Clonazepam

Clonazepam is a long-acting benzodiazepine used for epilepsy (myoclonic, absence and other seizure types), panic disorder, and, off-label, REM sleep behaviour disorder and restless legs. It is potent at low doses, tolerance to its antiseizure effect develops, and withdrawal must be gradual.

Classification. Benzodiazepine, long-acting, nitrobenzodiazepine.

Mechanism. Positive allosteric modulation of GABA-A receptors, which increases chloride channel opening and neuronal inhibition.

Pharmacokinetics. Well absorbed orally, peak in 1 to 4 hours. Metabolised by CYP3A4 through nitroreduction to inactive metabolites. Half-life 30 to 40 hours. Approximate equivalence for switching: clonazepam 0.5 mg is about diazepam 10 mg.

All regimens are oral with no loading dose.

Epilepsy, adults (adjunct or monotherapy for myoclonic, absence and other generalised seizures).

• Start no more than 1 mg at night for 4 nights (0.5 mg in older adults); give in three or four divided doses as the dose rises.
• Titration: increase by 0.25 to 0.5 mg every 3 to 7 days, over 2 to 4 weeks.
• Maintenance 4 to 8 mg daily in divided doses. Maximum 20 mg daily.

Epilepsy, children. Start 0.01 to 0.03 mg/kg daily in 2 to 3 divided doses (maximum 0.05 mg/kg); increase by 0.25 to 0.5 mg every 3 days to a maintenance of 0.1 to 0.2 mg/kg daily. Infants and children under 10 years or 30 kg: lower initial doses.

Panic disorder, adults. Start 0.25 mg twice daily; increase to 1 mg daily after 3 days. Maximum 4 mg daily. Review at 4 to 6 weeks; use is short term.

REM sleep behaviour disorder (off-label, specialist use). 0.25 to 2 mg at bedtime.

Dose limits. Older adults: start 0.25 to 0.5 mg daily. Liver impairment: reduce doses; avoid in severe disease. Kidney impairment: start low.

Contraindications. Significant liver disease, respiratory depression, severe sleep apnoea, myasthenia gravis, acute narrow-angle glaucoma, hypersensitivity. Major warning of profound sedation and death with opioids; abuse and misuse; dependence and withdrawal.

Serious adverse effects. Respiratory depression, dependence and withdrawal seizures, increased seizure frequency or status epilepticus on abrupt stopping, paradoxical agitation, depression, falls, hypersalivation and aspiration in children.

Common adverse effects. Drowsiness, ataxia, dizziness, fatigue, memory impairment, hypersalivation, irritability in children.

Interactions. Phenytoin, carbamazepine and phenobarbital lower levels. Opioids, alcohol and other sedatives add respiratory depression. Valproate combined with clonazepam can rarely cause absence status. CYP3A4 inhibitors may raise levels modestly.

Common prescribing errors. Rapid dose escalation; abrupt stopping in epilepsy; long-term use for anxiety; not adjusting in older adults; combining with opioids.

Special groups.

• Pregnancy: avoid when possible; floppy infant syndrome and neonatal withdrawal with late exposure; weigh against seizure control.
• Breastfeeding: avoid; infant sedation and poor feeding reported.
• Children: used for epilepsy with weight-based doses; hypersalivation may occur.
• Older adults: start 0.25 to 0.5 mg; falls and delirium.
• Kidney impairment: start low.
• Liver impairment: reduce doses; avoid in severe disease.

Formulations. Tablets 0.5 mg and 2 mg; oral drops 2.5 mg/mL in some regions; orally disintegrating tablets 0.125 mg to 2 mg; injection 1 mg/mL in some regions. Give at night when starting, then in divided doses.

Baseline. Seizure type and frequency, respiratory status, alcohol and sedative use, liver function, mood history, pregnancy status, medicines list.

Monitoring. Review seizure control and sedation at 2 to 4 weeks and after each dose change. Check mood and suicidality because depression can worsen. Reassess the need for panic disorder treatment at 4 to 6 weeks.

Stopping. Reduce slowly, for example by 0.125 mg to 0.25 mg every 1 to 2 weeks, and more slowly at the lowest doses; epilepsy treatment stops only on specialist advice. Abrupt stopping can cause seizures and status epilepticus.

Referral and escalation. Refer to neurology for epilepsy and to psychiatry or addiction services for dependence. A seizure lasting more than 5 minutes needs emergency care.