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Clorazepate

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

Medically reviewed by Drugs.com on Nov 9, 2020. Written by ASHP.

Warning

Special Alerts:

[Posted 09/23/2020]

TOPIC: Benzodiazepine Drug Class: Drug Safety Communication - Boxed Warning Updated to Improve Safe Use

AUDIENCE: Patient, Health Professional, Pharmacy

ISSUE: The FDA is requiring the Boxed Warning, FDA's most prominent warning, be updated by adding other information to the prescribing information for all benzodiazepine medicines. This information will describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class. The FDA is also requiring updates to the existing patient Medication Guides to help educate patients and caregivers about these risks.

Other changes are also being required to several sections of the prescribing information, including to the Warnings and Precautions, Drug Abuse and Dependence, and Patient Counseling Information sections.

BACKGROUND: Benzodiazepines are a class of medicines approved to treat generalized anxiety disorder, insomnia, seizures, social phobia, and panic disorder.

RECOMMENDATION:

Health Care Professionals

  • Consider the patient's condition and the other medicines being taken, and assess the risk of abuse, misuse, and addiction, available at: [Web].

  • Limit the dosage and duration of each medicine to the minimum needed to achieve the desired clinical effect when prescribing benzodiazepines, alone or in combination with other medicines.

  • Use a gradual taper to reduce the dosage or to discontinue benzodiazepines to reduce the risk of acute withdrawal reactions.

  • Take precautions when benzodiazepines are used in combination with opioid addiction medications, available at: [Web].

Patients, Parents, and Caregivers

  • Always tell your health care professionals about all the prescription and over-the-counter (OTC) medicines you are taking or any other substances you are using, including alcohol.

  • Take benzodiazepines and all medicines exactly as prescribed by your health care professional

  • Discuss a plan for slowly decreasing the dose and frequency of your benzodiazepine(s) with your health care professional.

  • Contact your health care professional if you experience withdrawal symptoms or your medical condition worsens.

  • Go to an emergency room or call 911 if you have trouble breathing or other serious side effects such as seizures.

For more information visit the FDA website at: [Web] and [Web].

Warning

    Concomitant Use with Opiates
  • Concomitant use of benzodiazepines and opiates may result in profound sedation, respiratory depression, coma, and death.

  • Reserve concomitant use for patients in whom alternative treatment options are inadequate; use lowest effective dosages and shortest possible duration of concomitant therapy and monitor closely for respiratory depression and sedation. (See Specific Drugs under Interactions.)

Introduction

Benzodiazepine. Anxiolytic, sedative, anticonvulsant.

Uses for Clorazepate

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Alcohol Withdrawal

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

Anxiety Disorders

Management of anxiety disorders and short-term relief of symptoms of anxiety.

Seizure Disorders

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

Clorazepate 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.

  • Consider the long elimination half-life of clorazepate’s metabolites when making dosage adjustments. (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.

Anxiety

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

Seizures

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

Administration

Oral Administration

Administer orally in 1–4 doses daily.

Dispensing Considerations

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

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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

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. Do not exceed 60 mg daily.

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. Do not exceed 90 mg daily.

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.

Day 2: 45–90 mg in divided doses.

Day 3: 22.5–45 mg in divided doses.

Day 4: 15–30 mg in divided doses.

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

Anxiety Disorders
Oral

Usual dosage: 30 mg daily in divided doses.

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

Gradually adjust dosage to 15–60 mg daily.

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. Do not exceed 90 mg daily.

Prescribing Limits

Pediatric Patients

Seizure Disorders
Adjunctive Therapy for Partial Seizures
Oral

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

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

Adults

Alcohol Withdrawal
Oral

Maximum 90 mg daily.

Seizure Disorders
Adjunctive Therapy for Partial Seizures
Oral

Maximum 90 mg daily.

Special Populations

Hepatic Impairment

Reduce dosage. Use smallest effective dosage.

Renal Impairment

No specific dosage recommendations.

Geriatric or Debilitated Patients

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

Anxiety Disorders

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

Cautions for Clorazepate

Contraindications

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • Known hypersensitivity to clorazepate.

  • 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; however, clinical rationale for this contraindication has been questioned.

Warnings/Precautions

Warnings

Concomitant Use with Opiates

Concomitant use of benzodiazepines, including clorazepate, and opiates may result in profound sedation, respiratory depression, coma, and death. Substantial proportion of fatal opiate overdoses involve concurrent benzodiazepine use.

Reserve concomitant use of clorazepate and opiates for patients in whom alternative treatment options are inadequate. (See Specific Drugs under Interactions.)

CNS Effects

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

Concurrent use of other CNS depressants may cause additive or potentiated CNS depression. (See Concomitant Use with Opiates under Cautions and also see Specific Drugs under Interactions.)

Psychiatric Indications

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

Abuse Potential

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

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.

Withdrawal Syndrome

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

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. Since use of anxiolytics is rarely urgent, their use during the first trimester almost always should be avoided.

General Precautions

Suicide

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

Laboratory Testing

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

Specific Populations

Pregnancy

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

Lactation

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

Pediatric Use

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

Geriatric Use

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

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. (See Geriatric Patients under Dosage and Administration.) Monitor closely.

Hepatic Impairment

Use with caution.

Renal Impairment

Use with caution.

Common Adverse Effects

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

Interactions for Clorazepate

Specific Drugs

Drug

Interaction

Comments

Antacids

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

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, phenothiazines)

Additive CNS depression

Use with caution to avoid overdosage

Avoid alcohol use

Disulfiram

Possible inhibition of clorazepate metabolism

Use with caution; consider possible need for clorazepate dosage reduction

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

Possible increased benzodiazepine concentrations

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

Opiate agonists and partial agonists

Risk of profound sedation, respiratory depression, coma, or death

Whenever possible, avoid concomitant use

Opiate analgesics: Use concomitantly only if alternative treatment options are inadequate; use lowest effective dosages and shortest possible duration of concomitant therapy; monitor closely for respiratory depression and sedation

In patients receiving clorazepate, initiate opiate analgesic, if required, at reduced dosage and titrate based on clinical response

In patients receiving an opiate analgesic, initiate clorazepate at lower dosage than indicated in the absence of opiate therapy and titrate based on clinical response

Opiate antitussives: Avoid concomitant use

Consider offering naloxone to patients receiving benzodiazepines and opiates concomitantly

Clorazepate Pharmacokinetics

Absorption

Bioavailability

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

Distribution

Extent

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

Desmethyldiazepam is distributed into milk.

Benzodiazepines and their metabolites generally cross the placenta.

Plasma Protein Binding

Desmethyldiazepam: 97–98%.

Elimination

Metabolism

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

Elimination Route

Excreted principally in urine.

Half-life

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

Special Populations

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

Benzodiazepines are not appreciably removed by hemodialysis.

Stability

Storage

Oral

Tablets

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

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

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

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • Risk of potentially fatal additive effects (e.g., profound sedation, respiratory depression, coma) if used concomitantly with opiates either therapeutically or illicitly. Avoid concomitant use of opiate antitussives; also avoid concomitant use of opiate analgesics unless use is supervised by clinician.

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

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

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

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

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

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

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

Preparations

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

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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)

GenXene (C-IV; scored)

Alra

7.5 mg*

Clorazepate Dipotassium Tablets (C-IV; scored)

GenXene (C-IV; scored)

Alra

Tranxene T-TAB (C-IV; scored)

Recordati

15 mg*

Clorazepate Dipotassium Tablets (C-IV; scored)

GenXene (C-IV; scored)

Alra

AHFS DI Essentials™. © Copyright 2022, Selected Revisions November 9, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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