Clonazepam

Clonazepam is a 1,4-benzodiazepine.

Authorised indications

UK-SmPC: all clinical forms of epileptic disease and seizures in infants, children, and adults, especially absence seizures, including atypical absences; primarily or secondarily generalised tonic–clonic, tonic or clonic seizures; focal seizures; various forms of myoclonic seizures, myoclonus and associated abnormal movements.

FDA-PI: alone or as an adjunct in the treatment of the Lennox–Gastaut syndrome (petit mal variant), akinetic and myoclonic seizures. In patients with absence seizures (petit mal) who have failed to respond to succinimides, clonazepam may be useful. Lower age limit is not specified.

Clinical applications

Clonazepam^2,3 is the most effective AED in the treatment of myoclonic jerks (superior to valproate), and is also effective in absences (although much more inferior to valproate and ethosuximide)¹ and focal seizures (it is much more inferior to carba mazepine and any other appropriate drug for this type of seizures). Opinions about its effectiveness in GTCSs are conflicting and range from beneficial⁴ to aggrevation.⁵

Clonazepam is the main AED for myoclonic jerks in all forms of idiopathic or symptomatic and progressive epilepsies (monotherapy, but mainly adjunctive therapy).

Clonazepam monotherapy is probably the first choice in reading epilepsy (better than valproate). It is particularly effective in juvenile myoclonic epilepsy (JME) if myoclonic jerks are not controlled by other drugs. Adding small doses of clonazepam (0.5–2 mg prior to going to sleep) to valproate, levetiracetam or lamotrigine is highly beneficial and may prevent an unnecessary increase of the main concomitant drug. It is widely used in epileptic encephalopathies, but may also be responsible for benzodiazepine-related ADRs (e.g. sialorrhoea and lethargy).

Dosage and titration

'Start low and go slow' is essential, both in adults and children.

Adults: start treatment with 0.25 mg/day at night and increase at weekly intervals in increments of 0.25 mg/day up to a total of 8–10 mg/day. In my experience, 0.5–2 mg of clonazepam taken before sleep is often highly effective in controlling myoclonic jerks either as monotherapy or as adjunctive therapy in resistant cases.

Children: start with 0.01–0.02 mg/kg/day and slowly increase up to 0.1–0.2 mg/kg/day.

Dosing: once or twice daily; a smaller dose in the day time and a larger dose prior to going to sleep.

TDM: not needed.

Reference range: 20–80 μg/l (80–250 nmol/l).

Main ADRs

Frequent and/or important: sedation, drowsiness, hypersalivation, hyper activity, lack of concentration and incoordination. Sedation is more serious than with clobazam. This may be partly prevented by administering the drug in small doses 1 hour prior to going to sleep.

Serious: withdrawal syndrome after chronic use.

See also benzodiazepines.

Main mechanism of action

GABA_A-receptor agonist

Pharmacokinetics

Oral bioavailability: >80%. Protein binding: 85%. Metabolism: hepatic. Elimination half-life: 20–80 hours.

Drug interactions

Minor and not clinically significant. Potentiates the effect of CNS depressants such as alcohol, barbiturates and neuroleptics.

Main disadvantages

Sedation and development of tolerance.

Useful clinical notes

• Clonazepam is the first-choice drug for the control of myoclonic jerks (either as monotherapy if this is the only seizure type, as in reading epilepsy, or mainly as adjunctive medication).
• Avoid overmedication. Small doses 1 hour prior to sleep may be effective and well tolerated.
• Withdrawal should be very slow, occuring over months. A rapid discontinuation often leads to withdrawal symptoms, seizures and status epilepticus.

References

1. Panayiotopoulos CP. Treatment of typical absence seizures and related epileptic syndromes. Paediatr Drugs 2001;3:379–403.
2. Shorvon S, Perucca E, Engel JJr, editors. The treatment of epilepsy (3nd edition). Oxford: Willey-Blackwell; 2009. p. 829-54.
3. Camfield P, Camfield C. Benzodiazepines used primarily for chronic treatment (clobazam, clonazepam, clorazepate and nitrazepam). In:Shorvon S, Perucca E, Engel JJr, eds. The treatment of epilepsy (3nd edition). Oxford: Willey-Blackwell, 2009:421-30
4. Naito H, Wachi M, Nishida M. Clinical effects and plasma concentrations of long-term clonazepam monotherapy in previously untreated epileptics. Acta Neurol Scand 1987;76:58–63.
5. Obeid T, Panayiotopoulos CP. Clonazepam in juvenile myoclonic epilepsy. Epilepsia 1989;30:603–6.