Clonazepam is a medication that belongs to the class of benzodiazepines. It has anticonvulsant, anxiolytic (anxiety-reducing), muscle relaxant, and sedative properties. Clonazepam is commonly prescribed for the treatment of various conditions, including:
- Seizure Disorders: Clonazepam treats certain types of seizures, particularly absence seizures and myoclonic seizures.
- Panic Disorder: It is also prescribed to manage panic disorder, a type of anxiety disorder characterized by recurrent panic attacks.
- Anxiety Disorders: Clonazepam alleviates generalized anxiety disorder (GAD) and social anxiety disorder symptoms.
- Movement Disorders: It may be prescribed for certain movement disorders, such as akathisia and restless legs syndrome (RLS).
Clonazepam works by enhancing the effect of a neurotransmitter called gamma-aminobutyric acid (GABA) in the brain. GABA is an inhibitory neurotransmitter that helps regulate brain activity.
Clonazepam has the potential for dependence and withdrawal symptoms, so it should be used under the supervision of a healthcare professional. Abrupt discontinuation of clonazepam can lead to withdrawal symptoms, and the dosage should be tapered gradually under the guidance of a healthcare provider.
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 metabolized in the liver, its principal metabolite being 7-amino clonazepam, 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 may be affected by use with other antiepileptics.
A single-dose pharmacokinetic study in healthy subjects found that absorption of clonazepam was slower, and intersubject variability was more significant 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.
Based on random evidence, it has been suggested that there may be differences in bioavailability, and hence in clinical effect, between formulations of clonazepam tablets.
Uses and Dosage
Clonazepam is a benzodiazepine derivative similar to diazepam, with marked antiepileptic properties.
It may treat all types of epilepsy and seizures, including status epilepticus. Still, its usefulness in chronic treatment is sometimes limited by the development of tolerance and sedation, and other antiepileptics are often preferred. It may also be used in myoclonus and associated abnormal movements and for treating panic disorder. 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 senior patients) at night for four nights, gradually increasing 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 three days are recommended.
Clonazepam may be an alternative to other benzodiazepines 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 to a maximum total dose of 20 mg if necessary. 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 treating panic disorder, clonazepam is given in an initial oral dose of 250 micrograms twice daily. This may be increased after three days to 1 mg daily; a few patients may benefit from further increases, up to a maximum of 4 mg daily. To minimize drowsiness, clonazepam may be taken as a single dose at bedtime. Withdrawal should again be gradual.
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. Still, the initial concentrations were too low to recommend its use as an alternative to intravenous clonazepam in managing status epilepticus. The nasal formulation used in this study contained dimethyl-β-cyclodextrin as a solubilizer 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 four 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 injection 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 three 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 12 years: 50 micrograms/kg (maximum 1 mg), repeated if necessary.
Older children may be given the usual adult dose. In children 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.
Clonazepam may be of benefit in some extrapyramidal disorders. It has been tried to manage 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 the benefit of clonazepam in antipsychotic-induced akathisia and tardive dyskinesia and of improvement in dysarthria in a study in patients with Parkinsonism.
Clonazepam may also be of value, especially in neurogenic hiccups.
Managing 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.
Although the risk of dependence on benzodiazepines may outweigh their benefits in panic disorder, clonazepam has been used to treat panic disorder with or without agoraphobia. The 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, although further studies are warranted. There was evidence to suggest that clonazepam may be helpful 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 lower doses.
Sleep-Associated Movement Disorders
Treatment of sleep-associated movement disorders, including sleep disorder, restless legs syndrome, and periodic limb movements in sleep, is mainly empirical, but benzodiazepines such as clonazepam are often used. Studies have provided evidence of the benefit of clonazepam therapy in these disorders, including bruxism.
Clonazepam has been used as an alternative to diazepam in managing stiff-man syndrome. It is reportedly effective for familial startle disease, a rare congenital form of stiff-man syndrome.
Clonazepam is one of many drugs that have been tried for tinnitus, but although it has been reported to be effective in some patients, it is rarely used because of problems with adverse effects.
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 this effect was transient. Withdrawal seizures and status might become an obstacle to removing useless or even harmful therapy with clonazepam because the transient nature of these effects was not always recognized. Clonazepam should not be used for more than 3 to 6 months and should be stopped if clear and lasting therapeutic benefits are not indicated.
Adverse Effects, Treatment, and Precautions
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.
Benzodiazepines, such as clonazepam, given to the mother may cause neonatal sedation, and breastfeeding should be avoided.
Effects on the Endocrine System
Precocious development of secondary sexual characteristics occurred in a 15-month-old girl two months after starting treatment with clonazepam 500 micrograms twice daily for convulsions. Symptoms regressed upon withdrawal of clonazepam.
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 three weeks.
Effects on Sexual Function
Sexual dysfunction was reported in 18 of 42 male patients receiving clonazepam for treating post-traumatic stress disorder; symptoms resolved when therapy was changed to diazepam in 17 patients and lorazepam in the remaining patients.
Clonazepam is also used to treat some extrapyramidal disorders, as discussed under Uses and Administration.
Clonazepam is considered unsafe in patients with porphyria. However, there is conflicting evidence of porphyrinogenicity.
Clonazepam can interact with various medications and substances, potentially affecting its effectiveness or increasing the risk of side effects. Inform your healthcare provider about all your medications, supplements, and herbal products. Some potential interactions with clonazepam include:
- Central Nervous System (CNS) Depressants: Combining clonazepam with other medications or substances with CNS depressant effects (e.g., alcohol, opioids, certain antipsychotics, sedative-hypnotics) can enhance sedation and increase the risk of respiratory depression.
- Antiepileptic Medications: Clonazepam may interact with other antiepileptic medications, potentially affecting their levels in the blood. Dosage adjustments may be necessary.
- Antidepressants: Combining clonazepam with certain antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs), may increase the risk of CNS depression and respiratory problems.
- Antihistamines: The sedative effects of clonazepam may be potentiated when taken with antihistamines.
- Oral Contraceptives: Some studies suggest that oral contraceptives may increase the half-life of clonazepam, potentially affecting its efficacy.
- CYP3A4 Inhibitors and Inducers: Medications that inhibit or induce the CYP3A4 enzyme may affect the metabolism of clonazepam. Inhibitors can increase Clonazepam levels, while inducers may decrease its effectiveness.
- Probenecid: Probenecid may inhibit the metabolism of clonazepam, potentially leading to increased blood levels.
- Grapefruit Juice: Grapefruit juice can inhibit the metabolism of certain medications, including clonazepam. It’s advisable to avoid excessive consumption of grapefruit juice while taking clonazepam.
Always consult your healthcare provider before starting or stopping any medication. Tell them your complete medical history and all the substances you are taking to ensure a safe and effective treatment plan. Your healthcare provider can help manage potential interactions and adjust your treatment plan accordingly.
(British Approved Name, US Adopted Name, rINN)
International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):
Synonyms: Clonazepam; Clonazepamum; Klonatsepaami; Klonazepám; Klonazepam; Klonazepamas; Ro-5-4023
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
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 the 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 with a faint odor. Insoluble in water; slightly soluble in alcohol and ether; sparingly soluble in acetone and 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.
British Pharmacopoeia 2008; Clonazepam Injection;
The United States Pharmacopeia 31, 2008, and Supplements 1 and 2: Clonazepam Oral Suspension; Clonazepam Tablets.
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;
Finland: Rivatril; France: Rivotril;
Germany: Antelepsin; Rivotril;
Hong Kong: Rivotril;
Hungary: Clonapam; Clonogal; Rivotril;
India: Epitril; Epizam; Ozepam;
Ireland: Rivotril; Israel: Clonex; Rivotril;
Italy: Rivotril; Mexico: Kenoket; Kriadex; Rivotril;
Norway: Rivotril; New Zealand: Paxam; Rivotril;
South Africa: Rivotril;
United Kingdom: Rivotril;
United States: Klonopin;