Clonazepam was patented in 1960 and went on sale in 1975 in the United States from
Roche. It is available as a
generic medication. In 2020, it was the 44th most commonly prescribed medication in the United States, with more than 14million prescriptions. In many areas of the world it is commonly used as a
Clonazepam, like other benzodiazepines, while being a first-line treatment for acute seizures, is not suitable for the long-term treatment of seizures due to the development of tolerance to the anticonvulsant effects.
Clonazepam has been found effective in treating epilepsy in children, and the inhibition of seizure activity seemed to be achieved at low plasma levels of clonazepam. As a result, clonazepam is sometimes used for certain rare childhood epilepsies; however, it has been found to be ineffective in the control of infantile spasms. Clonazepam is mainly prescribed for the acute management of epilepsies. Clonazepam has been found to be effective in the acute control of non-convulsive
status epilepticus; however, the benefits tended to be transient in many people, and the addition of
phenytoin for lasting control was required in these patients.
Benzodiazepines, such as clonazepam, are sometimes used for the treatment of
mania or acute
psychosis-induced aggression. In this context, benzodiazepines are given either alone, or in combination with other first-line drugs such as
risperidone. The effectiveness of taking benzodiazepines along with
antipsychotic medication is unknown, and more research is needed to determine if benzodiazepines are more effective than antipsychotics when urgent sedation is required.
In September 2020, the U.S.
Food and Drug Administration (FDA) required the
boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.
Some users report
hangover-like symptoms of drowsiness, headaches, sluggishness, and irritability upon waking up if the medication was taken before sleep. This is likely the result of the medication's long half-life, which continues to affect the user after waking up. While benzodiazepines induce sleep, they tend to reduce the quality of sleep by suppressing or disrupting REM sleep. After regular use,
rebound insomnia may occur when discontinuing clonazepam.
Clonazepam, like other benzodiazepines, may impair a person's ability to drive or operate machinery. The central nervous system depressing effects of the drug can be intensified by alcohol consumption, and therefore alcohol should be avoided while taking this medication. Benzodiazepines have been shown to cause dependence. Patients dependent on clonazepam should be slowly titrated off under the supervision of a qualified healthcare professional to reduce the intensity of withdrawal or rebound symptoms.
Suicidal thoughts or urges
Potential to exacerbate existing panic disorder upon discontinuation
Benzodiazepines such as clonazepam can be very effective in controlling
status epilepticus, but, when used for longer periods of time, some potentially serious side-effects may develop, such as interference with
cognitive functions and behavior. Many individuals treated on a long-term basis develop a dependence.
Physiological dependence was demonstrated by
flumazenil-precipitated withdrawal. Use of alcohol or other
CNS depressants while taking clonazepam greatly intensifies the effects (and side effects) of the drug.
A recurrence of symptoms of the underlying disease should be separated from withdrawal symptoms.
Like all benzodiazepines, clonazepam is a GABA-positive
allosteric modulator. One-third of individuals treated with benzodiazepines for longer than four weeks develop a dependence on the drug and experience a withdrawal syndrome upon dose reduction. High dosage and long-term use increase the risk and severity of dependence and withdrawal symptoms. Withdrawal seizures and psychosis can occur in severe cases of withdrawal, and anxiety and insomnia can occur in less severe cases of withdrawal. A gradual reduction in dosage reduces the severity of the
benzodiazepine withdrawal syndrome. Due to the risks of tolerance and withdrawal seizures, clonazepam is generally not recommended for the long-term management of epilepsies. Increasing the dose can overcome the effects of tolerance, but tolerance to the higher dose may occur and adverse effects may intensify. The mechanism of tolerance includes receptor desensitization, down regulation, receptor decoupling, and alterations in subunit composition and in
gene transcription coding.
Tolerance to the anticonvulsant effects of clonazepam occurs in both animals and humans. In humans, tolerance to the anticonvulsant effects of clonazepam occurs frequently. Chronic use of benzodiazepines can lead to the development of tolerance with a decrease of benzodiazepine binding sites. The degree of tolerance is more pronounced with clonazepam than with
chlordiazepoxide. In general, short-term therapy is more effective than long-term therapy with clonazepam for the treatment of epilepsy. 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.
Abrupt or over-rapid withdrawal from clonazepam may result in the development of the benzodiazepine withdrawal syndrome, causing psychosis characterised by
dysphoric manifestations, irritability, aggressiveness, anxiety, and hallucinations. Sudden withdrawal may also induce the potentially life-threatening condition,
status epilepticus. Anti-epileptic drugs, benzodiazepines such as clonazepam in particular, should be reduced in dose slowly and gradually when discontinuing the drug to mitigate withdrawal effects.Carbamazepine has been tested in the treatment of clonazepam withdrawal but was found to be ineffective in preventing clonazepam withdrawal-induced
status epilepticus from occurring.
Coma can be cyclic, with the individual alternating from a comatose state to a hyper-alert state of consciousness, which occurred in a four-year-old boy who overdosed on clonazepam. The combination of clonazepam and certain barbiturates (for example,
amobarbital), at prescribed doses has resulted in a
synergistic potentiation of the effects of each drug, leading to serious respiratory depression.
Overdose symptoms may include extreme drowsiness, confusion, muscle weakness, and fainting.
Detection in biological fluids
Clonazepam and 7-aminoclonazepam may be quantified in
whole blood in order to monitor compliance in those receiving the drug therapeutically. Results from such tests can be used to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage. Both the parent drug and 7-aminoclonazepam are unstable in biofluids, and therefore specimens should be preserved with sodium fluoride, stored at the lowest possible temperature and analyzed quickly to minimize losses.
The elderly metabolize benzodiazepines more slowly than younger people and are also more sensitive to the effects of benzodiazepines, even at similar blood plasma levels. Doses for the elderly are recommended to be about half of that given to younger adults and are to be administered for no longer than two weeks. Long-acting benzodiazepines such as clonazepam are not generally recommended for the elderly due to the risk of drug accumulation.
The elderly are especially susceptible to increased risk of harm from motor impairments and drug accumulation side effects. Benzodiazepines also require special precaution if used by individuals that may be pregnant, alcohol- or drug-dependent, or may have
comorbidpsychiatric disorders. Clonazepam is generally not recommended for use in elderly people for insomnia due to its high potency relative to other benzodiazepines.
Clonazepam is not recommended for use in those under 18. Use in very young children may be especially hazardous. Of anticonvulsant drugs, behavioural disturbances occur most frequently with clonazepam and
Doses higher than 0.5–1 mg per day are associated with significant sedation.
Clonazepam is not recommended for patients with chronic
schizophrenia. A 1982 double-blinded, placebo-controlled study found clonazepam increases violent behavior in individuals with chronic schizophrenia.
Clonazepam has similar effectiveness to other benzodiazepines at often a lower dose.
Clonazepam decreases the levels of
carbamazepine, and, likewise, clonazepam's level is reduced by carbamazepine. Azole antifungals, such as
ketoconazole, may inhibit the metabolism of clonazepam. Clonazepam may affect levels of
phenytoin (diphenylhydantoin). In turn, Phenytoin may lower clonazepam plasma levels by increasing the speed of clonazepam clearance by approximately 50% and decreasing its half-life by 31%.
Clonazepam increases the levels of
There is some medical evidence of various malformations (for example, cardiac or facial deformations when used in early pregnancy); however, the data is not conclusive. The data are also inconclusive on whether benzodiazepines such as clonazepam cause developmental deficits or decreases in IQ in the developing fetus when taken by the mother during pregnancy. Clonazepam, when used late in pregnancy, may result in the development of a severe benzodiazepine withdrawal syndrome in the
neonate. Withdrawal symptoms from benzodiazepines in the
neonate may include
cyanosis, and impaired
metabolic responses to cold stress.
The safety profile of clonazepam during pregnancy is less clear than that of other benzodiazepines, and if benzodiazepines are indicated during pregnancy,
diazepam may be a safer choice. The use of clonazepam during pregnancy should only occur if the clinical benefits are believed to outweigh the clinical risks to the
fetus. Caution is also required if clonazepam is used during breastfeeding. Possible adverse effects of use of benzodiazepines such as clonazepam during pregnancy include:
intrauterine growth retardation, functional deficits,
mutagenesis. Neonatal withdrawal syndrome associated with benzodiazepines include
irritability, abnormal sleep patterns, inconsolable crying,
tremors, or jerking of the extremities,
apnea, risk of aspiration of feeds,
diarrhea and vomiting, and
growth retardation. This syndrome can develop between three days to three weeks after birth and can have a duration of up to several months. The pathway by which clonazepam is metabolized is usually impaired in newborns. If clonazepam is used during pregnancy or
breastfeeding, it is recommended that serum levels of clonazepam are monitored and that signs of
central nervous system depression and
apnea are also checked for. In many cases, non-pharmacological treatments, such as relaxation therapy, psychotherapy, and avoidance of
caffeine, can be an effective and safer alternative to the use of benzodiazepines for anxiety in pregnant women.
Benzodiazepines do not have any effect on the levels of GABA in the brain. Clonazepam has no effect on GABA levels and has no effect on gamma-aminobutyric acid transaminase. Clonazepam does, however, affect
glutamate decarboxylase activity. It differs from other anticonvulsant drugs it was compared to in a study.
mechanism of action is the modulation of
GABA function in the brain, by the benzodiazepine receptor, located on
GABAA receptors, which, in turn, leads to enhanced GABAergic inhibition of neuronal firing. Benzodiazepines do not replace GABA, but instead enhance the effect of GABA at the GABAA receptor by increasing the opening frequency of chloride ion channels, which leads to an increase in GABA's inhibitory effects and resultant central nervous system depression. In addition, clonazepam decreases the utilization of
5-HT (serotonin) by neurons and has been shown to bind tightly to central-type benzodiazepine receptors. Because clonazepam is effective in low milligram doses (0.5 mg clonazepam = 10 mg diazepam), it is said to be among the class of "highly potent"
benzodiazepines. The anticonvulsant properties of benzodiazepines are due to the enhancement of
synaptic GABA responses, and the inhibition of sustained, high-frequency repetitive firing.
Benzodiazepines, including clonazepam, bind to mouse
glial cell membranes with high affinity. Clonazepam decreases release of
acetylcholine in the feline brain and decreases
prolactin release in rats. Benzodiazepines inhibit cold-induced
thyroid-stimulating hormone (also known as TSH or thyrotropin) release. Benzodiazepines act via
micromolar benzodiazepine binding sites as
Ca2+ channel blockers and significantly inhibit depolarization-sensitive calcium uptake in experimentation on rat brain cell components. This has been conjectured as a mechanism for high-dose effects on seizures in the study.
Clonazepam is lipid-soluble, rapidly crosses the
blood–brain barrier, and penetrates the placenta. It is extensively metabolised into pharmacologically inactive metabolites, with only 2% of the unchanged drug excreted in the urine. Clonazepam is metabolized extensively via nitroreduction by
cytochrome P450 enzymes, including
cimetidine, and grapefruit juice are inhibitors of CYP3A4 and can affect the metabolism of benzodiazepines. It has an
elimination half-life of 19–60 hours. 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.
Clonazepam passes rapidly into the central nervous system, with levels in the brain corresponding with levels of unbound clonazepam in the blood serum. Clonazepam plasma levels are very unreliable amongst patients. Plasma levels of clonazepam can vary as much as tenfold between different patients.
Clonazepam has plasma protein binding of 85%. Clonazepam passes through the blood–brain barrier easily, with blood and brain levels corresponding equally with each other. The metabolites of clonazepam include 7-aminoclonazepam, 7-acetaminoclonazepam and 3-hydroxy clonazepam. These metabolites are excreted by the kidney.
It is effective for 6–8 hours in children, and 6–12 in adults.
A 2006 US government study of hospital emergency department (ED) visits found that sedative-hypnotics were the most frequently implicated pharmaceutical drug in visits, with benzodiazepines accounting for the majority of these. Clonazepam was the second most frequently implicated benzodiazepine in ED visits. Alcohol alone was responsible for over twice as many ED visits as clonazepam in the same study. The study examined the number of times the non-medical use of certain drugs was implicated in an ED visit. The criteria for non-medical use in this study were purposefully broad, and include, for example,
drug abuse, accidental or intentional
overdose, or adverse reactions resulting from legitimate use of the medication.
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 as tablets and orally disintegrating tablets (wafers) an oral solution (drops), and as a solution for injection or intravenous infusion.
In some countries, clonazepam is used by criminals to subdue their victims.
Brand name clonazepam tablets
It is marketed under the trade name Rivotril by
Roche in Argentina, Australia, Austria, Bangladesh, Belgium, Brazil, Bulgaria, Canada, Colombia, Costa Rica, Croatia, the Czech Republic, Denmark, Estonia, Germany, Hungary, Iceland, Ireland, Italy, China, Mexico, the Netherlands, Norway, Portugal, Peru, Pakistan, Romania, Serbia, South Africa, South Korea, Spain, Turkey, and the United States; Emcloz, Linotril, Lonazep and Clonotril in India and other parts of Europe; under the name Riklona in Indonesia and Malaysia; and under the trade name Klonopin by
Roche in the United States. Other names, such as Antelepsin, Clonoten, Ravotril, Rivotril, Iktorivil, Clonex (Israel), Paxam, Petril, Naze, Zilepam and Kriadex, are used throughout the world. In August 2021, Roche Australia transferred Rivotril to Pharmaco Australia Ltd.
abEbel S, Schütz H (February 1977). "[Studies on the detection of clonazepam and its main metabolites considering in particular thin-layer chromatography discrimination of nitrazepam and its major metabolic products (author's transl)]". Arzneimittel-Forschung. 27 (2): 325–337.
^Steentoft A, Linnet K (January 2009). "Blood concentrations of clonazepam and 7-aminoclonazepam in forensic cases in Denmark for the period 2002-2007". Forensic Science International. 184 (1–3): 74–79.
^Hrachovy RA, Frost JD, Kellaway P, Zion TE (October 1983). "Double-blind study of ACTH vs prednisone therapy in infantile spasms". The Journal of Pediatrics. 103 (4): 641–645.
^Davidson JR, Potts N, Richichi E, Krishnan R, Ford SM, Smith R, Wilson WH (December 1993). "Treatment of social phobia with clonazepam and placebo". Journal of Clinical Psychopharmacology. 13 (6): 423–428.
^Huynh NT, Rompré PH, Montplaisir JY, Manzini C, Okura K, Lavigne GJ (2006). "Comparison of various treatments for sleep bruxism using determinants of number needed to treat and effect size". The International Journal of Prosthodontics. 19 (5): 435–441.
^Lipton SA, Rosenberg PA (March 1994). "Excitatory amino acids as a final common pathway for neurologic disorders". The New England Journal of Medicine. 330 (9): 613–622.
^Sjö O, Hvidberg EF, Naestoft J, Lund M (April 1975). "Pharmacokinetics and side-effects of clonazepam and its 7-amino-metabolite in man". European Journal of Clinical Pharmacology. 8 (3–4): 249–254.
^Ishizu T, Chikazawa S, Ikeda T, Suenaga E (July 1988). "[Multiple types of seizure induced by clonazepam in an epileptic patient]". No to Hattatsu = Brain and Development (in Japanese). 20 (4): 337–339.
^Adjeroud S, Tonon MC, Leneveu E, Lamacz M, Danger JM, Gouteux L, et al. (May 1987). "The benzodiazepine agonist clonazepam potentiates the effects of gamma-aminobutyric acid on alpha-MSH release from neurointermediate lobes in vitro". Life Sciences. 40 (19): 1881–1887.
^Loiseau P (1983). "[Benzodiazepines in the treatment of epilepsy]". L'Encephale. 9 (4 Suppl 2): 287B–292B.
^Scherkl R, Scheuler W, Frey HH (December 1985). "Anticonvulsant effect of clonazepam in the dog: development of tolerance and physical dependence". Archives Internationales de Pharmacodynamie et de Therapie. 278 (2): 249–260.
^Bacia T, Purska-Rowińska E, Okuszko S (1980). "Clonazepam in the treatment of drug-resistant epilepsy: a clinical short and long term follow-up study". Monographs in Neural Sciences. Frontiers of Neurology and Neuroscience. 5: 153–159.
^Sironi VA, Miserocchi G, De Riu PL (April 1984). "Clonazepam withdrawal syndrome". Acta Neurologica. 6 (2): 134–139.
^Sechi GP, Zoroddu G, Rosati G (September 1984). "Failure of carbamazepine to prevent clonazepam withdrawal status epilepticus". Italian Journal of Neurological Sciences. 5 (3): 285–287.
^Honer WG, Rosenberg RG, Turey M, Fisher WA (November 1986). "Respiratory failure after clonazepam and amobarbital". The American Journal of Psychiatry. 143 (11): 1495b–1495.
abWindorfer A, Sauer W (February 1977). "Drug interactions during anticonvulsant therapy in childhood: diphenylhydantoin, primidone, phenobarbitone, clonazepam, nitrazepam, carbamazepin and dipropylacetate". Neuropadiatrie. 8 (1): 29–41.
^Windorfer A, Weinmann HM, Stünkel S (March 1977). "[Laboratory controls in long-term treatment with anticonvulsive drugs (author's transl)]". Monatsschrift Fur Kinderheilkunde. 125 (3): 122–128.
^Khoo KC, Mendels J, Rothbart M, Garland WA, Colburn WA, Min BH, et al. (September 1980). "Influence of phenytoin and phenobarbital on the disposition of a single oral dose of clonazepam". Clinical Pharmacology and Therapeutics. 28 (3): 368–375.
^Bendarzewska-Nawrocka B, Pietruszewska E, Stepień L, Bidziński J, Bacia T (1980). "[Relationship between blood serum luminal and diphenylhydantoin level and the results of treatment and other clinical data in drug-resistant epilepsy]". Neurologia I Neurochirurgia Polska. 14 (1): 39–45.
^Lehoullier PF, Ticku MK (March 1987). "Benzodiazepine and beta-carboline modulation of GABA-stimulated 36Cl-influx in cultured spinal cord neurons". European Journal of Pharmacology. 135 (2): 235–238.
^Varotto M, Roman G, Battistin L (April 1981). "[Pharmacological influences on the brain level and transport of GABA. I) Effect of various antipileptic drugs on brain levels of GABA]". Bollettino della Societa Italiana di Biologia Sperimentale. 57 (8): 904–908.
^Battistin L, Varotto M, Berlese G, Roman G (February 1984). "Effects of some anticonvulsant drugs on brain GABA level and GAD and GABA-T activities". Neurochemical Research. 9 (2): 225–231.
^Meldrum BS (1986). "Drugs acting on amino acid neurotransmitters". Advances in Neurology. 43: 687–706.
^Jenner P, Pratt JA, Marsden CD (1986). "Mechanism of action of clonazepam in myoclonus in relation to effects on GABA and 5-HT". Advances in Neurology. 43: 629–643.
^Petkov V, Georgiev VP, Getova D, Petkov VV (1982). "Effects of some benzodiazepines on the acetylcholine release in the anterior horn of the lateral cerebral ventricle of the cat". Acta Physiologica et Pharmacologica Bulgarica. 8 (3): 59–66.
^Parry GJ (1976). "An animal model for the study of drugs in the central nervous system". Proceedings of the Australian Association of Neurologists. 13: 83–88.
^Gerna M, Morselli PL (January 1976). "A simple and sensitive gas chromatographic method for the determination of clonazepam in human plasma". Journal of Chromatography. 116 (2): 445–450.