Introduction to Clonazepam

Clonazepam is an intermediate-onset and long acting benzodiazepine drug with a half-life of 30-40 hours. Clonazepam is a CNS depressant with anxiolytic, anticonvulsant, and hypnotic effects, prescribed to prevent myoclonic seizures, manage absent seizures, for treatment of anxiety and panic disorders, certain types of migraines, as an initial treatment of mania and acute psychosis, to help manage perceptual effects of hallucinogen persistent perceptual disorder, and for the short-term treatment of bruxism (teeth grinding).[1][2][3][4]

In addition to it's official labelled uses, it has other off-label (for example, restless legs syndrome)and is sometime used recreationally as well. It is also used to counteract the effects of overdose symptoms for many licit and illicit drugs.

Using Clonazepam

Branded clonazepam (Klonopin) is supplied as tablets with a K-shaped perforation containing 0.5 mg of clonazepam and unscored tablets with a K-shaped perforation containing 1 mg or 2 mg of clonazepam. These tablets also contain the following inactive ingredients: lactose, magnesium stearate, microcrystalline cellulose and corn starch, with the following colorants: 0.5 mg—FD&C Yellow No. 6 Lake; 1 mg—FD&C Blue No. 1 Lake and FD&C Blue No. 2 Lake.

Clonazepam is also supplied as scored orally disintegrating tablets containing 0.125 mg, 0.25 mg, 0.5 mg, 1 mg or 2 mg clonazepam. These tablets are usually dissolved sub-lingually. These contain the following inactive ingredients: gelatin, mannitol, methylparaben sodium, propylparaben sodium and xanthan gum.

Generic clonazepam are supplied in the form of 0.5 mg, 1 mg or 2 mg scored orally disintegrating tablets.

Clonazepam is also supplied as Rivotril in 1mg/ml sterile solution as listed in the attached information from electronic Medicines Compendium.

Ways of Administration

Orally

Tablets taken orally are swallowed according to the desired dosage. Scored tablets may be broken to adjust dosage.

Sub-lingual

The orally disintegrating tablets are administered sublingually where some of the dose is absorbed through the mucous membrane, but more so the tablet is dissolved in saliva so it can be administered either with or without water.

Insufflation

Tablets may be ground into a powder and insufflated, but this is not really more effective than sublingual absorption. Additionally, unless it is extracted the binders and fillers will be insufflated as well.

IV

Rivotril sterile concentrate is for intravenous administration. For the treatment of accute seizures (status epilepticus) with the dose and rate of administration governed by the response of the patient.

Adults
1mg (one ampoule of active substance mixed with one ampoule of solvent for parenteral use) by slow intravenous injection.

Elderly
Special care and monitoring must be taken with use of clonazepam in the elderly because they tend to metabolize drugs more slowly. Clonazepam has a half-life longer than a day. With daily or more frequent dosing clonazapam levels can accumulate and rise to dangerous levels possibly causing respiratory depression which is potentially fatal.

Children
0.5mg (equivalent to half an ampoule of active substance mixed with half an ampoule of solvent for parenteral use) by slow intravenous injection. Clonazepam is indicated in children only for the treatment of seizures. [5]

Special dosage instructions
Rivotril can be administered with one or several other antiepileptic agents, in which case the dosage of each drug must be adjusted to achieve optimum effect.

As with all antiepileptic agents, treatment with Rivotril must not be stopped abruptly, but must be reduced in a stepwise fashion (see section 4.8 Undesirable effects).

Mode of administration
Rivotril must be diluted prior to administration in order to avoid irritation of the veins, see section 6.6 Instructions for use/handling.

Intravenous injection of Rivotril should be into a large vein of the antecubital fossa. The injection should be given slowly - in adults, the rate of injection must not exceed 0.25mg – 0.5mg (0.5 – 1.0ml of the prepared solution) per minute – and should be administered with continuous monitoring of EEG, respiration and blood pressure. This will greatly diminish the rare possibility of hypotension or apnoea occurring. Nevertheless, facilities for resuscitation should always be available. A total dose of 20mg should not be exceeded.

Rivotril sterile concentrate may be diluted when given in intravenous infusions of saline or glucose, such as are customary in the treatment of status epilepticus.

Rectally

Effects of Clonazepam

The precise mechanism by which clonazepam exerts its antiseizure and antipanic effects is unknown, although it is believed to be related to its ability to enhance the activity of gamma aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Convulsions produced in rodents by pentylenetetrazol or, to a lesser extent, electrical stimulation are antagonized, as are convulsions produced by photic stimulation in susceptible baboons. A taming effect in aggressive primates, muscle weakness and hypnosis are also produced. In humans, clonazepam is capable of suppressing the spike and wave discharge in absence seizures (petit mal) and decreasing the frequency, amplitude, duration and spread of discharge in minor motor seizures.

Because benzodiazepines have the potential to impair judgment, thinking or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that clonazepam therapy does not affect them adversely.

Combinations with Clonazepam

Clonazepam can interact dangerously with other central nervous system depressants, increasing the likelihood of greater respiratory depression and in other effects such as lack of coordination, dizziness, low blood pressure, unconsciousness and even coma. These depressants include alcohol, other benzodiazepines, barbiturates, antipsychotics, sedative antihistamines, anticonvulsants, delirant and dissociative drugs, muscle relaxants, opioids/opiates, sedative/hypnotics, anxiolytics, narcotic analgesics, anesthetics, MAO inhibitors, and other antidepressants.[6][7]

Alcohol

Alcohol use with clonazepam is not recommended because the two have a tendency to potentiate CNS depressant effects which can include somnolence, confusion, coma and diminished reflexes and even death.

Antidepressants

With some antidepressants clonazepam is indicated to reduce the potential risk of seizure.

Cocaine

Clonazepam has been known to moderate the anxiety associated with cocaine use.

Benzodiazepines such as clonazepam are indicated for acute cocaine ingestion in order to moderate the effects, though sometimes additional treatments such as nitroglycerine therapy are require in extreme cases.(need reference)

LSD

Some users have reported that regular daily use of clonazepam can significantly reduce the effects of LSD.

Anecdotally, clonazepam is indicated for acute LSD ingestion in order to moderate the effects.(need reference)

Other Drugs

Clonazepam does not appear to alter the pharmacokinetics of phenytoin, carbamazepine or phenobarbital. The effect of clonazepam on the metabolism of other drugs has not been investigated.

Different Uses for Clonazepam

Seizure Disorders

Clonazepam is useful 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.

In some studies, up to 30% of patients have shown a loss of anticonvulsant activity, often within 3 months of administration. In some cases, dosage adjustment may reestablish efficacy.

Panic Disorder

Clonazepam is indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks.

The efficacy of clonazepam was established in two 6- to 9-week trials in panic disorder patients whose diagnoses corresponded to the DSM-IIIR category of panic disorder.

Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, ie, a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.

The effectiveness of clonazepam in long-term use, that is, for more than 9 weeks, has not been systematically studied in controlled clinical trials. The physician who elects to use clonazepam for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

Pharmacology of Clonazepam

LD₅₀ : >4000mg/kg (orally in mice)

Pharmacodynamics

The precise mechanism by which clonazepam exerts its antiseizure and antipanic effects is unknown, although it is believed to be related to its ability to enhance the activity of gamma aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Convulsions produced in rodents by pentylenetetrazol or, to a lesser extent, electrical stimulation, are antagonized, as are convulsions produced by photic stimulation in susceptible baboons. A taming effect in aggressive primates, muscle weakness and hypnosis are also produced. In humans, clonazepam is capable of suppressing the spike and wave discharge in absence seizures (petit mal) and decreasing the frequency, amplitude, duration and spread of discharge in minor motor seizures.
Additionally, Clonazepam upregulates the Serotoning Transporter (SERT)[FOONOTE]Meldrum BS (1986). "Drugs acting on amino acid neurotransmitters". Adv Neurol 43: 687–706.[/FOOTNOTE][FOONOTE]Meldrum BS (1986). "Drugs acting on amino acid neurotransmitters". Adv Neurol 43: 687–706.[/FOONOTE], which means that Clonazepam reduces the levels of Serotonin (5-HT) in the brain.

Pharmacokinetics

Clonazepam is rapidly and completely absorbed after oral administration. The absolute bioavailability of clonazepam is about 90%. Maximum plasma concentrations of clonazepam are reached within 1 to 4 hours after oral administration. Clonazepam is approximately 85% bound to plasma proteins. Clonazepam is highly metabolized, with less than 2% unchanged clonazepam being excreted in the urine. Biotransformation occurs mainly by reduction of the 7-nitro group to the 4-amino derivative. This derivative can be acetylated, hydroxylated and glucuronidated. Cytochrome P-450 including CYP3A, may play an important role in clonazepam reduction and oxidation. The elimination half-life of clonazepam is typically 30 to 40 hours. Clonazepam pharmacokinetics are dose-independent throughout the dosing range. There is no evidence that clonazepam induces its own metabolism or that of other drugs in humans.

Pharmacokinetics in Demographic Subpopulations and in Disease States

At the time the attached referenced monograph was written it states that, controlled studies examining the influence of gender and age on clonazepam pharmacokinetics have not been conducted, nor have the effects of renal or liver disease on clonazepam pharmacokinetics been studied. Because clonazepam undergoes hepatic metabolism, it is possible that liver disease will impair clonazepam elimination. Thus, caution should be exercised when administering clonazepam to these patients.

There is new updated information from patient studies done to recommend that monitoring liver function be done during extended clonazepam therapy. (need reference)

Chemistry of Clonazepam

Column 1	Column 2
Systematic (IUPAC) name:	5-(2-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one
Synonyms:	7-nitro-5-(2-chlorophenyl)-3H-1,4-benzodiazepin-2(1H)-one, Ro-5-4023, Iktorivil, Klonopin, Rivotril, Lonazep, NSC 179913, Kenoket, Antilepsin, Apetryl, Clonex
Molecular Formula:	C15H10ClN3O3
Molar mass:	315.71 g/mol [2]
CAS Registry Number:	1622-61-3
Melting Point:	236.5-238.5 °C
Boiling Point:	no data
Flash Point:	no data
Solubility:	(mg/mL @ 25°C) acetone 31, chloroform 15, methanol 8.6, ether 0.7, benzene 0.5, water <0.1
Additionnal data:	pK1 1.5, pK2 10.5
Notes:	Aspect : white crystals from ethanol-methylene chloride

[1]

The dangers of Clonazepam

Clonazepam can cause anterograde amnesia (the inability to form long term memories from short term memories). In many cases clonazepam leads to complete "black outs", snd inhibitions drop sharply, especially when clonazepam is combined with alcohol.

Pharmacodynamic Interactions

The CNS-depressant action of the benzodiazepine class of drugs may be potentiated by alcohol, narcotics, barbiturates, nonbarbiturate hypnotics, antianxiety agents, the phenothiazines, thioxanthene and butyrophenone classes of antipsychotic agents, monoamine oxidase inhibitors and the tricyclic antidepressants, and by other anticonvulsant drugs.

Warnings

Because benzodiazepines have the potential to impair judgment, thinking or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that clonazepam therapy does not affect them adversely.

Overdosage

Human Experience: Symptoms of clonazepam overdosage, like those produced by other CNS depressants, include sleepiness, confusion, coma and diminished reflexes and possibly death.

Overdose Management: Treatment includes monitoring of respiration, pulse and blood pressure, general supportive measures and immediate gastric lavage. Intravenous fluids should be administered and an adequate airway maintained. Hypotension may be combated by the use of levarterenol or metaraminol. Dialysis is of no known value.

Flumazenil, a specific benzodiazepine-receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for resedation, respiratory depression and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert, including CONTRAINDICATIONS, WARNINGS and PRECAUTIONS, should be consulted prior to use.

Flumazenil is not indicated in patients with epilepsy who have been treated with benzodiazepines. Antagonism of the benzodiazepine effect in such patients may provoke seizures.

Serious sequelae are rare unless other drugs or alcohol have been taken concomitantly.

Forms of Clonazepam

Legal status of Clonazepam

United Nations

USA

EU

Other Countries

History of Clonazepam

More Clonazepam Sections

References

1. ^Cloos, Jean-Marc (2005). The Treatment of Panic Disorder. Curr Opin Psychiatry 18 (1): 45–50.
2. ^Maria G Dahlin, Per E Åmark, Arne R Nergårdh (2003) Reduction of seizures with low-dose clonazepam in children with epilepsy (2003) Pediatric Neurology (28):1;48–52.
3. ^Roche Laboratories Inc. Klonopin (clonazepam) tablets prescribing information. Nutley, NJ; 1997 Oct.
4. ^Clonazepam treatment of lysergic acid diethylamide-induced hallucinogen persisting perception disorder with anxiety features.Lerner AG, Gelkopf M, Skladman I, Rudinski D, Nachshon H, Bleich A. (32003) Int Clin Psychopharmacol. 2003 Mar;18(2):101-5.
5. ^Dahlin MG, Amark PE, Nergardh AR (2003). Reduction of seizures with low-dose clonazepam in children with epilepsy. Pediatric Neurology 28(1):48–52.
6. ^ Roche Laboratories Inc. Klonopin (clonazepam) tablets prescribing information. Nutley, NJ; 1997 Oct
7. ^E. Tanaka Clinically significant pharmacokinetic drug interactions with benzodiazepines (1999) Journal of Clinical Pharmacy and Therapeutics (1999) 24, 347–355.

[1]Merck Index, fifteenth edition (2013)
[2]Calculated from Atomic Weights of the Elements, 2007