Adult: Usual dose: 30 mg daily in divided doses, gradually adjust dose within the range of 15-60 mg daily depending on the patient's response. Alternatively, 15 mg may be given as a single daily dose at bedtime, then subsequent doses are adjusted according to patient's response. Elderly: Initially, 7.5-15 mg daily.
Oral Adjunct in partial seizures
Adult: Initially, up to 7.5 mg tid; increase dose by ≤7.5 mg increments at weekly intervals. Max: 90 mg daily. Child: 9-12 years Initially, up to 7.5 mg bid; increase dose by ≤7.5 mg increments at weekly intervals. Max: 60 mg daily. >12 years Same as adult dose.
Oral Alcohol withdrawal
Adult: For the symptomatic relief of acute cases: Day 1: Initially, 30 mg, followed by 30-60 mg in divided doses. 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. Thereafter, gradually decrease the dose to 7.5-15 mg daily. Max: 90 mg daily. Avoid excessive dose reduction. Discontinue treatment upon stabilisation of the condition.
Special Patient Group
Short-term management of anxiety
Debilitated patients: Initially, 7.5-15 mg daily.
Contraindications
Acute narrow-angle glaucoma. Lactation.
Special Precautions
Patient with a history of alcohol use disorder, psychiatric or personality disorders, psychological potential for drug dependence; at risk of falls. Not for use in patients with depression, respiratory disease (e.g. COPD, sleep apnoea), depressive neuroses, or psychotic reactions. Avoid abrupt withdrawal. Children, elderly, and debilitated patients. Hepatic and renal impairment. Pregnancy.
Adverse Reactions
Significant: Physical dependence (prolonged use and high doses); increased risk of suicidal thoughts or behaviour; anterograde amnesia, CNS depression; paradoxical reactions (e.g. hyperactive or aggressive behaviour), sleep-related activities (e.g. sleep-driving, making phone calls, and cooking and eating food while asleep), worsening mood symptoms, falls, traumatic injury; protracted withdrawal syndrome; tolerance to antiseizure effects. Eye disorders: Blurred vision, diplopia. Gastrointestinal disorders: Xerostomia, various gastrointestinal complaints. General disorders and administration site conditions: Fatigue. Investigations: Decreased haematrocrit; abnormal LFTs and renal function tests. Nervous system disorders: Ataxia, confusion, dizziness, drowsiness, headache, irritability, nervousness, slurred speech, tremor. Psychiatric disorders: Insomnia. Renal and urinary disorders: Genitourinary complaints. Skin and subcutaneous tissue disorders: Rash. Vascular disorders: Systolic hypotension. Potentially Fatal: Increased risk of abuse, misuse, and addiction; withdrawal reactions following abrupt discontinuation or rapid dose reduction.
This medicine may cause CNS depression, if affected, do not drive or operate machinery.
Monitoring Parameters
Assess the risk for abuse, misuse, and addiction prior to treatment initiation and throughout treatment. Monitor excessive CNS depression, respiratory rate, and CV status; CBC, LFTs, renal function (prolonged use). Assess for signs and symptoms of suicidal ideation (e.g. anxiety, depression, behavioural changes).
Overdosage
Symptoms: Varying degrees of CNS depression ranging from slight sedation to coma. Rarely, hypotension in high doses. Management: Supportive treatment. Immediately empty gastric contents by either inducing emesis, performing gastric lavage, or both. Consider giving norepinephrine bitartrate or metaraminol bitartrate to treat hypotension. Secure airway, ventilation, and IV access prior to the administration of flumazenil for the complete or partial reversal of sedation.
Drug Interactions
Barbiturates, narcotic analgesics, phenothiazines, MAO inhibitors or other antidepressants may enhance the activity of clorazepate. Potentially Fatal: Increased risk of extreme sedation, respiratory depression, and coma with opioids.
Food Interaction
May increase the CNS depressant effect of alcohol.
Action
Description: Mechanism of Action: Clorazepate, a long-acting benzodiazepine, binds to stereospecific benzodiazepine receptors on the postsynaptic GABA neuron at multiple sites within the CNS, including the limbic system and reticular formation. The enhancement of the inhibitory effect of GABA causes hyperpolarisation and stabilisation through the increased permeability to chloride ions. Its effects are primarily linked to GABA-A receptors. Pharmacokinetics: Absorption: Time to peak plasma concentration: Approx 0.5- 2 hours. Distribution: Crosses the placenta and enters breast milk (nordiazepam). Volume of distribution: 0.7-2.2 L/kg (nordiazepam). Plasma protein binding: 97-98% (nordiazepam). Metabolism: Rapidly metabolised in the acidic stomach via decarboxylation into the active metabolite nordiazepam prior to absorption; nordiazepam is then further metabolised in the liver via hydroxylation by the CYP2C19 and CYP3A4 isoenzymes into oxazepam (active) which undergoes glucuronidation to form a glucuronide conjugate (3-hydroxynordiazepam). Excretion: Mainly via urine (62-67%, primarily as 3-hydroxynordiazepam); faeces (15-19%). Elimination half-life: 20-160 hours (nordiazepam).
Chemical Structure
Clorazepate Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 2809, Clorazepate. https://pubchem.ncbi.nlm.nih.gov/compound/2809. Accessed Aug. 25, 2022.
Storage
Store between 20-25°C. Protect from light and moisture.
N05BA05 - potassium clorazepate ; Belongs to the class of benzodiazepine derivatives anxiolytics. Used in the management of anxiety, agitation or tension.
References
Anon. Clorazepate (Briggs Drugs in Pregnancy and Lactation). Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 23/08/2022.Anon. Clorazepate. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 01/08/2022.Anon. Clorazepate. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 01/08/2022.Buckingham R (ed). Clorazepic Acid. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 01/08/2022.Clorazepate Dipotassium (Aurolife Pharma, LLC). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 01/08/2022.Clorazepate. Gold Standard Drug Database in ClinicalKey [online]. Elsevier Inc. https://www.clinicalkey.com. Accessed 23/08/2022.Tranxene T-Tab Tablets (Recordati Rare Diseases, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 01/08/2022.
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