Clonazepam, Rivotril®

Preparations

Tablets: 0.5 mg; 2 mg
Liquid: 2.5 mg/mL clonazepam (one drop contains 0.1 mg clonazepam)
Ampoules 1 mg/ml

Indications

Epilepsy in infants and children, especially absences (petit mal)
Myoclonic seizures
Tonic-clonic seizure
Partial epilepsy (including psychomotor seizures).
Status epilepticus
Social phobia: as good as cognitive behavioural therapy and even better if given for more than 12 week. [Jonathan 1993; Otto 2000]
Obsessive Compulsive Disorders: results of an RCT found that clonazepam was no better than placebo in treatment of OCD [Hollander 2003]

Pharmacology

Clonazepam is rapidly and almost completely (82 – 98%) absorbed after oral administration
Peak serum levels being reached between 2-3 h.
The absorption half-life is 24 min.
The therapeutic serum level appears to be between 10 and 80 ngr/mL.
A steady state is usually reached within 2 – 3 weeks.
Renal Failure does not affect the pharmacokinetics of clonazepam.
Hepatic Failure influence on clonazepam pharmacokinetics has not been investigated. However, due to the sole hepatic metabolism of clonazepam, the pharmacokinetics of clonazepam are expected to be affected on theoretical grounds.
The pharmacokinetics of clonazepam in the elderly has not been established.

Metabolism

Clonazepam is metabolised in the liver. Hepatic cytochrome P-450 3A4 is implicated in the nitroreduction of clonazepam to pharmacologically inactive metabolites.
Elimination
- The mean elimination half-life is 39.0 ± 8.3 h.
- The mean clearance ± SD is 55.1 ± 8.2 mL/min following a single dose of 2 mg clonazepam given IV.
- 50 – 70% of the dose is excreted in the urine and 10 – 30% in the faeces as metabolites.
- The urinary excretion of unchanged clonazepam is usually less than 2% of the administered dose.
- The metabolites are present in urine both as free and conjugated (glucuronide and sulphate) compounds.
With chronic dosing, accumulation occurs

Dosing

Infants: 0.3 mg/day (1 drop in the morning, 2 drops in the evening).
Children 2 – 5 years: 0.5 mg/day (half a 0.5 mg tablet morning and evening);
Children 6 – 12 years: 0.75 mg/day (half a 0.5 mg tablet in the morning, one 0.5 mg tablet in the evening).
Adults: 1 mg/day (one 0.5 mg tablet morning and evening).
Average dosage for maintenance therapy: 4 – 8 mg
The maximum daily dose for adults is 20 mg/day.
Parenteral treatment:
Treatment of status epilepticus.
Infants and children: half an ampoule (0.5 mg) by slow IV injection or infusion.
- Adults: one ampoule (1 mg) by slow IV injection or infusion. The rate must not exceed 0.25 to 0.5 mg (0.5 to 1.0 mL of the prepared solution) per minute. This dose may be repeated as required by oral route or slow IV injection or infusion until status is controlled. A total dose of 10 mg should not be exceeded.
Impaired hepatic function: The safety and efficacy of clonazepam in patients with hepatic impairment has not been studied.
Impaired renal failure: The safety and efficacy of clonazepam in patients with renal impairment has not been studied.

Drug Interactions

The anti-epileptic medicines (phenytoin, phenobarbitone, carbamazepine, and valproate) may increase the clearance of clonazepam, thereby decreasing the plasma concentrations of the latter during combined treatment.
Phenytoin – the effect of clonazepam on phenytoin plasma levels is not clear as the latter may increase or decrease according to study reports.
Carbamazepine – levels may be lowered by clonazepam.
SSRIs do not significantly affect the pharmacokinetics of clonazepam when administered concomitantly.
The benzodiazepines produce additive CNS depressant effects when co-administered with other medications which themselves produce CNS depression:
- other anticonvulsant (anti-epileptic) agents
- Lithium
- Barbiturates
- Sedatives
- Tricyclic antidepressants
- Non-selective MAO inhibitors
- Phenothiazines and other antipsychotics
- Skeletal muscle relaxants
- Antihistamines
- Narcotic analgesics
- Anaesthetics
Some specific interactions noted with clonazepam are:
- Alcohol – epileptic patients should not under any circumstances consume alcohol while being treated with clonazepam
- Sodium valproate – reports of sodium valproate causing petit mal status epilepticus with clonazepam exist.

Adverse Effects

Respiratory:
- Bronchial hypersecretion occurs relatively commonly.
- Pharyngeal oedema has been reported in rare cases.
- Respiratory depression is possible, especially when clonazepam is administered IV.
- Depression of respiration may be increased if there is obstruction of the airways or preexisting brain damage, or if other medications, which depress respiration, have been given.
- This effect can be avoided by careful adjustment of the final dose.
- Benzodiazepine respiratory depressant effects are more serious in patients with respiratory disease. Benzodiazepines increase the effects of other central nervous system depressants, including alcohol. When combined with other CNS depressants, the effects of over dosage are likely to be severe and may prove fatal.
Nervous System:
- Drowsiness, somnolence, slowed reaction, muscular hypotonia, dizziness, ataxia.
- Vertigo occurs relatively commonly.
- Particularly when treatment is over prolonged periods or at high doses, reversible disorders such as a slowing or slurring of speech (dysarthria), reduced coordination of gait and movements (ataxia) or nystagmus may occur.
- Anterograde amnesia may occur with the use of benzodiazepines at therapeutic dosages. Amnesic effects may be associated with inappropriate behaviour.
- With certain forms of epilepsy, an increase in the frequency of seizures during long-term treatment is possible.
Gastrointestinal:
- Hypersalivation occurs relatively commonly
- Nausea
- Epigastric discomfort
Cardiovascular:
- Cardiac failure including cardiac arrest
Genitourinary:
- Urinary incontinence may occur
- Erectile dysfunction may occur
Dermatologic:
- Urticarial
- Pruritus
- Skin rash
- Transient hair loss (alopecia)
- Angioneurotic oedema,
- Pigmentation disorder
Overdose:
- Over-dosage of benzodiazepines is usually manifested by:
  - Ataxia
  - Dysarthria
  - Nystagmus
  - Hypotonia
  - Hypotension
  - Drowsiness Respiratory depression
  - CNS depression
  - Mental confusion and lethargy
  - Coma and very rarely death

Contraindications

Known hypersensitivity to benzodiazepines
COPD with incipient respiratory failure
Severe hepatic insufficiency
Dependence on drugs of abuse and CNS depressants including alcohol

Pregnancy and Breastfeeding

Use in Pregnancy:
- Category B3
Use in Lactation
- must not be given to nursing women.
- is excreted in human breast milk, and may cause drowsiness and feeding difficulties in the infant.

Precautions

Extreme caution should be taken in patient with:
- Antidepressants or lithium
- Sleep apnoea
- Hypotension. Although hypotension has occurred rarely. This is particularly important in elderly patients.
- Amnesia
- Abusing clonazepam [Frauger 2006; Frauger 2009]
- Impaired Respiratory Function
- Depression, Psychosis and Schizophrenia. Clonazepam is not recommended as primary therapy in patients with depression and/or psychosis.
- Epilepsy: When administered to persons with convulsive disorders, an increase in the frequency and/or severity of grand mal seizures may occur, necessitating increased anticonvulsant medication.
- Abuse [Albeck 1987]
- Use in the Elderly: Elderly patients may be particularly susceptible to the sedative effects of benzodiazepines

Warning

An individualised withdrawal timetable needs to be planned for each patient in whom dependence is known or suspected.
Periods from 4 weeks to 4 months have been suggested.
Only a small minority of patients with the common seizure types achieves a lasting remission with clonazepam.
Withdrawal symptoms similar in character to those noted with barbiturates and alcohol have occurred following abrupt discontinuation of benzodiazepines.
- Insomnia
- Anxiety
- Dysphoria
- Palpitations
- Panic attacks
- Vertigo
- Myoclonus
- Akinesia
- Hypersensitivity to light, sound and touch, abnormal body sensations (e.g. feeling of motion, metallic taste),
- Depersonalisation
- Derealisation
- Delusional beliefs,
- hyperreflexia and
- loss of short term memory
Tolerance to the anticonvulsant effect of clonazepam may occur after 4 weeks to 6 months of continuous treatment in the majority of patients leading to increased seizure frequency.
Tolerance to sedation may occur with benzodiazepines, especially in those with drug seeking behaviour.
Dependence. The use of benzodiazepines may lead to dependence, as defined by the presence of a withdrawal syndrome on discontinuation of the medicine. [Frauger 2006; Frauger 2009]
- convulsions, tremor, abdominal and muscle cramps, confusional state, delirium, hallucinations, hyperthermia, psychosis, vomiting and sweating. Such manifestations of withdrawal, especially the more serious ones, are more common in patients who have received excessive doses over a prolonged period.
- However, withdrawal symptoms have been reported following abrupt discontinuation of benzodiazepines taken continuously at therapeutic levels.
Rebound insomnia and anxiety mean an increase in the severity of these symptoms beyond pre-treatment levels following cessation of benzodiazepines.
Some patients prescribed benzodiazepines with very short half-lives (in the order of 2 – 4 h) may experience relatively mild rebound symptoms in between their regular doses. Withdrawal/rebound symptoms may follow high doses for relatively short periods.

This document is prepared by the “Mental Health for All” team. This document is provided for information purposes only and does not necessarily represent endorsement by or an official position of the Essentials of Medicine. Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient’s medical history.

References

Michael W Otto, Ph.D. Mark H Pollack, M.D., Robert A Gould, Ph.D., John J Worthington III, M.D., Eliza T McArdle, B.A., Jerrold F Rosenbaum, M.D., Richard G Heimberg, Ph.D. A Comparison of the Efficacy of Clonazepam and Cognitive-Behavioral Group Therapy for the Treatment of Social Phobia. Journal of Anxiety Disorders. Volume 14, Issue 4, 2000, 345–358
Hollander E, Kaplan A, Stahl SM. A Double-Blind, Placebo-Controlled Trial of Clonazepam in Obsessive-Compulsive Disorder. 2003, Vol. 4, No. 1 , Pages 30-34
Albeck JH. Withdrawal and detoxification from benzodiazepine dependence: a potential role for clonazepam. J Clin Psychiatry. 1987 Oct;48 Suppl:43-9.
Frauger E, Pauly V, Thirion X, Natali F, Pradel V, Reggio P, Rouby F, Coudert H, Micallef J. Estimation of clonazepam abuse liability: a new method using a reimbursed drug database. Int Clin Psychopharmacol. 2009 Nov;24(6):318-24.
Frauger E, Pradel V, Natali F, Thirion X, Reggio P, Micallef J.Misuse of clonazepam (Rivotril): recent trends. Therapie. 2006 Jan-Feb;61(1):49-55.
Jonthan RTD; Nicholas P; Emilia R; RangaK; Stephen MF; Rebecca S; William HW. Treatment of Social Phobia With Clonazepam and Placebo. J Clin Psychopharmacol 1993;13:423-428.