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TraZODone


General


Pronunciation

(TRAZ oh done)


Brand Names: U.S.

  • Oleptro [DSC]

Indications


Use: Labeled Indications

Treatment of major depressive disorder


Contraindications


Hypersensitivity to trazodone or any component of the formulation; use of MAO inhibitors intended to treat psychiatric disorders (concurrently or within 14 days of discontinuing either trazodone or the MAO inhibitor); initiation of trazodone in a patient receiving linezolid or intravenous methylene blue


ALERT: U.S. Boxed Warning

Suicidality and antidepressant drugs:

Antidepressants increase the risk, compared with 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 or any other antidepressant in a child, adolescent, or young adult must balance the risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared with placebo in adults older than 24 years of age; there was a reduction in risk with antidepressants compared with placebo in adults 65 years of age and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Appropriately monitor patients of all ages who are started on antidepressant therapy and observe them closely for clinical worsening, suicidality, or unusual changes in behavior. Advise families and caregivers of the need for close observation and communication with the prescriber. Trazodone is not approved for use in children.


Dosing and Administration


Dosing: Adult

Depression: Oral: Initial: 150 mg daily in divided doses (may increase by 50 mg daily every 3 to 4 days); maximum dose (manufacturer 's labeling): 600 mg daily (inpatients); 400 mg daily (outpatients). Note: Clinical practice guidelines recommend doses up to 600 mg daily without noted consideration to inpatient or outpatient status (APA 2010; Bauer 2013).

Extended release formulation: Initial: 150 mg once daily at bedtime (may increase by 75 mg daily every 3 days); maximum dose: 375 mg daily; once adequate response obtained, gradually reduce with adjustment based on therapeutic response

Note: Therapeutic effects may take up to 6 weeks. Therapy is normally maintained for 6 to 12 months after optimum response is reached to prevent recurrence of depression.

Insomnia (off-label use): 50 mg to 100 mg at bedtime (Mendelson 2005; Roth 2011). Doses up to 600 mg have been evaluated in patients with insomnia associated with depression (typical ranges of 50 to 300 mg); however, the quality of the evidence precludes definitive conclusions of efficacy (Mendelson 2005).

Discontinuation of therapy: Upon discontinuation of antidepressant therapy, gradually taper the dose to minimize the incidence of withdrawal symptoms and allow for the detection of re-emerging symptoms. Evidence supporting ideal taper rates is limited. APA and NICE guidelines suggest tapering therapy over at least several weeks with consideration to the half-life of the antidepressant; antidepressants with a shorter half-life may need to be tapered more conservatively. In addition for long-term treated patients, WFSBP guidelines recommend tapering over 4 to 6 months. If intolerable withdrawal symptoms occur following a dose reduction, consider resuming the previously prescribed dose and/or decrease dose at a more gradual rate (APA 2010; Bauer 2002; Haddad 2001; NCCMH 2010; Schatzberg 2006; Shelton 2001; Warner 2006).

MAO inhibitor recommendations:

Switching to or from an MAO inhibitor intended to treat psychiatric disorders:

Allow 14 days to elapse between discontinuing an MAO inhibitor intended to treat psychiatric disorders and initiation of trazodone.

Allow 14 days to elapse between discontinuing trazodone and initiation of an MAO inhibitor intended to treat psychiatric disorders.

Use with other MAO inhibitors (linezolid or IV methylene blue):

Do not initiate trazodone in patients receiving linezolid or IV methylene blue; consider other interventions for psychiatric condition.

If urgent treatment with linezolid or IV methylene blue is required in a patient already receiving trazodone and potential benefits outweigh potential risks, discontinue trazodone promptly and administer linezolid or IV methylene blue. Monitor for serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or IV methylene blue, whichever comes first. May resume trazodone 24 hours after the last dose of linezolid or IV methylene blue.


Dosing: Geriatric

Immediate release: Oral: 25 to 50 mg at bedtime with 25 to 50 mg daily dose increase every 3 days for inpatients and weekly for outpatients, if tolerated; usual dose: 75 to 150 mg daily

Extended release: Refer to adult dosing. Use with caution in the elderly; clinical experience is limited.

Discontinuation of therapy: Refer to adult dosing.

MAO inhibitor recommendations: Refer to adult dosing.


Dosing: Pediatric

Depression (off-label use):

Children 6 to 12 years: Initial: 1.5 to 2 mg/kg/day in divided doses; increase gradually every 3 to 4 days as needed; maximum: 6 mg/kg/day in 3 divided doses

Adolescents: Initial: 25 to 50 mg daily; increase to 100 to 150 mg daily in divided doses

Note: Once daily doses at bedtime may be considered to minimize adverse effects (Haria,1994; Rawls,1982).

Discontinuation of therapy: Refer to adult dosing.

MAO inhibitor recommendations: Refer to adult dosing.


Dosing: Renal Impairment

There are no dosage adjustments provided in manufacturer 's labeling (has not been studied). Use with caution.


Dosing: Hepatic Impairment

There are no dosage adjustments provided in manufacturer 's labeling (has not been studied). Use with caution.


Administration

Immediate release tablet: Dosing after meals may decrease lightheadedness and postural hypotension

Extended release tablet: Take on an empty stomach; swallow whole or as a half tablet without food. Tablet may be broken along the score line, but do not crush or chew.


Storage

Immediate release tablet: Store at room temperature; avoid temperatures >40 ‚ °C (>104 ‚ °F). Protect from light.

Extended release tablet: Store at room temperature of 15 ‚ ºC to 30 ‚ ºC (59 ‚ ºF to 86 ‚ ºF). Protect from light.


Dosage Forms/Strengths


Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, Oral, as hydrochloride:

Generic: 50 mg, 100 mg, 150 mg, 300 mg

Tablet Extended Release 24 Hour, Oral, as hydrochloride:

Oleptro: 150 mg [DSC], 300 mg [DSC] [scored]


Drug Interactions

Alcohol (Ethyl): May enhance the adverse/toxic effect of TraZODone. Specifically, effects on sleepiness, dizziness, and manual dexterity may be enhanced. Monitor therapy

Analgesics (Opioid): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Antipsychotic Agents: Serotonin Modulators may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Antipsychotic Agents (Phenothiazines): May enhance the adverse/toxic effect of Antidepressants (Serotonin Reuptake Inhibitor/Antagonist). Specifically, this may be manifest as symptoms consistent with serotonin syndrome or neuroleptic malignant syndrome. Antidepressants (Serotonin Reuptake Inhibitor/Antagonist) may enhance the hypotensive effect of Antipsychotic Agents (Phenothiazines). Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Atazanavir: May increase the serum concentration of TraZODone. Management: Consider using a lower dose of trazodone when used in combination with atazanavir. Consider therapy modification

Boceprevir: May increase the serum concentration of TraZODone. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

BusPIRone: May enhance the serotonergic effect of Antidepressants (Serotonin Reuptake Inhibitor/Antagonist). Management: The combination of a serotonin reuptake inhibitor,antagonist and buspirone should be undertaken with great caution. When combined treatment is clinically indicated, monitor closely for signs of serotonin toxicity/serotonin syndrome. Consider therapy modification

Clarithromycin: TraZODone may enhance the QTc-prolonging effect of Clarithromycin. Clarithromycin may increase the serum concentration of TraZODone. Management: Consider an alternative to this combination whenever possible. If combined, use a lower trazodone dose and monitor for increased effects of trazodone. Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dapoxetine: May enhance the adverse/toxic effect of Serotonin Modulators. Avoid combination

Darunavir: May increase the serum concentration of TraZODone. Management: Consider using a lower dose of trazodone when used in combination with darunavir. Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Fosamprenavir: May increase the serum concentration of TraZODone. Management: Consider using a lower dose of trazodone when used in combination with fosamprenavir. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fosphenytoin: May decrease the serum concentration of TraZODone. TraZODone may increase the serum concentration of Fosphenytoin. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Indinavir: May increase the serum concentration of TraZODone. Management: Consider using a lower dose of trazodone when used in combination with indinavir. Consider therapy modification

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Linezolid: May enhance the serotonergic effect of TraZODone. This could result in serotonin syndrome. Avoid combination

Lopinavir: May enhance the QTc-prolonging effect of TraZODone. Lopinavir may increase the serum concentration of TraZODone. Management: Avoid this combination when possible due to the potential for enhanced QT prolongation. If used, consider decreasing the trazodone dose and monitor closely for toxicity. Avoid combination

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

MAO Inhibitors: May enhance the adverse/toxic effect of Antidepressants (Serotonin Reuptake Inhibitor/Antagonist). While methylene blue and linezolid are expected to interact, specific recommendations for their use differ from other monoamine oxidase inhibitors. Refer to monographs specific to those agents for details. Exceptions: Linezolid; Methylene Blue; Tedizolid. Avoid combination

Metaxalone: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Methylene Blue: TraZODone may enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Avoid combination

Metoclopramide: Serotonin Modulators may enhance the adverse/toxic effect of Metoclopramide. This may be manifest as symptoms consistent with serotonin syndrome or neuroleptic malignant syndrome. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Nelfinavir: May increase the serum concentration of TraZODone. Management: Consider using a lower dose of trazodone when used in combination with nelfinavir. Consider therapy modification

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Osimertinib: May increase the serum concentration of CYP3A4 Substrates. Osimertinib may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Phenytoin: May decrease the serum concentration of TraZODone. TraZODone may increase the serum concentration of Phenytoin. Monitor therapy

Ritonavir: May increase the serum concentration of TraZODone. Management: Consider using a lower dose of trazodone when used in combination with ritonavir. Consider therapy modification

Saquinavir: May enhance the QTc-prolonging effect of TraZODone. Saquinavir may increase the serum concentration of TraZODone. Avoid combination

Selective Serotonin Reuptake Inhibitors: May enhance the serotonergic effect of Antidepressants (Serotonin Reuptake Inhibitor/Antagonist). This may cause serotonin syndrome. Management: Consider alternatives, and use conservative initial dosing. Monitor patients receiving these combinations for signs/symptoms of serotonin toxicity. Consider therapy modification

Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Exceptions: Nicergoline; Tedizolid. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

St Johns Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tedizolid: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Telaprevir: May increase the serum concentration of TraZODone. Monitor therapy

Tipranavir: May increase the serum concentration of TraZODone. Management: Consider using a lower dose of trazodone when used in combination with tipranavir. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

TraMADol: Serotonin Modulators may enhance the adverse/toxic effect of TraMADol. The risk of seizures may be increased. TraMADol may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy

Venlafaxine: May enhance the serotonergic effect of TraZODone. This could result in serotonin syndrome. Consider therapy modification

Warfarin: TraZODone may diminish the anticoagulant effect of Warfarin. Monitor therapy


Monitoring Parameters

Baseline liver function prior to and periodically during therapy; suicide ideation (especially at the beginning of therapy or when doses are increased or decreased); suicide ideation (especially at the beginning of therapy or when doses are increased or decreased); signs/symptoms of serotonin syndrome


Lab Test Interferences


Test Interactions

May interfere with urine detection of amphetamine/methamphetamine (false-positive).


Adverse Reactions


>10%:

Central nervous system: Sedation (46%), headache (33%), dizziness (25%), fatigue (15%)

Gastrointestinal: Xerostomia (25%), nausea (21%)

1% to 10%:

Cardiovascular: Edema ( ≥1%)

Central nervous system: Agitation ( ≥1%), ataxia ( ≥1%), confusion ( ≥1%), disorientation ( ≥1%), memory impairment ( ≥1%), migraine ( ≥1%)

Dermatologic: Night sweats ( ≥1%)

Endocrine & metabolic: Decreased libido (2%)

Gastrointestinal: Constipation (8%), abdominal pain ( ≥1%), dysgeusia ( ≥1%), vomiting ( ≥1%)

Genitourinary: Ejaculatory disorder (2%), urinary urgency ( ≥1%)

Neuromuscular & skeletal: Back pain (5%), myalgia ( ≥1%), tremor ( ≥1%)

Ophthalmic: Blurred vision (5%), visual disturbance ( ≥1%)

Respiratory: Dyspnea ( ≥1%)

<1% (Limited to important or life-threatening): Abnormal dreams, abnormal orgasm, acne, akathisia, allergic reactions, alopecia, amylase increased, anemia, angle-closure glaucoma, anxiety, aphasia, apnea, appetite increased, arrhythmia, ataxia, atrial fibrillation, bladder pain, bradycardia, breast enlargement/engorgement, cardiac arrest, cardiospasm, cerebrovascular accident, chest pain, CHF, chills, cholestasis, clitorism, conduction block, diplopia, dry eyes, early menses, erectile dysfunction, extrapyramidal symptoms, eye pain, flushing, gait disturbance, hallucination, hearing loss (partial), hematuria, hemolytic anemia, hepatitis, hirsutism, hyperbilirubinemia, hyperhidrosis, hypersalivation, hypersensitivity, hypoesthesia, hypomania, impaired speech, impotence, insomnia, jaundice, lactation, leukocytosis, leukonychia, libido increased, liver enzyme alteration, methemoglobinemia, MI, muscle twitching, orthostatic hypotension, palpitation, paranoia, photophobia, photosensitivity reaction, priapism, pruritus, psoriasis, psychosis, QT prolongation, rash, reflux esophagitis, retrograde ejaculation, salivation increased, seizure, SIADH, speech impairment, stupor, tachycardia, tardive dyskinesia, tinnitus, torsade de pointes, urinary frequency increased, urinary incontinence, urinary retention, urticaria, vasodilation, ventricular ectopy, ventricular tachycardia, vertigo, weakness


Warnings/Precautions


Major psychiatric warnings:

- Suicidal thinking/behavior: [U.S. Boxed Warning]: Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18 to 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 of age. Closely monitor patients for clinical worsening, suicidality, or unusual changes in behavior, particularly during the initial 1 to 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. 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 patients 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.

Concerns related to adverse effects:

- Bleeding risk: Drugs that interfere with serotonin reuptake (eg, SSRIs) have been associated with bleeding ranging from relatively minor bruising and epistaxis to life-threatening hemorrhage; similar to these agents, trazodone may also impair platelet aggregation resulting in increased risk of bleeding events, particularly if used concomitantly with aspirin, NSAIDs, warfarin or other anticoagulants.

- Fractures: Bone fractures have been associated with antidepressant treatment. Consider the possibility of a fragility fracture if an antidepressant-treated patient presents with unexplained bone pain, point tenderness, swelling, or bruising (Rabenda, 2013; Rizzoli, 2012).

- Ocular effects: May cause mild pupillary dilation which in susceptible individuals can lead to an episode of narrow-angle glaucoma. Consider evaluating patients who have not had an iridectomy for narrow-angle glaucoma risk factors.

- Orthostatic hypotension/syncope: May cause orthostatic hypotension and syncope (risk is high relative to other antidepressants); use with caution in patients at risk of these effects 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).

- Priapism: Painful erection >6 hours in duration; rare. Instruct patient to seek medical assistance for erection lasting >4 hours. Use with caution in patients who have conditions which may predispose them to priapism (eg, sickle cell anemia, multiple myeloma, leukemia).

- QT prolongation/proarrhythmia: Although the risk of conduction abnormalities is low relative to other antidepressants, QT prolongation (with or without torsade de pointes) and ventricular tachycardia has been observed with the use of trazodone (reports limited to immediate-release formulation); use with caution in patients with pre-existing cardiac disease. Other arrhythmias reported include isolated PVCs, ventricular couplets, and tachycardia with syncope. Concurrent use of CYP3A4 inhibitors may increase the risk of QT prolongation and/or proarrhythmia.

- 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.

- Serotonin syndrome: Potentially life-threatening serotonin syndrome (SS) has occurred with serotonergic agents (eg, SSRIs, SNRIs), particularly when used in combination with other serotonergic agents (eg, triptans, TCAs, fentanyl, lithium, tramadol, buspirone, St John 's wort, tryptophan) or agents that impair metabolism of serotonin (eg, MAO inhibitors intended to treat psychiatric disorders, other MAO inhibitors [ie, linezolid and intravenous methylene blue]). Monitor patients closely for signs of SS such as mental status changes (eg, agitation, hallucinations, delirium, coma); autonomic instability (eg, tachycardia, labile blood pressure, diaphoresis); neuromuscular changes (eg, tremor, rigidity, myoclonus); GI symptoms (eg, nausea, vomiting, diarrhea); and/or seizures. Discontinue treatment (and any concomitant serotonergic agent) immediately if signs/symptoms arise.

- SIADH and hyponatremia: Some antidepressant agents (eg, SSRIs) have been associated with the development of SIADH; hyponatremia has been reported (including severe cases with serum sodium <110 mmol/L), predominately in the elderly. Volume depletion and/or concurrent use of diuretics likely increases risk.

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.

- Mania/hypomania: 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.

- 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:

- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

- Elderly: Use with caution in the elderly.

Other warnings/precautions:

- Discontinuation syndrome: Abrupt discontinuation or interruption of antidepressant therapy has been associated with a discontinuation syndrome. Symptoms arising may vary with antidepressant however commonly include nausea, vomiting, diarrhea, headaches, lightheadedness, dizziness, diminished appetite, sweating, chills, tremors, paresthesias, fatigue, somnolence, and sleep disturbances (eg, vivid dreams, insomnia). Less common symptoms include electric shock-like sensations, cardiac arrhythmias (more common with tricyclic antidepressants), myalgias, parkinsonism, arthralgias, and balance difficulties. Psychological symptoms may also emerge such as agitation, anxiety, akathisia, panic attacks, irritability, aggressiveness, worsening of mood, dysphoria, mood lability, hyperactivity, mania/hypomania, depersonalization, decreased concentration, slowed thinking, confusion, and memory or concentration difficulties. Greater risks for developing a discontinuation syndrome have been associated with antidepressants with shorter half-lives, longer durations of treatment, and abrupt discontinuation. For antidepressants of short or intermediate half-lives, symptoms may emerge within 2 to 5 days after treatment discontinuation and last 7 to 14 days (APA, 2010; Fava, 2006; Haddad, 2001; Shelton, 2001; Warner, 2006).

- Electroconvulsive therapy: May increase the risks associated with electroconvulsive therapy; consider discontinuing, when possible, prior to ECT treatment.


Pregnancy Risk Factor

C


Pregnancy Considerations

Adverse effects were observed in some animal reproduction studies. When trazodone is taken during pregnancy, an increased risk of major malformations has not been observed in the limited number of pregnancies studied (Einarson 2003; Einarson 2009). The long-term effects of in utero trazodone exposure on infant development and behavior are not known.

The ACOG recommends that therapy with antidepressants during pregnancy be individualized; treatment of depression during pregnancy should incorporate the clinical expertise of the mental health clinician, obstetrician, primary health care provider, and pediatrician. According to the American Psychiatric Association (APA), the risks of medication treatment should be weighed against other treatment options and untreated depression. Consideration should be given to using agents with safety data in pregnancy. For women who discontinue antidepressant medications during pregnancy and who may be at high risk for postpartum depression, the medications can be restarted following delivery. Treatment algorithms have been developed by the ACOG and the APA for the management of depression in women prior to conception and during pregnancy (ACOG 2008; APA 2010; Yonkers 2009).

Pregnant women exposed to antidepressants during pregnancy are encouraged to enroll in the National Pregnancy Registry for Antidepressants (NPRAD). Women 18 to 45 years of age or their health care providers may contact the registry by calling 844-405-6185. Enrollment should be done as early in pregnancy as possible.


Actions


Pharmacology

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.


Absorption

Well absorbed; Extended release: Cmax increases ~86% when taken shortly after ingestion of a high-fat meal compared to fasting conditions


Metabolism

Hepatic via CYP3A4 (extensive) to an active metabolite (mCPP)


Excretion

Primarily urine (74%, <1% excreted unchanged); secondarily feces (~21%)


Onset of Action

Therapeutic (antidepressant): Up to 6 weeks; sleep aid: 1 to 3 hours


Time to Peak

Immediate release: 30 to 100 minutes; delayed with food (up to 2.5 hours)

Extended release: 9 hours; not significantly affected by food


Half-Life Elimination

5 to 9 hours, prolonged in obese patients


Protein Binding

85% to 95%


Patient and Family Education


Patient Education

- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

- Patient may experience fatigue, constipation, diarrhea, dry mouth, headache, or insomnia. Have patient report immediately to prescriber signs of depression (suicidal ideation, anxiety, emotional instability, illogical thinking), signs of low sodium (headache, trouble focusing, memory problems, illogical thinking, weakness, seizures, or change in balance), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that will not stop), vision changes, eye pain, eye irritation, severe dizziness, passing out, loss of strength and energy, loss of libido, sexual dysfunction, priapism, or signs of serotonin syndrome (dizziness, severe headache, agitation, hallucinations, tachycardia, arrhythmia, flushing, tremors, sweating a lot, change in balance, severe nausea, severe diarrhea) (HCAHPS).

- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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