeated in 2-4 hours as necessary to a maximum of 300 mg/24 hours

Dosing adjustment in renal impairment: Cl_cr <10 mL/minute: Administer 50% of dose

Hemodialysis: Not dialyzable (0% to 5%)

Dosing adjustment/comments in hepatic impairment: Avoid use

Alcohol: Additive CNS effects, avoid use

Respiratory and cardiovascular status, mental status, check for orthostasis

Therapeutic: 0.1-3 mg/mL (SI: 0-10 mmol/L); Toxic: >23 mg/mL (SI: >77 mmol/L)

HDL, triglycerides (S)

No information available to require special precautions

>10% of patients will experience dry mouth which disappears with cessation of drug therapy

Oral: Take exactly as directed (do not increase dose or frequency); may cause physical and/or psychological dependence. Do not use excessive alcohol or 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, lightheadedness, impaired coordination, dizziness, or blurred vision (use caution when driving or engaging in tasks requiring alertness until response to drug is known); 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); or altered sexual drive or ability (reversible). Report persistent CNS effects (eg, euphoria, confusion, increased sedation, depression); chest pain, palpitations, or rapid heartbeat; muscle cramping, weakness, tremors, rigidity, or altered gait; or worsening of condition. Pregnancy/breast-feeding precautions: Do not get pregnant while taking this medication; use appropriate barrier contraceptive measures. Breast-feeding is not recommended.

Raise bed rails; initiate safety measures; aid with ambulation

Capsule, as hydrochloride: 5 mg, 10 mg, 25 mg

Powder for injection, as hydrochloride: 100 mg

Tablet: 10 mg, 25 mg

Bailey DN, "Blood Concentrations and Clinical Findings Following Overdose of Chlordiazepoxide Alone and Chlordiazepoxide Plus Ethanol," Clin Toxicol, 1984, 22(5):433-46.

Burkhart KK and Kulig KW, "The Diagnostic Utility of Flumazenil (A Benzodiazepine Antagonist) in Coma of Unknown Etiology," Ann Emerg Med, 1990, 19(3):319-21.

Hicks R, Dysken MW, Davis JM, et al, "The Pharmacokinetics of Psychotropic Medication in the Elderly: A Review," J Clin Psychiatry, 1981, 42(10):374-85.

Minder EI, "Toxicity in a Case of Acute and Massive Overdose of Chlordiazepoxide and Its Correlation to Blood Concentration," J Toxicol Clin Toxicol, 1989, 27(1-2):117-27.

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.