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Clonazepam

(British Approved Name, US Adopted Name, rINN)

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Synonyms: Clonazepam; Clonazepamum; Klonatsepaami; Klonazepám; Klonazepam; Klonazepamas; Ro-5-4023
BAN: Clonazepam
USAN: Clonazepam
INN: Clonazepam [rINN (en)]
INN: Clonazepam [rINN (es)]
INN: Clonazépam [rINN (fr)]
INN: Clonazepamum [rINN (la)]
INN: Клоназепам [rINN (ru)]
Chemical name: 5-(2-Chlorophenyl)-1,3-dihydro-7-nitro-1,4-benzodiazepin-2-one
Molecular formula: C15H10ClN3O3 =315.7
CAS: 1622-61-3
ATC code: N03AE01
Read code: y00Jy [Status Epilepsy]; y08DB [Epilepsy Control]; y02DH

Note. The following terms have been used as ’street names’ or slang names for various forms of clonazepam: K-Pins; Klondike Bars; Klonnies; Klons; La Roche; Pins; R2; R-2; Roaches; Roachies; Roche.

Pharmacopoeias. In China Europe, Japan, and US.

European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Clonazepam). A slightly yellowish, crystalline powder. Practically insoluble in water; slightly soluble in alcohol and in methyl alcohol. Protect from light.

The United States Pharmacopeia 31, 2008, and Supplements 1 and 2 (Clonazepam). A light yellow powder having a faint odour. Insoluble in water; slightly soluble in alcohol and in ether; sparingly soluble in acetone and in chloroform. Store in airtight containers. Protect from light.

Sorption. Significant loss of clonazepam (up to 50% over 24 hours) has been reported from solutions infused through PVC tubing; the effect was concentration dependent. The authors recommended that non-PVC tubing should always be used.

Dependence and Withdrawal

As for Diazepam.

Withdrawal. A study of the withdrawal of clonazepam therapy in 40 epileptic children found that 19 had withdrawal symptoms of increased seizure frequency, either alone or with other symptoms but that this effect was transient. Withdrawal seizures and status might become an obstacle to the removal of useless or even deleterious therapy with clonazepam because the transient nature of these effects was not always recognised. Clonazepam should not be used for more than 3 to 6 months and should be stopped if clear and lasting therapeutic benefit could not be shown.

See also Uses and Administration, below.

Adverse Effects, Treatment, and Precautions

As for Diazepam.

The principal adverse effect of clonazepam is drowsiness, which occurs in about 50% of all patients when starting therapy. Salivary or bronchial hypersecretion may cause respiratory problems in children. Thrombophlebitis has been associated with intravenous use and may be avoided by injection into a large vein at a rate not exceeding 500 micrograms/minute. Respiration and blood pressure should also be monitored. Care is required when withdrawing clonazepam therapy — see above.

Breast feeding. Benzodiazepines, such as clonazepam, given to the mother may cause neonatal sedation and breast feeding should be avoided. For comments on antiepileptic therapy and breast feeding.

Driving. For a comment on antiepileptic drugs and driving.

Effects on the endocrine system. Precocious development of secondary sexual characteristics occurred in a 15-month-old girl 2 months after starting treatment with clonazepam 500 micrograms twice daily for convulsions. Symptoms regressed upon withdrawal of clonazepam.

Effects on mental function. For a review of the effects of antiepileptic therapy, including clonazepam, on cognition and mood, including the risk of suicidal ideation.

Effects on the mouth. A 52-year-old woman developed burning mouth syndrome after starting clonazepam; some improvement was noted when the dose was reduced but symptoms were still intolerable and clonazepam was withdrawn. Subsequently, symptoms resolved within 3 weeks.

Effects on sexual function. Sexual dysfunction was reported in 18 of 42 male patients receiving clonazepam for the treatment of post-traumatic stress disorder; symptoms resolved when therapy was changed to diazepam in 17 patients and lorazepam in the remaining patient.

Extrapyramidal disorders. For reference to extrapyramidal disorders associated with the use of benzodiazepines including clonazepam, see Effects on the Nervous System in Diazepam. However, clonazepam is also used in the treatment of some extrapyramidal disorders as discussed under Uses and Administration, below.

Porphyria. Clonazepam is considered to be unsafe in patients with porphyria although there is conflicting evidence of porphyrinogenicity.

For comments on the use of benzodiazepines in porphyria.

Pregnancy. For comments on the management of epilepsy during pregnancy.

Interactions

As for Diazepam.

Antiepileptics. For reference to possible interactions between clonazepam and other antiepileptics, see under Diazepam and Benzodiazepines under Interactions of Phenytoin.

Pharmacokinetics

Clonazepam is quickly absorbed after oral doses with a bioavailability of about 90%; peak plasma concentrations are reached between 1 and 4 hours after ingestion. It is extensively metabolised in the liver, its principal metabolite being 7-aminoclonazepam, which has no antiepileptic activity; minor metabolites are the 7-acetamido- and 3-hydroxy-derivatives. It is excreted mainly in the urine almost entirely as its metabolites in free or conjugated form. It is about 85% bound to plasma proteins and estimations of its elimination half-life range from about 20 to 40 hours, and occasionally more.

A therapeutic range of plasma concentrations has not been established.

Clonazepam crosses the placental barrier and is distributed into breast milk.

The pharmacokinetics of clonazepam maybe affected by use with other antiepileptics (see under Interactions, above).

A single-dose pharmacokinetic study in healthy subjects found that absorption of clonazepam was slower and intersubject variability was greater after intramuscular injection than after an oral dose. The pharmacokinetics of a modified-release subcutaneous injection have also been studied in healthy subjects; plasma-clonazepam concentrations were sustained and elimination occurred slowly over 13 days.

Bioavailability. It has been suggested, on the basis of anecdotal evidence, that there may be differences in bioavailability, and hence in clinical effect, between formulations of clonazepam tablets.

Uses and Administration

Clonazepam is a benzodiazepine derivative similar to diazepam, with marked antiepileptic properties.

It may be used in the treatment of all types of epilepsy and seizures, including status epilepticus, but its usefulness in chronic treatment is sometimes limited by the development of tolerance and by sedation, and other antiepileptics are often preferred. It may also be used in myoclonus and associated abnormal movements, and for the treatment of panic disorder (see Psychiatric Disorders, below). For epilepsy and myoclonus treatment is started with small doses that are progressively increased to an optimum dose according to response. Total daily doses may initially be taken in 3 or 4 divided doses; however, once the maintenance dose has been reached, the daily amount may be given as a single dose at night. In the UK the initial oral dose is 1 mg (500 micrograms in the elderly) at night for 4 nights gradually increased over 2 to 4 weeks to a usual maintenance dose of 4 to 8 mg daily; it is recommended that the total dose should not exceed 20 mg daily. Dosage recommendations in the USA are generally similar although initial doses of up to 1.5 mg daily are permitted and dosage increments of 0.5 to 1 mg every 3 days are recommended. There is little value in routinely monitoring plasma-clonazepam concentrations.

Clonazepam may be an alternative to other benzodi-azepines in the emergency management of status epilepticus. The usual dose is 1 mg given by slow intravenous injection over at least 2 minutes or by intravenous infusion, repeated if necessary to a maximum total dose of 20 mg. For doses in children, see below. As with other antiepileptics, withdrawal of clonazepam therapy or transition to or from another type of antiepileptic therapy should be made gradually to avoid precipitating an increase in the frequency of seizures. For a discussion on whether or not to withdraw antiepileptic therapy in seizure-free patients.

In the treatment of panic disorder, clonazepam is given in an initial oral dose of 250 micrograms twice daily. This may be increased after 3 days to a total of 1 mg daily; a few patients may benefit from further increases, up to a maximum of 4 mg daily. In order to minimise drowsiness, clonazepam may be taken as a single dose at bedtime. Withdrawal should again be gradual.

Administration. Serum concentrations of clonazepam after buccal, intranasal, or intravenous dosage were measured in a crossover study in 7 healthy males. The results showed that intranasal clonazepam may offer an alternative to buccal use in patients with serial seizures but the initial concentrations were too low to recommend its use as an alternative to intravenous clonazepam in the management of status epilepticus. The nasal formulation used in this study contained dimethyl-β-cyclodextrin as a solubiliser and absorption enhancer.

Administration in children. For epilepsy and myoclonus treatment with clonazepam is started with small doses that are progressively increased to an optimum dose according to response. Total daily doses are taken in 3 divided doses; however, once the maintenance dose has been reached, the daily amount may be given as a single dose at night. Alternatively, the BNFC suggests giving the initial dose at night for 4 nights and gradually increasing it over 2 to 4 weeks. In the UK, the recommended initial oral daily dose is up to 250 micrograms for infants and children aged up to 5 years, or up to 500 micrograms for older children. The following usual maintenance doses are given according to age:

• neonate to 1 year (although the BNFC recommends a minimum age of 1 month): 0.5 to 1 mg daily

• 1 to 5 years: 1 to 3 mg daily

• 5 to 12 years: 3 to 6 mg daily

Older children may be given the usual adult dose (see above). If control of childhood epilepsy ceases to be adequate with clonazepam, the dose may be increased, or treatment interrupted for 2 or 3 weeks. The BNFC states that the UK inj ection formulation (Rivotril; Roche, UK) can be given orally if necessary; this may not apply to other injection formulations available elsewhere.

In the USA, doses may be given according to body weight. Infants and children aged up to 10 years or weighing up to 30 kg may be given an initial daily dose of 10 to 30 micrograms/kg (maximum 50 micrograms/kg) in 2 or 3 divided doses. This may be increased by a total of 250 to 500 micrograms every 3 days to a maintenance dose of 100 to 200 micrograms/kg daily given in 3 divided doses.

In the emergency management of status epilepticus, clonazepam is used as an alternative to other benzodiazepines. The usual dose in children is 500 micrograms given by slow intravenous injection or by intravenous infusion. Alternatively, the BNFC suggests giving the following doses by slow intravenous injection over at least 2 minutes according to age:

• neonates: 100 micrograms/kg, repeated if necessary after 24 hours

• 1 month to 12years: 50 micrograms/kg (maximum 1 mg), repeated if necessary

Older children may be given the usual adult dose. In children aged over 1 month, these doses by injection may be followed by an intravenous infusion of 10 micrograms/kg per hour, adjusted according to response to a maximum of 60 micrograms/kg per hour.

Extrapyramidal disorders. Clonazepam may be of benefit in some extrapyramidal disorders. It has been tried in the management of patients with tic disorders such as Tourette ’s syndrome but evidence of efficacy from controlled studies is limited. Some use clonazepam in preference to haloperidol since it does not carry the risk of tardive dyskinesia associated with such antipsychotics and a case report described the successful use of clonazepam for haloperidol-induced tardive Tourette’s syndrome in an adult patient. There is also limited evidence of benefit with clonazepam in antipsychotic-induced akathisia and tardive dyskinesia (see under Extrapyramidal Disorders), and of improvement in dysarthria in a study in patients with parkinsonism.

Hiccup. For the management of intractable hiccups see under Chlorpromazine, p.976. Clonazepam may also be of value, especially in neurogenic hiccups.

Neuropathic pain. The management of phantom limb pain can be difficult, and tricyclic antidepressants and antiepileptics are used for the neuropathic components of the pain. Rapid and marked pain relief was achieved in 2 patients with lancinating phantom limb pain after treatment with clonazepam with or without amitriptyline.

Although carbamazepine is the drug of choice in the treatment of trigeminal neuralgia, clonazepam may be used in carbamazepine-intolerant patients.

Psychiatric disorders. Although the risk of dependence with benzodiazepines may outweigh their benefits in panic disorder, clonazepam has been used for the treatment of panic disorder with or without agoraphobia, and reported benefit in such patients suggests a similar action to alprazolam. A literature review evaluated the use of clonazepam in a range of psychiatric disorders and found that it may also be effective in the treatment of social anxiety disorder (see Phobic Disorders although further studies are warranted. There was evidence to suggest that clonazepam may be useful in acute mania and for the augmentation of antidepressant therapy with SSRIs in depression. A study found that augmentation was significantly more effective with a daily dose of 3 mg of clonazepam than with lower doses.

Sleep-associated movement disorders. Treatment of sleep-associated movement disorders including sleep behaviour disorder, restless legs syndrome, and periodic limb movements in sleep is largely empirical, but benzodiazepines such as clonazepam are often used. Small studies have provided some evidence for benefit with clonazepam therapy in these disorders, including bruxism.

Stiff-man syndrome. Clonazepam has been used as an alternative to diazepam in the management of stiff-man syndrome (see under Muscle Spasm) and is reported to be effective for familial startle disease, a rare congenital form of stiff-man syndrome.

Tinnitus. Clonazepam is one of many drugs that have been tried in tinnitus, but although it has been reported to be effective in some patients it is rarely used because of problems with adverse effects.

Preparations

British Pharmacopoeia 2008; Clonazepam Injection;

The United States Pharmacopeia 31, 2008, and Supplements 1 and 2: Clonazepam Oral Suspension; Clonazepam Tablets.

Single-ingredient Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.

Argentina: Alerion; Ciclox; Clonagin; Clonax; Cloner; Diocam; Edictum; Felanor; Induzepam; Leptic; Neuryl; Olimer; Riuclonaz; Rivotril; Sedovanon; Sensaton; Solfidin; Australia: Paxam; Rivotril; Austria: Rivotril; Belgium: Rivotril; Brazil: Clonotril; Rivotril; Canada: Clonapam¤; Rivotril; Chile: Acepran; Clonapam; Clonex; Clozanil; Crismol; Neuryl; Ravotril; Ropsil; Valpax; Czech Republic: Antelepsin; Rivotril; Denmark: Rivotril; Finland: Rivatril; France: Rivotril; Germany: Antelepsin; Rivotril; Greece: Rivotril; Hong Kong: Rivotril; Hungary: Clonapam; Clonogal; Rivotril; India: Epitril; Epizam; Ozepam; Ireland: Rivotril; Israel: Clonex; Rivotril; Italy: Rivotril; Mexico: Kenoket; Kriadex; Rivotril; Netherlands: Rivotril; Norway: Rivotril; New Zealand: Paxam; Rivotril; Portugal: Rivotril; South Africa: Rivotril; Singapore: Rivotril¤; Spain: Rivotril; Sweden: Iktorivil; Switzerland: Rivotril; Thailand: Rivotril; United Kingdom: Rivotril; United States: Klonopin; Venezuela: Rivotril

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