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clozapine 🐶 Veterinary Use | Indications/Contra | FAERs-F | FAERs-M | Orange Bk | BioActivity |

Stem definition	Drug id	CAS RN
psychoactive	722	5786-21-0

Description:

Molecule	Description
Molfile Inchi Smiles Synonyms: clozapine asaleptin azaleptine clozapin clozaril fazaclo klozapol leponex	A tricylic dibenzodiazepine, classified as an atypical antipsychotic agent. It binds several types of central nervous system receptors, and displays a unique pharmacological profile. Clozapine is a serotonin antagonist, with strong binding to 5-HT 2A/2C receptor subtype. It also displays strong affinity to several dopaminergic receptors, but shows only weak antagonism at the dopamine D2 receptor, a receptor commonly thought to modulate neuroleptic activity. Agranulocytosis is a major adverse effect associated with administration of this agent. Molecular weight: 326.83 Formula: C18H19ClN4 CLOGP: 3.56 LIPINSKI: 0 HAC: 4 HDO: 1 TPSA: 30.87 ALOGS: -3.25 ROTB: 0 Status: OFP Legend: OFP - off patent OFM - off market ONP - on patent

Molecule

Description

Molfile Inchi Smiles

Synonyms:

clozapine
asaleptin
azaleptine
clozapin
clozaril
fazaclo
klozapol
leponex

A tricylic dibenzodiazepine, classified as an atypical antipsychotic agent. It binds several types of central nervous system receptors, and displays a unique pharmacological profile. Clozapine is a serotonin antagonist, with strong binding to 5-HT 2A/2C receptor subtype. It also displays strong affinity to several dopaminergic receptors, but shows only weak antagonism at the dopamine D2 receptor, a receptor commonly thought to modulate neuroleptic activity. Agranulocytosis is a major adverse effect associated with administration of this agent.

Molecular weight: 326.83
Formula: C18H19ClN4
CLOGP: 3.56
LIPINSKI: 0
HAC: 4
HDO: 1
TPSA: 30.87
ALOGS: -3.25
ROTB: 0

Status: OFP

Legend:
OFP - off patent
OFM - off market
ONP - on patent

Drug dosage:

Dose	Unit	Route
0.30	g	O
0.30	g	P

ADMET properties:

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Property	Value	Reference
BA (Bioavailability)	55 %	Kim MT, Sedykh A, Chakravarti SK, Saiakhov RD, Zhu H
MRTD (Maximum Recommended Therapeutic Daily Dose)	45.90 µM/kg/day	Contrera JF, Matthews EJ, Kruhlak NL, Benz RD
CL (Clearance)	2.50 mL/min/kg	Lombardo F, Berellini G, Obach RS
BDDCS (Biopharmaceutical Drug Disposition Classification System)	2	Benet LZ, Broccatelli F, Oprea TI
t_half (Half-life)	10 hours	Lombardo F, Berellini G, Obach RS
Vd (Volume of distribution)	1.60 L/kg	Lombardo F, Berellini G, Obach RS
EoM (Fraction excreted unchanged in urine)	0.50 %	Benet LZ, Broccatelli F, Oprea TI
fu (Fraction unbound in plasma)	0.06 %	Lombardo F, Berellini G, Obach RS
S (Water solubility)	0.01 mg/mL	Benet LZ, Broccatelli F, Oprea TI

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Approvals:

Date	Agency	Company	Orphan
Sept. 26, 1989	FDA	NOVARTIS

FDA Adverse Event Reporting System (Female)

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MedDRA adverse event term	Likelihood ratio	Likelihood ratio threshold	Patients taking drug having adverse event	Patients taking drug not having adverse event	Patients not taking drug having adverse event	Patients not taking drug not having adverse event
Hospitalisation	4856.78	16.33	2399	90275	82682	63313666
Neutropenia	4824.27	16.33	3055	89619	171950	63224398
Granulocytopenia	2978.62	16.33	824	91850	4848	63391500
Neutrophil count increased	2941.82	16.33	1050	91624	15477	63380871
Neutrophilia	2819.06	16.33	748	91926	3658	63392690
White blood cell count increased	2482.26	16.33	1273	91401	47288	63349060
Death	2472.87	16.33	2874	89800	371507	63024841
Antipsychotic drug level increased	1825.97	16.33	504	92170	2931	63393417
Salivary hypersecretion	1314.04	16.33	474	92200	7192	63389156
Psychotic disorder	1194.86	16.33	633	92041	25079	63371269

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FDA Adverse Event Reporting System (Male)

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MedDRA adverse event term	Likelihood ratio	Likelihood ratio threshold	Patients taking drug having adverse event	Patients taking drug not having adverse event	Patients not taking drug having adverse event	Patients not taking drug not having adverse event
Hospitalisation	7022.94	14.94	3815	143558	53087	34756471
Neutropenia	5284.57	14.94	4724	142649	152054	34657504
Neutrophil count increased	4772.25	14.94	2014	145359	15132	34794426
White blood cell count increased	3987.53	14.94	2359	145014	38792	34770766
Neutrophilia	3434.48	14.94	1089	146284	3048	34806510
Granulocytopenia	3415.91	14.94	1216	146157	5351	34804207
Differential white blood cell count abnormal	2759.95	14.94	729	146644	730	34808828
Death	2184.04	14.94	5008	142365	393041	34416517
Antipsychotic drug level increased	2018.07	14.94	718	146655	3147	34806411
Myocarditis	1945.04	14.94	1011	146362	12671	34796887

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FDA Adverse Event Reporting System (Geriatric)

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MedDRA adverse event term	Likelihood ratio	Likelihood ratio threshold	Patients taking drug having adverse event	Patients taking drug not having adverse event	Patients not taking drug having adverse event	Patients not taking drug not having adverse event
Neutropenia	22953.09	15.93	11534	163472	276176	79293206
Neutrophil count increased	6919.67	15.93	2553	172453	26843	79542539
Neutrophilia	6344.81	15.93	1751	173255	6200	79563182
White blood cell count increased	5680.35	15.93	2921	172085	71712	79497670
Granulocytopenia	5344.49	15.93	1663	173343	9768	79559614
Differential white blood cell count abnormal	3721.35	15.93	873	174133	1204	79568178
Hospitalisation	2765.66	15.93	2005	173001	92231	79477151
Antipsychotic drug level increased	2621.89	15.93	828	174178	5129	79564253
Death	2515.65	15.93	4464	170542	562050	79007332
White blood cell count decreased	2495.09	15.93	2538	172468	185750	79383632

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FDA Adverse Event Reporting System (Pediatric)

None

Pharmacologic Action:

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Source	Code	Description
ATC	N05AH02	NERVOUS SYSTEM PSYCHOLEPTICS ANTIPSYCHOTICS Diazepines, oxazepines, thiazepines and oxepines
CHEBI has role	CHEBI:35703	Xenobiotic
CHEBI has role	CHEBI:37887	adrenergic blockers
CHEBI has role	CHEBI:37956	antihistamines
CHEBI has role	CHEBI:48279	serotonin antagonists
CHEBI has role	CHEBI:48561	dopaminergic antagonists
CHEBI has role	CHEBI:48876	muscarinic antagonists
CHEBI has role	CHEBI:65191	atypical antipsychotic agent
CHEBI has role	CHEBI:65259	GABA antagonists
CHEBI has role	CHEBI:76779	post-proline endopeptidase inhibitors

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Drug Use | Suggest Off label Use Form| |View source of the data|

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Disease	Relation	SNOMED_ID	DOID
Treatment-Resistant Schizophrenia	indication
Suicidal Behavior in Schizophrenia	indication
Suicidal Behavior in Schizoaffective Disorder	indication
Bipolar disorder in remission	off-label use	85248005
Bipolar affective disorder, current episode manic	off-label use	191618007
Sinus tachycardia	contraindication	11092001
Constipation	contraindication	14760008	DOID:2089
Neuroleptic malignant syndrome	contraindication	15244003	DOID:14464
Senile dementia	contraindication	15662003
Agranulocytosis	contraindication	17182001	DOID:12987

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🐶 Veterinary Drug Use

None

🐶 Veterinary products

None

Acid dissociation constants calculated using MoKa v3.0.0

Dissociation level	Dissociation constant	Type (acidic/basic)
pKa1	7.59	Basic
pKa2	4.17	Basic

Orange Book patent data (new drug applications)

None

Orange Book exclusivity data (new drug applications)

None

Bioactivity Summary:

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Target	Class	Pharos	UniProt	Action	Type	Activity value (-log[M])	Bioact source	MoA source
D(2) dopamine receptor	GPCR	P14416	DRD2_HUMAN	ANTAGONIST	Ki	6.86	WOMBAT-PK	CHEMBL
5-hydroxytryptamine receptor 2A	GPCR	P28223	5HT2A_HUMAN	ANTAGONIST	Ki	8.30	WOMBAT-PK	CHEMBL
Beta-1 adrenergic receptor	GPCR	P08588	ADRB1_HUMAN		Ki	5.30	PDSP
Beta-2 adrenergic receptor	GPCR	P07550	ADRB2_HUMAN		Ki	5.78	PDSP
D(1A) dopamine receptor	GPCR	P21728	DRD1_HUMAN		Ki	6.89	WOMBAT-PK
Alpha-2A adrenergic receptor	GPCR	P08913	ADA2A_HUMAN		Ki	7.15	WOMBAT-PK
Sigma non-opioid intracellular receptor 1	Membrane receptor	Q99720	SGMR1_HUMAN		IC50	5.20	WOMBAT-PK
Potassium voltage-gated channel subfamily H member 2	Ion channel	Q12809	KCNH2_HUMAN		IC50	6.60	WOMBAT-PK
Sodium-dependent serotonin transporter	Transporter	P31645	SC6A4_HUMAN		Ki	5.41	CHEMBL
Sodium-dependent noradrenaline transporter	Transporter	P23975	SC6A2_HUMAN		Ki	5.83	WOMBAT-PK

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External reference:

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ID	Source
003526	NDDF
11496	MMSL
135398737	PUBCHEM_CID
216102	RXNORM
2612	INN_ID
38	IUPHAR_LIGAND_ID
387568001	SNOMEDCT_US
4019488	VUID
4019488	VANDF
4024939	VANDF

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Pharmaceutical products:

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Product	Category	Ingredients	NDC	Form	Quantity	Route	Marketing	Label
Clozapine	HUMAN PRESCRIPTION DRUG LABEL	1	0093-3010	TABLET, ORALLY DISINTEGRATING	100 mg	ORAL	NDA authorized generic	28 sections
Clozapine	HUMAN PRESCRIPTION DRUG LABEL	1	0093-3010	TABLET, ORALLY DISINTEGRATING	100 mg	ORAL	NDA authorized generic	28 sections
Clozapine	HUMAN PRESCRIPTION DRUG LABEL	1	0093-3011	TABLET, ORALLY DISINTEGRATING	12.50 mg	ORAL	NDA authorized generic	28 sections
Clozapine	HUMAN PRESCRIPTION DRUG LABEL	1	0093-3011	TABLET, ORALLY DISINTEGRATING	12.50 mg	ORAL	NDA authorized generic	28 sections
Clozapine	HUMAN PRESCRIPTION DRUG LABEL	1	0093-3012	TABLET, ORALLY DISINTEGRATING	25 mg	ORAL	NDA authorized generic	28 sections
Clozapine	HUMAN PRESCRIPTION DRUG LABEL	1	0093-3012	TABLET, ORALLY DISINTEGRATING	25 mg	ORAL	NDA authorized generic	28 sections
Clozapine	HUMAN PRESCRIPTION DRUG LABEL	1	0093-3086	TABLET, ORALLY DISINTEGRATING	150 mg	ORAL	NDA authorized generic	28 sections
Clozapine	HUMAN PRESCRIPTION DRUG LABEL	1	0093-3086	TABLET, ORALLY DISINTEGRATING	150 mg	ORAL	NDA authorized generic	28 sections
Clozapine	HUMAN PRESCRIPTION DRUG LABEL	1	0093-3087	TABLET, ORALLY DISINTEGRATING	200 mg	ORAL	NDA authorized generic	28 sections
Clozapine	HUMAN PRESCRIPTION DRUG LABEL	1	0093-3087	TABLET, ORALLY DISINTEGRATING	200 mg	ORAL	NDA authorized generic	28 sections

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