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Pronunciation:

(klor AZ e pate)

U.S. Brand Names:

Tranxene®; Tranxene® SD™; Tranxene® SD™-Half Strength; T-Tab®

Synonyms:

Clorazepate Dipotassium; Tranxene T-Tab®

Generic Available:

Yes

Canadian Brand Names:

Apo-Clorazepate®; Novo-Clopate

Use:

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

Restrictions:

C-IV

Pregnancy Risk Factor:

Lactation:

Excretion in breast milk unknown/not recommended

Contraindications:

Hypersensitivity to clorazepate or any component of the formulation (cross-sensitivity with other benzodiazepines may exist); narrow-angle glaucoma; pregnancy

Warnings/Precautions:

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. Avoid use in patients with sleep apnea.

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 (eg, 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. 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.

Adverse Reactions:

Frequency not defined.

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

Overdosage/Toxicology:

May produce somnolence, confusion, ataxia, diminished reflexes, and 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.

Drug Interactions:

Substrate of CYP3A4 (major)

CNS depressants: Sedative effects and/or respiratory depression may be additive with CNS depressants; includes ethanol, barbiturates, narcotic analgesics, and other sedative agents; monitor for increased effect

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of clorazepate. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

CYP3A4 inhibitors: May increase the levels/effects of clorazepate. Example inhibitors include azole antifungals, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, and verapamil.

Levodopa: Therapeutic effects may be diminished in some patients following the addition of a benzodiazepine; limited/inconsistent data

Oral contraceptives: May decrease the clearance of some benzodiazepines (those which undergo oxidative metabolism); monitor for increased benzodiazepine effect

Theophylline: May partially antagonize some of the effects of benzodiazepines; monitor for decreased response; may require higher doses for sedation

Ethanol/Nutrition/Herb Interactions:

Ethanol: Avoid ethanol (may increase CNS depression).

Food: Serum concentrations/toxicity may be increased by grapefruit juice.

Herb/Nutraceutical: Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).

Mechanism of Action:

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.

Pharmacodynamics/Kinetics:

Onset of action: 1-2 hours

Duration: Variable, 8-24 hours

Distribution: Crosses placenta; appears in urine

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

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

Time to peak, serum: ~1 hour

Excretion: Primarily urine

Dosage:

Oral:

Children 9-12 years: Anticonvulsant: Initial: 3.75-7.5 mg/dose twice daily; increase dose by 3.75 mg at weekly intervals, not to exceed 60 mg/day in 2-3 divided doses

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:

Regular release tablets (Tranxene® T-Tab®): 7.5-15 mg 2-4 times/day

Sustained release (Tranxene®-SD): 11.25 or 22.5 mg once daily at bedtime

Ethanol 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

Monitoring Parameters:

Respiratory and cardiovascular status, excess CNS depression

Reference Range:

Therapeutic: 0.12-1 mcg/mL (SI: 0.36-3.01 mol/L)

Patient Education:

Take exactly as directed; do not increase dose or frequency. Drug may cause physical and/or psychological dependence. 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, 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, fruit, or 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 contraceptive measures. Breast-feeding is not recommended.

Nursing Implications:

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

Additional Information:

Abrupt discontinuation after sustained use (generally >10 days) may cause withdrawal symptoms.

Anesthesia and Critical Care Concerns/Other Considerations:

Abrupt discontinuation after sustained use (generally >10 days) may cause withdrawal symptoms.

Dental Health: Effects on Dental Treatment:

Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation). Many patients will experience drowsiness; orthostatic hypotension is possible. It is suggested that narcotic analgesics not be given for pain control to patients taking clorazepate due to enhanced sedation.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions:

No information available to require special precautions

Dosage Forms:

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

Tranxene®-SD™: 22.5 mg [once daily]

Tranxene®-SD™ Half Strength: 11.25 mg [once daily]

Tranxene® T-Tab®: 3.75 mg, 7.5 mg, 15 mg

International Brand Names:

Anksen® (TR); Anxielax® (TH); Apo-Clorazepate® (CA, SG); Cloramed® (TH); Cloranxen® (PL); Cloraxene® (TH); Clorazepate Dipotassium® (CY); Diposef® (TH); Dipot® (TH); Flulium® (TH); Justum® (AR); Lacort® (SI); Manotran® (TH); Medipax® (PT); Mendon® (JP); Modival® (CL); Noctran® (CY, EG, JO, KW, LB); Novo-Clopate (CA); Polizep® (TH); Pomadom® (TH); Posene® (TH); Sanor® (TH); Serene® (TH); Tencilan® (AR); Trancap® (TH); Tranclor® (TH); Trancon® (TH); Tranex® (YU); Transene® (IT); Tranxene® (BE, CY, CZ, EG); Tranxène® (FR); Tranxene® (GB, HK, IE, JO, KW, LB, LU, MX); Tranxène® (NL); Tranxene® (PL, PT, RO, RU, TH); Tranxilene® (BR, TR); Tranxilium® (AT, CH, CL, DE, ES); Uni-Tranxene® (BE, LU); Zetran-5® (TH)

References

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.

Mokhlesi B, Leikin JB, Murray P, et al, "Adult Toxicology in Critical Care: Part II: Specific Poisonings,"Chest, 2003, 123(3):897-922.

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

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