Clonazepam


Generic Medicine Info
Indications and Dosage
Intravenous
Status epilepticus
Adult: 1 mg via slow IV inj over at least 2 minutes or infusion, repeated if necessary. Max: 10 mg.
Child: 0.5 mg via slow IV inj or infusion.

Oral
Epilepsy
Adult: Monotherapy or adjunctive therapy in the treatment of most forms of epilepsy including Lennox-Gastaut syndrome (petit mal variant), absence, primary or secondary generalised tonic-clonic, partial and akinetic seizures, and various forms of myoclonic seizures, myoclonus and associated abnormal movements: Initially, 1 mg at night for 4 days, gradually increased over 2-4 weeks. Maintenance: 4-8 mg daily. Max: 20 mg daily. Daily doses are divided into 3 or 4 doses; largest dose must be given at bedtime if doses are not equally divided. Once maintenance dose is obtained, daily amount may be given at night as a single dose. Alternatively, initial doses of up to 1.5 mg daily divided into 3 doses, may be increased in increments of 0.5-1 mg every 3 days until seizure control is reached. Max: 20 mg daily. Dose is individually adjusted according to patient's needs, clinical response and tolerance. Dosage recommendations may vary among individual products or between countries (refer to specific product guidelines).
Child: ≤10 years or ≤30 kg: Initially, 0.01-0.03 mg/kg daily (Max initial dose: 0.05 mg/kg daily) given in 2 or 3 divided doses, may be increased by no more than 0.25-0.5 mg every 3rd day until seizure control is achieved. Maintenance: 0.1-0.2 mg/kg daily in 3 divided doses. Max: 0.2 mg/kg daily. Alternatively, in ≤1 year Initially, up to 0.25 mg daily, gradually increased over 2-4 weeks to maintenance dose of 0.5-1 mg daily; 2-5 years Initially, up to 0.25 mg daily, gradually increased over 2-4 weeks to maintenance dose of 1-3 mg daily; 6-12 years Initially, 0.5 mg daily, gradually increased over 2-4 weeks to maintenance dose of 3-6 mg daily. Daily doses are divided into 3 or 4 doses; largest dose must be given at bedtime if doses are not equally divided. Once maintenance dose is obtained, daily amount may be given at night as single dose. Dosage recommendations may vary among individual products or between countries (refer to specific product guidelines).
Elderly: Initially, 0.5 mg at night for 4 days, gradually increased over 2-4 weeks. Maintenance: 4-8 mg daily, adjusted according to response and tolerance. Daily doses are divided into 3 or 4 doses; largest dose must be given at bedtime if doses are not equally divided. Once maintenance dose is obtained, daily amount may be given at night as a single dose.

Oral
Panic disorder with or without agoraphobia
Adult: Initially, 0.25 mg bid, increased after 3 days to target dose of 1 mg daily. Some patients may require higher doses of up to Max 4 mg daily. Doses may be taken as a single dose at bedtime to minimise drowsiness.
Elderly: Start with low doses and observe closely.
Special Patient Group
Concomitant use with opioids: Use the lowest effective dose and shortest possible duration. Reserve use in patients for whom alternative treatment options are inadequate.
Hepatic Impairment
Epilepsy; status epilepticus:
Mild to moderate: Dose adjustment may be necessary. Severe: Contraindicated.

Panic disorder with or without agoraphobia:
Significant: Contraindicated.
Administration
May be taken with or without food.
Reconstitution
IV inj: Dilute with 1 mL of provided diluent before administration. IV infusion: Dilute (ampoule with clonazepam only) with a ratio of 1 ampoule (1 mg) to at least 85 mL (e.g. 3 ampoules in 250 mL) of 0.9% NaCl, 5% or 10% glucose, or 0.45% NaCl + 2.5% glucose solutions.
Incompatibility
IV: May precipitate with Na bicarbonate. May lead to significant reduction of clonazepam concentration (up to 50% particularly if stored over 24 hours) when infused using PVC-containing plastic infusion bags and sets.
Contraindications
Acute narrow-angle glaucoma, acute pulmonary insufficiency, severe respiratory insufficiency, sleep apnoea syndrome, myasthenia gravis. Patient in a coma, or with known alcohol or drug abuse. Severe (epilepsy/status epilepticus) or significant (panic disorder) hepatic impairment.
Special Precautions
Patient with depression and/or suicide attempts; open-angle glaucoma, chronic pulmonary insufficiency, porphyria, compromised respiratory function (e.g. COPD), difficulty handling secretions, spinal or cerebellar ataxia, history of alcohol or drug dependence or abuse. Patient at increased risk of falls or whom a drop in blood pressure may result in cardiac or cerebral complications. Concomitant use with opioids. Avoid abrupt withdrawal. Renal and mild to moderate hepatic impairment. Debilitated patient. Children and elderly. Pregnancy and lactation.
Adverse Reactions
Significant: Suicidal thoughts or behaviour, anterograde amnesia, worsening of seizures (in patients with multiple seizure types), CNS depression, paradoxical reactions, including hyperactive or aggressive behaviour; sleep-related activities (e.g. sleep-driving, cooking or eating food, making phone calls while asleep); respiratory depression, salivary or bronchial hypersecretion (infants and children); may precipitate hepatic encephalopathy; drug tolerance, dependence, misuse and abuse; withdrawal reactions. Rarely, hypotension.
Eye disorders: Blurred vision, nystagmus, diplopia.
Gastrointestinal disorders: Constipation, abdominal pain, nausea.
General disorders and administration site conditions: Fatigue, ataxia; thrombophlebitis (rapid IV inj/infusion).
Immune system disorders: Allergic reactions.
Injury, poisoning and procedural complications: Falls.
Musculoskeletal and connective tissue disorders: Muscle weakness.
Nervous system disorders: Drowsiness, dizziness, light-headedness, headache.
Psychiatric disorders: Excitability, irritability, agitation, nervousness, hostility, anxiety, poor concentration, restlessness, confusion, disorientation, dysarthria, sleep disturbances, nightmares, vivid dreams.
Skin and subcutaneous tissue disorders: Rarely, urticaria, pruritus, transient hair loss, pigmentation changes.
Patient Counseling Information
This drug may cause CNS depression, if affected, do not drive or operate machinery.
Monitoring Parameters
Monitor CBC, liver and renal function tests periodically with prolonged treatment; signs of suicidality (e.g. emergence or worsening of depression, suicidal thoughts, behavioural changes). Closely observe for signs and symptoms of sedation and respiratory depression (patients receiving concomitant opioids).
Overdosage
Symptoms: Somnolence, confusion, dysarthria, nystagmus, ataxia, areflexia, apnoea, hypotension, cardiorespiratory depression, or coma. Management: Supportive and symptomatic treatment. Maintain clear airway and adequate ventilation. Consider administration of activated charcoal within 1-2 hours of ingestion and protect airway for drowsy patients. Gastric lavage may be considered in case of mixed ingestion. Flumazenil may be used for severe CNS depression; use with extreme caution particularly in those receiving chronic therapy and in presence of TCAs. Hypotension may be treated with levarterenol or metaraminol.
Drug Interactions
Additive CNS depressant effects with other anticonvulsants, TCAs, MAOIs, sedative and hypnotics, barbiturates, antihistamines, anxiolytics, antipsychotics and anaesthetics. May increase or decrease the serum levels of phenytoin. May rarely cause absence status epilepticus with valproic acid. CYP3A4 inhibitors (e.g. fluconazole, cimetidine) may impair the metabolism of clonazepam.
Potentially Fatal: Increased risk of profound sedation, respiratory depression and coma when used concomitantly with opioids.
Food Interaction
Additive CNS depression with alcohol; avoid concomitant use.
Action
Description: Clonazepam is a benzodiazepine derivative that exhibits anticonvulsive, sedative, muscle relaxing and anxiolytic properties. Its exact mechanism of action is unknown; however, it is believed to be related to its ability to increase the activity of GABA. It reduces the nerve transmission in the motor cortex, thereby suppressing the spike and wave discharge in absence seizures.
Onset: Approx 20-40 minutes.
Duration: ≤12 hours (adults); 6-8 hours (children).
Pharmacokinetics:
Absorption: Rapidly and completely absorbed from the gastrointestinal tract. Bioavailability: Approx 90%. Time to peak plasma concentration: 1-4 hours.
Distribution: Crosses the placenta and enters breast milk. Volume of distribution: 1.5-6.4 L/kg. Plasma protein binding: Approx 85%.
Metabolism: Extensively metabolised in the liver via glucuronide and sulfate conjugation; converted to 7-aminoclonazepam (major inactive metabolite), and 7-acetamido- and 3-hydroxy-derivatives (minor metabolites).
Excretion: Mainly via urine (50-70%, <2% as unchanged drug), faeces (10-30%); almost exclusively as free or conjugated metabolites. Elimination half-life: Approx 17-60 hours.
Chemical Structure

Chemical Structure Image
Clonazepam

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 2802, Clonazepam. https://pubchem.ncbi.nlm.nih.gov/compound/Clonazepam. Accessed Sept. 27, 2021.

Storage
Orally disintegrating tab: Store between 20-25°C. Conventional tab, oral solution, concentrated solution for inj: Store below 30°C. Protect from light.
MIMS Class
Anticonvulsants / Anxiolytics
ATC Classification
N03AE01 - clonazepam ; Belongs to the class of benzodiazepine derivatives antiepileptic.
References
Anon. Clonazepam. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 01/09/2021.

Anon. Clonazepam. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 01/09/2021.

Buckingham R (ed). Clonazepam. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 01/09/2021.

Clonazepam Auden 500 mcg Tablets (Teva UK Limited). MHRA. https://products.mhra.gov.uk. Accessed 01/09/2021.

Clonazepam Orally Disintegrating Tablets (Teva Pharmaceuticals USA, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 01/09/2021.

Clonazepam Rosemont 0.5 mg/5 mL Oral Solution (Rosemont Pharmaceuticals Ltd). MHRA. https://products.mhra.gov.uk. Accessed 01/09/2021.

Clonazepam Tablets (Actavis Pharma, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 01/09/2021.

Clonotril 500 mcg and 2 mg Tablet (Torrent Pharma Philippines Inc.). MIMS Philippines. http://www.mims.com/philippines. Accessed 22/09/2021.

Joint Formulary Committee. Clonazepam. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 01/09/2021.

Mylan New Zealand Ltd. Paxam 0.5 mg, 2 mg Tablets data sheet 02 May 2019. Medsafe. http://www.medsafe.govt.nz. Accessed 01/09/2021.

Rivotril 0.5 and 2 mg Tablets (Roche [Malaysia] Sdn. Bhd.). National Pharmaceutical Regulatory Agency - Ministry of Health Malaysia. https://www.npra.gov.my. Accessed 22/09/2021.

Roche Products (New Zealand) Limited. Rivotril 2.5 mg/mL Oral Solution and 1 mg/mL Concentrated Injection Solution data sheet 19 June 2017. Medsafe. http://www.medsafe.govt.nz. Accessed 22/09/2021.

Disclaimer: This information is independently developed by MIMS based on Clonazepam from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2021 MIMS. All rights reserved. Powered by MIMS.com
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