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Trazodone

PubChem CID
5533
Structure
Trazodone_small.png
Trazodone_3D_Structure.png
Molecular Formula
Synonyms
  • trazodone
  • 19794-93-5
  • Trazodon
  • Beneficat
  • Trazalon
Molecular Weight
371.9 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2005-03-25
  • Modify:
    2025-01-18
Description
Trazodone is an N-arylpiperazine in which one nitrogen is substituted by a 3-chlorophenyl group, while the other is substituted by a 3-(3-oxo[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)propyl group. It has a role as an antidepressant, a sedative, an adrenergic antagonist, a H1-receptor antagonist, a serotonin uptake inhibitor and an anxiolytic drug. It is a N-alkylpiperazine, a N-arylpiperazine, a triazolopyridine and a member of monochlorobenzenes.
Trazodone is triazolopyridine derivative from the serotonin receptor antagonists and reuptake inhibitors (SARIs) class of antidepressants. It is used in adults and has been shown to be comparable in efficacy to other drugs such as tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine receptor inhibitor (SNRIs) in the treatment of depression. A unique feature of this drug is that it does not promote the anxiety symptoms, sexual symptoms, or insomnia, which are commonly associated with SSRI and SNRI therapy. Trazodone acts on various receptors, including certain histamine, serotonin, and adrenergic receptors, distinguishing it from other antidepressants that cover a narrow range of neurotransmitters. It was initially granted FDA approval in 1981.
Trazodone is a Serotonin Reuptake Inhibitor.

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Trazodone.png

1.2 3D Conformer

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

2-[3-[4-(3-chlorophenyl)piperazin-1-yl]propyl]-[1,2,4]triazolo[4,3-a]pyridin-3-one
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 InChI

InChI=1S/C19H22ClN5O/c20-16-5-3-6-17(15-16)23-13-11-22(12-14-23)8-4-10-25-19(26)24-9-2-1-7-18(24)21-25/h1-3,5-7,9,15H,4,8,10-14H2
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

PHLBKPHSAVXXEF-UHFFFAOYSA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 SMILES

C1CN(CCN1CCCN2C(=O)N3C=CC=CC3=N2)C4=CC(=CC=C4)Cl
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C19H22ClN5O
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

2.3.2 European Community (EC) Number

2.3.3 UNII

2.3.4 ChEBI ID

2.3.5 ChEMBL ID

2.3.6 DrugBank ID

2.3.7 DSSTox Substance ID

2.3.8 HMDB ID

2.3.9 KEGG ID

2.3.10 Metabolomics Workbench ID

2.3.11 NCI Thesaurus Code

2.3.12 Nikkaji Number

2.3.13 PharmGKB ID

2.3.14 Pharos Ligand ID

2.3.15 RXCUI

2.3.16 Wikidata

2.3.17 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • AF 1161
  • AF-1161
  • AF1161
  • Apo Trazodone
  • Apo-Trazodone
  • Deprax
  • Desyrel
  • Gen Trazodone
  • Gen-Trazodone
  • Molipaxin
  • Novo Trazodone
  • Novo-Trazodone
  • Nu Trazodone
  • Nu-Trazodone
  • PMS Trazodone
  • PMS-Trazodone
  • ratio Trazodone
  • ratio-Trazodone
  • RatioTrazodone
  • Thombran
  • Tradozone
  • Trazodon Hexal
  • Trazodon neuraxpharm
  • Trazodon-neuraxpharm
  • Trazodone
  • Trazodone Hydrochloride
  • TrazodonNeuraxpharm
  • Trazon
  • Trittico

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
371.9 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3-AA
Property Value
2.8
Reference
Computed by XLogP3 3.0 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
0
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
4
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
5
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
371.1512880 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
371.1512880 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
42.4 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
26
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
611
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Physical Description

Solid

3.2.2 Color / Form

Crystals
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1775

3.2.3 Boiling Point

3.2.4 Melting Point

231-234
86-87 °C, also reported as mp 96 °C
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1775
White, odorless plates from ethanol, MP: 223 °C. Sparingly soluble in water, ethanol, methanol, chloroform. Practically insoluble in common organic solvents. UV max (water): 211, 246, 274, 312 nm (epsilon = 50100, 11730, 3840, 3840) /Trazodone hydrochloride/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1775
86 - 87 °C

3.2.5 Solubility

2.90e-01 g/L

3.2.6 LogP

2.68
2.9

3.2.7 LogS

3.2.8 Stability / Shelf Life

Stable under recommended storage conditions. /Trazadone hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Trazodone hydrochloride. Product Number: T6154, Version 4.4 (Revision Date 06/29/2014). Available from, as of January 26, 2016: https://www.sigmaaldrich.com/safety-center.html

3.2.9 Decomposition

When heated to decomposition it emits toxic fumes of /chlorides, hydrogen chloride and nitrogen oxides/.
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 3502

3.2.10 Ionization Efficiency

Ionization mode
Positive
logIE
4.22
pH
2.09
Instrument
Thermo LTQ
Ion source
Electrospray ionization
Additive
oxalic acid (10nM)
Organic modifier
MeCN (90%)
Reference

3.2.11 Dissociation Constants

Basic pKa
6.79
Comparison of the accuracy of experimental and predicted pKa values of basic and acidic compounds. Pharm Res. 2014; 31(4):1082-95. DOI:10.1007/s11095-013-1232-z. PMID:24249037
pKa
6.74
pKa = 6.14 (50 percent ethanol)
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1775

3.2.12 Collision Cross Section

175.76 Ų [M+H-H2O]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

191.55 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

188.66 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Ross et al. JASMS 2022; 33; 1061-1072. DOI:10.1021/jasms.2c00111

3.2.13 Kovats Retention Index

Standard non-polar
3345 , 3300 , 3345
Semi-standard non-polar
3311.4 , 3298.4

3.2.14 Other Experimental Properties

Highly lipophilic
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1775

3.3 Chemical Classes

3.3.1 Drugs

Pharmaceuticals -> Listed in ZINC15
S55 | ZINC15PHARMA | Pharmaceuticals from ZINC15 | DOI:10.5281/zenodo.3247749
Pharmaceuticals -> Antidepressants
S57 | GREEKPHARMA | Suspect Pharmaceuticals from the National Organization of Medicine, Greece | DOI:10.5281/zenodo.3248883
Pharmaceuticals -> unsed in Switzerland 2014-2016
S113 | SWISSPHARMA24 | 2024 Swiss Pharmaceutical List with Metabolites | DOI:10.5281/zenodo.10501043
Pharmaceuticals
S10 | SWISSPHARMA | Pharmaceutical List with Consumption Data | DOI:10.5281/zenodo.2623484
3.3.1.1 Human Drugs
Breast Feeding; Lactation; Milk, Human; Antidepressive Agents; Serotonin Uptake Inhibitors
Pharmaceuticals
S72 | NTUPHTW | Pharmaceutically Active Substances from National Taiwan University | DOI:10.5281/zenodo.3955664

4 Spectral Information

4.1 Mass Spectrometry

4.1.1 GC-MS

1 of 7
View All
NIST Number
248796
Library
Main library
Total Peaks
140
m/z Top Peak
205
m/z 2nd Highest
70
m/z 3rd Highest
176
Thumbnail
Thumbnail
2 of 7
View All
NIST Number
379596
Library
Replicate library
Total Peaks
215
m/z Top Peak
205
m/z 2nd Highest
70
m/z 3rd Highest
78
Thumbnail
Thumbnail

4.1.2 MS-MS

1 of 14
View All
Spectra ID
Ionization Mode
Positive
Top 5 Peaks

96.0444 100

148.0505 98.85

176.0819 9.51

133.076 9.05

93.0448 7.48

Thumbnail
Thumbnail
2 of 14
View All
Spectra ID
Ionization Mode
Positive
Top 5 Peaks

96.0443 100

148.0505 28.13

78.0338 11.61

120.0318 5.91

93.0447 5.91

Thumbnail
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4.1.3 LC-MS

1 of 30
View All
Authors
Nikiforos Alygizakis, Katerina Galani, Nikolaos Thomaidis, University of Athens
Instrument
Bruker maXis Impact
Instrument Type
LC-ESI-QTOF
MS Level
MS2
Ionization Mode
POSITIVE
Ionization
ESI
Collision Energy
10 eV
Fragmentation Mode
CID
Column Name
Acclaim RSLC C18 2.2um, 2.1x100mm, Thermo
Retention Time
6.015 min
Precursor m/z
372.1586
Precursor Adduct
[M+H]+
Top 5 Peaks

372.159 999

374.1559 326

373.1614 232

176.0803 6

Thumbnail
Thumbnail
License
CC BY
2 of 30
View All
Authors
Nikiforos Alygizakis, Katerina Galani, Nikolaos Thomaidis, University of Athens
Instrument
Bruker maXis Impact
Instrument Type
LC-ESI-QTOF
MS Level
MS2
Ionization Mode
POSITIVE
Ionization
ESI
Collision Energy
20 eV
Fragmentation Mode
CID
Column Name
Acclaim RSLC C18 2.2um, 2.1x100mm, Thermo
Retention Time
6.006 min
Precursor m/z
372.1586
Precursor Adduct
[M+H]+
Top 5 Peaks

372.1591 999

176.0808 400

374.156 392

373.1615 251

148.0492 27

Thumbnail
Thumbnail
License
CC BY

4.2 IR Spectra

4.2.1 ATR-IR Spectra

Instrument Name
Bio-Rad FTS
Technique
ATR-Film (MeCl2) (DuraSamplIR II)
Source of Spectrum
Forensic Spectral Research
Source of Sample
Alltech Associates, Inc., Grace Davison Discovery Sciences
Catalog Number
Free base of 01466
Lot Number
Free base of 230
Copyright
Copyright © 2012-2024 John Wiley & Sons, Inc. All Rights Reserved.
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6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug Indication

Trazodone is indicated for the treatment of major depressive disorder (MDD). It has been used off-label for adjunct therapy in alcohol dependence, and off-label to treat anxiety and insomnia. It may also be used off-label to treat symptoms of dementia, Alzheimer’s disease, schizophrenia, eating disorders, and fibromyalgia due to its effects on various neurotransmitter receptors.

7.2 LiverTox Summary

Trazodone is a serotoninergic modulating antidepressant that is used in therapy of depression, aggressive behavior and panic disorder. Trazodone therapy can be associated with transient, usually asymptomatic elevations in serum aminotransferase levels and has been linked to rare instances of clinically apparent acute liver injury.

7.3 Drug Classes

Breast Feeding; Lactation; Milk, Human; Antidepressive Agents; Serotonin Uptake Inhibitors
Antidepressant Agents

7.4 Drug Labels

Drug and label

7.5 Clinical Trials

7.5.1 ClinicalTrials.gov

7.5.2 EU Clinical Trials Register

7.6 Therapeutic Uses

Anti-Anxiety Agents; Antidepressive Agents, Second-Generation; Serotonin Uptake Inhibitors
National Library of Medicine's Medical Subject Headings. Trazodone. Online file (MeSH, 2016). Available from, as of January 19, 2016: https://www.nlm.nih.gov/mesh/2016/mesh_browser/MBrowser.html
/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Trazodone is included in the database.
NIH/NLM; ClinicalTrials.Gov. Available from, as of March 17, 2016: https://clinicaltrials.gov/ct2/results?term=trazodone&Search=Search
Trazodone hydrochloride tablets USP are indicated for the treatment of major depressive disorder (MDD) in adults. The efficacy of trazodone hydrochloride tablets has been established in trials with the immediate release formulation of trazodone. /Included in US product label/
NIH; DailyMed. Current Medication Information for Trazodone Hydrochloride (Trazodone Hydrochloride) Tablet, Film Coated (Updated: August 2015). Available from, as of February 29, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=324d2543-477d-4c0b-bfa0-d76cb4e5cd48
Although trazodone has been used in the treatment of schizophrenic disorder, the drug is less effective than chlorpromazine. Depressive symptomatology may improve during trazodone therapy, but the drug does not appear to relieve psychotic symptoms in most schizophrenic patients. Based on limited data, trazodone has little value when used alone in patients with chronic schizophrenic disorder without depression; however, it may be a useful adjunct to antipsychotic agents (e.g., phenothiazines) in patients with chronic schizophrenic disorder and associated depression. Unlike tricyclic antidepressants, trazodone does not appear to worsen psychotic symptoms in these patients. /NOT included in US product label/
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2378
For more Therapeutic Uses (Complete) data for TRAZODONE (11 total), please visit the HSDB record page.

7.7 Drug Warnings

/BOXED WARNING/ WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS. Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of trazodone hydrochloride tablets or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Trazodone hydrochloride tablets are not approved for use in pediatric patients.
NIH; DailyMed. Current Medication Information for Trazodone Hydrochloride (Trazodone Hydrochloride) Tablet, Film Coated (Updated: August 2015). Available from, as of February 29, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=324d2543-477d-4c0b-bfa0-d76cb4e5cd48
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
NIH; DailyMed. Current Medication Information for Trazodone Hydrochloride (Trazodone Hydrochloride) Tablet, Film Coated (Updated: August 2015). Available from, as of February 29, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=324d2543-477d-4c0b-bfa0-d76cb4e5cd48
The development of a potentially life-threatening serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions have been reported with antidepressants alone and may occur with trazodone treatment, but particularly with concomitant use of other serotoninergic drugs (including SSRIs, SNRIs and triptans) and with drugs that impair metabolism of serotonin (including monoamine oxidase inhibitors (MAOIs)), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes.
NIH; DailyMed. Current Medication Information for Trazodone Hydrochloride (Trazodone Hydrochloride) Tablet, Film Coated (Updated: August 2015). Available from, as of February 29, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=324d2543-477d-4c0b-bfa0-d76cb4e5cd48
A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described for clinical worsening and suicide risk represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that trazodone hydrochloride tablets is not approved for use in treating bipolar depression.
NIH; DailyMed. Current Medication Information for Trazodone Hydrochloride (Trazodone Hydrochloride) Tablet, Film Coated (Updated: August 2015). Available from, as of February 29, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=324d2543-477d-4c0b-bfa0-d76cb4e5cd48
For more Drug Warnings (Complete) data for TRAZODONE (32 total), please visit the HSDB record page.

8 Pharmacology and Biochemistry

8.1 Pharmacodynamics

Trazodone treats depressed mood and other depression-related symptoms and shows benefit in the treatment of insomnia due to its sedating effects. It is known to prolong the cardiac QT-interval. Memory, alertness, and cognition may be decreased by trazodone, especially in elderly patients due to its central nervous system depressant effects. A note on priapism Trazodone has been associated with the occurrence of priapism, a painful and persistent incidence of penile tissue erection that is unrelievable and can cause permanent neurological damage if left untreated. Patients must be advised to seek immediate medical attention if priapism is suspected.

8.2 MeSH Pharmacological Classification

Antidepressive Agents, Second-Generation
A structurally and mechanistically diverse group of drugs that are not tricyclics or monoamine oxidase inhibitors. The most clinically important appear to act selectively on serotonergic systems, especially by inhibiting serotonin reuptake. (See all compounds classified as Antidepressive Agents, Second-Generation.)
Anti-Anxiety Agents
Agents that alleviate ANXIETY, tension, and ANXIETY DISORDERS, promote sedation, and have a calming effect without affecting clarity of consciousness or neurologic conditions. ADRENERGIC BETA-ANTAGONISTS are commonly used in the symptomatic treatment of anxiety but are not included here. (See all compounds classified as Anti-Anxiety Agents.)
Selective Serotonin Reuptake Inhibitors
Compounds that specifically inhibit the reuptake of serotonin in the brain. (See all compounds classified as Selective Serotonin Reuptake Inhibitors.)

8.3 FDA Pharmacological Classification

FDA UNII
YBK48BXK30
Active Moiety
TRAZODONE
Pharmacological Classes
Established Pharmacologic Class [EPC] - Serotonin Reuptake Inhibitor
FDA Pharmacology Summary
Trazodone is a Serotonin Reuptake Inhibitor.

8.4 ATC Code

S76 | LUXPHARMA | Pharmaceuticals Marketed in Luxembourg | Pharmaceuticals marketed in Luxembourg, as published by d'Gesondheetskeess (CNS, la caisse nationale de sante, www.cns.lu), mapped by name to structures using CompTox by R. Singh et al. (in prep.). List downloaded from https://cns.public.lu/en/legislations/textes-coordonnes/liste-med-comm.html. Dataset DOI:10.5281/zenodo.4587355

N - Nervous system

N06 - Psychoanaleptics

N06A - Antidepressants

N06AX - Other antidepressants

N06AX05 - Trazodone

8.5 Absorption, Distribution and Excretion

Absorption
Trazodone is rapidly absorbed in the gastrointestinal tract after oral administration, with a bioavailability ranging from 63-91% and an AUC0−t of 18193.0 ng·h/mL. Food may impact absorption in a variable fashion, and may sometimes lead to decreases in the Cmax of trazodone. In the fed state in 8 healthy volunteers, the Cmax was measured to be 1.47 +/- 0.16 micrograms/mL, and in the fasted state, was measured at 1.88 +/- 0.42 micrograms/mL. The average Tmax after a single dose of 300 mg was 8 hours. Food may increase absorption by up to 20%.
Route of Elimination
Less than 1% of an oral dose is excreted unchanged in the urine. In a pharmacokinetic study, about 60-70% of radiolabeled was excreted urine within 48 hours. Approximately 9-29% was found to be excreted in feces over a range of 60 to 100 hours. According to the FDA medical review, the kidneys are responsible for 70 to 75% of trazodone excretion. About 21% of trazodone is reported to be excreted by the fecal route and 0.13% of the parent drug is eliminated in the urine as unchanged drug.
Volume of Distribution
A single-dose pharmacokinetic study of 8 volunteers taking trazodone determined a volume of distribution of 0.84 +/- 0.16 L/kg. The FDA medical review of trazodone reports a volume of distribution of 0.47 to 0.84 L/kg.
Clearance
A decrease in total apparent clearance (5.1 versus 10.8 L/h) was seen elderly volunteers in the fasted state when compared with younger volunteers. Another pharmacokinetic study determined the total body clearance of trazodone to be 5.3 +/- 0.9 L/hr in 8 healthy patients taking a single dose of trazodone.
Following oral administration of single doses of 25, 50, or 100 mg of trazodone to healthy, fasted adults in another study, mean peak plasma trazodone concentrations were 490, 860, and 1620 ng/mL, respectively. The areas under the plasma concentration-time curves (AUCs) were 3.44, 5.95, and 11.19 ug-hr/mL, for the 25-, 50-, and 100-mg doses, respectively. Limited crossover data are available comparing AUCs in fasted and nonfasted patients; however, it appears that the presence of food slightly increases the AUC for trazodone.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2381
Following oral administration of a single 25-mg dose of radiolabeled trazodone to healthy adults in one study, mean peak plasma drug concentrations of 650 and 480 ng/mL occurred at 1.5 and 2.5 hours after ingestion, in the fasted and nonfasted state, respectively.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2381
/MILK/ The excretion of breast milk was studied in six lactating women following the oral administration of a single trazodone tablet (50 mg). The milk/plasma ratio of trazodone based on area under the plasma and milk curves was small: 0.142 +/- 0.045 (mean +/- s.d.). Assuming that the babies would drink 500 mL 12 h-1, they would be exposed to less than 0.005 mg kg-1 as compared to 0.77 mg kg-1 for the mothers. It is concluded that exposure of babies to trazodone via breast milk is very small.
Verbeeck RK et al; Br J Clin Pharmacol. 1986 Sep;22(3):367-70 (1986)
Peak plasma concentrations of trazodone occur approximately 1 hour after oral administration when the drug is taken on an empty stomach or 2 hours after oral administration when taken with food. Following oral administration of multiple doses of trazodone (25 mg 2 or 3 times daily), steady-state plasma concentrations of the drug are usually attained within 4 days and exhibit wide interpatient variation.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2381
For more Absorption, Distribution and Excretion (Complete) data for TRAZODONE (8 total), please visit the HSDB record page.

8.6 Metabolism / Metabolites

Trazodone is heavily metabolized and activated in the liver by CYP3A4 enzyme to the active metabolite, m-chlorophenylpiperazine (mCPP). The full metabolism of trazodone has not been well characterized. Some other metabolites that have been identified are a dihydrodiol metabolite and carboxylic acid.
Trazodone is extensively metabolized in the liver via hydroxylation, oxidation, N-oxidation, and splitting of the pyridine ring. A hydroxylated metabolite and oxotriazolopyridinpropionic acid (an inactive metabolite excreted in urine) are conjugated with glucuronic acid. Results of in vitro studies indicate that metabolism of trazodone to an active metabolite, m-chlorophenylpiperazine, is mediated by the cytochrome P-450 (CYP) 3A4 isoenzyme. The manufacturers state that other metabolic pathways involved in metabolism of trazodone have not been well characterized. Results from animal studies indicate that trazodone does not induce its own metabolism.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2382
In vitro studies in human liver microsomes show that trazodone is metabolized, via oxidative cleavage, to an active metabolite, m-chlorophenylpiperazine (mCPP) by CYP3A4. Other metabolic pathways that may be involved in the metabolism of trazodone have not been well characterized. Trazodone is extensively metabolized; less than 1% of an oral dose is excreted unchanged in the urine.
NIH; DailyMed. Current Medication Information for Trazodone Hydrochloride (Trazodone Hydrochloride) Tablet, Film Coated (Updated: August 2015). Available from, as of January 26, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=324d2543-477d-4c0b-bfa0-d76cb4e5cd48
Approximately 70-75% of an oral dose of trazodone is excreted in urine within 72 hours of administration, principally as metabolites. About 20% of an oral dose of trazodone is excreted in urine as oxotriazolopyridinpropionic acid and its conjugates, and about 10% as a dihydrodiol metabolite; less than 1% of a dose is excreted unchanged. The remainder of an oral dose of the drug is excreted in feces via biliary elimination, principally as metabolites.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2382
Trazodone has known human metabolites that include 1-(3-Chlorophenyl)piperazine, Trazodone epoxide, and p-Hydroxytrazodone.
S73 | METXBIODB | Metabolite Reaction Database from BioTransformer | DOI:10.5281/zenodo.4056560
Undergoes extensive hepatic metabolism via hydroxylation, N-dealkylation, N-oxidation and splitting of the pyridine ring. Cytochrome P450 (CYP) 3A4 catalyzes the formation of the major active metabolite, m-chlorophenylpiperazine (m-CPP). Metabolites may be further conjugated to glucuonic acid or glutathione. CYP2D6 is responsible for 4'-hydroxylation of m-CPP and the formation of at least one glutathione conjugates of m-CPP, a quinone imine-sulhydryl adduct. Oxotriazolopyridinpropionic acid, an inactive metabolite, and its conjugates account for about 20% of the total excreted oral dose. Less than 1% of the oral dose is excreted unchanged. Approximately 70-75% of the dose is eliminated in urine with the remainder being excreted in feces via biliary elimination. Half Life: Undergoes biphasic elimination with an initial phase t1/2 α of 3-6 hours and a terminal phase t1/2 β of 5-9 hours.

8.7 Biological Half-Life

The plasma elimination half-life was markedly prolonged (13.6 versus 6 hours) elderly volunteers in the fasted state when compared with younger volunteers. Another study of 8 healthy individuals taking a single dose of trazodone indicated a terminal elimination half-life of 7.3 +/- 0.8 hr. A two-phase pattern of trazodone elimination has been reported. Initially, the half-life is reported to range from 3 to 6 hours and the second phase of elimination to range from 5 to 9 hours.
The half-life of trazodone in the initial phase is about 3-6 hours and the half-life in the terminal phase is about 5-9 hours.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2382
... Following IV administration /of trazodone HCl to beagle dogs/, the mean +/- SD elimination half-life /was/ 169 +/- 53 minutes ... . Following oral administration, the mean +/- SD elimination half-life /was/ 166 +/- 47 minutes ... .
Jay AR et al; Am J Vet Res 74 (11): 1450-6 (2013)
In dogs after 8 mg/kg IV, volume of distribution was (all value are means ) 2.53 L/kg, elimination half life 169 minutes, and plasma total body clearance was 11.15 mL/min/kg. After 8 mg/kg PO, bioavailability was 85%, and elimination half life was 166 minutes, peak plasma levels occurred at 445 minutes (mean), but there was wider inter-subject variation (+ or - 271 minutes).
Plumb D.C. Veterinary Drug Handbook. 8th ed. (pocket). Ames, IA: Wiley-Blackwell, 2015., p. 1438

8.8 Mechanism of Action

The mechanism of action of trazodone is not fully understood, however, it is known to inhibit the reuptake of serotonin and block both histamine and alpha-1-adrenergic receptors. Despite the fact that trazodone is frequently considered a selective serotonin reuptake inhibitor, several reports have shown that other mechanisms including antagonism at serotonin 5-HT1a, 5-HT1c, and 5-HT2 receptor subtypes may occur. The strongest antagonism of trazodone is reported to occur at the serotonin 5-HT21c receptors, preventing serotonin uptake. In addition to acting on serotonin receptors, trazodone has been shown to inhibit serotonin transporters. The antidepressant effects of trazodone result from the inhibition of receptor uptake, which normally decreases circulating neurotransmitters, contributing to depressive symptoms.
The precise mechanism of antidepressant action of trazodone is unclear, but the drug has been shown to selectively block the reuptake of serotonin (5-HT) at the presynaptic neuronal membrane. The effects of serotonin may thus be potentiated. Unlike other antidepressant agents (e.g., tricyclic antidepressants), trazodone may have a dual effect on the central serotonergic system. Animal studies indicate that trazodone acts as a serotonin agonist at high doses (6-8 mg/kg), while at low doses (0.05-1 mg/kg), it antagonizes the actions of serotonin. Trazodone does not appear to influence the reuptake of dopamine or norepinephrine within the CNS; however, animal studies indicate that trazodone may enhance release of norepinephrine from neuronal tissue. Trazodone does not cause serotonin release in vitro.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2380

8.9 Human Metabolite Information

8.9.1 Cellular Locations

  • Extracellular
  • Membrane

8.10 Transformations

9 Use and Manufacturing

9.1 Uses

Anti-Anxiety Agents; Antidepressive Agents, Second-Generation; Serotonin Uptake Inhibitors
National Library of Medicine's Medical Subject Headings. Trazodone. Online file (MeSH, 2016). Available from, as of January 19, 2016: https://www.nlm.nih.gov/mesh/2016/mesh_browser/MBrowser.html
MEDICATION
MEDICATION (VET)

Use (kg; approx.) in Germany (2009): >500

Use (kg) in USA (2002): 20900

Consumption (g per capita; approx.) in Germany (2009): 0.00611

Consumption (g per capita) in the USA (2002): 0.0741

Calculated removal (%): 7.9

For the treatment of depression.

9.1.1 Use Classification

Pharmaceuticals
S72 | NTUPHTW | Pharmaceutically Active Substances from National Taiwan University | DOI:10.5281/zenodo.3955664

9.2 Methods of Manufacturing

Semicarbazide and 2-chloropyridine are condensed with loss of water and ammonia to form 1,2,4-triazolo[4,3-alpha]pyridin3(2H)-one, with on treatment with 1-(3-chlorophenyl)4,3-chlorophenyl)piperazine and sodamide, yields trazodone.
Troy, D.B. (Ed); Remmington The Science and Practice of Pharmacy. 21 st Edition. Lippincott Williams & Williams, Philadelphia, PA 2005, p. 1522

9.3 Impurities

...1-(3-chloropropyl)-4-(3-chlorophenyl)piperazine HCl (CCP HCl) a process related impurity in trazodone. /Genotoxic Impurity/
Venugopal N et al; Arabian J Chem (2014)

9.4 Formulations / Preparations

Beneficat; Depyrel; Taxagon; Trazodil
Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present., p. VA22 (1993) 364
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1775
The main ingredient in the drug Desyrel ... (tablets)
Murray L, ed; Physicians' Desk Reference. 55th ed. Montvale, NJ: Medical Economics Co. p. 561 (2001)
Table: Trazodone Hydrochloride Preparations
Route of Administration
Oral
Dosage Form
Tablets
Strength
50 mg
Brand or Generic Form (Manufacturer)
Trazodone Hydrochloride Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets
Strength
100 mg
Brand or Generic Form (Manufacturer)
Trazodone Hydrochloride Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets
Strength
150 mg
Brand or Generic Form (Manufacturer)
Trazodone Hydrochloride Dividose, scored (Sandoz)
Route of Administration
Oral
Dosage Form
Tablets
Strength
150 mg
Brand or Generic Form (Manufacturer)
Trazodone Hydrochloride Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets
Strength
300 mg
Brand or Generic Form (Manufacturer)
Trazodone Hydrochloride Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2382

10 Identification

10.1 Analytic Laboratory Methods

Analyte: trazodone hydrochloride; matrix: pharmaceutical preparation (tablet); procedure: liquid chromatography with detection at 254 nm and comparison to standards (assay purity)
U.S. Pharmacopeia. The United States Pharmacopeia, USP 26/The National Formulary, NF 21; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p1859 (2003)
Analyte: trazodone hydrochloride; matrix: pharmaceutical preparation (tablet); procedure: retention time of liquid chromatogram with comparison to standards (chemical identification)
U.S. Pharmacopeia. The United States Pharmacopeia, USP 26/The National Formulary, NF 21; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p1859 (2003)
Analyte: trazodone hydrochloride; matrix: pharmaceutical preparation (tablet); procedure: thin-layer chromatography with comparison to standards (chemical identification)
U.S. Pharmacopeia. The United States Pharmacopeia, USP 26/The National Formulary, NF 21; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p1859 (2003)
Analyte: trazodone hydrochloride; matrix: chemical purity; procedure: liquid chromatography with detection at 254 nm and comparison to standards
U.S. Pharmacopeia. The United States Pharmacopeia, USP 26/The National Formulary, NF 21; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p1858 (2003)
For more Analytic Laboratory Methods (Complete) data for TRAZODONE (7 total), please visit the HSDB record page.

11 Safety and Hazards

11.1 Hazards Identification

11.1.1 GHS Classification

1 of 2
View All
Pictogram(s)
Irritant
Signal
Warning
GHS Hazard Statements
H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]
Precautionary Statement Codes

P264, P270, P301+P317, P330, and P501

(The corresponding statement to each P-code can be found at the GHS Classification page.)

ECHA C&L Notifications Summary

Aggregated GHS information provided per 4 reports by companies from 1 notifications to the ECHA C&L Inventory.

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

11.1.2 Hazard Classes and Categories

Acute Tox. 4 (100%)

11.2 Fire Fighting

11.2.1 Fire Fighting Procedures

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. /Trazadone hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Trazodone hydrochloride. Product Number: T6154, Version 4.4 (Revision Date 06/29/2014). Available from, as of January 26, 2016: https://www.sigmaaldrich.com/safety-center.html
Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary. /Trazadone hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Trazodone hydrochloride. Product Number: T6154, Version 4.4 (Revision Date 06/29/2014). Available from, as of January 26, 2016: https://www.sigmaaldrich.com/safety-center.html

11.3 Accidental Release Measures

11.3.1 Cleanup Methods

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust; Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains; Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal. /Trazadone hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Trazodone hydrochloride. Product Number: T6154, Version 4.4 (Revision Date 06/29/2014). Available from, as of January 26, 2016: https://www.sigmaaldrich.com/safety-center.html

11.3.2 Disposal Methods

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.
Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material; Contaminated packaging:Dispose of as unused product. /Trazadone hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Trazodone hydrochloride. Product Number: T6154, Version 4.4 (Revision Date 06/29/2014). Available from, as of January 26, 2016: https://www.sigmaaldrich.com/safety-center.html
SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

11.3.3 Preventive Measures

Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed. Normal measures for preventive fire protection. /Trazadone hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Trazodone hydrochloride. Product Number: T6154, Version 4.4 (Revision Date 06/29/2014). Available from, as of January 26, 2016: https://www.sigmaaldrich.com/safety-center.html
Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday. /Trazadone hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Trazodone hydrochloride. Product Number: T6154, Version 4.4 (Revision Date 06/29/2014). Available from, as of January 26, 2016: https://www.sigmaaldrich.com/safety-center.html
Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. /Trazadone hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Trazodone hydrochloride. Product Number: T6154, Version 4.4 (Revision Date 06/29/2014). Available from, as of January 26, 2016: https://www.sigmaaldrich.com/safety-center.html
SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

11.4 Handling and Storage

11.4.1 Storage Conditions

Store at 20 deg to 25 °C (68 deg to 77 °F).
NIH; DailyMed. Current Medication Information for Trazodone Hydrochloride (Trazodone Hydrochloride) Tablet, Film Coated (Updated: August 2015). Available from, as of February 29, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=324d2543-477d-4c0b-bfa0-d76cb4e5cd48
Keep container tightly closed in a dry and well-ventilated place. Keep in a dry place. /Trazadone hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Trazodone hydrochloride. Product Number: T6154, Version 4.4 (Revision Date 06/29/2014). Available from, as of January 26, 2016: https://www.sigmaaldrich.com/safety-center.html

11.5 Exposure Control and Personal Protection

11.5.1 Personal Protective Equipment (PPE)

Eye/face protection: Safety glasses with side-shields conforming to EN166. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /Trazadone hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Trazodone hydrochloride. Product Number: T6154, Version 4.4 (Revision Date 06/29/2014). Available from, as of January 26, 2016: https://www.sigmaaldrich.com/safety-center.html
Skin protection: Handle with gloves. /Trazadone hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Trazodone hydrochloride. Product Number: T6154, Version 4.4 (Revision Date 06/29/2014). Available from, as of January 26, 2016: https://www.sigmaaldrich.com/safety-center.html
Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace. /Trazadone hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Trazodone hydrochloride. Product Number: T6154, Version 4.4 (Revision Date 06/29/2014). Available from, as of January 26, 2016: https://www.sigmaaldrich.com/safety-center.html
Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face particle respirator type N100 (US) or type P3 (EN 143) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /Trazadone hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Trazodone hydrochloride. Product Number: T6154, Version 4.4 (Revision Date 06/29/2014). Available from, as of January 26, 2016: https://www.sigmaaldrich.com/safety-center.html

11.6 Stability and Reactivity

11.6.1 Hazardous Reactivities and Incompatibilities

Incompatible materials: Strong oxidizing agents /Trazadone hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Trazodone hydrochloride. Product Number: T6154, Version 4.4 (Revision Date 06/29/2014). Available from, as of January 26, 2016: https://www.sigmaaldrich.com/safety-center.html

11.7 Regulatory Information

REACH Registered Substance

11.7.1 FDA Requirements

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including trazodone hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Trazodone hydrochloride/
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of March 23, 2016: https://www.fda.gov/cder/ob/

11.8 Other Safety Information

11.8.1 Toxic Combustion Products

Special hazards arising from the substance or mixture: Carbon oxides, nitrogen oxides (NOx), Hydrogen chloride gas /Trazadone hydrochloride/
Sigma-Aldrich; Safety Data Sheet for Trazodone hydrochloride. Product Number: T6154, Version 4.4 (Revision Date 06/29/2014). Available from, as of January 26, 2016: https://www.sigmaaldrich.com/safety-center.html

12 Toxicity

12.1 Toxicological Information

12.1.1 Toxicity Summary

IDENTIFICATION AND USE: Trazodone is in the form of crystals. Trazodone hydrochloride tablets USP are indicated for the treatment of major depressive disorder (MDD) in adults. Trazodone has been used in dogs for events that trigger anxiety. HUMAN EXPOSURE AND TOXICITY: The most severe reactions reported to have occurred with overdose of trazodone alone have been priapism, respiratory arrest, seizures, and ECG changes. The reactions reported most frequently have been drowsiness and vomiting. Trazodone is known to prolong the QT/QTc interval. Some drugs that prolong the QT/QTc interval can cause Torsades de Pointes with sudden, unexplained death. A study of pregnant women who had been exposed to trazodone suggested that the drug does not increase the rate of major malformations above the baseline rate. ANIMAL STUDIES: Tremors, vomiting and clonic convulsions were produced in dogs given 50 and 100 mg/kg/day orally for one month. Administration of approximately 250 mg/kg/day in the diet of rats for 6 months resulted in significantly greater liver weights and slightly lower weight gain in males. Rats were used to conduct a two year carcinogenicity study. In both treatment groups, larger numbers of female rats died sooner than controls; most deaths were related to the presence of pituitary tumors. In both treatment groups at 12, 13 and 14 months, the incidence of palpable masses (mammary tumors, cysts, etc.) was increased also. Two developmental rat studies were conducted: one in which rats were given 100 and 210 mg/kg/day orally during days 10-15 and 6-15 of gestation, respectively; and another in which doses of 150-450 mg/kg/day were given orally during days 9-14 of gestation. Only a sedative effect on dams was noted at 100 mg/kg. Increased sedation, decreased maternal and fetal weights and retarded ossification were produced at doses of 150 mg/kg and higher. A significant increase in resorptions and stillborn fetuses, in addition to retarded fetal growth, occurred with 300 and 450 mg/kg.
Trazodone binds at 5-HT2 receptor, it acts as a serotonin agonist at high doses and a serotonin antagonist at low doses. Like fluoxetine, trazodone's antidepressant activity likely results from blockage of serotonin reuptake by inhibiting serotonin reuptake pump at the presynaptic neuronal membrane. If used for long time periods, postsynaptic neuronal receptor binding sites may also be affected. The sedative effect of trazodone is likely the result of alpha-adrenergic blocking action and modest histamine blockade at H1 receptor. It weakly blocks presynaptic alpha2-adrenergic receptors and strongly inhibits postsynaptic alpha1 receptors. Trazodone does not affect the reuptake of norepinephrine or dopamine within the CNS.

12.1.2 Hepatotoxicity

Liver test abnormalities occur in a proportion of patients on trazodone, but elevations are usually modest and usually do not require dose modification or discontinuation. At least a dozen instances of acute, clinically apparent episodes of liver injury with marked liver enzyme elevations with or without jaundice have been reported in patients on trazodone. The onset of injury varies from a few days to 6 months and the pattern of serum enzyme elevations is usually hepatocellular, but mixed and cholestatic forms have also been described. Several cases have had immunoallergic features (rash, fever, eosinophilia), but these were not prominent. Autoimmune (autoantibodies) features are uncommon. Rare instances of acute liver failure and death from trazodone have been reported. Nefazodone, an antidepressant similar in structure and mechanism of action to trazodone, was approved for use in 1998, but is currently not commonly used because of multiple reports of acute hepatocellular injury, with a high mortality rate arising 2 weeks to 6 months after starting therapy.

Likelihood score: B (likely but rare cause of clinically apparent liver injury).

12.1.3 Drug Induced Liver Injury

Compound
trazodone
DILI Annotation
Less-DILI-Concern
Severity Grade
5
Label Section
Adverse reactions
References

M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007

M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

12.1.4 Carcinogen Classification

Carcinogen Classification
No indication of carcinogenicity to humans (not listed by IARC).

12.1.5 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

Limited information indicates that trazodone levels in milk are low and would not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months or when doses of 100 mg or less are used at bedtime for sleep. A safety scoring system finds trazodone use to be possible to use cautiously during breastfeeding.

◉ Effects in Breastfed Infants

One woman was 6.5 weeks postpartum and taking trazodone 75 mg, venlafaxine 75 mg and quetiapine 75 mg daily before conception, during pregnancy and during breastfeeding. Her breastfed infant's development was tested at 12 months of age with the Bayley Scales. Measurements were within normal limits on the mental, psychomotor and behavior scales.

One infant whose mother took trazodone 200 mg daily for 12 weeks starting at 4 weeks postpartum was followed up at 12 months of age. No adverse effects on growth and development were found.

One exclusively breastfed 15-week-old infant was breastfed during maternal therapy with trazodone 100 mg daily and venlafaxine 150 mg daily. No adverse reactions were reported by the mother or found in the medical records.

A woman took etizolam 1 mg and trazodone 50 mg once daily for 3 months postpartum. Her infant was over 50% breastfed and demonstrated no adverse reactions at the 1- and 3-month checkups. The infant’s Denver Developmental Screening Test II was normal at 6 months of age.

◉ Effects on Lactation and Breastmilk

A nonpregnant woman with depression was treated with citalopram 20 mg daily, then 40 mg daily. Trazodone 50 mg at bedtime was added to treat insomnia and then increased to 100 mg at bedtime. One week later the patient noticed milk leakage from her breasts, which stained her clothing. Her serum prolactin was somewhat elevated, but no other abnormalities were noted. The trazodone dosage was tapered and then discontinued. One month later, the galactorrhea had resolved and her serum prolactin was in the normal range.

An observational study looked at outcomes of 2859 women who took an antidepressant during the 2 years prior to pregnancy. Compared to women who did not take an antidepressant during pregnancy, mothers who took an antidepressant during all 3 trimesters of pregnancy were 37% less likely to be breastfeeding upon hospital discharge. Mothers who took an antidepressant only during the third trimester were 75% less likely to be breastfeeding at discharge. Those who took an antidepressant only during the first and second trimesters did not have a reduced likelihood of breastfeeding at discharge. The antidepressants used by the mothers were not specified.

A retrospective cohort study of hospital electronic medical records from 2001 to 2008 compared women who had been dispensed an antidepressant during late gestation (n = 575) to those who had a psychiatric illness but did not receive an antidepressant (n = 1552) and mothers who did not have a psychiatric diagnosis (n = 30,535). Women who received an antidepressant were 37% less likely to be breastfeeding at discharge than women without a psychiatric diagnosis, but no less likely to be breastfeeding than untreated mothers with a psychiatric diagnosis. None of the mothers were taking trazodone.

In a study of 80,882 Norwegian mother-infant pairs from 1999 to 2008, new postpartum antidepressant use was reported by 392 women and 201 reported that they continued antidepressants from pregnancy. Compared with the unexposed comparison group, late pregnancy antidepressant use was associated with a 7% reduced likelihood of breastfeeding initiation, but with no effect on breastfeeding duration or exclusivity. Compared with the unexposed comparison group, new or restarted antidepressant use was associated with a 63% reduced likelihood of predominant, and a 51% reduced likelihood of any breastfeeding at 6 months, as well as a 2.6-fold increased risk of abrupt breastfeeding discontinuation. Specific antidepressants were not mentioned.

◈ What is trazodone?

Trazodone is an antidepressant and sedative that has been used to treat depression and symptoms of insomnia (trouble sleeping). Some brand names for trazodone include Desyrel®, Oleptro®, and Trazorel®.Sometimes when people find out they are pregnant, they think about changing how they take their medication, or stopping their medication altogether. However, it is important to talk with your healthcare providers before making any changes to how you take your medication. Your healthcare providers can talk with you about the benefits of treating your condition and the risks of untreated illness during pregnancy.Some people may have a return of their symptoms (relapse) if they stop this medication during pregnancy. If you stop taking this medication, it is important to have other forms of support in place (e.g. counseling or therapy) and a plan to restart the medication after delivery, if needed. If you plan to stop this medication, your healthcare provider may suggest that you slowly lower the dose instead of stopping all at once. Stopping this medication suddenly can cause some people to have withdrawal symptoms. It is not known if or how withdrawal might affect a pregnancy.

◈ I take trazodone. Can it make it harder for me to get pregnant?

Studies have not been done to see if trazodone could make it harder to get pregnant. Some conditions, including depression, can make it harder to get pregnant. This makes it hard to know if the medication, the condition being treated, or other factors might affect fertility (ability to get pregnant). For more information on depression, please see our fact sheet at https://mothertobaby.org/fact-sheets/depression-pregnancy/.

◈ Does taking trazodone increase the chance of miscarriage?

Miscarriage is common and can occur in any pregnancy for many different reasons. Two studies, with over 200 hundred people, found no increase in miscarriage when trazodone was taken during pregnancy. Some studies have reported a higher chance of miscarriage when depression is left untreated in pregnancy.

◈ Does taking trazodone increase the chance of birth defects?

Every pregnancy starts out with a 3-5% chance of having a birth defect. This is called the background risk. Studies have looked at over 300 pregnancies where trazodone was taken during the first trimester. These studies did not find an increased chance of birth defects above the background risk.

◈ Does taking trazodone in pregnancy increase the chance of other pregnancy-related problems?

One study found no greater chance for preterm delivery (delivery before week 37) or low birth weight (weighing less than 5 pounds, 8 ounces [2500 grams] at birth) in babies who had been exposed to trazodone during pregnancy.Another study of over 200 pregnancies found no greater chance for low birth weight but did find a slightly higher chance for preterm delivery. However, research has also shown that when depression is left untreated during pregnancy, there could be an increased chance for pregnancy complications. This makes it hard to know if the medication, the condition being treated, or other factors might increase the chance of pregnancy complications.

◈ I need to take trazodone throughout my entire pregnancy. Will it cause withdrawal symptoms in my baby after birth?

The use of trazodone during pregnancy can cause temporary symptoms in newborns soon after birth. These symptoms are sometimes referred to as withdrawal. Symptoms include jitteriness, breathing problems, or trouble feeding. Not all babies exposed to trazodone will have these symptoms. No withdrawal symptoms were reported in one study of 18 infants exposed to 50 mg/day of trazodone for insomnia in the third trimester. It is important that your healthcare providers know you are taking trazodone so that if symptoms do occur, your baby can get the care that is best for them.

◈ Does taking trazodone in pregnancy affect future behavior or learning for the child?

Studies have not been done to see if trazodone can cause behavior or learning issues for the child.

◈ Breastfeeding while taking trazodone:

Information on the use of trazodone in breastfeeding is limited. Small amounts of trazodone have been found in breast milk. If you suspect the baby has any symptoms (such as being more sleepy than usual), contact the child’s healthcare provider. Be sure to talk to your healthcare provider about all your breastfeeding questions.

◈ If a male takes trazodone, could it affect fertility or increase the chance of birth defects?

Studies have not been done to see if trazodone could affect male fertility (ability to get partner pregnant) or increase the chance of birth defects. People with conditions such as depression may have lower sex drive (desire to have sex), which might make it harder for them to get their partner pregnant. In general, exposures that fathers or sperm donors have are unlikely to increase risks to a pregnancy. For more information, please see the MotherToBaby fact sheet Paternal Exposures at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

12.1.6 Exposure Routes

Rapidly and almost completely absorbed following oral administration. Food may decrease the rate and extent of absorption.

12.1.7 Acute Effects

12.1.8 Toxicity Data

LD50: 96mg/kg (Intravenous, Mouse) (A308)
A308: Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. PMID:18048412

12.1.9 Treatment

There is no specific antidote for Trazodone. Treatment should be symptomatic and supportive in the case of hypotension or excessive sedation. Any patient suspected of having taken an overdose should have the stomach emptied by gastric lavage. Forced diuresis may be useful in facilitating elimination of the drug. (L1712)
L1712: RxList: The Internet Drug Index (2009). http://www.rxlist.com/

12.1.10 Interactions

Concomitant use of trazodone with inhibitors of CYP3A4 can result in substantially increased plasma concentrations of trazodone and increase the potential for adverse effects. In one study, concomitant use of ritonavir (200 mg twice daily for 2 days) and trazodone (a single 50-mg dose) in healthy individuals increased maximum plasma concentrations and decreased clearance of trazodone by 34 and 52%, respectively, and increased area under the plasma concentration-time curve (AUC) and half-life of trazodone by greater than twofold. Adverse effects (e.g., nausea, hypotension, syncope) also were observed with concomitant use of trazodone and ritonavir. The manufacturers of trazodone state that a reduction in trazodone dosage should be considered in patients receiving a potent inhibitor of the CYP3A4 isoenzyme (e.g., indinavir, itraconazole, ketoconazole, nefazodone, ritonavir) concomitantly with trazodone.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2380
... Three clinically significant cases of suspected trazodone & warfarin interactions were identified in a retrospective chart review based on changes in the prothrombin time (PT) & international normalized ratio (INR) that were not explained by other factors. In each of the cases, the INR changed by > or = 1.0 after the initiation or discontinuation of trazodone. In the patients who started trazodone, a subsequent decr in the PT & INR resulted; conversely, the PT & INR increased in the patient who stopped trazodone therapy. Although none of the patients experienced adverse effects due to the marked changes in PT & INR, the warfarin dosages had to be adjusted accordingly on initiation & discontinuation of trazodone. ... These cases show that there is a potentially clinically significant interaction between trazodone & warfarin. The time to onset of the interaction is variable; the mechanism behind it is not known, but it may involve substrate or protein-binding competition. ... The use of trazodone on an as-needed basis for sleep is strongly discouraged in patients who are receiving warfarin, due to the difficulty of achieving a therapeutic PT & INR. Until more is known, patients & clinicians should be educated about this potential interaction & monitor for changes in the anticoagulant effects when trazodone is initiated or stopped.
Small NL, Giamonna KA; Ann Pharmacother 34(6): 734-736 (2000)
... Pharmacologic treatment of emotional disorders in HIV-infected patients can be more easily optimized by understanding of potential interactions of psychotropic drugs with medications used to treat HIV infection & its sequelae. ... Biotransformation of the antidepressant trazodone to its principal metabolite, meta-chlorophenylpiperazine (mCPP), was studied in vitro using human liver microsomes & heterologously expressed individual human cytochromes. Interactions of trazodone with the azole antifungal agent, ketoconazole, & with human immunodeficiency virus protease inhibitors (HIVPIs) were studied in the same system. ... Formation of mCPP from trazodone in liver microsomes had a mean (+/- SE) K(m) value of 163 (+/- 21) micromol/l. Ketoconazole, a relatively specific CYP3A inhibitor, impaired mCPP formation consistent with a competitive mechanism, having an inhibition constant (K(i)) of 0.12 (+/- 0.01) micromol/l. Among heterologously expressed human cytochromes, only CYP3A4 mediated formation of mCPP from trazodone; the K(m) was 180 micromol/l, consistent with the value in microsomes. The HIVPI ritonavir was a potent inhibitor of mCPP formation in liver microsomes (K(i) = 0.14 +/- 0.04 micromol/l). The HIVPI indinavir was also a strong inhibitor, whereas saquinavir & nelfinavir were weaker inhibitors. ... CYP3A-mediated clearance of trazodone is inhibited by ketoconazole, ritonavir & indinavir, & indicates the likelihood of pharmacokinetic interactions in vivo.
Zalma A, et al; Biol Psychiatry 47(7): 655-661 (2000)
The effects of trazodone on subjective & objective sleep parameters were compared to those of placebo in a double-blind design in seven patients who developed insomnia during treatment with the selective & reversible MAO-A inhibitor, brofaromine. Trazodone significantly increased deep sleep & altered the architecture of sleep in these patients. Subjectively, patients reported a better & deeper sleep. No negative interactions between brofaromine & trazodone were observed & side-effects were minimal. A low dose of trazodone may be a safe & effective agent in the treatment of MAO-I induced insomnia.
Haffmans PM, Vos MS; Eur Psychiatry 14(3): 167-171 (1999)
For more Interactions (Complete) data for TRAZODONE (18 total), please visit the HSDB record page.

12.1.11 Antidote and Emergency Treatment

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3rd revised edition, Elsevier Mosby, St. Louis, MO 2007, p. 160
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3rd revised edition, Elsevier Mosby, St. Louis, MO 2007, p. 160
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3rd revised edition, Elsevier Mosby, St. Louis, MO 2007, p. 160-1
There is no specific antidote for trazodone hydrochloride overdose. Treatment should consist of those general measures employed in the management of overdosage with any drug effective in the treatment of major depressive disorder. Ensure an adequate airway, oxygenation and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients. Activated charcoal should be administered. Forced diuresis may be useful in facilitating elimination of the drug. In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose.
NIH; DailyMed. Current Medication Information for Trazodone Hydrochloride (Trazodone Hydrochloride) Tablet, Film Coated (Updated: August 2015). Available from, as of February 29, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=324d2543-477d-4c0b-bfa0-d76cb4e5cd48
For more Antidote and Emergency Treatment (Complete) data for TRAZODONE (8 total), please visit the HSDB record page.

12.1.12 Human Toxicity Excerpts

/SIGNS AND SYMPTOMS/ All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
NIH; DailyMed. Current Medication Information for Trazodone Hydrochloride (Trazodone Hydrochloride) Tablet, Film Coated (Updated: August 2015). Available from, as of February 29, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=324d2543-477d-4c0b-bfa0-d76cb4e5cd48
/SIGNS AND SYMPTOMS/ The most severe reactions reported to have occurred with overdose of trazodone alone have been priapism, respiratory arrest, seizures, and ECG changes, including QT prolongation. The reactions reported most frequently have been drowsiness and vomiting. Overdosage may cause an increase in incidence or severity of any of the reported adverse reactions.
NIH; DailyMed. Current Medication Information for Trazodone Hydrochloride (Trazodone Hydrochloride) Tablet, Film Coated (Updated: August 2015). Available from, as of February 29, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=324d2543-477d-4c0b-bfa0-d76cb4e5cd48
/SIGNS AND SYMPTOMS/ The development of a potentially life-threatening serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions have been reported with antidepressants alone and may occur with trazodone treatment, but particularly with concomitant use of other serotoninergic drugs (including SSRIs, SNRIs and triptans) and with drugs that impair metabolism of serotonin (including monoamine oxidase inhibitors (MAOIs)), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes.
NIH; DailyMed. Current Medication Information for Trazodone Hydrochloride (Trazodone Hydrochloride) Tablet, Film Coated (Updated: August 2015). Available from, as of February 29, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=324d2543-477d-4c0b-bfa0-d76cb4e5cd48
/SIGNS AND SYMPTOMS/ Trazodone is known to prolong the QT/QTc interval. Some drugs that prolong the QT/QTc interval can cause Torsades de Pointes with sudden, unexplained death. The relationship of QT prolongation is clearest for larger increases (20 msec and greater), but it is possible that smaller QT/QTc prolongations may also increase risk, especially in susceptible individuals, such as those with hypokalemia, hypomagnesemia, or a genetic predisposition to prolonged QT/QTc. Although Torsades de Pointes has not been observed with the use of trazodone hydrochloride tablets at recommended doses in premarketing trials, experience is too limited to rule out an increased risk. However, there have been postmarketing reports of Torsades de Pointes with the immediate-release form of trazodone (in the presence of multiple confounding factors), even at doses of 100 mg per day or less.
NIH; DailyMed. Current Medication Information for Trazodone Hydrochloride (Trazodone Hydrochloride) Tablet, Film Coated (Updated: August 2015). Available from, as of February 29, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=324d2543-477d-4c0b-bfa0-d76cb4e5cd48
For more Human Toxicity Excerpts (Complete) data for TRAZODONE (17 total), please visit the HSDB record page.

12.1.13 Non-Human Toxicity Excerpts

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Administration of approximately 250 mg/kg/day in the diet of rats for 6 months resulted in significantly greater liver weights than in control rats and slightly lower weight gain in males.
Health Canada; Product Monograph for Trazodone (Trazodone Hydrochloride), Drug Identification Number (DIN): 02348772 (Date of Preparation: July 23, 2014). Available from, as of February 29, 2016: https://webprod5.hc-sc.gc.ca/dpd-bdpp/start-debuter.do?lang=eng
/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Tremors, vomiting and clonic convulsions were produced in dogs given 50 and 100 mg/kg/day p.o. for one month.
Health Canada; Product Monograph for Trazodone (Trazodone Hydrochloride), Drug Identification Number (DIN): 02348772 (Date of Preparation: July 23, 2014). Available from, as of February 29, 2016: https://webprod5.hc-sc.gc.ca/dpd-bdpp/start-debuter.do?lang=eng
/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Several subacute studies were conducted in rats using doses ranging from 100 to 450 mg/kg/day p.o. for one to four months. The main toxic effects observed were decreased body weight gain and slight liver enlargement in males. There were some deaths at the highest dose.
Health Canada; Product Monograph for Trazodone (Trazodone Hydrochloride), Drug Identification Number (DIN): 02348772 (Date of Preparation: July 23, 2014). Available from, as of February 29, 2016: https://webprod5.hc-sc.gc.ca/dpd-bdpp/start-debuter.do?lang=eng
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Rats were used to conduct a two year carcinogenicity study at doses of 0, 40 and 80 mg/kg/day. In both treatment groups, larger numbers of female rats died sooner than controls; most deaths were related to the presence of pituitary tumors. In both treatment groups at 12, 13 and 14 months, the incidence of palpable masses (mammary tumors, cysts, etc.) was increased also. These observations may be related to trazodone's effects on prolactin secretion. (Acute administration caused an increase in prolactin blood levels whereas chronic administration did not. Turnover, however, was not studied. When a neuroleptic was used as a positive control, similar results were produced.) The relative incidences of male rats with pituitary tumors were reversed. These results may have been influenced by the early deaths due to nephritis and other causes, however.
Health Canada; Product Monograph for Trazodone (Trazodone Hydrochloride), Drug Identification Number (DIN): 02348772 (Date of Preparation: July 23, 2014). Available from, as of February 29, 2016: https://webprod5.hc-sc.gc.ca/dpd-bdpp/start-debuter.do?lang=eng
For more Non-Human Toxicity Excerpts (Complete) data for TRAZODONE (8 total), please visit the HSDB record page.

12.1.14 Non-Human Toxicity Values

LD50 Rat oral 690 mg/kg
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 3502
LD50 Rat iv 91 mg/kg
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 3502
LD50 Rat ip 178 mg/kg
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 3502
LD50 Mouse oral 610 mg/kg
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 3502
LD50 Mouse iv 91 mg/kg
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 3502

12.1.15 Populations at Special Risk

Angle-Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs including trazodone hydrochloride tablets may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
NIH; DailyMed. Current Medication Information for Trazodone Hydrochloride (Trazodone Hydrochloride) Tablet, Film Coated (Updated: August 2015). Available from, as of February 29, 2016: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=324d2543-477d-4c0b-bfa0-d76cb4e5cd48

12.1.16 Protein Binding

The plasma protein binding of trazodone is 89-95% according to in vitro studies.

12.2 Ecological Information

12.2.1 Artificial Pollution Sources

Trazodone's production and administration as an antidepressant(1) may result in its release to the environment through various waste streams(SRC).
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 1775

12.2.2 Body Burden

A fatal case of suicide with trazodone alone in a 40-yr-old patient is reported. ... Blood collected at admission contained a trazodone toxic concn of 25.4 ug/ml. ... /Salt not specified/
de Meester A, et al; Acta Clin Belg 56(4): 258-261 (2001)

13 Associated Disorders and Diseases

14 Literature

14.1 Consolidated References

14.2 NLM Curated PubMed Citations

14.3 Springer Nature References

14.4 Thieme References

14.5 Wiley References

14.6 Nature Journal References

14.7 Chemical Co-Occurrences in Literature

14.8 Chemical-Gene Co-Occurrences in Literature

14.9 Chemical-Disease Co-Occurrences in Literature

15 Patents

15.1 Depositor-Supplied Patent Identifiers

15.2 WIPO PATENTSCOPE

15.3 Chemical Co-Occurrences in Patents

15.4 Chemical-Disease Co-Occurrences in Patents

15.5 Chemical-Gene Co-Occurrences in Patents

16 Interactions and Pathways

16.1 Chemical-Target Interactions

16.2 Drug-Drug Interactions

16.3 Drug-Food Interactions

  • Avoid alcohol.
  • Avoid St. John's Wort. The risk of serotonin syndrome may be increased.
  • Take after a meal. Should be taken shortly after a light meal or snack.

17 Biological Test Results

17.1 BioAssay Results

18 Classification

18.1 MeSH Tree

18.2 NCI Thesaurus Tree

18.3 ChEBI Ontology

18.4 KEGG: ATC

18.5 KEGG: Target-based Classification of Drugs

18.6 KEGG: Drug Groups

18.7 WHO ATC Classification System

18.8 FDA Pharm Classes

18.9 ChemIDplus

18.10 IUPHAR / BPS Guide to PHARMACOLOGY Target Classification

18.11 ChEMBL Target Tree

18.12 UN GHS Classification

18.13 NORMAN Suspect List Exchange Classification

18.14 CCSBase Classification

18.15 EPA DSSTox Classification

18.16 EPA Substance Registry Services Tree

18.17 MolGenie Organic Chemistry Ontology

19 Information Sources

  1. CAS Common Chemistry
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  14. Open Targets
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  17. ClinicalTrials.gov
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  20. IUPHAR/BPS Guide to PHARMACOLOGY
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    https://www.guidetopharmacology.org/about.jsp#license
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    https://www.guidetopharmacology.org/targets.jsp
  21. Therapeutic Target Database (TTD)
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  25. Drugs and Lactation Database (LactMed)
  26. Mother To Baby Fact Sheets
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  28. NIST Mass Spectrometry Data Center
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  29. Japan Chemical Substance Dictionary (Nikkaji)
  30. KEGG
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    https://www.kegg.jp/kegg/legal.html
    Anatomical Therapeutic Chemical (ATC) classification
    http://www.genome.jp/kegg-bin/get_htext?br08303.keg
    Target-based classification of drugs
    http://www.genome.jp/kegg-bin/get_htext?br08310.keg
  31. Kruve Lab, Ionization & Mass Spectrometry, Stockholm University
    trazodone
  32. MassBank Europe
  33. MassBank of North America (MoNA)
    LICENSE
    The content of the MoNA database is licensed under CC BY 4.0.
    https://mona.fiehnlab.ucdavis.edu/documentation/license
  34. Metabolomics Workbench
  35. Nature Chemical Biology
  36. SpectraBase
  37. NLM RxNorm Terminology
    LICENSE
    The RxNorm Terminology is created by the National Library of Medicine (NLM) and is in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from NLM. Credit to the U.S. National Library of Medicine as the source is appreciated but not required. The full RxNorm dataset requires a free license.
    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
  38. WHO Anatomical Therapeutic Chemical (ATC) Classification
    LICENSE
    Use of all or parts of the material requires reference to the WHO Collaborating Centre for Drug Statistics Methodology. Copying and distribution for commercial purposes is not allowed. Changing or manipulating the material is not allowed.
    https://www.whocc.no/copyright_disclaimer/
  39. PharmGKB
    LICENSE
    PharmGKB data are subject to the Creative Commons Attribution-ShareALike 4.0 license (https://creativecommons.org/licenses/by-sa/4.0/).
    https://www.pharmgkb.org/page/policies
  40. Pharos
    LICENSE
    Data accessed from Pharos and TCRD is publicly available from the primary sources listed above. Please respect their individual licenses regarding proper use and redistribution.
    https://pharos.nih.gov/about
  41. Springer Nature
  42. Thieme Chemistry
    LICENSE
    The Thieme Chemistry contribution within PubChem is provided under a CC-BY-NC-ND 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc-nd/4.0/
  43. Wikidata
  44. Wikipedia
  45. Wiley
  46. Medical Subject Headings (MeSH)
    LICENSE
    Works produced by the U.S. government are not subject to copyright protection in the United States. Any such works found on National Library of Medicine (NLM) Web sites may be freely used or reproduced without permission in the U.S.
    https://www.nlm.nih.gov/copyright.html
    Antidepressive Agents, Second-Generation
    https://www.ncbi.nlm.nih.gov/mesh/68018687
    Selective Serotonin Reuptake Inhibitors
    https://www.ncbi.nlm.nih.gov/mesh/68017367
  47. PubChem
  48. GHS Classification (UNECE)
  49. EPA Substance Registry Services
  50. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  51. PATENTSCOPE (WIPO)
  52. NCBI
CONTENTS