Clonazepam

Source: Wikipedia, the free encyclopedia.
Not to be confused with
clorazolam
.

Clonazepam
Clinical data
Pronunciationkləˈnazɪpam, kloe-NAZ-e-pam
Trade namesKlonopin, Rivotril, Paxam,[1] others[2]
AHFS/Drugs.comMonograph
MedlinePlusa682279
License data
Pregnancy
category
Dependence
liability		Physical: Very High
By mouth, intramuscular, intravenous, sublingual
Drug classBenzodiazepine
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability90%
Protein binding≈85%
MetabolismLiver (CYP3A)[11]
Metabolites7-aminoclonazepam
7-acetaminoclonazepam
3-hydroxy clonazepam[7][8]
Onset of actionWithin an hour[9]
Elimination half-life19–60 hours[10]
Duration of action8–12 hours[9][1]
ExcretionKidney
Identifiers
  • 5-(2-Chlorophenyl)-7-nitro-1,3-dihydro-1,4-benzodiazepin-2-one
JSmol)
  • O=C1CN=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2N1
  • InChI=1S/C15H10ClN3O3/c16-12-4-2-1-3-10(12)15-11-7-9(19(21)22)5-6-13(11)18-14(20)8-17-15/h1-7H,8H2,(H,18,20) checkY
  • Key:DGBIGWXXNGSACT-UHFFFAOYSA-N checkY
  (verify)

Clonazepam, sold under the brand names Klonopin and Rivotril, is a

skeletal muscle relaxant properties. It is typically taken by mouth but is also used intravenously.[11][13] Effects begin within one hour and last between eight and twelve hours in adults.[9][1]

Common side effects may include sleepiness, poor coordination, and agitation.

γ-aminobutyric acid (GABA).[10]

Clonazepam was patented in 1960 and went on sale in 1975 in the United States from

Roche.[16][17] It is available as a generic medication.[11] In 2021, it was the 46th-most commonly prescribed medication in the United States, with more than 14 million prescriptions.[18][19] In many areas of the world, it is commonly used as a recreational drug.[20][21]

Medical uses

Clonazepam is prescribed for short-term management of epilepsy, anxiety, OCD and panic disorder with or without agoraphobia.[22][23][24]

Seizures

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.[25] As a result, clonazepam is sometimes used for certain rare childhood epilepsies, but it has been found to be ineffective in the control of infantile spasms.[26] Clonazepam is mainly prescribed for the acute management of epilepsies. Clonazepam has been found to be effective in the acute control of nonconvulsive status epilepticus; the benefits, though, tended to be transient in many people, and the addition of phenytoin for lasting control was required in these patients.[27]

It is also approved for treatment of typical and atypical absences (seizures), infantile myoclonic, myoclonic, and akinetic seizures.[28] A subgroup of people with treatment resistant epilepsy may benefit from long-term use of clonazepam; the benzodiazepine clorazepate may be an alternative due to its slow onset of tolerance.[10][29]

Anxiety disorders

The effectiveness of clonazepam in the short-term treatment of panic disorder has been demonstrated in controlled clinical trials. Some long-term trials have suggested a benefit of clonazepam for up to three years without the development of tolerance.[33] Clonazepam is also effective in the management of acute mania.[34]

Muscle disorders

Restless legs syndrome can be treated using clonazepam as a third-line treatment option, as the use of clonazepam is still investigational.[35][36] Bruxism also responds to clonazepam in the short term.[37] REM sleep behavior disorder responds well to low doses of clonazepam.[38] It is also used for:

Other

Contraindications

  • Coma
  • Current
    alcohol use disorder
  • Current substance use disorder
  • Respiratory depression[47]

Adverse effects

In September 2020, the U.S. Food and Drug Administration 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.[48]

Common

Less common

Occasional

Rare

The

long-term effects of clonazepam can include depression,[10] disinhibition, and sexual dysfunction.[73]

Drowsiness

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, so 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.

Withdrawal-related

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.[75] Many individuals treated on a long-term basis develop a dependence. Physiological dependence was demonstrated by flumazenil-precipitated withdrawal.[76] 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.[77]

Tolerance and withdrawal

Main article: Benzodiazepine withdrawal syndrome

Like all benzodiazepines, clonazepam is a GABA-positive allosteric modulator.[78][79] 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.[10]

Tolerance to the anticonvulsant effects of clonazepam occurs in both animals and humans. In humans, tolerance to the anticonvulsant effects of clonazepam occurs frequently.[80][81] 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.[82] In general, short-term therapy is more effective than long-term therapy with clonazepam for the treatment of epilepsy.[83] 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.[28]

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.[84][85][86] 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.[66] 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.[87]

Overdose

Main article: Benzodiazepine overdose

Excess doses may result in:

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.[88] 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.[89]

Overdose symptoms may include extreme drowsiness, confusion, muscle weakness, and fainting.[90]

Detection in biological fluids

Clonazepam and 7-aminoclonazepam may be quantified in plasma, serum, or 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.[91]

Special precautions

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.[10]

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 comorbid psychiatric disorders.[92] Clonazepam is generally not recommended for use in elderly people for insomnia due to its high potency relative to other benzodiazepines.[93]

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 phenobarbital.[92][94]

Doses higher than 0.5–1 mg per day are associated with significant sedation.[95]

Clonazepam may aggravate hepatic porphyria.[96][97]

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.[98]

Clonazepam has similar effectiveness to other benzodiazepines at often a lower dose.[99]

Interactions

Clonazepam decreases the levels of carbamazepine,[100][101] and, likewise, clonazepam's level is reduced by carbamazepine. Azole antifungals, such as ketoconazole, may inhibit the metabolism of clonazepam.[10] Clonazepam may affect levels of phenytoin (diphenylhydantoin).[100][102][103][104] 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%.[105] Clonazepam increases the levels of primidone[103] and phenobarbital.[106]

Combined use of clonazepam with certain antidepressants, anticonvulsants (such as phenobarbital, phenytoin, and carbamazepine), sedative antihistamines, opiates, and antipsychotics, nonbenzodiazepines (such as zolpidem), and alcohol may result in enhanced sedative effects.[10]

Pregnancy

See also:
Long-term effects of benzodiazepines § Neonatal effects

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 hypotonia, apnoeic spells, cyanosis, and impaired metabolic responses to cold stress.[107]

The safety profile of clonazepam during pregnancy is less clear than that of other benzodiazepines, and if benzodiazepines are indicated during pregnancy, chlordiazepoxide and 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: miscarriage, malformation, intrauterine growth retardation, functional deficits, carcinogenesis, and mutagenesis. Neonatal withdrawal syndrome associated with benzodiazepines include hypertonia, hyperreflexia, restlessness, irritability, abnormal sleep patterns, inconsolable crying, tremors, or jerking of the extremities, bradycardia, cyanosis, suckling difficulties, 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.[108]

Pharmacology

Mechanism of action

Clonazepam enhances the activity of the inhibitory neurotransmitter

gamma-aminobutyric acid (GABA) in the central nervous system to give its anticonvulsant, skeletal muscle relaxant, and anxiolytic effects.[109] It acts by binding to the benzodiazepine site of the GABA receptors, which enhances the electric effect of GABA binding on neurons, resulting in an increased influx of chloride ions into the neurons. This further results in an inhibition of synaptic transmission across the central nervous system.[110][111]

Benzodiazepines do not have any effect on the levels of GABA in the brain.[112] 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.[113]

Clonazepam's primary

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.[10] In addition, clonazepam decreases the utilization of 5-HT (serotonin) by neurons[114][115] and has been shown to bind tightly to central-type benzodiazepine receptors.[116] Because clonazepam is effective in low milligram doses (0.5 mg clonazepam = 10 mg diazepam),[117][118] it is said to be among the class of "highly potent" benzodiazepines.[119] The anticonvulsant properties of benzodiazepines are due to the enhancement of synaptic GABA responses, and the inhibition of sustained, high-frequency repetitive firing.[120]

Benzodiazepines, including clonazepam, bind to mouse glial cell membranes with high affinity.[121][122] Clonazepam decreases release of acetylcholine in the feline brain[123] and decreases prolactin release in rats.[124] Benzodiazepines inhibit cold-induced thyroid-stimulating hormone (also known as TSH or thyrotropin) release.[125] 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.[126]

Clonazepam is a 2'-chlorinated derivative of nitrazepam, which increases its potency due to electron-attracting effect of the halogen in the ortho-position.[127][9]

Pharmacokinetics

Clonazepam is lipid-soluble, rapidly crosses the

elimination half-life of 19–60 hours.[10] 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.[130]

Clonazepam passes rapidly into the central nervous system, with levels in the brain corresponding with levels of unbound clonazepam in the blood serum.[131] Clonazepam plasma levels are very unreliable amongst patients. Plasma levels of clonazepam can vary as much as tenfold between different patients.[132]

Clonazepam has plasma protein binding of 85%.[133][128] Clonazepam passes through the blood–brain barrier easily, with blood and brain levels corresponding equally with each other.[134] The metabolites of clonazepam include 7-aminoclonazepam, 7-acetaminoclonazepam and 3-hydroxy clonazepam.[7][135] These metabolites are excreted by the kidney.[128]

It is effective for 6–8 hours in children, and 8–12 in adults.[136][1]

Society and culture

Recreational use

See also:
Benzodiazepine misuse

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.[137]

Formulations

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.[138]

Crime

In some countries, clonazepam is used by criminals to subdue their victims.[139]

Brand names

Brand name clonazepam tablets

It is marketed under the trade name Rivotril 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.[2][138] In August 2021, Roche Australia transferred Rivotril to Pharmaco Australia Ltd.[141]

  • Klonopin 0.5 mg tablet
    Klonopin 0.5 mg tablet
  • Klonopin 1 mg tablet
    Klonopin 1 mg tablet
  • Klonopin 2 mg tablet
    Klonopin 2 mg tablet
  • Clonazepam orally disintegrating tablet, 0.25 mg
    Clonazepam orally disintegrating tablet, 0.25 mg

References

  1. ^ a b c d "Paxam Data Sheet" (PDF). medsafe.govt.nz. 18 October 2023. Retrieved 14 March 2024.
  2. ^ a b "Clonazepam International". Drugs.com. Archived from the original on 25 August 2017.
  3. ^ "Clonazepam Use During Pregnancy". Drugs.com. 4 May 2020. Retrieved 17 May 2020.
  4. PMID 10779253
    .
  5. ISBN 9780323226875
    .
  6. FDA
    . Retrieved 22 October 2023.
  7. ^
    PMID 577149
    .
  8. PMID 19150586
    .
  9. ^
    ISBN 9781597452472. Archived
    from the original on 19 August 2016.
  10. ^
    S2CID 24453988
    .
  11. ^ a b c d e f g h i "Clonazepam". The American Society of Health-System Pharmacists. Archived from the original on 5 September 2015. Retrieved 15 August 2015.
  12. PMID 32310470
    . Retrieved 15 March 2024.
  13. PMID 27073337
    .
  14. PMID 34842811
    .
  15. ^
    PMID 28257172
    .
  16. ISBN 9783527607495
    .
  17. ISBN 9780190292010. Archived
    from the original on 2 October 2015.
  18. ^ "The Top 300 of 2021". ClinCalc. Archived from the original on 15 January 2024. Retrieved 14 January 2024.
  19. ^ "Clonazepam - Drug Usage Statistics". ClinCalc. Retrieved 14 January 2024.
  20. ISBN 9780124115613. Archived
    from the original on 2 October 2015. In several countries, prescription and use is now severely limited due to abusive recreational use of clonazepam.
  21. ISBN 9781412950848. Archived
    from the original on 12 August 2016. frequently abused
  22. S2CID 350479
    .
  23. S2CID 2017627
    .
  24. ^ "Clonazepam: medicine to control seizures or fits, muscle spasms and restless legs syndrome". nhs.uk. 6 January 2020. Retrieved 19 April 2020.
  25. PMID 12657420
    .
  26. PMID 6312008
    .
  27. S2CID 26694857
    .
  28. ^
    PMID 817697
    .
  29. PMID 32309880
    .
  30. PMID 16639183. Archived
    from the original on 4 April 2011. Retrieved 25 September 2007.
  31. PMID 8120156
    .
  32. ISBN 978-1-4614-2012-5
    .
  33. S2CID 801184
    .
  34. S2CID 29469943
    .
  35. PMID 17876423
    .
  36. S2CID 91440. Archived from the original
    (PDF) on 29 December 2009. Retrieved 19 January 2010.
  37. PMID 17323720
    .
  38. S2CID 43692512
    .
  39. S2CID 45721265. Archived from the original
    on 23 March 2009. Retrieved 1 March 2009.
  40. S2CID 27621771
    .
  41. PMID 7905600
    .
  42. PMID 15013244
    .
  43. ^
    PMID 23633309
    .
  44. S2CID 40864297
    .
  45. PMID 17580590
    .
  46. S2CID 24233098
    .
  47. ^ Joint Formulary Committee. "British National Formulary (online)". London: BMJ Group and Pharmaceutical Press. Retrieved 2 February 2020.
  48. ^ "FDA expands Boxed Warning to improve safe use of benzodiazepine drug". U.S. Food and Drug Administration (FDA). 23 September 2020. Retrieved 23 September 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  49. S2CID 40376995
    .
  50. PMID 121707
    .
  51. PMID 6120763
    .
  52. PMID 3870855
    .
  53. ISBN 978-0-444-53266-4
    .
  54. ^ "Clonazepam Side Effects". Drugs.com. 2010. Archived from the original on 28 April 2010.
  55. ISBN 978-0-7817-7906-7
    .
  56. ISBN 978-1-58562-309-9
    .
  57. ^ "Get Some Sleep: Beware the sleeping pill hangover". Archived from the original on 21 July 2017. Retrieved 21 June 2017.
  58. ISBN 978-1-4419-0853-7
    .
  59. ISBN 978-0-471-25401-0
    .
  60. ISBN 978-0-19-530659-0
    .
  61. ISBN 978-0-07-148869-3
    .
  62. S2CID 27095161
    .
  63. S2CID 39403793
    .
  64. PMID 3214607
    .
  65. S2CID 31409580
    .
  66. ^
    PMID 371777
    .
  67. S2CID 40893264
    .
  68. PMID 7057171
    .
  69. S2CID 36023934
    .
  70. PMID 6879368
    .
  71. PMID 4032590
    .
  72. PMID 2019899
    .
  73. PMID 2889724
    .
  74. S2CID 31346286
    .
  75. PMID 3528811
    .
  76. S2CID 24348950
    .
  77. ISBN 978-1-107-67502-5
    .
  78. PMID 3033417
    .
  79. PMID 11906969
    .
  80. PMID 6373234
    .
  81. PMID 4096613
    .
  82. S2CID 24771398
    .
  83. PMID 7033770
    .
  84. PMID 6741654
    .
  85. PMID 490178
    .
  86. PMID 3711371
    .
  87. S2CID 23094043
    .
  88. PMID 862377
    .
  89. PMID 3777263
    .
  90. ^ "Clonazepam, Prescription Marketed Drugs". Archived from the original on 25 April 2012.
  91. ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 335-337.
  92. ^
    PMID 19900604
    .
  93. PMID 17485699
    .
  94. S2CID 20440040
    .
  95. PMID 1223993
    .
  96. S2CID 21137619
    .
  97. S2CID 40044726
    .
  98. PMID 6756174
    .
  99. ^ "Benzodiazepine Equivalency Table: Benzodiazepine Equivalency". 28 April 2017. Retrieved 19 February 2018.
  100. ^
    PMID 2912
    .
  101. S2CID 22680377
    .
  102. PMID 4082246
    .
  103. ^
    S2CID 9487285
    .
  104. PMID 323695
    .
  105. S2CID 21980890
    .
  106. PMID 7374896
    .
  107. PMID 7881198
    .
  108. PMID 11773648. Archived from the original
    on 11 July 2003.
  109. ^ "FDA clonazepam" (PDF). Retrieved 24 January 2019.
  110. PMID 6135616
    .
  111. PMID 3034628
    .
  112. PMID 7272065
    .
  113. S2CID 34328063
    .
  114. PMID 2868623
    .
  115. PMID 2418652
    .
  116. PMID 2997409
    .
  117. ^ "Benzodiazepine Equivalency Table" based on NRHA Drug Newsletter, April 1985 and Benzodiazepines: How they Work & How to Withdraw (The Ashton Manual), 2002.[1]
  118. ^ "What are the equivalent doses of oral benzodiazepines?". SPS - Specialist Pharmacy Service. Archived from the original on 26 July 2020. Retrieved 25 July 2020.
  119. PMID 15078112
    .
  120. PMID 2871724
    .
  121. S2CID 34346051
    .
  122. PMID 6267221
    .
  123. PMID 6133407
    .
  124. PMID 6979001
    .
  125. S2CID 5520697
    .
  126. PMID 6328498
    .
  127. ISBN 9780470752456
    .
  128. ^ a b c "Clonazepam". www.drugbank.ca. Retrieved 24 January 2019.
  129. S2CID 37743328
    .
  130. ^ "Monograph - Clonazepam -- Pharmacokinetics". Medscape. January 2006. Retrieved 30 December 2007.
  131. PMID 1029011
    .
  132. PMID 1245581
    .
  133. S2CID 25137468
    .
  134. PMID 2822672
    .
  135. PMID 699288. Archived
    (PDF) from the original on 7 June 2011.
  136. ISBN 9781597452472
    .
  137. ^ "Drug Abuse Warning Network, 2006: National Estimates of Drug-Related Emergency Department Visits". Substance Abuse and Mental Health Services Administration. 2006. Archived from the original on 16 March 2014. Retrieved 9 February 2009.
  138. ^ a b Buckingham R (ed.). "Clonazepam". Martindale: The Complete Drug Reference. London: Pharmaceutical Press. Retrieved 18 January 2019.
  139. ^ Carabajal G (8 December 2022). "Burundanga y Clonazepan. El cóctel de pastillas que usaba una "viuda negra" para doblegar a sus incautos pretendientes" [Burundanga and Clonazepan. The cocktail of pills that a "black widow" used to subdue her unwary suitors]. La Nacion [The Nation] (in Spanish).
  140. ^ "Register of Medicinal Products". ravimiregister.ravimiamet.ee. Retrieved 18 January 2019.
  141. ^ "Rivotril". NPS MedicineWise. 13 November 2020. Retrieved 9 January 2023.

Further reading

External links

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