ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Clorazepate: Drug information

Clorazepate: Drug information
(For additional information see "Clorazepate: Patient drug information" and see "Clorazepate: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning
Risks from concomitant use with opioids:

Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms or respiratory depression and sedation.

Abuse, misuse, and addiction:

The use of benzodiazepines, including clorazepate, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing clorazepate and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction.

Dependence and withdrawal reactions:

The continued use of benzodiazepines, including clorazepate, may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Abrupt discontinuation or rapid dosage reduction of clorazepate after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use a gradual taper to discontinue clorazepate or reduce the dosage.

Brand Names: US
  • Tranxene-T [DSC]
Pharmacologic Category
  • Antiseizure Agent, Benzodiazepine;
  • Benzodiazepine
Dosing: Adult

Dosage guidance:

Safety: Reduce dose or avoid use in patients receiving opioids or with significant chronic disease (eg, respiratory compromise) (Ref). Avoid use in patients with a history of substance use, misuse of medications, or depression (Ref).

Anxiety disorders

Anxiety disorders (adjunctive therapy or monotherapy) (alternative agent):

Note: Generally used short term for symptom relief until preferred therapy (eg, serotonin reuptake inhibitor) is effective (eg, 4 to 6 weeks followed by tapering). Long-term, low-dose therapy (eg, 3.75 mg) may be considered in select patients only when other treatments are ineffective or poorly tolerated (Ref). Use with caution in patients with comorbid posttraumatic stress disorder; benzodiazepines may worsen symptoms (Ref).

Initial: Oral: 7.5 to 15 mg at bedtime or 7.5 mg 2 to 3 times daily; if needed, may increase daily dose gradually (eg, in 7.5 mg increments every 3 to 4 days) based on response and tolerability up to 60 mg/day in 3 to 4 divided doses (Ref). Usual dosage: 30 mg/day in divided doses.

Focal onset seizures

Focal (partial) onset seizures (adjunctive therapy):

Note: FDA-approved for focal (partial) onset seizures; however, also used off label in other seizure types, including myoclonic and atonic seizures (Ref).

Initial: Ora l: Up to 7.5 mg 3 times daily; increase daily dose in ≤7.5 mg increments at weekly intervals; maximum dose: 90 mg/day.

Discontinuation of therapy: Unless safety concerns require a more rapid withdrawal, gradually taper to detect reemerging symptoms and minimize rebound and withdrawal symptoms (Ref).

Low or moderate dose, no concerns for benzodiazepine use disorder: Taper total daily dose by 20% to 25% every week based on response and tolerability (taper increments will be limited by available dosage forms) (Ref).

Extended or high-dose therapy, or suspected benzodiazepine use disorder: Taper total daily dose by ~25% every 1 to 2 weeks based on response, tolerability and individual patient factors (taper increments will be limited by available dosage forms) (Ref). Reduce dose more rapidly in the beginning, and slow the dose reduction as the taper progresses because earlier stages of withdrawal are easier to tolerate (Ref). The optimal duration and taper increment will vary; up to 6 months may be necessary for some patients on higher doses, and a taper rate of 50% every week may be tolerated in some patients (Ref).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling. Use with caution; clorazepate is primarily excreted in urine.

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling. Use with caution; clorazepate undergoes hepatic metabolism.

Dosing: Older Adult

If use is necessary, start with low doses and titrate slowly to effect.

Anxiety disorders: Oral: Initial: 7.5 to 15 mg/day

Focal (partial) onset seizures: Refer to adult dosing.

Dosing: Pediatric

(For additional information see "Clorazepate: Pediatric drug information")

Partial seizures, adjunctive therapy

Partial seizures, adjunctive therapy:

Children <9 years: Limited data available: Oral: Initial: 0.3 to 0.75 mg/kg/day in 1 to 3 divided doses or 3.75 mg once to three times daily; maximum initial daily dose: 1 mg/kg/day. Titrate weekly as needed; maximum daily dose: 3 mg/kg/day or 60 mg/day, whichever is less. In trials, subjects observed as having an excellent response reported a mean dose range of 0.79 to 1.33 mg/kg/day (Ref).

Children 9 to 12 years: Oral: Initial: Up to 7.5 mg twice daily; increase in ≤7.5 mg increments at weekly intervals, maximum daily dose: 60 mg/day.

Adolescents: Oral: Initial: Up to 7.5 mg 3 times daily; increase in ≤7.5 mg increments at weekly intervals; usual dose range: 0.5 to 1 mg/kg/day; maximum daily dose: 90 mg/day.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling; use with caution.

Dosing: Hepatic Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling; use with caution.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

Frequency not defined:

Cardiovascular: Systolic hypotension

Dermatologic: Skin rash

Gastrointestinal: Gastrointestinal signs and symptoms, xerostomia

Genitourinary: Genitourinary signs and symptoms

Hematologic & oncologic: Decreased hematocrit

Hepatic: Abnormal hepatic function tests

Nervous system: Ataxia, confusion, depression, dizziness, drowsiness, drug abuse, drug dependence, fatigue, headache, insomnia, irritability, nervousness, slurred speech, suicidal ideation, suicidal tendencies, tremor

Ophthalmic: Blurred vision, diplopia

Renal: Renal function test abnormality

Contraindications

Hypersensitivity to clorazepate or any component of the formulation; acute narrow-angle glaucoma

Canadian labeling: Additional contraindications (not in US labeling): Myasthenia gravis.

Warnings/Precautions

Concerns related to adverse effects:

• Anterograde amnesia: Benzodiazepines have been associated with anterograde amnesia (Nelson 1999).

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).

• Paradoxical reactions: Paradoxical reactions, including hyperactive or aggressive behavior, have been reported with benzodiazepines; risk may be increased in adolescent/pediatric patients, geriatric patients, or patients with a history of alcohol use disorder or psychiatric/personality disorders (Mancuso 2004).

• Sleep-related activities: Hazardous sleep-related activities such as sleep-driving, cooking and eating food, and making phone calls while asleep have been noted with benzodiazepines (Dolder 2008).

• Suicidal ideation: Pooled analysis of trials involving various antiseizure medications (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify health care provider immediately if symptoms occur.

Disease-related concerns:

• Depression: Avoid use in patients with depression because of concerns about worsening mood symptoms, particularly if suicidal risk may be present, except for acute or emergency situations (eg, acute agitation, status epilepticus) (Craske 2022).

• Hepatic impairment: Use with caution in patients with hepatic impairment.

• Renal impairment: Use with caution in patients with renal impairment.

• Respiratory disease: Reduce dose or avoid use in patients with respiratory disease, including chronic obstructive pulmonary disease or sleep apnea. Benzodiazepines may cause significant respiratory depression.

Special populations:

• Debilitated patients: Use with caution in patients who are debilitated (eg, patients with organ dysfunction, comorbid conditions); dosage adjustment recommended.

• Older adult: Avoid or use with extreme caution in older adult patients. Older adult patients may be at an increased risk of death with use; risk has been found highest within the first 4 months of use in older adult dementia patients (Jennum 2015; Saarelainen 2018).

• Fall risk: Use with extreme caution in patients who are at risk of falls; benzodiazepines have been associated with falls and traumatic injury (Nelson 1999).

Other warnings/precautions:

• Abuse, misuse, and substance use disorder: Counsel patients at increased risk on proper use and monitoring for signs and symptoms of abuse, misuse, and substance use disorder. Institute early treatment or refer patients in whom substance use disorder is suspected. Limit dosages and durations to the minimum required.

• Appropriate use: Does not have analgesic, antidepressant, or antipsychotic properties. Not recommended for use in psychotic reactions.

• Dependence and withdrawal reactions: Some patients may develop a protracted withdrawal syndrome lasting >12 months; may be difficult to differentiate withdrawal symptoms from reemergence or continuation of symptoms for which benzodiazepines were prescribed. Flumazenil may cause withdrawal in patients receiving long-term benzodiazepine therapy.

• Tolerance: Clorazepate is a long half-life benzodiazepine. Duration of action after a single dose is determined by redistribution rather than metabolism. Tolerance develops to the antiseizure effects. It does not develop to the anxiolytic effects (Vinkers 2012). Chronic use of this agent may increase the perioperative benzodiazepine dose needed to achieve desired effect.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, Oral, as dipotassium:

Tranxene-T: 7.5 mg [DSC] [contains fd&c yellow #6 (sunset yellow)]

Generic: 3.75 mg, 7.5 mg, 15 mg

Generic Equivalent Available: US

Yes

Pricing: US

Tablets (Clorazepate Dipotassium Oral)

3.75 mg (per each): $1.19 - $4.03

7.5 mg (per each): $1.67 - $5.02

15 mg (per each): $2.75 - $5.45

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Generic: 3.75 mg, 7.5 mg, 15 mg

Controlled Substance

C-IV

Administration: Adult

May administer with food or water to decrease GI upset.

Administration: Pediatric

Oral: May administer with food or water to decrease GI upset

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/017105s085lbl.pdf#page=14, must be dispensed with this medication.

Use: Labeled Indications

Anxiety disorders: Management of anxiety disorders and short-term relief of the symptoms of anxiety.

Focal (partial) onset seizures: Adjunct therapy in the management of focal (partial) onset seizures.

Medication Safety Issues
Sound-alike/look-alike issues:

Clorazepate may be confused with clofibrate, clonazepam, KlonoPIN

Older Adult: High-Risk Medication:

Beers Criteria: Clorazepate is identified in the Beers Criteria as a potentially inappropriate medication to be avoided in patients 65 years and older due to risk of abuse, misuse, physical dependence, and addiction. In addition, older adults have an increased risk of impaired cognition, delirium, falls, fractures, and motor vehicle accidents with benzodiazepine use. Older adults also have slower metabolism of long-acting benzodiazepines (eg, clorazepate). However, benzodiazepines may be appropriate in the elderly when used for seizure disorders, rapid eye movement sleep behavior disorder, benzodiazepine or ethanol withdrawal, severe generalized anxiety disorder, or periprocedural anesthesia (Beers Criteria [AGS 2023]).

Metabolism/Transport Effects

Substrate of CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification

Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification

Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy

CloZAPine: Benzodiazepines may enhance the adverse/toxic effect of CloZAPine. Management: Consider decreasing the dose of (or possibly discontinuing) benzodiazepines prior to initiating clozapine. Monitor for respiratory depression, hypotension, and other toxicities if these agents are combined. Risk D: Consider therapy modification

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy

Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification

Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Doxylamine: CNS Depressants may enhance the CNS depressant effect of Doxylamine. Risk C: Monitor therapy

DroPERidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification

Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification

Fosamprenavir: May increase the serum concentration of Clorazepate. Risk C: Monitor therapy

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification

Ilaprazole: May increase the serum concentration of Benzodiazepines. Risk C: Monitor therapy

Ixabepilone: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification

Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Melatonin: May enhance the sedative effect of Benzodiazepines. Risk C: Monitor therapy

Methadone: Benzodiazepines may enhance the CNS depressant effect of Methadone. Management: Clinicians should generally avoid concurrent use of methadone and benzodiazepines when possible; any combined use should be undertaken with extra caution. Risk D: Consider therapy modification

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification

Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Nirmatrelvir and Ritonavir: May increase the serum concentration of Clorazepate. Risk C: Monitor therapy

OLANZapine: Benzodiazepines may enhance the adverse/toxic effect of OLANZapine. Management: Monitor closely for hypotension, respiratory or central nervous system depression, and bradycardia if olanzapine is combined with benzodiazepines. Use of parenteral benzodiazepines with IM olanzapine is not recommended. Risk C: Monitor therapy

Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Oxybate Salt Products: Benzodiazepines may enhance the CNS depressant effect of Oxybate Salt Products. Risk X: Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy

Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Ritonavir: May increase the serum concentration of Clorazepate. Risk C: Monitor therapy

Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy

Saquinavir: May increase the serum concentration of Clorazepate. Risk C: Monitor therapy

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

Teduglutide: May increase the serum concentration of Benzodiazepines. Risk C: Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination

Theophylline Derivatives: May diminish the therapeutic effect of Benzodiazepines. Risk C: Monitor therapy

Tobacco (Smoked): May decrease serum concentrations of the active metabolite(s) of Clorazepate. Risk C: Monitor therapy

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Yohimbine: May diminish the therapeutic effect of Antianxiety Agents. Risk C: Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification

Zuranolone: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. Risk D: Consider therapy modification

Reproductive Considerations

Therapy for anxiety should be individualized (BAP [McAllister-Williams 2017]); avoid the use of benzodiazepines for the treatment of anxiety disorders in patients planning to become pregnant (Larsen 2015).

Pregnancy Considerations

Nordiazepam, the active metabolite of clorazepate, crosses the placenta and is measurable in cord blood and amniotic fluid (Rey 1979).

In-utero exposure to benzodiazepines has the potential to cause harm to the fetus. Teratogenic effects have been observed in some studies; however, a clear association has not been reported and additional data are needed (Bellantuono 2013; Freeman 2018; Grigoriadis 2019; Noh 2022; Szpunar 2022; Tinker 2019; Wikner 2007). Exposure to a benzodiazepine late in pregnancy may cause neonatal sedation (hypotonia, lethargy, respiratory depression) and/or symptoms of neonatal withdrawal (feeding difficulties, hyperreflexia, inconsolable crying, irritability, restlessness, tremors). Data related to long-term effects on neurodevelopment are inconclusive (Chen 2022; Radojčić 2017; Sundbakk 2022; Wang 2022). Newborns exposed to clorazepate in utero should be monitored for feeding problems, respiratory depression, sedation, and withdrawal.

Therapy for anxiety during pregnancy should be individualized. Untreated or inadequately treated psychiatric illness may lead to poor adherence to prenatal care and adverse pregnancy outcomes (ACOG 2008). Benzodiazepines are not preferred when pharmacologic treatment for anxiety disorders is needed during pregnancy (BAP [McAllister-Williams 2017]; Larsen 2015) and when a benzodiazepine is needed, the use of clorazepate is not preferred. If possible, avoid scheduled doses of benzodiazepines in the month prior to delivery to reduce the risk of withdrawal symptoms in the newborn (Larsen 2015).

When treating pregnant patients for seizure disorders, monotherapy with the lowest effective dose and avoidance of medications known to have a high incidence of teratogenic effects is recommended (Harden 2009; Wlodarczyk 2012).

Data collection to monitor pregnancy and infant outcomes following exposure to clorazepate is ongoing. Health care providers are encouraged to enroll patients exposed to clorazepate during pregnancy in the National Pregnancy Registry for Psychiatric Medications (1-866-961-2388).

Breastfeeding Considerations

Nordiazepam, the active metabolite of clorazepate, is present in breast milk (Rey 1979).

Following a single dose of clorazepate 20 mg IM to 7 postpartum patients, nordiazepam was measurable in the serum of breastfeeding infants for 4 days following the injection (Rey 1979). Drowsiness, lethargy, or weight loss in breastfeeding infants have been observed in case reports following maternal use of some benzodiazepines (Iqbal 2002).

Breastfeeding during benzodiazepine therapy is not recommended due to the potential for drowsiness in the breastfed infant (Larsen 2015); breastfeeding during clorazepate therapy is not recommended by the manufacturer. If a benzodiazepine is needed in breastfeeding patients, the use of a short-acting agent is preferred, and infants should be monitored (WHO 2002).

Monitoring Parameters

Excessive CNS depression, respiratory rate, and cardiovascular status; with prolonged use: CBC, liver enzymes, renal function; signs and symptoms of suicidality (eg, anxiety, depression, behavior changes).

Mechanism of Action

Long-acting benzodiazepine (Griffin 2013). Binds to stereospecific benzodiazepine receptors on the postsynaptic GABA neuron at several sites within the central nervous system, including the limbic system and 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. Benzodiazepine receptors and effects appear to be linked to the GABA-A receptors. Benzodiazepines do not bind to GABA-B receptors (Nelson 1999).

Pharmacokinetics (Adult Data Unless Noted)

Duration of action: Classified as a long-acting benzodiazepine; classification based on benzodiazepines with half-life >40 hours (Griffin 2013).

Distribution: Nordiazepam: Vd: 0.7 to 2.2 L/kg (Riss, 2008)

Protein binding: Nordiazepam: 97% to 98%

Metabolism: Rapidly decarboxylated to nordiazepam (active) in acidic stomach prior to absorption; nordiazepam is hepatically hydroxylated by CYP 2C19 and CYP3A4 to oxazepam (active) and undergoes glucuronidation to form a glucuronide conjugate (Riss, 2008)

Half-life elimination: Nordiazepam: 20 to 160 hours; Oxazepam: 6 to 24 hours (Riss, 2008)

Time to peak, serum: ~0.5 to 2 hours (Carrigan, 1977; Riss, 2008)

Excretion: Urine (62% to 67%; primarily metabolites of conjugated oxazepam); feces (15% to 19%)

Brand Names: International
International Brand Names by Country
For country code abbreviations (show table)

  • (AE) United Arab Emirates: Tranxene;
  • (AR) Argentina: Justum | Moderane | Modiur Disgrelent | Tencilan | Tranxilium;
  • (AT) Austria: Tranxilium;
  • (BE) Belgium: Tranxene | Uni-tranxene;
  • (BG) Bulgaria: Tranxene;
  • (BR) Brazil: Tranxilene;
  • (CH) Switzerland: Clorazepate zentiva | Tranxilium;
  • (CL) Chile: Calner | Modival | Tranxilium;
  • (CZ) Czech Republic: Tranxene;
  • (DE) Germany: Tranxilium;
  • (DO) Dominican Republic: Nansius | Tranxene;
  • (EC) Ecuador: Tranxene;
  • (EE) Estonia: Tranxene;
  • (EG) Egypt: Tranxene;
  • (ES) Spain: Clorazepato Normon | Nansius | Tranxilium;
  • (FI) Finland: Anxidin | Tranxilen;
  • (FR) France: Clorazepate dipota | Tranxene;
  • (GB) United Kingdom: Tranxene;
  • (GR) Greece: Tranxene;
  • (HK) Hong Kong: Tranxene;
  • (ID) Indonesia: Tranxene;
  • (IE) Ireland: Tranxene;
  • (IL) Israel: Tranxal;
  • (IT) Italy: Transene;
  • (JO) Jordan: Tranxene;
  • (JP) Japan: Mendon;
  • (KR) Korea, Republic of: Tranxene | Trisan;
  • (LB) Lebanon: Tranxene;
  • (LT) Lithuania: Tranxene;
  • (LU) Luxembourg: Tranxene;
  • (LV) Latvia: Tranxene;
  • (MA) Morocco: Tranxene | Tranxilium;
  • (MX) Mexico: Tranxene;
  • (MY) Malaysia: Apo-clorazepate | Sanor | Tranxene;
  • (NL) Netherlands: Clorazepaat | Clorazepaatdik | Clorazepaatdikalium pch | Tranxene | Tranxilium;
  • (PE) Peru: Ansiopaz | Tranxene;
  • (PH) Philippines: Tranxene;
  • (PK) Pakistan: Tranconil | Tranxene;
  • (PL) Poland: Cloranxen | Tranxene;
  • (PT) Portugal: Medipax | Tranxene;
  • (RU) Russian Federation: Tranxene;
  • (SA) Saudi Arabia: Tranxene;
  • (SE) Sweden: Tranxilen;
  • (SG) Singapore: Tranxene;
  • (SI) Slovenia: Tranxene;
  • (SK) Slovakia: Tranxene;
  • (TH) Thailand: Anxielax | Cexene | Chloraze | Cloramed | Cloraxene | Clozene | Deda | Diposep | Dipot | Dipotassium chlorazepate | Flulium | Frexene | Gaxene | Manotran | Polizep | Pomadom | Posene | Sanor | Serene | Trancap | Tranclor | Trancon | Tranmed | Tranpate | Tranpon | Transon | Tranxene | Tranzep | Uptran | Zetran-5;
  • (TN) Tunisia: Tranxene;
  • (TR) Turkey: Anksen | Tranxilene;
  • (TW) Taiwan: Clozene | Tranxene | Tranxilium;
  • (UA) Ukraine: Tranxene;
  • (UY) Uruguay: Ansiopax | Tranxene;
  • (VE) Venezuela, Bolivarian Republic of: Tranxen;
  • (ZA) South Africa: Tranxene
  1. 2023 American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2023 updated AGS Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2023;71(7):2052-2081. doi:10.1111/jgs.18372 [PubMed 37139824]
  2. American College of Obstetricians and Gynecologists (ACOG) Committee on Practice Bulletins--Obstetrics. ACOG Practice Bulletin No. 92: Use of psychiatric medications during pregnancy and lactation. Obstet Gynecol. 2008;111(4):1001-1020. doi:10.1097/AOG.0b013e31816fd910 [PubMed 18378767]
  3. American Society of Addiction Medicine (ASAM). The ASAM clinical practice guideline on alcohol withdrawal management. J Addict Med. 2020;14(3S)(suppl 1):1-72. doi:10.1097/ADM.0000000000000668 [PubMed 32511109]
  4. Bandelow B, Allgulander C, Baldwin DS, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for treatment of anxiety, obsessive-compulsive and posttraumatic stress disorders - version 3. Part I: anxiety disorders. World J Biol Psychiatry. 2023;24(2):79-117. doi:10.1080/15622975.2022.2086295 [PubMed 35900161]
  5. Bellantuono C, Tofani S, Di Sciascio G, Santone G. Benzodiazepine exposure in pregnancy and risk of major malformations: a critical overview. Gen Hosp Psychiatry. 2013;35(1):3-8. doi:10.1016/j.genhosppsych.2012.09.003 [PubMed 23044244]
  6. Carrigan PJ, Chao GC, Barker WM, Hoffman DJ, Chun AH. Steady-state bioavailability of two clorazepate dipotassium dosage forms. J Clin Pharmacol. 1977;17(1):18-28. [PubMed 13089]
  7. Chen VC, Wu SI, Lin CF, et al. Association of prenatal exposure to benzodiazepines with development of autism spectrum and attention-deficit/hyperactivity disorders. JAMA Netw Open. 2022;5(11):e2243282. doi:10.1001/jamanetworkopen.2022.43282 [PubMed 36413366]
  8. Clorazepate [product monograph]. Vaughan, Ontario, Canada: AA Pharma Inc; December 2021.
  9. Clorazepate dipotassium tablets, USP [prescribing information]. East Windsor, NJ: Novitium Pharma LLC; February 2023.
  10. Clorazepate dipotassium tablets, USP [prescribing information]. Hawthrone, NY: Taro Pharmaceuticals U.S.A., Inc; November 2023.
  11. Craske M, Bystritsky A. Generalized anxiety disorder in adults: management. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed January 19, 2022.
  12. Currow DC, Agar MR. Benzodiazepine prescribing in people with chronic obstructive pulmonary disease: clinical considerations. Drugs Aging. 2020;37(4):263-270. doi:10.1007/s40266-020-00756-z [PubMed 32107742]
  13. Dolder CR, Nelson MH. Hypnosedative-induced complex behaviours: incidence, mechanisms and management. CNS Drugs. 2008;22(12):1021-1036. doi:10.2165/0023210-200822120-00005. [PubMed 18998740]
  14. Freeman MP, Góez-Mogollón L, McInerney KA, et al. Obstetrical and neonatal outcomes after benzodiazepine exposure during pregnancy: results from a prospective registry of women with psychiatric disorders. Gen Hosp Psychiatry. 2018;53:73-79. doi:10.1016/j.genhosppsych.2018.05.010 [PubMed 29958100]
  15. Fujii T, Okuno T, Go T, et al, “Clorazepate Therapy for Intractable Epilepsy,” Brain Dev, 1987, 9(3):288-91. [PubMed 2889387]
  16. Grigoriadis S, Graves L, Peer M, et al. Benzodiazepine use during pregnancy alone or in combination with an antidepressant and congenital malformations: systematic review and meta-analysis. J Clin Psychiatry. 2019;80(4):18r12412. doi:10.4088/JCP.18r12412 [PubMed 31294935]
  17. Griffin CE 3rd, Kaye AM, Bueno FR, Kaye AD. Benzodiazepine pharmacology and central nervous system-mediated effects. Ochsner J. 2013;13(2):214-223. [PubMed 23789008]
  18. Harden CL, Meador KJ, Pennell PB, et al, "Practice Parameter Update: Management Issues for Women With Epilepsy-Focus on Pregnancy (an Evidence-Based Review): Teratogenesis and Perinatal Outcomes: Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society," Neurology, 2009, 73(2):133-41. [PubMed 19398681]
  19. Iqbal MM, Sobhan T, Ryals T. Effects of commonly used benzodiazepines on the fetus, the neonate, and the nursing infant. Psychiatr Serv. 2002;53(1):39-49. [PubMed 11773648]
  20. Jennum P, Baandrup L, Ibsen R, et al. Increased all-cause mortality with use of psychotropic medication in dementia patients and controls: A population-based register study. Eur Neuropsychopharmacol. 2015;25(11):1906-1913. doi: 10.1016/j.euroneuro.2015.08.014. [PubMed 26342397]
  21. Katzman MA, Bleau P, Blier P, et al; Canadian Anxiety Guidelines Initiative Group on behalf of the Anxiety Disorders Association of Canada/Association Canadienne des troubles anxieux and McGill University. Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders. BMC Psychiatry. 2014;14(suppl 1):S1. doi:10.1186/1471-244X-14-S1-S1 [PubMed 25081580]
  22. Lader M. Benzodiazepines revisited--will we ever learn? Addiction. 2011;106(12):2086‐2109. doi:10.1111/j.1360-0443.2011.03563.x [PubMed 21714826]
  23. Larsen ER, Damkier P, Pedersen LH, et al; Danish Psychiatric Society; Danish Society of Obstetrics and Gynecology; Danish Paediatric Society; Danish Society of Clinical Pharmacology. Use of psychotropic drugs during pregnancy and breast-feeding. Acta Psychiatr Scand Suppl. 2015;(445):1-28. doi:10.1111/acps.12479 [PubMed 26344706]
  24. Mancuso CE, Tanzi MG, Gabay M. Paradoxical reactions to benzodiazepines: literature review and treatment options. Pharmacotherapy. 2004;24(9):1177-1185. [PubMed 15460178]
  25. McAllister-Williams RH, Baldwin DS, Cantwell R, et al. British Association for Psychopharmacology consensus guidance on the use of psychotropic medication preconception, in pregnancy and postpartum 2017. J Psychopharmacol. 2017;31(5):519-552. doi:10.1177/0269881117699361 [PubMed 28440103]
  26. Menninger JA. Assessment and treatment of alcoholism and substance-related disorders in the elderly. Bull Menninger Clin. 2002;66(2):166-183. [PubMed 12141383]
  27. Mimaki T, Tagawa T, Ono J, et al. Antiepileptic effect and serum levels of clorazepate on children with refractory seizures. Brain Dev. 1984;6(6):539-544. [PubMed 6152517]
  28. Naidu S, Gruener G, Brazis P. Excellent results with clorazepate in recalcitrant childhood epilepsies. Pediatr Neurol. 1986;2(1):18-22. [PubMed 2907857]
  29. Nelson J, Chouinard G. Guidelines for the clinical use of benzodiazepines: pharmacokinetics, dependency, rebound and withdrawal. Canadian Society for Clinical Pharmacology. Can J Clin Pharmacol. 1999;6(2):69-83. [PubMed 10519733]
  30. Noh Y, Lee H, Choi A, et al. First-trimester exposure to benzodiazepines and risk of congenital malformations in offspring: a population-based cohort study in South Korea. PLoS Med. 2022;19(3):e1003945. doi:10.1371/journal.pmed.1003945 [PubMed 35235572]
  31. Park TW. Benzodiazepine use disorder. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed May 12, 2022.
  32. Patel DA and Patel AR, “Clorazepate and Congenital Malformations,” JAMA, 1980, 244(2):135-6. [PubMed 6103970]
  33. Radojčić MR, El Marroun H, Miljković B, et al. Prenatal exposure to anxiolytic and hypnotic medication in relation to behavioral problems in childhood: a population-based cohort study. Neurotoxicol Teratol. 2017;61:58-65. doi:10.1016/j.ntt.2017.02.005 [PubMed 28259732]
  34. Refer to manufacturer's labeling.
  35. Rey E, Giraux P, d'Athis P, Turquais JM, Chavinie J, Olive G. Pharmacokinetics of the placental transfer and distribution of clorazepate and its metabolite nordiazepam in the feto-placental unit and in the neonate. Eur J Clin Pharmacol. 1979;15(3):181-185. doi:10.1007/BF00563103 [PubMed 37090]
  36. Rickels K, Schweizer E, Csanalosi I, Case WG, Chung H. Long-term treatment of anxiety and risk of withdrawal. Prospective comparison of clorazepate and buspirone. Arch Gen Psychiatry. 1988;45(5):444-450. doi:10.1001/archpsyc.1988.01800290060008 [PubMed 2895993]
  37. Riss J, Cloyd J, Gates J, Collins S. Benzodiazepines in epilepsy: pharmacology and pharmacokinetics. Acta Neurol Scand. 2008;118(2):69-86. doi:10.1111/j.1600-0404.2008.01004.x [PubMed 18384456]
  38. Saarelainen L, Tolppanen AM, Koponen M, et al. Risk of death associated with new benzodiazepine use among persons with Alzheimer disease: A matched cohort study. Int J Geriatr Psychiatry. 2018;33(4):583-590. doi: 10.1002/gps.4821. [PubMed 29143367]
  39. Soyka M, Kranzler HR, Hesselbrock V, Kasper S, Mutschler J, Möller HJ; WFSBP Task Force on Treatment Guidelines for Substance Use Disorders. Guidelines for biological treatment of substance use and related disorders, part 1: alcoholism, first revision. World J Biol Psychiatry. 2017;18(2):86-119. doi:10.1080/15622975.2016.1246752 [PubMed 28006997]
  40. Sugai K. Clobazam as a new antiepileptic drug and clorazepate dipotassium as an alternative antiepileptic drug in Japan. Epilepsia. 2004;45 (Suppl 8):20-25. [PubMed 15610190]
  41. Sundbakk LM, Gran JM, Wood ME, et al. Association of prenatal exposure to benzodiazepines and z-hypnotics with risk of attention-deficit/hyperactivity disorder in childhood. JAMA Netw Open. 2022;5(12):e2246889. doi:10.1001/jamanetworkopen.2022.46889 [PubMed 36520439]
  42. Szpunar MJ, Freeman MP, Kobylski LA, et al. Risk of major malformations in infants after first-trimester exposure to benzodiazepines: results from the Massachusetts General Hospital National Pregnancy Registry for Psychiatric Medications. Depress Anxiety. 2022;39(12):751-759. doi:10.1002/da.23280 [PubMed 35909254]
  43. Tinker SC, Reefhuis J, Bitsko RH, et al; National Birth Defects Prevention Study. Use of benzodiazepine medications during pregnancy and potential risk for birth defects, National Birth Defects Prevention Study, 1997-2011. Birth Defects Res. 2019;111(10):613-620. doi:10.1002/bdr2.1497 [PubMed 30891943]
  44. Tranxene (clorazepate) [prescribing information]. Bristol, TN: UPM Pharmaceuticals; January 2023.
  45. US Department of Veterans Affairs/Department of Defense (VA/DoD). VA/DoD clinical practice guideline for the management of posttraumatic stress disorder and acute stress reaction. https://www.healthquality.va.gov/guidelines/mh/ptsd/. Updated 2017. Accessed September 8, 2021.
  46. US Department of Veterans Affairs/US Department of Defense. VA/DoD clinical practice guideline for the management of substance use disorders. https://www.healthquality.va.gov/guidelines/MH/sud/VADoDSUDCPG.pdf. Published August 2021. Accessed May 12, 2022.
  47. Vinkers CH, Olivier B. Mechanisms underlying tolerance after long-term benzodiazepine use: a future for subtype-selective gaba(a) receptor modulators? Adv Pharmacol Sci. 2012;2012:1-19. [PubMed 22536226]
  48. Wang X, Zhang T, Ekheden I, et al. Prenatal exposure to benzodiazepines and Z-drugs in humans and risk of adverse neurodevelopmental outcomes in offspring: a systematic review. Neurosci Biobehav Rev. 2022;137:104647. doi:10.1016/j.neubiorev.2022.104647 [PubMed 35367514]
  49. Webster LR, Karan S. The physiology and maintenance of respiration: a narrative review. Pain Ther. 2020;9(2):467-486. doi:10.1007/s40122-020-00203-2 [PubMed 33021707]
  50. Wikner BN, Stiller CO, Bergman U, Asker C, Källén B. Use of benzodiazepines and benzodiazepine receptor agonists during pregnancy: neonatal outcome and congenital malformations. Pharmacoepidemiol Drug Saf. 2007;16(11):1203-1210. doi:10.1002/pds.1457 [PubMed 17894421]
  51. Wlodarczyk BJ, Palacios AM, George TM, et al, "Antiepileptic Drugs and Pregnancy Outcomes," Am J Med Genet A, 2012, 158A(8):2071-90. [PubMed 22711424]
  52. World Health Organization. Breastfeeding and maternal medication: recommendations for drugs in the Eleventh WHO Model List of Essential Drugs. https://apps.who.int/iris/handle/10665/62435. Published 2002. Accessed March 24, 2023.
Topic 9286 Version 418.0

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟