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Clonazepam
Systematic (IUPAC) name
6-(2-chlorophenyl)-9-nitro- 2,5-diazabicyclo[5.4.0]undeca- 5,8,10,12-tetraen-3-one
Identifiers
CAS number	1622-61-3
ATC code	N03AE01
PubChem	2802
DrugBank	APRD00054
Chemical data
Formula	C15H10ClN3O3
Mol. mass	315.715
Pharmacokinetic data
Bioavailability	90%
Metabolism	Hepatic CYP3A4
Half life	18–50 hours
Excretion	Renal
Therapeutic considerations
Pregnancy cat.	C(AU) D(US)
Legal status	Schedule IV(US)
Routes	Oral, I.M., I.V, sublingual

Clonazepam (marketed by Roche under the trade-names Klonopin in the United States and Rivotril or Rivatril in Europe, South America, Canada, India, and Australia) is a drug which is a benzodiazepine derivative. It is a highly potent anticonvulsant, anxiolytic and muscle relaxant. Clonazepam is also used in cases of amphetamine overdose to reverse some of the adverse effects. Clonazepam, also known as 5-(2-chlorphenyl)-1, 3-dihydro-7-nitro-2H-1,4benzodiazepin-2-one, is a close relative both structurally and pharmacologically to nitrazepam.^[1]

Contents 1 Pharmacology 2 Mechanism of action 3 Pharmacokinetics 4 Tolerance 5 Indications 6 Availability 7 Side effects 8 Special precautions 9 Interactions 9.1 Warnings 10 Protracted withdrawal 11 Pregnancy 12 Overdose 13 Recreational use and abuse 14 References 15 External links

Clonazepam is a chlorinated derivative of nitrazepam.^[2] Clonazepam is classed as a nitrobenzodiazepine along with nitrazepam and flunitrazepam.^[3] Aromatic nitro-containing compounds such as clonazepam produce superoxide free radicals during cellular metabolism by endothelial cells. The nitro anion radical produced during clonazepam metabolism rapidly reacts with oxygen to form the free radical superoxide.^[4][5]

Clonazepam is chemically related to quinazolines and is a hapten.^[6] Like other benzodiazepines, clonazepam acts on benzodiazepine receptors which enhance the binding of GABA to the GABA_A receptor which results in inhibitory effects on the central nervous system.^[7] Because of its powerful anxiolytic properties, it is said to be among the class of "highly potent" benzodiazepines. Although benzodiazepines are invaluable in the treatment of anxiety disorders, they carry a high potential for physical and psychological dependence with profound withdrawal symptoms, especially if discontinued abruptly or overrapidly in certain individuals. Caution is advised when taking this or any benzodiazepine medication longer than a few weeks.

One milligram of clonazepam is approximately equivalent to twenty milligrams of diazepam.^[8]

Clonazepam appears to also have a secondary effect on the neurotransmitter serotonin.^[9] It has shown itself to be highly effective as a short-term (3 weeks) adjunct to SSRI treatment in obsessive-compulsive disorder and clinical depression in reducing SSRI side effects with the combination being superior to SSRI treatment alone in a study funded by the manufacturers of clonazepam, Hoffman LaRoche Inc.^[10] Similar results have been found with some other anxiety disorders, but the role of the serotonergic effects enhancing the action of the SSRI treatment remains unclear in these cases due to clonazepam's primary anxiolytic mechanism of action.

Peak blood concentrations of 6.5–13.5 ng/mL were usually reached within 1–2 hours following a single 2 mg oral dose of micronized clonazepam in healthy adults. In some individuals, however, peak blood concentrations were reached at 4–8 hours.^[11]

The anticonvulsant properties of clonazepam and other benzodiazepines may be in part or entirely due to binding to voltage-dependent sodium channels rather than benzodiazepine receptors. Sustained repetitive firing seems to be limited by benzodiazepines effect of slowing recovery of sodium channels from inactivation.^[12] Benzodiazepine drugs including clonazepam increase the inhibitory processes in the cerebral cortex.^[13]

Clonazepam passes rapidly into the central nervous system with levels in the brain corresponding with levels of unbound clonazepam in the blood serum.^[14] Clonazepam plasma levels are very unreliable amongst patients. Plasma levels of clonazepam can vary as much as 10 fold between different patients.^[15]

Clonazepam is broken down and metabolised to a benzophenone compound.^[16] The metabolites of clonazepam include 7-aminoclonazepam, 7-acetaminoclonazepam, 2-amino-2'-chloro-5-nitrobenzophenone and 2,5-diamino-2'-chlorobenzophenone.^[17]

Many studies have found that tolerance develops to the anticonvulsant properties of clonazepam with chronic use, which limits its long term effectiveness as an anticonvulsant.^[18]

Clonazepam is sometimes used for refractory epilepsies; however, long-term prophylactic treatment of epilepsy has considerable limitations, most notably the loss of antiepileptic effects due to tolerance, which renders the drug useless with long-term use, and also side effects such as sedation, which is why clonazepam and benzodiazepines as a class should generally only be prescribed for the acute management of epilepsies.^[19] Clonazepam is less effective and potent as an anticonvulsant in bringing infantile seizures under control compared with nitrazepam in the treatment of West syndrome, which is an age-dependent epilepsy affecting the very young. However, as with other epilepies treated with benzodiazepines, long-term therapy becomes ineffective with prolonged therapy, and the side effects of hypotonia and drowsiness are troublesome with clonazepam therapy; other antiepileptic agents are therefore recommended for long-term therapy, possibly Corticotropin (ACTH) or vigabatrin. Clonazepam is therefore not recommended for widespread use in the management of seizures related to West syndrome.^[20] Also with long-term use, abrupt or overrapid withdrawal from clonazepam can precipitate withdrawal-related seizures if tolerance and physical dependence have developed.

Clonazepam has been used in the management of seizure disorders in children and also for infantile spasms. However, usefulness of clonazepam is limited due to its deleterious effect on neurological function, especially its negative effect on cognition. Clobazam, a 1,5-benzodiazepine, has shown to be less neurotoxic than 1,4-benzodiazepines such as clonazepam.^[21][22]

Clonazepam may be prescribed for:

• Epilepsy^[23]
• Anxiety disorders
• Panic attacks due to the often chronic nature of panic disorders, long-term therapy may be advocated. SSRIs are considered the primary drug, along with cognitive-behavioral therapy, with ^[24]

Initial treatment of mania, together with firstline drugs such as lithium, haloperidol or risperidone

• Restless legs syndrome

Clonazepam is rarely used as a treatment for insomnia due to its relatively weak hypnotic effects. It has not been marketed for the treatment of insomnia mainly because its long half life makes it unsuitable for this application.

Clonazepam was approved in the United States as a generic drug in 1997 and is now manufactured and marketed by several companies.

Clonazepam is available in the U.S. as tablets (0.5, 1.0, and 2 mg), orally disintegrating tablets (wafers) (0.125, 0.25, 0.5, 1.0, and 2 mg), liquid solutions (2.5 mg/mL) and for injection (1 mg/mL)

Like all benzodiazepines, clonazepam is a benzodiazepine receptor agonist. Long-term use (more than 2–4 weeks) can lead to a number of problems, including muscle weakness and fatigue, tolerance, physical dependence and withdrawal syndromes upon discontinuation. The benzodiazepine withdrawal syndrome, which may appear during reduction or withdrawal of clonazepam treatment, can be reduced in intensity with gradual reduction of dosage.

Common:

• Nausea
• Drowsiness
• Impairment of cognition and judgment
• Impaired motor function
  • Impaired coordination
  • Impaired balance
  • Dizziness
• Anterograde amnesia (common with higher doses)

Occasional:

• Serious dysphoria^[25]
• Thrombocytopenia^[26]
• Serious psychological symptoms^[27]
• Increased frequency of seizures^[28]

Rare:

• Paradoxical disinhibition^[29] (most frequently in children, the elderly, and in persons with developmental disabilities)
  • Rage
  • Excitement
  • Irritability
  • Impulsivity
  • Some users report hangover-like symptoms of being drowsy, having a headache, being sluggish, and being irritable after waking up if the medication is taken before sleep. This is likely the result of the medication's long half-life, which continues to affect the user after waking up, as well as its disruption of the REM cycle.

Withdrawal-related:

• Anxiety, irritability, insomnia
• Panic attacks, tremor
• Seizures similar to delirium tremens (with long-term use of excessive doses)

Many individuals treated on a long-term basis develop a form of dependence known as "low-dose dependence", as was shown in one double-blind, placebo-controlled study of 34 therapeutic low-dose benzodiazepine users—physiological dependence was demonstrated via flumazenil-precipitated withdrawal.^[30] Use of alcohol or other CNS depressants while taking clonazepam greatly intensifies the effects (and side effects) of the drug. Side effects of the drug itself are generally benign, but sudden withdrawal after long-term use can cause severe, even fatal, symptoms.

Caution in the Elderly. Increased risk of impairments, falls and drug accumulation.^{[citation needed]}

Caution in children. Clonazepam is not recommended for use in those under 18. Use in very young children may be especially hazardous. Clonazepam was implicated along with the drugs diphenylhydantoin and nitrazepam in the death of a 7 and a half month old girl. She developed inclusions consisting of lamellar profiles, situated in membrane-bound cytosomes which were found mainly in astrocytes, but also in neurones and in axons of peripheral nerves before dying. Lipofuscin bodies were also found to be increased in number.^[31]

Caution using high dosages of clonazepam. Doses higher than 0.5 - 1 mg per day is associated with significant sedation.^[32]

Clonazepam decreases the levels of carbamazepine and phenytoin.^[33]

Clonazepam increases the levels of diphenylhydantoin.^[34][35]

Clonazepam increases the levels of primidone.^[34]

Cannabidiol a drug with anticonvulsant properties, reduces the anticonvulsant protency of clonazepam.^[36]

Clonazepam, like many other benzodiazepines, may impair one's ability to drive or operate heavy machinery. The central nervous system depressing effects of the drug can be augmented by alcohol consumption. Benzodiazepines have been shown to cause both psychological and physical dependence. Patients physically dependent on clonazepam should be slowly titrated off under the supervision of a qualified healthcare professional to avoid withdrawal or rebound symptoms.

10–15% of individuals treated with clonazepam on a long-term basis (in excess of 30 days of continuous use) develop a protracted withdrawal syndrome. Protracted withdrawal lasts for months, years, or a lifetime after clonazepam is discontinued. Protracted withdrawal results from structural brain damage, which is often irreversible.^[37] Common protracted withdrawal symptoms include:^[38]

• Anxiety
• Insomnia
• Depression
• Tinnitus
• Tingling and numbness in limbs
• Muscle pain and tension
• Weakness
• Cramps
• Tremors
• Irritable bowel
• Cognitive dysfunction

Benzodiazepines including clonazepam may inhibit the glucuronidation of morphine leading to increased levels of and prolongation of the effects of morphine. Clonazepam may inhibit morphine metabolism more than any other benzodiazepine.^[39]

There is some medical evidence of various malformations eg cardiac or facial deformations when used in early pregnancy, however the data is not conclusive. The data is also inconclusive whether benzodiazepines such as clonazepam cause developmental deficits or decreases in IQ when taken during pregnancy. Clonazepam when used late in pregnancy may result in the development of a severe benzodiazepine withdrawal syndrome in the neonate and also floppy infant syndrome. Withdrawal symptoms from benzodiazepines in the neonate may include hypotonia, and reluctance to suck, to apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. These symptoms may persist for hours or months after birth.^[40]

An individual who has consumed too much clonazepam will display one or more of the following symptoms:

• Coma
• Hypotension
• Impaired motor functions
  • Impaired reflexes
  • Impaired coordination
  • Impaired balance
  • Dizziness
• Labored breathing
• Mental confusion
• Somnolence (difficulty staying awake)
• Nausea

Coma may be cyclic with the individual alternating from a comatose state to a hyperalert state of consciousness, as occurred in a 4-year-old boy who suffered an overdose of clonazepam.^[41]

Unless combined with other drugs, deep coma or other manifestations of severe central nervous system depression are rare, and the mortality rate associated with poisoning is very low. As with other benzodiazepines, overdose symptoms of clonazepam may be reversed with flumazenil (Romazicon®). In epileptic patients medicated with benzodiazepines, including clonazepam, flumazenil should not be given, however, even in a benzodiazepine overdose, since it may precipitate status epilepticus. Instead, intubation, controlled or supported ventilation and circulatory support within intensive care is indicated in epileptics overdosed by benzodiazepines. Flumazenil should only be considered as a last resort and administered very slowly, fractionally, after an evaluation by a neurologist, specialised in epileptology, possibly under continuous EEG-monitoring in order to record possible early signs of a seizure.

Relatively few cases of addiction arise from legitimate use of benzodiazepines.^[42] If in tablet form, they are most commonly used as a secondary drug to increase the pleasure resulting from a primary drug, or to lessen or prevent some of the primary drug's negative side effects.^{[citation needed]} It is important to note, however, that addiction and physical dependence are distinct conditions.^[43]

• Wallace, Christina. "Kpin, a hit drug with teens, can be deadly, officials say." Boston Metro, Wednesday April 12, 2006. Page 2.
• Carlos, Jean-Marc: The Treatment of Panic Disorder http://www.medscape.com/viewarticle/497207
• Rx-List - Clonazepam
• Poisons Information Monograph - Clonazepam
• FDA prescription insert

v • d • e Benzodiazepines (N05BA, N05CD)
1,4-Benzodiazepines	Bromazepam • Camazepam • Chlordiazepoxide • Cinolazepam • Clonazepam • Clorazepate • Cyprazepam • Delorazepam • Diazepam • Doxefazepam • Elfazepam • Ethyl loflazepate • Fletazepam • Fludiazepam • Fosazepam • Flunitrazepam • Flurazepam • Flutoprazepam • Gidazepam • Halazepam • Iclazepam • Lorazepam • Lormetazepam • Meclonazepam • Medazepam • Menitrazepam • Metaclazepam • Nimetazepam • Nitrazepam • Nordazepam • Oxazepam • Phenazepam • Pinazepam • Pivoxazepam • Prazepam • Quazepam • QH-II-66 • Reclazepam • Sulazepam • Temazepam • Tetrazepam • Uldazepam
Triazolobenzodiazepines	Adinazolam • Alprazolam • Estazolam • Triazolam • Zapizolam
Imidazobenzodiazepines	Bretazenil • Flumazenil • Imidazenil • Loprazolam • Midazolam • Ro15-4513
Oxazolobenzodiazepines	Cloxazolam • Flutazolam • Haloxazolam • Mexazolam • Oxazolam
Thienobenzodiazepines	Brotizolam • Clotiazepam • Etizolam
1,5-Benzodiazepines	Arfendazam • Clobazam • Lofendazam • Triflubazam
2,3-Benzodiazepines	Girisopam • GYKI-52895 • Nerisopam • Tofisopam
Benzodiazepine Prodrugs	Avizafone • Rilmazafone
Others	Bentazepam • Ketazolam • Tifluadom • Zolazepam

v • d • e Anticonvulsants (N03)
Barbiturates	Barbexaclone, Metharbital, Methylphenobarbital, Pentobarbital, Phenobarbital, Primidone
Hydantoins	Ethotoin, Fosphenytoin, Mephenytoin, Phenytoin
Oxazolidinediones	Ethadione, Paramethadione, Trimethadione
Succinimides	Ethosuximide, Mesuximide, Phensuximide
Benzodiazepines	Clobazam, Clonazepam, Clorazepate, Diazepam, Lorazepam, Midazolam, Nitrazepam, Temazepam
Carboxamides	Carbamazepine, Oxcarbazepine, Rufinamide
Fatty acid derivatives	Valpromide, Valnoctamide
Carboxylic acids	Valproic acid (Sodium valproate & Valproate semisodium), Tiagabine
Others	GABA analogs: Gabapentin, Pregabalin, Progabide, Vigabatrin -- Monosaccharides: Topiramate -- Aromatic allylic alcohols: Stiripentol -- Ureas: Phenacemide, Pheneturide -- Phenyltriazines: Lamotrigine Carbamates: Emylcamate, Felbamate, Meprobamate -- Pyrrolidines: Brivaracetam, Levetiracetam, Nefiracetam, Seletracetam Sulfa drugs: Acetazolamide, Ethoxzolamide, Sultiame, Zonisamide -- Propionates: Beclamide -- Aldehydes: Paraldehyde -- Bromides: Potassium bromide, Sodium bromide