Clorazepate Dipotassium

Pronunciation

Pronunciation: klor-AZ-e-PATE DYE-poe-TAS-ee-um
Class: Benzodiazepine

Trade Names

Tranxene T-Tab
- Tablets, oral 3.75 mg
- Tablets, oral 7.5 mg
- Tablets, oral 15 mg

Apo-Clorazepate (Canada)

Pharmacology

Potentiates action of GABA, inhibitory neurotransmitter, resulting in increased neuronal inhibition and CNS depression, especially in limbic system and reticular formation.

Slideshow: Flashback: FDA Drug Approvals 2013

Pharmacokinetics

Distribution

97% to 98% protein bound.

Metabolism

Rapidly decarboxylated to form nordiazepam. Nordiazepam is further metabolized by hydroxylation. Major urinary metabolite is conjugated oxazepam (3-hydroxynordiazepam), and smaller amounts of conjugated p-hydroxynordiazepam and nordiazepam are also found in the urine.

Elimination

Excreted in urine (62% to 67%) and feces (15% to 19%). The half-life is 40 to 50 h.

Indications and Usage

Management of anxiety disorders or short-term relief of symptoms of anxiety; relief of acute alcohol withdrawal symptoms; adjunctive therapy in management of partial seizures.

Unlabeled Uses

Tardive dyskinesia.

Contraindications

Hypersensitivity to any component of the product; acute narrow-angle glaucoma.

Dosage and Administration

Acute Alcohol Withdrawal
Adults Day 1

PO Initial dose is 30 mg, then 30 to 60 mg in divided doses.

Day 2

PO 45 to 90 mg in divided doses (max, 90 mg/day).

Day 3

PO 22.5 to 45 mg in divided doses.

Day 4

PO 15 to 30 mg in divided doses.

Beyond day 4

PO Gradually reduce to 7.5 to 15 mg/day; avoid excessive reductions in the total amount of drug administered on successive days. Discontinue when patient is stable.

Anxiety
Adults

PO 30 mg/day in divided doses. Adjust dose gradually within the range of 15 to 60 mg/day in divided doses.

Single bedtime dosing

PO Initial dose is 15 mg; response of the patient may require subsequent dosage adjustment.

Elderly or Debilitated Patients

PO Initial dose is 7.5 to 15 mg/day.

Partial Seizures
Adults and Children older than 12 y

PO 7.5 mg 3 times daily initially; increase by no more than 7.5 mg/wk (max, 90 mg/day).

Children 9 to 12 y of age

PO 7.5 mg twice daily initially; increase by no more than 7.5 mg/wk (max, 60 mg/day).

General Advice

  • Administer with or without food.
  • Drowsiness may occur at the initiation of treatment and with dosage increases.
  • Avoid abrupt discontinuation after extended therapy. Follow a gradual tapering schedule.

Storage/Stability

Store at 68° to 77°F.

Drug Interactions

Alcohol and CNS depressants (eg, antidepressants, barbiturates, MAOIs, opioid analgesics, phenothiazines)

Possible additive CNS depressant effects (eg, impaired psychomotor function, increased sedation). Avoid coadministration.

Cimetidine, disulfiram, oral contraceptives

May increase effects of clorazepate, with excessive sedation and impaired psychomotor function.

Clozapine

Delirium, sedation, sialorrhea, and ataxia may occur. Severe orthostatic hypotension and respiratory depression may occur when clozapine is added to, or started with, clorazepate. Do not start agents simultaneously. The addition of clorazepate to an established clozapine regimen may carry less risk than adding clozapine to clorazepate. Careful clinical monitoring is warranted, especially during the first 48 h of coadministration.

Digoxin

Digoxin plasma concentrations may be increased. Toxicity, characterized by GI and neuropsychiatric symptoms and cardiac arrhythmias, may occur. Monitor digoxin plasma concentrations and adjust digoxin dosage as needed.

Hydantoins (eg, phenytoin)

Clorazepate pharmacologic effects may be reduced. Hydantoin plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Close clinical and plasma concentration monitoring is warranted.

Methadone

Coadministration may substantially increase the potential of a fatal outcome because of potentiation of respiratory depressant effects. Use with caution.

Nefazodone

Nefazodone may decrease the metabolism of clorazepate, increasing the pharmacologic effects and risk of adverse reactions. Clorazepate dosage reduction may be needed.

Omeprazole

Clorazepate pharmacologic effects and risk of adverse reactions may be increased. Toxicity may occur. If an interaction is suspected, lower the dosage of clorazepate or discontinue one or both drugs.

Protease inhibitors (eg, saquinavir)

The risk of serious CNS depression may be increased. Avoid coadministration.

Rifamycins (eg, rifampin)

Pharmacologic effects of clorazepate may be decreased. Larger dosages of clorazepate may be needed.

Sodium oxybate

Concurrent use may result in an increase in sleep duration and CNS depression. Coadministration is contraindicated.

Theophyllines

May antagonize sedative effects of clorazepate. Monitor the clinical response and adjust the clorazepate dose as needed.

Valproic acid

Toxicity of clorazepate may be increased, while the therapeutic effects of both drugs may be reduced (increased seizure risk). Teratogenic effects of both agents during the first trimester may be enhanced. Avoid coadministration during early pregnancy.

Adverse Reactions

Cardiovascular

Decrease in systolic BP.

CNS

Ataxia; confusion; depression; dizziness; drowsiness; fatigue; headache; insomnia; irritability; nervousness; slurred speech; tremor.

Dermatologic

Transient skin rash.

EENT

Blurred vision; diplopia.

GI

Dry mouth; GI complaints.

Miscellaneous

Abnormal liver and kidney function tests; decrease in Hct; GU complaints.

Precautions

Monitor

Ensure that CBC with differential and liver enzymes is evaluated periodically in patients on prolonged therapy. Frequently assess patients for response to treatment. Ensure that therapy is periodically reviewed to determine if it needs to be continued without change or if a dose change (eg, increase, decrease, discontinuation) is indicated. Monitor patients for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.


Pregnancy

Category undetermined. Avoid use in pregnancy.

Lactation

Excreted in breast milk. Avoid use during breast-feeding.

Children

Not recommended in children younger than 9 y.

Elderly

Elderly patients are especially sensitive to the effects of benzodiazepines. Per the Beers list, avoid use for the treatment of agitation, delirium, or insomnia in elderly patients.

Renal Function

Observe caution to avoid accumulation of drug.

Hepatic Function

Observe caution to avoid accumulation of drug.

Hazardous Tasks

Patients should avoid engaging in hazardous occupations requiring mental alertness, such as driving or operating dangerous machinery.

Debilitated patients

Initial dose should be small and gradually increased.

Drug dependency

Prolonged use may lead to dependence.

Psychiatric disorders

Not intended for use in depressive neuroses or in psychotic reactions.

Suicidal behavior and ideation

Antiepileptic drugs increase the risk of suicidal thoughts or behavior.

Withdrawal

Withdrawal syndrome has occurred within 4 to 6 wk of treatment, especially if abruptly discontinued. If treatment is to be discontinued or the dose reduced, gradually taper the dose. Avoid abrupt discontinuation.

Overdosage

Symptoms

CNS depression ranging from slight sedation to coma; hypotension.

Patient Information

  • Advise patients or caregivers to read the Medication Guide before starting therapy and with each refill.
  • Instruct patients with seizure disorder to continue to take other medications for the condition unless advised otherwise by health care provider.
  • Advise patients that medication is usually started at a low dose and then gradually increased until maximum benefit is obtained.
  • Caution patients that medication may be habit-forming and to take as prescribed and not to stop taking or change the dose unless advised by health care provider.
  • Advise patients to take each dose without regard to meals, but to take with food if stomach upset occurs.
  • Advise patients that if medication needs to be discontinued, it will be slowly withdrawn unless safety concerns (eg, rash) require a more rapid withdrawal.
  • Instruct patients to avoid alcoholic beverages and other depressants while taking this medication.
  • Instruct patients to contact health care provider if symptoms (eg, anxiety, panic attacks, seizures) do not appear to be getting better or are getting worse, or if bothersome adverse reactions (eg, drowsiness, memory impairment) occur.
  • Advise patients that drug may cause drowsiness or impair judgment, thinking, or reflexes and to use caution while driving or performing other tasks requiring mental alertness until tolerance is determined.
  • Encourage patients with seizure disorder to carry identification (eg, Medic Alert ) indicating condition and medication being used as treatment.
  • Counsel patients, caregivers, and families that antiepileptic drugs may increase the risk of suicidal thoughts and behaviors, and advise them of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts of self-harm. Instruct them to immediately report behaviors of concern.
  • Instruct patients to notify their health care provider if they become pregnant or intend to become pregnant during therapy. Encourage patients to enroll in the North American Antiepileptic Drug Pregnancy Registry if they become pregnant.

Copyright © 2009 Wolters Kluwer Health.

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