Clonazepam

Clonazepam is a first-generation antiepileptic drug (AED) known under the proprietary brand name of Rivotril® (Roche, Basel) in the UK and Klonopin® (Roche, Basel) in the USA.

MHRA/ CHM advice to minimize risk when switching patients with epilepsy between different manufacturers’ products (including generic products):

• The need for continued supply of a particular manufacturer’s product should be based on clinical judgment, and consultation with the patient and/ or carer, taking into account factors such as seizure frequency and treatment history.

Epilepsy: monotherapy and adjunctive therapy of focal and generalized seizures. Recommendations summarized from NICE (2012)

• Seizure types: on referral to tertiary care (absence seizures, myoclonic seizures).
• Epilepsy types: on referral to tertiary care (absence syndromes, juvenile myoclonic epilepsy, idiopathic generalized epilepsy).

Epilepsy: 1 mg nocte for 4 days, then increased over 2– 4 weeks; usual maintenance dose 4–8 mg nocte or divided into 3 or 4 doses.

• Patients with depression/ suicidal ideation.
• Patients with brain damage.
• Patients with cerebellar/ spinal ataxia.
• Patients with acute porphyrias.
• Patients with airways obstruction.

With AEDs
Plasma concentration of clonazepam can be reduced by carbamazepine, phenobarbital, phenytoin, and primidone.

With other drugs

• Plasma concentration of clonazepam is decreased by rifampicin and can be reduced by theophylline.
• Plasma concentration of clonazepam is increased by cimetidine, disulfiram, fluvoxamine, and ritonavir
• There is an increased risk of prolonged sedation and respiratory depression when clonazepam is given with amprenavir.
• There are enhanced hypotensive and sedative effects when clonazepam is given with alpha- blockers or moxonidine.
• There is an enhanced hypotensive effect when clonazepam is given with ACE inhibitors, adrenergic neurone blockers, angiotensin- II receptor antagonists, beta- blockers, calcium channel blockers, clonidine, diazoxide, diuretics, hydralazine, methyldopa, minoxidil, nitrates, or nitroprusside.
• There is an increased sedative effect when clonazepam is given with general anaesthetics, tricyclic antidepressants, antihistamines, antipsychotics, baclofen, lofexidine, mirtazapine, nabilone, opioid analgesics, tizanidine.
• Clonazepam may possibly antagonize the effects of levodopa.

Hepatic impairment

• Start with smaller initial dose or reduce maintenance dose.
• Avoid in severe impairment.

Renal impairment

• Start with smaller dose in significant impairment.

Pregnancy

• As a precautionary measure, it is preferable to avoid the use of clonazepam and clobazam during pregnancy. Clonazepam and clobazam should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
• Administration of clonazepam in the last trimester of pregnancy or during labour can result in hypothermia, hypotonia, respiratory depression, and feeding difficulties in the neonate.
• Infants born to mothers who have taken clonazepam during the later stages of pregnancy may develop physical dependence, and may be at risk for developing withdrawal symptoms in the postnatal period.
• Clonazepam, like all benzodiazepines, are present in milk and should be avoided if possible during breastfeeding.

Behavioural effects include sleepiness, poor coordination, and agitation with paradoxical aggression/ disinhibition (usually dose- dependent). Long- term use may result in tolerance, dependence, and withdrawal symptoms if stopped abruptly. In addition to seizure exacerbation, abrupt discontinuation of benzodiazepines can be accompanied by changes in mental status, including anxiety, agitation, confusion, depression, psychosis, and delirium. Dependence occurs in one- third of patients who take clonazepam for longer than 4 weeks. Moreover, clonazepam may aggravate symptoms in patients who are depressed. Benzodiazepines are more frequently associated with adverse cognitive effects than most other AEDs. Among these, anterograde amnesia has been reported in patients treated with clonazepam (mainly at high doses).

Clonazepam has been found to be effective in the short- term treatment of anxiety disorders, including generalized anxiety disorder, social phobia, and panic disorder. Catatonia, alcohol withdrawal, and insomnia are other common indications supported by evidence. Clonazepam is also sometimes used for the treatment of acute mania, or psychosis- induced aggression and agitation (adjunctive treatment for bipolar disorder and schizophrenia).

Clonazepam (Item No. 14263) is an analytical reference material categorized as a benzodiazepine. Clonazepam is regulated as a Schedule IV compound in the United States. This product is intended for research and forensic applications.

Tan Solid

Rivotril,Roche,France,1973

Antiepileptic agent with anxiolytic and antimanic properties. Anticonvulsant. This is a controlled substance (depressant)

ChEBI: 1,3-Dihydro-2H-1,4-benzodiazepin-2-one in which the hydrogens at positions 5 and 7 are substituted by 2-chlorophenyl and nitro groups, respectively. It is used in the treatment of all types of epilepsy and seizures, as well as myoclonus nd associated abnormal movements, and panic disorders. However, its use can be limited by the development of tolerance and by sedation.

The following description is taken from US Patent 3,116,203. A stirred solution of 75 g of 2-amino-2'-nitrobenzophenone in 700 ml of hot concentrated hydrochloric acid was cooled to 0°C and a solution of 21.5 g of sodium nitrite in 50 ml of water was added in the course of 3 hours. The temperature of the suspension was kept at 2° to 7°C during the addition. The resulting clear solution was poured into a stirred solution of 37 g of cuprous chloride in 350 ml of hydrochloric acid 1:1. The solid which had formed after a few minutes was filtered off, washed with water and recrystallized from ethanol. Crystals of 2-chloro-2'-nitrobenzophenone melting at 76° to 79°C were obtained.
A solution of 20 g of 2-chloro-2'-nitrobenzophenone in 450 ml of ethanol was hydrogenated at normal pressure and room temperature with Raney nickel. After uptake of about 6 liters of hydrogen the catalyst was filtered off, and the alcohol then removed in vacuo. The residue was distilled in a bulb tube at 0.4 mm and a bath temperature of 150° to 165°C giving a yellow oil. The oil was dissolved in alcohol, and on addition of water, needles of 2-amino-2'- chlorobenzophenone melting at 58° to 60°C were obtained.
To a solution of 42 g of 2-amino-2'-chlorobenzophenone in 500 ml of benzene, 19 ml of bromoacetyl bromide was added dropwise. After refluxing for 2 hours, the solution was cooled, washed with 2 N sodium hydroxide and evaporated. The residue was recrystallized from methanol giving crystals of 2- bromo-2'-(2-chlorobenzoyl)acetanilide melting at 119° to 121°C.
To a solution of 14.5 g of 2-bromo-2'-(2-chlorobenzoyl)acetanilide in 100 ml of tetrahydrofuran, an excess of liquid ammonia (ca 150 ml) was added. The ammonia was kept refluxing with a dry-ice condenser for 3 hours after which time the ammonia was allowed to evaporate and the solution was poured into water. Crystals of 2-amino-2'-(2-chlorobenzoyl)acetanilide were collected, which after recrystallization from ethanol melted at 162° to 164°C.
A solution of 3 g of 2-amino-2'-(2-chlorobenzoyl)acetanilide in 50 ml of pyridine was refluxed for 24 hours after which time the pyridine was removed in vacuo. The residue was recrystallized from methanol and a mixture of dichloromethane and ether giving crystals of 5-(2-chlorophenyl)-3H-1,4- benzodiazepin-2(1H)-one melting at 212° to 213°C.
To a solution of 13.5 g of 5-(2-chlorophenyl)-3H-1,4-benzodiazepin-2(1H)-one in 60 ml of concentrated sulfuric acid, a solution of 5.5 g of potassium nitrate in 20 ml concentrated sulfuric acid was added dropwise. The solution then was heated in a bath at 45° to 50°C for 2.5 hours, cooled and poured on ice. After neutralizing with ammonia, the formed precipitate was filtered off and boiled with ethanol. A small amount of white insoluble material was then filtered off. The alcoholic solution on concentration yielded crystals of 7-nitro-5-(2- chlorophenyl)-3H-1,4-benzodiazepin-2(1H)-one which, after recrystallization from dichloromethane, melted at 238° to 240°C.

Klonopin (Roche). Antelepsin (Arzneimittelwerk Dresden), Clonopin/ Rivotril (Roche).

Anticonvulsant

Clonazepam is useful in absence seizures and in myoclonicseizures. Tolerance to the anticonvulsant effect of the clonazepamoften developed rather quickly, and it is a commonproblem with the BZDs. Metabolism involves hydroxylationof the C-3 position, followed by glucuronidation andnitro group reduction, followed by acetylation.

Moderately toxic.

Benzodiazepine:
Anticonvulsant

Anxiolytic

Restless leg syndrome

Potentially hazardous interactions with other drugs
Antibacterials: metabolism possibly increased by rifampicin.
Antipsychotics: increased sedative effects; increased risk of hypotension, bradycardia and respiratory depression with parenteral clonazepam and IM olanzapine; risk of serious adverse effects in combination with clozapine.
Antivirals: concentration possibly increased by ritonavir.
Disulfiram: metabolism inhibited, increased sedative effects.
Sodium oxybate: enhanced effects of sodium oxybate - avoid.

Clonazepam 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.