clonazepam

Benzodiazepine anticonvulsant/anxiolytic· Brands: Klonopin, Rivotril, Paxam, Epitril, ClonotrilIVPO

Mechanism of action

Clonazepam enhances the inhibitory effect of gamma-aminobutyric acid (GABA) at GABA-A receptors by binding to the benzodiazepine site, increasing the frequency of chloride channel opening. This results in hyperpolarization of neurons, reducing neuronal excitability and producing anticonvulsant, anxiolytic, and muscle relaxant effects.

Pharmacokinetics

Clonazepam is well absorbed after oral administration, with peak plasma concentrations reached within 1 to 4 hours. It is approximately 85% bound to plasma proteins. Metabolism occurs extensively in the liver via CYP3A4 to inactive metabolites, with a mean elimination half-life of 20 to 50 hours. Excretion is primarily renal, mostly as metabolites.

Indications & dosing

Panic disorder

Initial dose 0.25 mg twice daily; increase by 0.25-0.5 mg every 3 days to a target of 1 mg daily. Discontinue gradually to avoid withdrawal.

adult · PO: 0.25–0.5 mg twice daily · Initial dose 0.25 mg twice daily; increase by 0.25-0.5 mg every 3 days to a target of 1 mg daily. Discontinue gradually to avoid withdrawal.

Epilepsy (adjunctive)

Initial dose 0.5 mg twice daily; increase by 0.5 mg every 3 days until seizures controlled or adverse effects occur. Usual maintenance 0.5-1 mg three times daily.

adult · PO: 0.5–1 mg three times daily · Initial dose 0.5 mg twice daily; increase by 0.5 mg every 3 days until seizures controlled or adverse effects occur. Usual maintenance 0.5-1 mg three times daily.

Status epilepticus

Administer slowly over 30 seconds; if seizures recur, a further dose may be given after 2 minutes. Alternative to diazepam.

adult · IV: 1 mg once, may repeat · Administer slowly over 30 seconds; if seizures recur, a further dose may be given after 2 minutes. Alternative to diazepam.

Contraindications & precautions

Hypersensitivity to benzodiazepines · Includes cross-sensitivity with other benzodiazepines.
Severe respiratory insufficiency · Risk of respiratory depression.
Sleep apnoea · May worsen apnoeic episodes.
Severe hepatic impairment · Caution in mild to moderate impairment; avoid in severe disease unless specialist advice.
Acute angle-closure glaucoma · Benzodiazepines may raise intraocular pressure.
Avoid concurrent use of alcohol and other CNS depressants, as this increases sedation and respiratory depression.
Withdraw gradually to limit risk of rebound seizures and withdrawal symptoms; abrupt discontinuation may precipitate status epilepticus.
Use with caution in hepatic impairment, as metabolism is hepatic.
Caution in elderly patients due to increased risk of falls, cognitive impairment, and prolonged sedation.
Monitor for signs of dependence or misuse, especially in patients with a history of substance abuse.
Use during pregnancy only if clearly needed, as benzodiazepines may cause risks to the fetus and withdrawal in the neonate.

Adverse effects

Drowsiness and sedation
Ataxia
Dizziness
Confusionserious
Depressionserious
Muscle weakness
Memory impairment
Respiratory depressionserious
Dependence and withdrawal reactionsserious
Paradoxical aggression or agitationserious

Renal & hepatic adjustment

eGFR 0+: No specific dose adjustment required; caution in severe renal impairment as elimination may be prolonged.
Hepatic impairment (mild): No adjustment required, but monitor for adverse effects.
Hepatic impairment (moderate): Reduce initial dose and titrate cautiously due to risk of accumulation.
Hepatic impairment (severe): Avoid in severe hepatic impairment as clonazepam is hepatically metabolised. (avoid)

Monitoring, pregnancy & toxicity

Level of consciousness and sedation · At each patient review, especially during dose titration
Ataxia and motor coordination · At each patient review
Respiratory rate and signs of respiratory depression · At each patient review, particularly in patients with respiratory disease or concomitant CNS depressants
Signs of dependence, tolerance, or withdrawal · Regularly in long-term use
Pregnancy: Clonazepam is generally not recommended in pregnancy due to potential fetal harm (congenital malformations, neonatal withdrawal syndrome, and floppy infant syndrome). Use only if the benefits outweigh the risks, such as in severe epilepsy where seizure control is critical.
Toxicity: CNS depression: drowsiness, ataxia, confusion, and coma · Supportive care: assess airway, breathing, and circulation; provide oxygen and ventilatory support if needed; monitor vital signs closely.
Toxicity: Respiratory depression · Provide ventilatory support as required. Flumazenil, a benzodiazepine antagonist, may be considered in non-dependent patients, but use with caution because it may precipitate seizures in benzodiazepine-dependent individuals.
Toxicity: Hypotension · Administer intravenous fluids and, if necessary, vasopressors to maintain blood pressure.

Antidotes & reversal

Flumazenil · Reversal is rarely required; prolonged observation is usually preferred.

Clinical notes

Clonazepam is used as an adjunctive treatment for various seizure types, including myoclonic, atonic, and absence seizures, and in the management of panic disorder. It has a long duration of action, allowing once or twice daily dosing. Doses should be started low and titrated gradually to minimize adverse effects such as sedation and ataxia. Abrupt discontinuation can precipitate withdrawal seizures, so gradual tapering is essential. Clonazepam has a potential for abuse and dependence, and is a controlled substance. Care is needed in patients with hepatic impairment, respiratory depression, or concomitant CNS depressants.

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BNF; local formulary