Yes

Benzodiazepine

Treatment of generalized anxiety disorder; management of alcohol withdrawal; adjunct anticonvulsant in management of partial seizures

C-IV

D

Hypersensitivity to this drug or any component of its formulation (cross-sensitivity with other benzodiazepines may exist); narrow angle glaucoma; lactation; pregnancy

Not recommended for use in patients <9 years of age or patients with depressive or psychotic disorders. 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. Use is not recommended in patients with depressive disorders or psychoses. Avoid use in patients with sleep apnea.

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.

Cardiovascular: Hypotension

Central nervous system: Drowsiness, fatigue, ataxia, lightheadedness, memory impairment, insomnia, anxiety, headache, depression, slurred speech, confusion, nervousness, dizziness, irritability

Dermatologic: Rash

Endocrine & metabolic: Decreased libido

Gastrointestinal: Xerostomia, constipation, diarrhea, decreased salivation, nausea, vomiting, increased or decreased appetite

Neuromuscular & skeletal: Dysarthria, tremor

Ocular: Blurred vision, diplopia

May produce somnolence, confusion, ataxia, diminished reflexes, coma

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.

Carbamazepine, rifampin, rifabutin may enhance the metabolism of clorazepate and decrease its therapeutic effect; consider using an alternative sedative/hypnotic agent

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 clorazepate; monitor for altered benzodiazepine response

Unstable in water

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.

Onset of action: ~1 hour

Duration: Variable, 8-24 hours

Distribution: Crosses the placenta; appears in urine

Metabolism: Rapidly decarboxylated to desmethyldiazepam (active) in acidic stomach prior to absorption; metabolized in the liver to oxazepam (active)

Half-life: Adults: Desmethyldiazepam: 48-96 hours; Oxazepam: 6-8 hours

Time to peak serum concentration: Oral: Within 1 hour

Elimination: Primarily in urine

Oral:

Children >12 years and Adults: Anticonvulsant: Initial: Up to 7.5 mg/dose 2-3 times/day; increase dose by 7.5 mg at weekly intervals; not to exceed 90 mg/day

Adults:

Anxiety: 7.5-15 mg 2-4 times/day, or given as single dose of 11.25 or 22.5 mg at bedtime

Alcohol withdrawal: Initial: 30 mg, then 15 mg 2-4 times/day on first day; maximum daily dose: 90 mg; gradually decrease dose over subsequent days

Alcohol: Additive CNS effects, avoid use

Respiratory and cardiovascular status, excess CNS depression

Therapeutic: 0.12-1 mg/mL (SI: 0.36-3.01 mmol/L)

hematocrit, abnormal liver and renal function tests

No information available to require special precautions

Many patients will experience drowsiness and dry mouth while taking clorazepate which will disappear with cessation of drug therapy; orthostatic hypotension is possible; it is suggested that narcotic analgesics not be given for pain control to patients taking clorazepate because of enhanced sedation

Take exactly as directed (do not increase dose or frequency); may cause physical and/or psychological dependence. Do not use excessive 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, lightheadedness, impaired coordination, dizziness, or blurred vision (use caution when driving or engaging in tasks requiring alertness until response to drug is known); nausea, vomiting, 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); altered sexual drive or ability (reversible); or photosensitivity (use sunscreen, wear protective clothing and eyewear, and avoid direct sunlight). Report persistent CNS effects (eg, confusion, depression, increased sedation, excitation, headache, agitation, insomnia or nightmares, dizziness, fatigue, impaired coordination, changes in personality, or changes in cognition); changes in urinary pattern; muscle cramping, weakness, tremors, or rigidity; ringing in ears or visual disturbances; chest pain, palpitations, or rapid heartbeat; excessive perspiration; excessive GI symptoms (cramping, constipation, vomiting, anorexia); or worsening of condition. Pregnancy/breast-feeding precautions: Do not get pregnant while using this medication; use appropriate barrier contraceptive measures. Breast-feeding is not recommended.

Observe patient for excess sedation, respiratory depression; raise bed rails, initiate safety measures, assist with ambulation

Capsule, as dipotassium: 3.75 mg, 7.5 mg, 15 mg

Tablet, as dipotassium: 3.75 mg, 7.5 mg, 15 mg

Tablet, as dipotassium, single dose: 11.25 mg, 22.5 mg

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.

Patel DA and Patel AR, "Clorazepate and Congenital Malformations," JAMA, 1980, 244(2):135-6.