Clorazepate Dipotassium

Pronunciation

Class: Benzodiazepines
VA Class: CN302
Molecular Formula: C16H11ClK2N2O4
CAS Number: 57109-90-7
Brands: GenXene, Tranxene

Warning(s)

REMS:

FDA approved a REMS for clorazepate to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Benzodiazepine.a b c Anxiolytic, sedative, anticonvulsant.a b c

Uses for Clorazepate Dipotassium

Alcohol Withdrawal

Relief of agitation and tremor and prevention or symptomatic relief of delirium tremens and hallucinations associated with acute alcohol withdrawal.a b c

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Anxiety Disorders

Management of anxiety disorders and short-term relief of symptoms of anxiety.a b c

Seizure Disorders

Has been used as an adjunct to other anticonvulsants in the prophylactic management of partial seizures.a b c

Clorazepate Dipotassium Dosage and Administration

General

  • Use the smallest effective dose (especially in geriatric or debilitated patients and in those with liver disease or low serum albumin) to avoid oversedation.a b

  • Consider the long elimination half-life of clorazepate’s metabolites when making dosage adjustments.a b (See Half-life under Pharmacokinetics.)

  • In patients who have received prolonged (e.g., for several months) therapy, avoid abrupt discontinuance, since manifestations of withdrawal can be precipitated; gradually taper dosage.a b c

Anxiety

  • Periodically reassess the usefulness of the drug.a b c Efficacy beyond 4 months not systematically evaluated.a b c Administer for the shortest possible period of time; frequent dosage adjustments may be required.b

Seizures

  • Do not discontinue clorazepate abruptly in patients with a history of seizure disorder, since seizures may be precipitated.a b

Administration

Oral Administration

Administer orally in 1–4 doses daily.a

Initiate therapy and titrate dosage using conventional (3.75-, 7.5-, 15-mg) tablets.a

Do not initiate therapy with single-dose tablets (e.g., Tranxene-SD) intended for once-daily administration.a c

Single-dose Tablets (Tranxene-SD, Tranxene-SD Half Strength)

Tranxene-SD 22.5-mg tablet may be administered once daily for patient convenience in individuals stabilized on a clorazepate dipotassium dosage of 7.5 mg 3 times daily.a c

Tranxene-SD 11.25-mg (half strength) tablet may be administered once daily for patient convenience in individuals stabilized on a clorazepate dipotassium dosage of 3.75 mg 3 times daily.a c

Dispensing Considerations

Do not remove desiccant packets from original container.a Consider use of desiccant packets when dispensing a large number of tablets in a multidose container.a In the presence of moisture, carbon dioxide may form, resulting in rapid tablet disintegration.a

Dosage

Available as clorazepate dipotassium; dosage expressed in terms of the salt.c

Pediatric Patients

Seizure Disorders
Adjunctive Therapy for Partial Seizures
Oral

Children 9–12 years of age: Initially, 7.5 mg twice daily; increase daily dosage by no more than 7.5 mg at weekly intervals.a c Do not exceed 60 mg daily.a c

Children >12 years of age: Initially, 7.5 mg 3 times daily; increase daily dosage by no more than 7.5 mg at weekly intervals.a c Do not exceed 90 mg daily.a c

Adults

Alcohol Withdrawal
Oral

Day 1: 30 mg initially, followed by an additional 30–60 mg in divided doses; not to exceed 90 mg daily.a c

Day 2: 45–90 mg in divided doses.a c

Day 3: 22.5–45 mg in divided doses.a c

Day 4: 15–30 mg in divided doses.a c

Gradually reduce dosage to 7.5–15 mg daily; discontinue when patient’s condition is stable.a c

Anxiety Disorders
Oral

Usual dosage: 30 mg daily in divided doses.a c

Alternatively, administer a single daily dose at bedtime.a c Initial dosage: 15 mg at bedtime.a c

Gradually adjust dosage to 15–60 mg daily.a c

Seizure Disorders
Adjunctive Therapy for Partial Seizures
Oral

Initially, 7.5 mg 3 times daily; increase daily dosage by no more than 7.5 mg at weekly intervals.a c Do not exceed 90 mg daily.a c

Prescribing Limits

Pediatric Patients

Seizure Disorders
Adjunctive Therapy for Partial Seizures
Oral

Children 9–12 years of age: Maximum 60 mg daily.a c

Children >12 years of age: Maximum 90 mg daily.a c

Adults

Alcohol Withdrawal
Oral

Maximum 90 mg daily.a c

Seizure Disorders
Adjunctive Therapy for Partial Seizures
Oral

Maximum 90 mg daily.a c

Special Populations

Hepatic Impairment

Reduce dosage.b Use smallest effective dosage.a

Renal Impairment

No specific dosage recommendations.c

Geriatric or Debilitated Patients

Reduce initial dosage.c Adjust dosage gradually, with careful monitoring, to avoid oversedation.c

Anxiety Disorders

Initially, 7.5–15 mg daily in divided doses or as a single bedtime dose.a c

Cautions for Clorazepate Dipotassium

Contraindications

  • Known hypersensitivity to clorazepate.c

  • Many manufacturers state that benzodiazepines (including clorazepate) are contraindicated in patients with acute angle-closure glaucoma but may be administered to patients with open-angle glaucoma who are receiving appropriate therapy;b c however, clinical rationale for this contraindication has been questioned.b

Warnings/Precautions

Warnings

CNS Effects

Performance of activities requiring mental alertness and physical coordination may be impaired.b c

Concurrent use of other CNS depressants may cause additive or potentiated CNS depression.b c (See Specific Drugs under Interactions.)

Psychiatric Indications

Avoid use in patients with depressive neuroses or psychotic reactions in which anxiety is not prominent.b c

Abuse Potential

Possible tolerance, psychologic dependence, and physical dependence following prolonged use.b c

Patients with a history of drug or alcohol dependence or abuse are at risk of habituation or dependence; benzodiazepines generally should be used only with careful surveillance in such patients.c e f

Withdrawal Syndrome

Abrupt discontinuance may result in symptoms of withdrawal (similar to barbiturates).b c Symptoms may be relieved by tapering the dosage.b c

Fetal/Neonatal Morbidity

Retrospective studies suggest increased risk of congenital malformations in infants of mothers who received anxiolytics (chlordiazepoxide, diazepam, meprobamate) during the first trimester of pregnancy.b c Since use of anxiolytics is rarely urgent, their use during the first trimester almost always should be avoided.b c

General Precautions

Suicide

Use with caution in depressed patients; potential for suicidal tendencies.b c Prescribe and dispense drug in the smallest feasible quantity.b c

Laboratory Testing

Monitor blood counts and liver function tests periodically during prolonged therapy.b c

Specific Populations

Pregnancy

Category D.d (See Fetal/Neonatal Morbidity under Cautions.)

Lactation

Metabolite of clorazepate, desmethyldiazepam, is distributed into milk.c Discontinue nursing or the drug.c

Pediatric Use

Safety and efficacy not established in children <9 years of age.a c

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.c Possibility of greater sensitivity to the drug in some geriatric individuals.c

Use reduced initial dosage because of potential for greater sensitivity to the drug and because of greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease and drug therapy observed in the elderly.c (See Geriatric Patients under Dosage and Administration.) Monitor closely.c

Hepatic Impairment

Use with caution.b c

Renal Impairment

Use with caution.b c

Common Adverse Effects

Drowsiness,b c dizziness,b c nervousness,c blurred vision,b c dry mouth,b c headache,b c confusion,b c GI complaints.b c

Interactions for Clorazepate Dipotassium

Specific Drugs

Drug

Interaction

Comments

Antacids

Possible decrease in rate and extent of conversion of clorazepate to desmethyldiazepam;b however, manufacturer states that usual antacid dosages do not substantially alter clorazepate bioavailabilityc

Cimetidine

Decreased plasma clearance and increased plasma half-lives and concentrations of the benzodiazepine

Clinical importance not well established; consider possible need for clorazepate dosage reduction

CNS depressants (e.g., alcohol, anticonvulsants, antidepressants, barbiturates, hypnotics, opiates, phenothiazines)

Additive CNS depressionb c

Use with caution to avoid overdosageb c

Disulfiram

Possible inhibition of clorazepate metabolism

Use with caution; consider possible need for clorazepate dosage reduction

HIV protease inhibitors (e.g., amprenavir, fosamprenavir, ritonavir, saquinavir)

Possible increased benzodiazepine concentrations

Clinical importance not established; consider possible need for clorazepate dosage reduction

Clorazepate Dipotassium Pharmacokinetics

Absorption

Bioavailability

Rapidly decarboxylated in the GI tract and absorbed as desmethyldiazepam (nordiazepam).b c Rate of decarboxylation decreases as gastric pH increases.b

Distribution

Extent

Benzodiazepines are widely distributed into body tissues and cross the blood-brain barrier.b

Desmethyldiazepam is distributed into milk.c

Benzodiazepines and their metabolites generally cross the placenta.b

Plasma Protein Binding

Desmethyldiazepam: 97–98%.b c

Elimination

Metabolism

Rapidly decarboxylated in the GI tract to form desmethyldiazepam;b c further metabolized in the liver via hydroxylation and subsequent conjugation with glucuronic acid.b c g g Major active metabolites are desmethyldiazepam and oxazepam.b

Elimination Route

Excreted principally in urine.b c

Half-life

Metabolites: Desmethyldiazepam: 40–50 hours (range: 30–200 hours).b c Oxazepam: 3–21 hours.b

Special Populations

In geriatric patients and patients with liver disease, half-life of desmethyldiazepam may be prolonged.b

Benzodiazepines are not appreciably removed by hemodialysis.b

Stability

Storage

Oral

Tablets

Tight, light-resistant containers at <25°C.c

Protect from moisture.c In the presence of moisture, carbon dioxide may form, resulting in rapid tablet disintegration.a Do not remove desiccant packets from drug container.a

Actions

  • Effects appear to be mediated through the inhibitory neurotransmitter GABA; the site and mechanism of action within the CNS appear to involve a macromolecular complex (GABAA-receptor-chloride ionophore complex) that includes GABAA receptors, high-affinity benzodiazepine receptors, and chloride channels.

Advice to Patients

  • Potential for drug to impair mental alertness or physical coordination; avoid driving or operating machinery until effects on individual are known.b c

  • Importance of informing clinicians of any behavioral or mental changes, memory impairment, tolerance, or dependence/withdrawal symptoms.b c

  • Importance of taking only as prescribed; do not increase dosage or duration of therapy or abruptly discontinue drug unless otherwise instructed by a clinician.b c

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.b c Importance of not consuming alcoholic beverages.c

  • Importance of informing clinicians about any concomitant illnesses, particularly depression.c

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.b c

  • Importance of informing patients of other important precautionary information.b c (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule IV (C-IV) drug.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Clorazepate Dipotassium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

3.75 mg*

Clorazepate Dipotassium Tablets (C-IV; scored)

Mylan, Ranbaxy, Taro, Watson

GenXene (C-IV; scored)

Alra

Tranxene T-TAB (C-IV; scored)

Ovation

7.5 mg*

Clorazepate Dipotassium Tablets (C-IV; scored)

Mylan, Ranbaxy, Taro, Watson

GenXene (C-IV; scored)

Alra

Tranxene T-TAB (C-IV; scored)

Ovation

11.25 mg

Tranxene-SD Half Strength (C-IV)

Ovation

15 mg*

Clorazepate Dipotassium Tablets (C-IV; scored)

Mylan, Ranbaxy, Taro, Watson

GenXene (C-IV; scored)

Alra

Tranxene T-TAB (C-IV; scored)

Ovation

22.5 mg

Tranxene-SD (C-IV)

Ovation

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Clorazepate Dipotassium 15MG Tablets (MYLAN): 90/$121.99 or 270/$349.95

Clorazepate Dipotassium 3.75MG Tablets (MYLAN): 90/$68.99 or 270/$200.97

Clorazepate Dipotassium 7.5MG Tablets (MYLAN): 90/$84.99 or 270/$249.98

Tranxene-T 15MG Tablets (LUNDBECK): 90/$485.97 or 270/$1,375.98

Tranxene-T 3.75MG Tablets (LUNDBECK): 90/$287.28 or 270/$836.84

Tranxene-T 7.5MG Tablets (LUNDBECK): 90/$340.64 or 270/$987.75

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

a. AHFS drug information 2008. McEvoy GK, ed. Clorazepate dipotassium. Bethesda, MD: American Society of Health-System Pharmacists; 2008:2583-4.

b. AHFS drug information 2008. McEvoy GK, ed. Benzodiazepines general statement. Bethesda, MD: American Society of Health-System Pharmacists, 2008:2571-80.

c. Ovation Pharmaceuticals, Inc. Tranxene T-TAB, Tranxexe- SD, and Tranxene-SD Half Strength (clorazepate dipotassium) tablets prescribing information. Deerfield, IL; 2005 Apr.

d. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 7th ed. Baltimore, MD: Williams & Wilkins; 2005:358-9.

e. Sandoz. Oxazepam capsules prescribing information. Princeton, NJ; 2007 Nov.

f. Valeant. Librium (chlordiazepoxide hydrochloride) capsules prescribing information. Costa Mesa, CA; 2005 Jul

g. Charney DS, Mihic SJ, Harris RA. Hypnotics and sedatives. In: Brunton LL, Lazo JS, Parker KL, eds. Goodman and Gilman’s the pharmacologic basis of therapeutics. 11th ed. New York; McGraw-Hill; 2006:401-28.

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