CLONAZEPAM

Details

Stereochemistry	ACHIRAL
Molecular Formula	C15H10ClN3O3
Molecular Weight	315.711
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

[O-][N+](=O)C1=CC2=C(NC(=O)CN=C2C3=C(Cl)C=CC=C3)C=C1

InChI

InChIKey=DGBIGWXXNGSACT-UHFFFAOYSA-N

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)

HIDE SMILES / InChI

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/017533s053,020813s009lbl.pdf | https://www.ncbi.nlm.nih.gov/pubmed/25798598

Clonazepam, a benzodiazepine, is used primarily as an anticonvulsant in the treatment of absence seizures, petit mal variant seizures (Lennox-Gastaut syndrome), akinetic and myoclonic seizures, and nocturnal myoclonus. Klonopin is the brand name for Clonazepam, an anxiolytic and anticonvulsant. 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. Allosteric interactions between central benzodiazepine receptors and gamma-aminobutyric acid (GABA) receptors potentiate the effects of GABA. As GABA is an inhibitory neurotransmitter, this results in increased inhibition of the ascending reticular activating system. Benzodiazepines, in this way, block the cortical and limbic arousal that occurs following stimulation of the reticular pathways.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
GABA-A receptor; anion channel 202 Target ID: CHEMBL2093872 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017533s055lbl.pdf \| https://www.ncbi.nlm.nih.gov/pubmed/8727390 \| https://www.ncbi.nlm.nih.gov/pubmed/25798598	Agonist 2678	0.06 nM [EC50]
GABA-A receptor; alpha-1/beta-2/gamma-2 27 Target ID: CHEMBL2095172 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25798598	Agonist 2678	57.0 µM [EC50]
GABA A receptor alpha-2/beta-2/gamma-2 6 Target ID: CHEMBL2111413 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25798598	Agonist 2678	40.0 µM [EC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Seizure disorders 4 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017533s055lbl.pdf	Primary		Approved 8429	KLONOPIN Approved Use INDICATIONS & USAGE Seizure Disorders: Clonazepam tablets, USP are useful alone or as an adjunct in the treatment of the Lennox-Gastaut syndrome (petit mal variant), akinetic and . 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 tablets, USP are 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. Launch Date 1975
Panic disorder 22 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017533s055lbl.pdf	Primary		Approved 8429	KLONOPIN Approved Use INDICATIONS & USAGE Seizure Disorders: Clonazepam tablets, USP are useful alone or as an adjunct in the treatment of the Lennox-Gastaut syndrome (petit mal variant), akinetic and . 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 tablets, USP are 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. Launch Date 1975

C_max

Value	Dose	Co-administered	Analyte	Population
2.3 ng/mL EXPERIMENT https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1177/0091270005280861	0.5 mg single, oral dose: 0.5 mg route of administration: Oral experiment type: SINGLE co-administered:		CLONAZEPAM plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
3 ng/mL REVIEW https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1177/0091270005280861	0.5 mg 3 times / day steady-state, oral dose: 0.5 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		CLONAZEPAM plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
102 ng × h/mL EXPERIMENT https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1177/0091270005280861	0.5 mg single, oral dose: 0.5 mg route of administration: Oral experiment type: SINGLE co-administered:		CLONAZEPAM plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
339 ng × h/mL REVIEW https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1177/0091270005280861	0.5 mg 3 times / day steady-state, oral dose: 0.5 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		CLONAZEPAM plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
40 h REVIEW https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1177/0091270005280861	0.5 mg 3 times / day steady-state, oral dose: 0.5 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		CLONAZEPAM plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
15% EXPERIMENT https://accp1.onlinelibrary.wiley.com/doi/epdf/10.1177/0091270005280861	0.5 mg single, oral dose: 0.5 mg route of administration: Oral experiment type: SINGLE co-administered:		CLONAZEPAM plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
2 mg single, intramuscular Dose: 2 mg Route: intramuscular Route: single Dose: 2 mg Sources: https://pubmed.ncbi.nlm.nih.gov/12646763	healthy, 30 years (range: 23–50 years) n = 12 Health Status: healthy Age Group: 30 years (range: 23–50 years) Sex: M+F Population Size: 12 Sources: https://pubmed.ncbi.nlm.nih.gov/12646763	Sources: https://pubmed.ncbi.nlm.nih.gov/12646763
2 mg single, intravenous Dose: 2 mg Route: intravenous Route: single Dose: 2 mg Sources: https://pubmed.ncbi.nlm.nih.gov/12646763	healthy, 30 years (range: 23–50 years) n = 12 Health Status: healthy Age Group: 30 years (range: 23–50 years) Sex: M+F Population Size: 12 Sources: https://pubmed.ncbi.nlm.nih.gov/12646763	Sources: https://pubmed.ncbi.nlm.nih.gov/12646763
2 mg single, oral Dose: 2 mg Route: oral Route: single Dose: 2 mg Sources: https://pubmed.ncbi.nlm.nih.gov/12646763	healthy, 30 years (range: 23–50 years) n = 12 Health Status: healthy Age Group: 30 years (range: 23–50 years) Sex: M+F Population Size: 12 Sources: https://pubmed.ncbi.nlm.nih.gov/12646763	Sources: https://pubmed.ncbi.nlm.nih.gov/12646763
1.5 mg 1 times / day multiple, oral Recommended Dose: 1.5 mg, 1 times / day Route: oral Route: multiple Dose: 1.5 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020813s010lbl.pdf	unhealthy n = 574 Health Status: unhealthy Condition: seizure disorders Population Size: 574 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020813s010lbl.pdf	Disc. AE: Somnolence, Depression... AEs leading to discontinuation/dose reduction: Somnolence (7%) Depression (4%) Nervousness (1%) Dizziness (1%) Ataxia (1%) Intellectual disability (1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020813s010lbl.pdf
6 mg 1 times / day steady, oral Studied dose Dose: 6 mg, 1 times / day Route: oral Route: steady Dose: 6 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/3279721	unhealthy Health Status: unhealthy Condition: depression Sources: https://pubmed.ncbi.nlm.nih.gov/3279721	Sources: https://pubmed.ncbi.nlm.nih.gov/3279721

AEs

AE	Significance	Dose	Population
Ataxia	1% Disc. AE	1.5 mg 1 times / day multiple, oral Recommended Dose: 1.5 mg, 1 times / day Route: oral Route: multiple Dose: 1.5 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020813s010lbl.pdf	unhealthy n = 574 Health Status: unhealthy Condition: seizure disorders Population Size: 574 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020813s010lbl.pdf
Dizziness	1% Disc. AE	1.5 mg 1 times / day multiple, oral Recommended Dose: 1.5 mg, 1 times / day Route: oral Route: multiple Dose: 1.5 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020813s010lbl.pdf	unhealthy n = 574 Health Status: unhealthy Condition: seizure disorders Population Size: 574 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020813s010lbl.pdf
Intellectual disability	1% Disc. AE	1.5 mg 1 times / day multiple, oral Recommended Dose: 1.5 mg, 1 times / day Route: oral Route: multiple Dose: 1.5 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020813s010lbl.pdf	unhealthy n = 574 Health Status: unhealthy Condition: seizure disorders Population Size: 574 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020813s010lbl.pdf
Nervousness	1% Disc. AE	1.5 mg 1 times / day multiple, oral Recommended Dose: 1.5 mg, 1 times / day Route: oral Route: multiple Dose: 1.5 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020813s010lbl.pdf	unhealthy n = 574 Health Status: unhealthy Condition: seizure disorders Population Size: 574 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020813s010lbl.pdf
Depression	4% Disc. AE	1.5 mg 1 times / day multiple, oral Recommended Dose: 1.5 mg, 1 times / day Route: oral Route: multiple Dose: 1.5 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020813s010lbl.pdf	unhealthy n = 574 Health Status: unhealthy Condition: seizure disorders Population Size: 574 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020813s010lbl.pdf
Somnolence	7% Disc. AE	1.5 mg 1 times / day multiple, oral Recommended Dose: 1.5 mg, 1 times / day Route: oral Route: multiple Dose: 1.5 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020813s010lbl.pdf	unhealthy n = 574 Health Status: unhealthy Condition: seizure disorders Population Size: 574 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020813s010lbl.pdf

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2B6 810 CYP2E1 882 UGT 35	CYP3A 191 BCRP 561	CYP 76 UGT 29

Drug as perpetrator

Target	Modality	Activity
CYP 147	inducer 1573 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3001218/	no
UGT 59	inducer 1573 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3001218/	no
UGT 59	inhibitor 3277 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3001218/	no
CYP2B6 1001	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/17101742/	weak
CYP2E1 970	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/9574817/	yes

Drug as victim

Target	Modality	Activity	Clinical evidence
BCRP 561	substrate 3367 Sources: https://www.wjgnet.com/2220-3192/full/v3/i4/153.htm	no
CYP3A 191	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/017533s061lbl.pdf#page=2 Page: 2.0	yes
CYP3A4 1737	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5203763/	yes	yes (pharmacogenomic study) Comment: The statistical analysis displayed significant association between the patients’ CYP3A4 expression and the stable plasma concentrations of clonazepam normalized by the dose and the patient’s bodyweight. Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5203763/

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:3756	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:3756
ZINC	ZINC000003813003	http://zinc15.docking.org/substances/ZINC000003813003
eMolecules	535779	https://www.emolecules.com/cgi-bin/more?vid=535779

PubMed

Title	Date	PubMed
Serum clonazepam concentrations in children with absence seizures.	1975 Mar	1089913
Obstructive sleep apnea syndrome induced by clonazepam in a narcoleptic patient with REM-sleep-behavior disorder.	1999 Dec	10646174
Efficacy, safety, and gradual discontinuation of clonazepam in panic disorder: a placebo-controlled, multicenter study using optimized dosages.	1999 Sep	10520979
Interstrain differences in cognitive functions in rats in relation to status epilepticus.	2000 Jul	10862938
Cerebellar Ataxia.	2000 May	11096749
LSD-induced Hallucinogen Persisting Perception Disorder treated with clonazepam: two case reports.	2001	11475916
Tourette syndrome: clinical characteristics and current management strategies.	2001	11393328
[Clonazepam in therapy of neurogenic syncopal states].	2001	11243029
Sensitivity to the effects of sedative-hypnotics on motor performance: influence of task difficulty and chronic phenobarbital administration.	2001 Apr	11396517
Expression of the peripheral-type benzodiazepine receptor and apoptosis induction in hepatic stellate cells.	2001 Apr	11266385
Mitochondria recycle Ca(2+) to the endoplasmic reticulum and prevent the depletion of neighboring endoplasmic reticulum regions.	2001 Aug 3	11358971
Direct LC analysis of five benzodiazepines in human urine and plasma using an ADS restricted access extraction column.	2001 Dec	11600302
Treatment of bipolar depression with twice-weekly fluoxetine: management of antidepressant-induced mania.	2001 Jan	11197585
Effects of antiepileptic drugs on rat platelet aggregation: ex vivo and in vitro study.	2001 Jan	11137387
[Piracetam in the treatment of a patient with idiopathic cortical myoclonus].	2001 Jul 16-31	11700615
Behavioral effects of agents active at the gamma-aminobutyric acid receptor complex in the staircase paradigm.	2001 May 18	11368960
West syndrome: the Philippine experience.	2001 Nov	11701266
Kinetic and pharmacological properties of GABA(A) receptors in single thalamic neurons and GABA(A) subunit expression.	2001 Nov	11698521
Diazepam inhibits HIV-1 Tat-induced migration of human microglia.	2001 Oct	11582521
Effect of clonazepam treatment on antipsychotic drug-induced Meige syndrome and changes in plasma levels of GABA, HVA, and MHPG during treatment.	2001 Oct	11555353
A successful clonazepam treatment without tolerance in a patient with spontaneous oral dyskinesia.	2001 Oct	11513361
Nutritional parameters modify muricidal behavior of male Wistar rats: preventive effects of amino acids and 4' Cl diazepam.	2001 Oct 26	11720079
Topiramate as a mood stabilizer.	2001 Sep	11552774
Evaluation of polymeric nanoparticles composed of cholic acid and methoxy poly(ethylene glycol).	2001 Sep 11	11532566
[Treatment and long-term follow-up of post-anoxic myoclonus].	2001 Sep 23	11697066

Patents

Sample Use Guides

In Vivo Use Guide

Seizure Disorders: Adults: The initial dose for adults with seizure disorders should not exceed 1.5 mg/day divided into three doses. Dosage may be increased in increments of 0.5 to 1 mg every 3 days until seizures are adequately controlled or until side effects preclude any further increase. Maintenance dosage must be individualized for each patient depending upon response. Maximum recommended daily dose is 20 mg. Clonazepam is available as a tablet or an orally disintegrating tablet (wafer). The tablets should be administered with water by swallowing the tablet whole. The orally disintegrating tablet should be administered as follows: After opening the pouch, peel back the foil on the blister. Do not push tablet through foil. Immediately upon opening the blister, using dry hands, remove the tablet and place it in the mouth. Tablet disintegration occurs rapidly in saliva so it can be easily swallowed with or without water.

Route of Administration: Oral

In Vitro Use Guide

Clonazepam (100 nM) increased inhibitory postsynaptic current (IPSC) decay time constants in rat thalamic nuclei-the reticular nucleus (nRt) (from 44.3 to 77.9 ms, P < 0.01) but not in the ventrobasal (VB) complex..

Name

Type

Language

CLONAZEPAM

Official Name

English

NSC-179913

Code

English

CLONAZEPAM [JAN]

Common Name

English

RIVOTRIL

Brand Name

English

RO-5-4023

Code

English

CLONAZEPAM [MART.]

Common Name

English

RIVATRIL

Brand Name

English

RO 5-4023

Code

English

2H-1,4-BENZODIAZEPIN-2-ONE, 5-(2-CHLOROPHENYL)-1,3-DIHYDRO-7-NITRO-

Systematic Name

English

Clonazepam [WHO-DD]

Common Name

English

CLONAZEPAM [ORANGE BOOK]

Common Name

English

5-(O-CHLOROPHENYL)-1,3-DIHYDRO-7-NITRO-2H-1,4-BENZODIAZEPIN-2-ONE

Common Name

English

CLONAZEPAM [MI]

Common Name

English

KLONOPIN

Brand Name

English

CLONAZEPAM [EP MONOGRAPH]

Common Name

English

RO-54023

Code

English

clonazepam [INN]

Common Name

English

RAVOTRIL

Brand Name

English

CLONAZEPAM [VANDF]

Common Name

English

CLONAZEPAM CIV [USP-RS]

Common Name

English

CLONAZEPAM [HSDB]

Common Name

English

CLONAZEPAM CIV

Common Name

English

CLONAZEPAM [USAN]

Common Name

English

CLONAZEPAM [USP MONOGRAPH]

Common Name

English

Classification Tree Code System Code

NDF-RT

N0000175694