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Trazodone Hydrochloride

Pronunciation

Class: Serotonin Modulators
VA Class: CN609
CAS Number: 25332-39-2

Warning(s)

  • Suicidality
  • Antidepressants increased risk of suicidal thinking and behavior (suicidality) compared with placebo in children, adolescents, and young adults (18–24 years of age) with major depressive disorder and other psychiatric disorders; balance this risk with clinical need.212 213 a Trazodone is not approved for use in pediatric patients.a (See Pediatric Use under Cautions.)

  • In pooled data analyses, risk of suicidality was not increased in adults >24 years of age and was reduced in adults ≥65 years of age with antidepressants compared with placebo.212 213 a

  • Depression and certain other psychiatric disorders are themselves associated with an increased risk of suicide.212 213 218 a

  • Appropriately monitor and closely observe all patients who are started on trazodone therapy for clinical worsening, suicidality, or unusual changes in behavior; involve family members and/or caregivers in this process.212 213 218 a (See Worsening of Depression and Suicidality Risk under Cautions.)

Introduction

Antidepressant; serotonin modulator.201 b

Uses for Trazodone Hydrochloride

Major Depressive Disorder

Management of major depressive disorder with or without anxiety.201

Effective in both inpatient and outpatient settings.201

Schizophrenic Disorder

Has been used for the short-term management of depressive episodes in patients with schizophrenia.b d

Alcohol Dependence

Has been used as adjunctive therapy for the management of alcohol dependence.b

Anxiety States

Has been used for the management of anxiety states.b

Trazodone Hydrochloride Dosage and Administration

General

  • Individualize dosages according to individual requirements and response.b

  • Monitor for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustments.212 213 218 (See Worsening of Depression and Suicidality Risk under Cautions.)

  • Sustained therapy may be required;201 use lowest effective dose and monitor periodically for need for continued therapy.201

Administration

Oral Administration

Administer orally after a meal or a light snack.201

If drowsiness occurs, administer a major portion of the daily dosage at bedtime or reduce dosage.201

Dosage

Available as trazodone hydrochloride; dosage is expressed in terms of the salt.201

Adults

Major Depressive Disorder
Oral

Initially, 150 mg daily, given in divided doses.201 Daily dosage may be increased in 50-mg increments every 3 or 4 days based on patient’s response and tolerance.201

Prescribing Limits

Adults

Major Depressive Disorder
Outpatients
Oral

Maximum 400 mg daily.201

Hospitalized Patients
Oral

Maximum 600 mg daily.201

Cautions for Trazodone Hydrochloride

Contraindications

  • Known hypersensitivity to trazodone or any ingredient in the formulation.201

Warnings/Precautions

Warnings

Worsening of Depression and Suicidality Risk

Possible worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior in both adult and pediatric patients with major depressive disorder, whether or not they are taking antidepressants; may persist until clinically important remission occurs.212 213 218 a However, suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.212 213 218

Appropriately monitor and closely observe patients receiving trazodone for any reason, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.212 213 218 a (See Boxed Warning and also see Pediatric Use under Cautions.)

Anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania may be precursors to emerging suicidality.212 218 a Consider changing or discontinuing therapy in patients whose depression is persistently worse or in those with emerging suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if severe, abrupt in onset, or not part of patient’s presenting symptoms.212 213 218 a If decision is made to discontinue therapy, taper trazodone dosage as rapidly as is feasible but consider risks of abrupt discontinuance.212 a

Prescribe in smallest quantity consistent with good patient management to reduce risk of overdosage.212 a

Observe these precautions for patients with psychiatric (e.g., major depressive disorder, obsessive-compulsive disorder) or nonpsychiatric disorders.212 a

Bipolar Disorder

May unmask bipolar disorder.212 Trazodone is not approved for use in treating bipolar depression.a

Screen for risk of bipolar disorder by obtaining detailed psychiatric history (e.g., family history of suicide, bipolar disorder, depression) prior to initiating therapy.212

Priapism

Risk of developing priapism; may require surgical or pharmacologic (e.g., epinephrine) intervention and result in impotence or permanent impairment of erectile function.201

Perform pharmacologic or surgical interventions under the supervision of a urologist or a physician familiar with the procedure; procedures should not be initiated without a urologic consultation if priapism persists for >24 hours.a

Discontinue immediately if prolonged or inappropriate erections occur.201

Cardiovascular Effects

Possible cardiac arrhythmias (e.g., PVCs, VT); use with caution in patients with preexisting cardiovascular disease.201

Do not use during initial recovery phase of MI.201

Hypotension, including orthostatic hypotension and syncope, reported.201

Concomitant administration of antihypertensive therapy may require a reduction in dosage of the antihypertensive agent(s).201

General Precautions

Elective Surgery

Discontinue several days prior to surgery requiring general anesthesia whenever possible.201

CNS Effects

Drowsiness reported in up to 50% of patients.201

Performance of activities requiring mental alertness and physical coordination may be impaired.201

Electroconvulsive Therapy (ECT)

Effects of concomitant use with ECT have not been systematically evaluated; avoid concomitant use.201

Specific Populations

Pregnancy

Category C.201

Lactation

Not known whether trazodone is distributed into milk; caution advised.200 201

Pediatric Use

Safety and efficacy not established in children <18 years of age.201

FDA warns that a greater risk of suicidal thinking or behavior (suicidality) occurred during the first few months of antidepressant treatment compared with placebo in children and adolescents with major depressive disorder, obsessive-compulsive disorder (OCD), or other psychiatric disorders based on pooled analyses of 24 short-term, placebo-controlled trials of 9 antidepressant drugs (SSRIs and others).212 213 218 However, a more recent meta-analysis of 27 placebo-controlled trials of 9 antidepressants (SSRIs and others) in patients <19 years of age with major depressive disorder, OCD, or non-OCD anxiety disorders suggests that the benefits of antidepressant therapy in treating these conditions may outweigh the risks of suicidal behavior or suicidal ideation.223 No suicides occurred in these pediatric trials.212 213 223 a

Carefully consider these findings when assessing potential benefits and risks of trazodone in a child or adolescent for any clinical use.212 218 223 a (See Suicidality in the Boxed Warning and also see Worsening of Depression and Suicidality Risk under Cautions.)

Common Adverse Effects

Drowsiness, dry mouth, dizziness or lightheadedness, headache, blurred vision, nausea or vomiting.201

Interactions for Trazodone Hydrochloride

Metabolized by CYP3A4.210 211

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors or inducers of CYP3A4: Potential pharmacokinetic interaction (altered plasma trazodone concentrations).210 211

Specific Drugs

Drug

Interaction

Comments

Anesthetics, general

Experience limited201

Discontinue trazodone for as long as clinically feasible prior to elective surgeryb

Antifungals, azoles (e.g., itraconazole, ketoconazole)

Substantially increased plasma trazodone concentrations possible, with potential for adverse effects210 211

If used concomitantly, consider reduction in trazodone dosage210 211

Carbamazepine

Substantially decreased plasma concentrations of trazodone and active metabolite, m-chlorophenylpiperazine210 211

Closely monitor during concomitant use; increase trazodone dosage if necessary210 211

CNS depressants (e.g., alcohol, anesthetics, barbiturates, opiates or other analgesics, other sedatives)

Additive CNS depressant effects (e.g., sedation)201

Use with caution201

Digoxin

Increased serum digoxin concentrations201

Monitor for digoxin toxicity201

Fluoxetine

Increased plasma trazodone concentrations205 209

Potential for serotonin syndrome201

Observe for adverse effects; monitor trazodone concentrations; adjust dosages as needed204 207

Hypotensive agents

Potential additive hypotensive effects201

Adjust dosages as needed201

Indinavir

Substantially increased plasma trazodone concentrations possible, with potential for adverse effects210 211

If used concomitantly, consider reduction in trazodone dosage210 211

MAO inhibitors

Limited experience201

Initiate trazodone therapy cautiously if MAO inhibitors are discontinued shortly before or are to be given concomitantly with trazodone201

Nefazodone

Substantially increased plasma trazodone concentrations possible, with potential for adverse effects210 211

If used concomitantly, consider reduction in trazodone dosage210 211

Phenytoin

Increased serum phenytoin concentrationsa

Ritonavir

Increased peak plasma concentration, AUC, and half-life and decreased clearance of trazodone; increased incidence of adverse effects of trazodone also observed210 211

If used concomitantly, consider reduction in trazodone dosage210 211

Serotonergic agents (e.g., buspirone, dextropropoxyphene, phenelzine)

Potential for serotonin syndrome201

Cautionb

Warfarin

Increased or decreased PTa

Trazodone Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Rapidly and almost completely absorbed from the GI tract; b peak plasma concentration usually attained within 1–2 hours.201

Onset

Antidepressant effects evident within 1 week; optimal antidepressant effects usually attained after 2–4 weeks.201

Food

Food reduces peak plasma concentrations, delays time to peak plasma concentration, and increases extent of absorption.b

Distribution

Extent

Distribution into human body tissues and fluids not determined.b

Widely distributed; crosses the blood-brain barrier and the placenta in animals.b

Distributed into milk in rats; not known whether trazodone is distributed into milk in humans.201

Plasma Protein Binding

89–95%.b

Elimination

Metabolism

Extensively metabolized in the liver via hydroxylation, oxidation, N-oxidation, and splitting of the pyridine ring.b In vitro studies indicate metabolism by CYP3A4 to an active metabolite, m-chlorophenylpiperazine; other metabolic pathways not well characterized.210 211

Elimination Route

Excreted principally in urine (70–75%) as metabolites and in feces via biliary elimination.b

Half-life

5–9 hours.201

Stability

Storage

Oral

Tablets

Room temperature.201 Protect from temperatures >40°C.201

Actions

  • Mechanism of action as an antidepressant is presumed to be linked to potentiation of serotonergic activity in the CNS resulting from inhibition of reuptake of serotonin (5-HT) at the presynaptic neuronal membrane.b

  • Does not influence reuptake of dopamine or norepinephrine; does not inhibit MAO; does not stimulate the CNS; exhibits little anticholinergic activity.b

  • Produces varying degrees of sedation resulting from its central α1-adrenergic and/or histamine blocking activity.b

Advice to Patients

  • Importance of providing copy of written patient information (medication guide) each time trazodone is dispensed.212 213 218 a Importance of advising patients to read the patient information before taking trazodone.a

  • Risk of suicidality; importance of patients, caregivers, and families being alert to and immediately reporting emergence of suicidality, worsening depression, or unusual changes in behavior, especially during the first few months of therapy or during periods of dosage adjustment.212 213 218 (See Worsening of Depression and Suicidality Risk under Cautions.)

  • Importance of men discontinuing the drug and notifying clinician if prolonged or inappropriate penile erection occurs.201

  • Risks associated with concomitant use with alcohol, barbiturates, and other CNS depressants.201

  • Potential for drug to impair mental alertness or physical coordination; avoid driving or operating machinery until effects on individual are known.201

  • Importance of taking trazodone shortly after a meal or light snack to enhance absorption and to minimize risk of dizziness/lightheadedness.201

  • Importance of continuing trazodone therapy even if improvement is evident within 2 weeks, unless directed otherwise by their clinician.201

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.201

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs.201

  • Importance of informing patients of other important precautionary information.201 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

traZODone Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

150 mg*

Trazodone Hydrochloride Dividose (with povidone; scored)

Sandoz

300 mg*

Trazodone Hydrochloride Tablets

Barr

Tablets, film-coated

50 mg*

100 mg*

AHFS DI Essentials. © Copyright 2017, Selected Revisions March 27, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

200. Verbeeck RK, Ross SG, McKenna EA. Excretion of trazodone in breast milk. Br J Clin Pharmacol. 1986; 22:367-70. [PubMed 3768252]

201. Mead Johnson Pharmaceutical. Desyrel prescribing information. In: Huff BB, ed. Physicians’ desk reference. 40th ed. Oradell NJ: Medical Economics Company Inc; 1986:1123-4.

202. Gartrell N. Increased libido in women receiving trazodone. Am J Psychiatry. 1986; 143:781-2. [PubMed 3717405]

203. Jani NN, Wise TN, Kass E et al. Trazodone and anorgasmia. Am J Psychiatry. 1988; 145:896. [PubMed 3381940]

204. Vaughan DA. Interaction of fluoxetine with tricyclic antidepressants. Am J Psychiatry. 1988; 145:1478. [PubMed 3263809]

205. Aranow RB, Hudson JI, Pope HG Jr et al. Elevated antidepressant plasma levels after addition of fluoxetine. Am J Psychiatry. 1989; 146:911-3. [PubMed 2787124]

206. Downs JM, Downs AD, Rosenthal TL et al. Increased plasma tricyclic antidepressant concentrations in two patients concurrently treated with fluoxetine. J Clin Psychiatry. 1989; 50:226-7. [PubMed 2785987]

207. Tricyclic antidepressants/fluoxetine. In: Tatro DS, Olin BR, eds. Drug interaction facts. St. Louis: JB Lippincott Co; 1990 (Apr):743a.

208. Swerdlow NR, Andia AM. Trazodone-fluoxetine combination for treatment of obsessive-compulsive disorder. Am J Psychiatry. 1989; 146:1637. [PubMed 2589561]

209. Metz A, Shader RI. Adverse interactions encountered when using trazodone to treat insomnia associated with fluoxetine. Int Clin Psychopharmacol. 1990; 5:191-4. [PubMed 2230063]

210. Lewis-Hall FC. Dear healthcare professional: changes to labeling for Desyrel (trazodone hydrochloride) tablets. Princeton, NJ: Bristol-Myers Squibb Company; 2004. From the FDA website.

211. Bristol-Myers Squibb Company. Desyrel (trazodone) tablets prescribing information. Princeton, NJ; 2003 Sep

212. Food and Drug Administration. Antidepressant use in children, adolescents, and adults: class revisions to product labeling. Rockville, MD; 2007 May 2. From the FDA web site.

213. Food and Drug Administration. FDA news: FDA proposes new warnings about suicidal thinking, behavior in young adults who take antidepressant medications. Rockville, MD; 2007 May 2. From the FDA web site.

214. Anon. FDA statement on recommendations of the psychopharmacologic drugs and pediatric advisory committees. Rockville, MD; 2004 Sep 16. From the FDA website.

215. American Psychiatric Association (APA). APA responds to FDA’s new warning on antidepressants. Arlington, VA; 2004 Oct. 15. From the APA website.

216. American Academy of Child and Adolescent Psychiatry (AACAP). AACAP responds to the new FDA warnings on pediatric antidepressant medications. Washington, D.C; 2004 Oct 15. From the AACAP website.

217. American Academy of Pediatrics (AAP). Children, antidepressants and a black box warning. Washington, D.C; 2004 Oct. 15. From the AAP web site.

218. Food and Drug Administration. Revisions to medication guide: antidepressant medicines, depression and other serious mental illnesses and suicidal thoughts or actions. Rockville, MD; 2007 May 2. From the FDA web site.

219. Erectile Dysfunction Guideline Update Panel, American Urological Association Education and Research. Management of erectile dysfunction: An update. 2005. Available at AUA website. Accessed 2005 Oct. 20.

220. Fink HA, MacDonald R, Rutks IR et al. Trazodone for erectile dysfunction: a systematic review and meta-analysis. Br J Urol. 2003; 92:441-6.

221. Meinhardt W, Schmitz PI, Kropman RF et al. Trazodone, a double blind trial for treatment of erectile dysfunction. Int J Impot Res. 1997; 9:163-5. [PubMed 9315494]

222. Enzlin P, Vanderschueren D, Bonte L et al. Trazodone: a double-blind, placebo-controlled, randomized study of its effects in patients with erectile dysfunction without major organic findings. Int J Impot Res. 2000; 12:223-8. [PubMed 11079363]

223. Bridge JA, Iyengar S, Salary CB. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. JAMA. 2007; 297:1683-96. [PubMed 17440145]

a. Watson Laboratories, Inc. Trazodone hydrochloride tablets prescribing information. Corona, CA; 2007 Aug.

b. AHFS drug information 2001. McEvoy GK, ed. Trazodone hydrochloride. Bethesda, MD: American Society of Health-System Pharmacists; 2001:2209-13.

d. American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatr. 2002; 159(4 Suppl):1-50.

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