Trazodone Hydrochloride

Pronunciation

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

Warning(s)

Special Alerts:

[Posted 05/02/2007] FDA notified healthcare professionals that the Agency proposed that makers of all antidepressant medications update the existing black box warning on the prescribing information for their products to include warnings about the increased risks of suicidal thinking and behavior in young adults ages 18 to 24 years old during the first one to two months of treatment. The proposed labeling changes also state that scientific data did not show this increased risk in adults older than 24 years of age and that adults 65 years of age and older taking antidepressants have a decreased risk of suicidality. The proposed updates apply to the entire category of antidepressants. Individuals currently taking prescribed antidepressant medications should not stop taking them and should notify their healthcare professional if they have concerns. Manufacturers of antidepressant medications will have 30 days to submit their revised product labeling and revised Medication Guides to FDA for review. See the FDA press release for the list of products affected by the proposed antidepressant product labeling changes. For more information visit the FDA website at: , and .

REMS:

FDA approved a REMS for trazodone to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page () or the ASHP REMS Resource Center ().

Warning(s)

  • Suicidality in Children and Adolescents
  • Antidepressants may increase risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder and other psychiatric disorders (see Pediatric Use under Cautions); balance this risk with clinical need.212 Trazodone is not approved for use in pediatric patients.a

  • Closely monitor pediatric 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 (See Worsening of Depression and Suicidality Risk under Cautions.)

Introduction

Antidepressant; serotonin modulator.201 b

Uses for Trazodone Hydrochloride

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Major Depressive Disorder

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Slideshow: View Frightful (But Dead Serious) Drug Side Effects

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

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • Individualize dosages according to individual requirements and response.b

  • Monitor for possible worsening of depression or suicidality, especially at the beginning of therapy or during periods of dosage adjustments.212 (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

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Possible worsening of depression and/or emergence of suicidal ideation and behavior (suicidality) in both adult and pediatric patients; may persist until clinically important remission occurs with therapy.212 Closely supervise pediatric patients receiving trazodone for any reason and adult patients with major depressive disorder or other psychiatric illness with comorbid depression during initiation of therapy and during periods of dosage adjustments.212 (See Boxed Warning.)

If anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and/or mania occur, consider changing or discontinuing therapy, particularly if severe, abrupt in onset, or not part of patient’s presenting symptoms.212

Prescribe in smallest quantity consistent with good patient management to reduce risk of overdosage.201 212

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

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

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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

Greater risk of suicidal thinking or behavior (suicidality) occurred during first few months of antidepressant treatment (4%) compared with placebo (2%) in children and adolescents with major depressive disorder, obsessive-compulsive disorder, or other psychiatric disorders based on pooled analyses of short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and others).212 No suicides occurred in these trials.212 If considering use of trazodone in a child or adolescent, balance potential risks with clinical need.212 (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 concentrationsb

Monitor for phenytoin toxicitya

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

Monitor PT closely and adjust warfarin dosages as neededa

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

  • Risk of suicidality; importance of patient, family, or caregiver immediately reporting emergence of suicidality, worsening depression, or other manifestations associated with increased risk of worsening depression or suicidality.212 218 FDA recommends providing written patient information (medication guide) explaining risks in pediatric patients each time the drug is dispensed.212 213 218

  • 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.

* 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*

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Oleptro 150MG 24-hr Tablets (ANGELINI LABOPHARM): 30/$109.99 or 90/$299.98

TraZODone HCl 100MG Tablets (TEVA PHARMACEUTICALS USA): 30/$13.99 or 60/$18.98

TraZODone HCl 150MG Tablets (TEVA PHARMACEUTICALS USA): 30/$20.87 or 90/$62.61

TraZODone HCl 300MG Tablets (TEVA PHARMACEUTICALS USA): 100/$402.20 or 300/$1,206.61

TraZODone HCl 50MG Tablets (TEVA PHARMACEUTICALS USA): 30/$11.99 or 90/$33.98

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, 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. [IDIS 221469] [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. [IDIS 216844] [PubMed 3717405]

203. Jani NN, Wise TN, Kass E et al. Trazodone and anorgasmia. Am J Psychiatry. 1988; 145:896. [IDIS 243207] [PubMed 3381940]

204. Vaughan DA. Interaction of fluoxetine with tricyclic antidepressants. Am J Psychiatry. 1988; 145:1478. [IDIS 248155] [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. [IDIS 257880] [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. [IDIS 256111] [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. [IDIS 261543] [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. Class suicidality labeling language for antidepressants. From the FDA website.

213. Food and Drug Administration. Public health advisory: suicidality in children and adolescents being treated with antidepressant medications. Rockville, MD; 2004 Oct 15. From the FDA website.

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. Medication guide: about using antidepressants in children or teenagers. Rockville, MD; 2005 Jan 16. From the FDA website.

a. Mead Johnson Pharmaceutical. Desyrel (trazodone hydrochloride) prescribing information. Princeton, NJ; 1993 Oct.

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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