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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section and/or refer to product labeling for additional detail.
Medication Safety Issues
Sound-alike/look-alike issues:
Desyrel® may be confused with Demerol®, Delsym®, Zestril®
TraZODone may be confused with traMADol
International issues:
Desyrel® may be confused with Deseril® which is a brand name for methysergide in multiple international markets
Pronunciation
(TRAZ oh done)
Index Terms
Generic Available
Yes
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of depression
Use: Unlabeled/Investigational
Potential augmenting agent for antidepressants, hypnotic
Restrictions
An FDA-approved medication guide concerning the use of antidepressants in children, adolescents, and young adults must be distributed when dispensing an outpatient prescription (new or refill) where this medication is to be used without direct supervision of a healthcare provider. Medication guides are available at http://www.fda.gov/cder/Offices/ODS/medication_guides.htm. Dispense to parents or guardians of children and adolescents receiving this medication.
Pregnancy Risk Factor
C
Pregnancy Considerations
Trazodone is classified as pregnancy category C due to adverse effects observed in animal studies. When trazodone is taken during pregnancy, an increased risk of major malformations has not been observed in the small number of pregnancies studied. The long-term effects on neurobehavior have not been evaluated.Women treated for major depression and who are euthymic prior to pregnancy are more likely to experience a relapse when medication is discontinued as compared to pregnant women who continue taking antidepressant medications. Therapy during pregnancy should be individualized; treatment of depression during pregnancy should incorporate the clinical expertise of the mental health clinician, obstetrician, primary healthcare provider, and pediatrician. If treatment during pregnancy is required, consider tapering therapy during the third trimester to prevent potential withdrawal symptoms in the infant. If this is done and the woman is considered to be at risk of relapse from her major depressive disorder, the medication can be restarted following delivery.
Lactation
Enters breast milk/use caution (AAP rates “of concern”)
Breast-Feeding Considerations
Trazodone is excreted into breast milk; breast milk concentrations peak ~2 hours following administration. It is not known if the trazodone metabolite is found in breast milk. The long-term effects on neurobehavior have not been studied. The manufacturer recommends that caution be exercised when administering trazodone to nursing women. The AAP considers trazadone to be a “drug for which the effect on the nursing infant is unknown, but may be of concern."
Contraindications
Hypersensitivity to trazodone or any component of the formulation
Warnings/Precautions
Boxed warnings:
• Suicidal thinking/behavior: See “Major psychiatric warnings” below.
Major psychiatric warnings:
• [U.S. Boxed Warning]: Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18-24 years of age) with major depressive disorder (MDD) and other psychiatric disorders; consider risk prior to prescribing. Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ?65 years. Closely monitor patients for clinical worsening, suicidality, or unusual changes in behavior, particularly during the initial 1-2 months of therapy or during periods of dosage adjustments (increases or decreases); the patient's family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. A medication guide concerning the use of antidepressants should be dispensed with each prescription.Trazodone is not FDA approved for use in children.
• The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Patients treated with antidepressants should be observed for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy.
• Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their healthcare provider if any of these symptoms or worsening depression or psychosis occur.
• May worsen psychosis in some patients or precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Patients presenting with depressive symptoms should be screened for bipolar disorder. Trazodone is not FDA approved for the treatment of bipolar depression.
Concerns related to adverse effects:
• Orthostatic hypotension: May cause orthostatic hypotension (risk is high relative to other antidepressants); use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, hypovolemia, or concurrent medication use which may predispose to hypotension/bradycardia).
• Sedation: May cause sedation, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). The degree of sedation is very high relative to other antidepressants.
• Sexual dysfunction: Priapism, including cases resulting in permanent dysfunction, has occurred with the use of trazodone.
Disease-related concerns:
• Cardiovascular disease: Use with caution in patients with a history of cardiovascular disease (including previous MI, stroke, tachycardia, or conduction abnormalities); the risk conduction abnormalities with this agent is low relative to other antidepressants. Not recommended for use in a patient during the acute recovery phase of MI.
• Hepatic impairment: Use with caution in patients with hepatic impairment.
• Renal impairment: Use with caution in patients with renal impairment.
• Seizure disorder: Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications which may lower seizure threshold.
Concurrent drug therapy issues:
• MAO inhibitors: Trazodone should be initiated with caution in patients who are receiving concurrent or recent therapy with a MAO inhibitor.
• Sedatives: Effects may be potentiated when used with other sedative drugs or ethanol.
Special populations:
• Elderly: Use with caution in the elderly.
Other warnings/precautions:
• Discontinuation of therapy: Therapy should not be abruptly discontinued in patients receiving high doses for prolonged periods.
• Electroconvulsive therapy: May increase the risks associated with electroconvulsive therapy; consider discontinuing, when possible, prior to ECT treatment.
Adverse Reactions
>10%:
Central nervous system: Dizziness, headache, sedation
Gastrointestinal: Nausea, xerostomia
Ocular: Blurred vision
1% to 10%:
Cardiovascular: Syncope, hyper-/hypotension, edema
Central nervous system: Confusion, decreased concentration, fatigue, incoordination
Gastrointestinal: Diarrhea, constipation, weight gain/loss
Neuromuscular & skeletal: Tremor, myalgia
Respiratory: Nasal congestion
<1% (Limited to important and life-threatening): Agitation, allergic reactions, alopecia, anxiety, bradycardia, extrapyramidal symptoms, hepatitis, priapism, rash, seizure, speech impairment, tachycardia, urinary retention
Metabolism/Transport Effects
Substrate of CYP2D6 (minor), 3A4 (major); Inhibits CYP2D6 (moderate), 3A4 (weak)
Drug Interactions
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
BusPIRone: May enhance the serotonergic effect of Antidepressants (Serotonin Reuptake Inhibitor/Antagonist). This may cause serotonin syndrome. Risk C: Monitor therapy
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy
Codeine: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Risk C: Monitor therapy
CYP2D6 Substrates: CYP2D6 Inhibitors (Moderate) may decrease the metabolism of CYP2D6 Substrates. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Nebivolol: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Nebivolol. Risk C: Monitor therapy
Protease Inhibitors: May increase the serum concentration of Trazodone. Risk D: Consider therapy modification
Selective Serotonin Reuptake Inhibitors: May enhance the serotonergic effect of Antidepressants (Serotonin Reuptake Inhibitor/Antagonist). This may cause serotonin syndrome. Risk C: Monitor therapy
Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Risk D: Consider therapy modification
Sibutramine: May enhance the serotonergic effect of Serotonin Modulators. This may cause serotonin syndrome. Risk X: Avoid combination
Tramadol: CYP2D6 Inhibitors (Moderate) may diminish the therapeutic effect of Tramadol. These CYP2D6 inhibitors may prevent the metabolic conversion of tramadol to its active metabolite that accounts for much of its opioid-like effects. Risk C: Monitor therapy
Venlafaxine: May enhance the serotonergic effect of Trazodone. This could result in serotonin syndrome. Risk D: Consider therapy modification
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (may increase CNS depression).
Food: Time to peak serum levels may be increased if trazodone is taken with food.
Herb/Nutraceutical: Avoid valerian, St John's wort, SAMe, kava kava (may increase risk of serotonin syndrome and/or excessive sedation).
Mechanism of Action
Inhibits reuptake of serotonin, causes adrenoreceptor subsensitivity, and induces significant changes in 5-HT presynaptic receptor adrenoreceptors. Trazodone also significantly blocks histamine (H1) and alpha1-adrenergic receptors.
Pharmacodynamics/Kinetics
Onset of action: Therapeutic (antidepressant): 1-3 weeks; sleep aid: 1-3 hours
Protein binding: 85% to 95%
Metabolism: Hepatic via CYP3A4 to an active metabolite (mCPP)
Half-life elimination: 7-8 hours, two compartment kinetics
Time to peak, serum: 30-100 minutes; delayed with food (up to 2.5 hours)
Excretion: Primarily urine; secondarily feces
Dosage
Oral: Therapeutic effects may take up to 6 weeks to occur; therapy is normally maintained for 6-12 months after optimum response is reached to prevent recurrence of depression
Children 6-12 years: Depression (unlabeled use): Initial: 1.5-2 mg/kg/day in divided doses; increase gradually every 3-4 days as needed; maximum: 6 mg/kg/day in 3 divided doses
Adolescents: Depression (unlabeled use): Initial: 25-50 mg/day; increase to 100-150 mg/day in divided doses
Adults:
Depression: Initial: 150 mg/day in 3 divided doses (may increase by 50 mg/day every 3-7 days); maximum: 600 mg/day
Sedation/hypnotic (unlabeled use): 25-50 mg at bedtime (often in combination with daytime SSRIs); may increase up to 200 mg at bedtime
Elderly: 25-50 mg at bedtime with 25-50 mg/day dose increase every 3 days for inpatients and weekly for outpatients, if tolerated; usual dose: 75-150 mg/day
Administration: Oral
Dosing after meals may decrease lightheadedness and postural hypotension.
Monitoring Parameters
Suicidal ideation (especially at the beginning of therapy or when doses are increased or decreased)
Reference Range
Plasma levels do not always correlate with clinical effectiveness
Therapeutic: 0.5-2.5 mcg/mL
Potentially toxic: >2.5 mcg/mL
Toxic: >4 mcg/mL
Patient Education
Do not take any new medication during therapy unless approved by prescriber. Take exactly as directed; do not increase dose or frequency. It may take 2-4 weeks to achieve desired results. Take after meals. Avoid excessive alcohol and caffeine. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. You may experience drowsiness, lightheadedness, dizziness (use caution when driving or engaging in tasks requiring alertness until response to drug is known); postural hypotension (use caution when climbing stairs or changing position from lying or sitting to standing); nausea, dry mouth (small frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); constipation (increased exercise, fluids, fruit, or fiber may help); or diarrhea (buttermilk, yogurt, or boiled milk may help). Report persistent dizziness or headache; muscle cramping, tremors, or altered gait; blurred vision or eye pain; chest pain or irregular heartbeat; suicidal ideation; or worsening of condition. Report prolonged or inappropriate erections. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Do not breast-feed.
Geriatric Considerations
Very sedating, but little anticholinergic effects.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Significant xerostomia (normal salivary flow resumes upon discontinuation).
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
Trazodone inhibits reuptake of both serotonin and norepinephrine and also blocks some serotonin receptors. No precautions with vasoconstrictors appear to be necessary.
Nursing: Physical Assessment/Monitoring
Assess potential and monitor closely for interactions with other prescriptions, OTC medications, or herbal products patient may be taking. Assess results of laboratory tests, therapeutic effectiveness according to rationale for therapy, and adverse reactions at beginning of therapy and periodically with long-term use. Initiate at lower doses and taper dosage slowly when discontinuing (allow 3-4 weeks between discontinuing Desyrel® and starting another antidepressant). Teach patient appropriate use, side effects/appropriate interventions, and adverse symptoms to report.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, as hydrochloride: 50 mg, 100 mg, 150 mg, 300 mg
Pricing: U.S. (www.drugstore.com)
Tablets (Desyrel)
100 mg (30): $103.98
Tablets (Trazodone HCl)
50 mg (30): $11.99
100 mg (30): $13.99
150 mg (30): $20.87
References
“American Academy of Pediatrics Committee on Drugs. The Transfer of Drugs and Other Chemicals Into Human Milk,” Pediatrics, 2001, 108(3):776-89.
Battistella PA, Ruffilli R, Cernetti R, et al, “A Placebo-Controlled Crossover Trial Using Trazodone in Pediatric Migraine,” Headache, 1993, 33(1):36-9.
Bayer AJ, Pathy MSJ, and Ankier SI, “Pharmacokinetic and Pharmacodynamic Characteristics of Trazodone in the Elderly,” Br J Clin Pharmacol, 1983, 16:371-6.
Fishbain DA, “Priapism Associated With Trazodone Therapy,” J Urol, 1989, 142(3):831.
Gerson SC, Plotkin DA, and Jarvik LF, “Antidepressant Drug Studies, 1964-1986: Empirical Evidence for Aging Patients,” J Clin Psychopharmacol, 1988, 8(5):311-21.
Lejoyeux M, et al, “Serotonin Syndrome: Incidence, Symptoms, and Treatment,” CNS Drugs, 1994, 2:132-43.
Lesar T, Kingston R, Dahms R, et al, “Trazodone Overdose,” Ann Emerg Med, 1982, 12(4):221-3.
Mokhlesi B, Leikin JB, Murray P, et al, “Adult Toxicology in Critical Care: Part II: Specific Poisonings,” Chest, 2003, 123(3):897-922.
Pass SE and Simpson RW, “Discontinuation and Reinstitution of Medications During the Perioperative Period,” Am J Health Syst Pharm, 2004, 61(9):899-912.
Reeves RR and Bullen JA, “Serotonin Syndrome Produced by Paroxetine and Low-Dose Trazodone,” Psychosomatics, 1995, 36(2):159-60.
Zmitek A, “Trazodone-Induced Mania,” Br J Psychiatry, 1987, 151:274-5.
Zubieta JK and Alessi NE, “Acute and Chronic Administration of Trazodone in the Treatment of Disruptive Behavior Disorders in Children,” J Clin Psychopharmacol, 1992, 12(5):346-51.
International Brand Names
Lexi-Comp.com
Last full review/revision August 2008
Content last modified August 2008
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