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TraZODone

Medically reviewed by Drugs.com. Last updated on May 16, 2019.

Pronunciation

(TRAZ oh done)

Index Terms

  • Desyrel
  • Trazodone Hydrochloride

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]

Brand Names: U.S.

  • Oleptro [DSC]

Pharmacologic Category

  • Antidepressant, Serotonin Reuptake Inhibitor/Antagonist

Pharmacology

Inhibits reuptake of serotonin, causes adrenoreceptor subsensitivity, acts as a 5HT2a receptor antagonist and induces significant changes in 5-HT presynaptic receptor adrenoreceptors. Trazodone also significantly blocks histamine (H1) and alpha1-adrenergic receptors.

Absorption

Well absorbed. Food increases absorption, decreases peak concentration and delays time to peak concentration of immediate release tablet; 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 (APA 2010)

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

89% to 95%

Use: Labeled Indications

Major depressive disorder (unipolar): Treatment of unipolar major depressive disorder

Off Label Uses

Aggressive or agitated behavior associated with dementia

Data from a limited number of patients studied suggest that trazodone may be beneficial in decreasing symptom frequency and severity, as well as decreasing use of adjunctive medications, in patients with aggression or agitation associated with dementia [Lebert 2004], [Sultzer 1997].

Based on the American Psychiatric Association guidelines for the treatment of Alzheimer disease and other dementias, trazodone may be appropriate for nonpsychotic patients with agitation, particularly those with mild agitation or those who cannot take antipsychotics. Based on the World Federation of Societies of Biological Psychiatry guidelines, trazodone may be appropriate as a last-line option for hyperactive symptoms in dementia (eg, screaming, aggression).

Insomnia

Data from a meta-analysis of a limited number of controlled trials in patients with and without comorbid conditions (including Alzheimer disease, depression, and opioid dependence) suggest that trazodone may be beneficial in the short-term to decrease number of awakenings and improve sleep quality in patients with insomnia [Yi 2018].

The American Academy of Sleep Medicine guidelines for the treatment of chronic insomnia suggest trazodone not be used for sleep-onset or sleep-maintenance insomnia due to insufficient evidence.

Contraindications

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

Dosing: Adult

Note: Oleptro, the extended-release formulation, has been discontinued in the United States for more than 1 year.

Aggressive or agitated behavior associated with dementia (alternative agent) (off-label use): Based on limited data: Oral: Immediate release: Initial: 25 to 50 mg once daily at bedtime; may increase dose gradually based on response and tolerability up to 300 mg/day in 1 to 3 divided doses (APA [Rabins 2007]; Lebert 2004; Sultzer 1997). Some experts target doses in the lower end of the dosing range, rarely using doses as high as 100 to 150 mg/day (Press 2019; WFSBP [Ihl 2011]).

Insomnia (alternative agent) (off-label use): Oral: Immediate release: Usual dose: 50 mg to 100 mg at bedtime (Yi 2018). Note: Lower initial doses of 12.5 to 50 mg at bedtime may be considered (eg, in palliative care patients) (McCleery 2014; Tanimukai 2013). May consider increasing dose based on response and tolerability up to 200 mg at bedtime (eg, in patients with substance use disorder) (Friedmann 2008; Le Bon 2003). In patients with substance use disorder, trazodone may be preferred due to its low abuse potential (APA 2006).

Insomnia in patients with depression (as adjunct to other appropriate antidepressant treatment [eg SSRI]): Oral: Immediate release: Usual dose: 50 to 300 mg at bedtime. Doses up to 600 mg/day have been evaluated; however, evidence of greater benefit is uncertain and adverse effects may be increased (Mendelson 2005).

Major depressive disorder (unipolar) (alternative agent): Oral:

Immediate release: Initial: 50 mg twice daily; may increase in increments of 50 mg/day every 3 to 7 days to a target dose of 75 to 150 mg twice daily. Thereafter may further increase by 50 to 100 mg/day every 2 to 4 weeks based on response and tolerability; usual dosage range 200 to 400 mg/day; maximum 600 mg/day. Note: Adverse effects are increased with doses >400 mg/day and are not recommended in patients with cardiovascular disease; sedative effects may be better tolerated by dividing the daily dose to give a smaller dose in daytime and larger dose before bedtime (Hirsch 2018c).

Manufacturer’s labeling: Dosing in prescribing information may not reflect current clinical practice. Initial: 150 mg/day in divided doses; maximum dose: 600 mg/day (inpatients); 400 mg/day (outpatients).

Extended release: Initial: 150 mg once daily at bedtime; may increase by 75 mg/day at intervals no less than every 3 days based on response, tolerability, and severity of symptoms; maximum dose: 375 mg/day

Discontinuation of therapy: When discontinuing antidepressants, gradually taper the dose (eg, over 2 to 4 weeks) to minimize the incidence of withdrawal symptoms and allow for the detection of re-emerging symptoms (APA 2010; WFSBP [Bauer 2015]); antidepressants with a shorter half-life may need to be tapered more slowly (APA 2010) (eg, over 4 weeks [Hirsch 2018a]). If intolerable withdrawal symptoms occur following a dose reduction, resume the previously prescribed dose and/or decrease dose at a more gradual rate (Shelton 2001). Select patients (eg, those with a history of discontinuation syndrome) on long-term treatment (>6 months) may benefit from tapering over >3 months (WFSBP [Bauer 2015]). Evidence supporting ideal taper rates is limited (Shelton 2001; WFSBP [Bauer 2015]).

Switching antidepressants: Evidence for ideal antidepressant switching strategies is limited; strategies include cross-titration (gradually discontinuing the first antidepressant while at the same time gradually increasing the new antidepressant) and direct switch (abruptly discontinuing the first antidepressant and then starting the new antidepressant at an equivalent dose or lower dose and increasing it gradually). Cross-titration (eg, over 1 to 4 weeks depending upon sensitivity to discontinuation symptoms and adverse effects) is standard for most switches, but is contraindicated when switching to or from an MAOI. A direct switch may be an appropriate approach when switching to another agent in the same or similar class (eg, when switching between two SSRIs), when the antidepressant to be discontinued has been used for <1 week, or when the discontinuation is for adverse effects. When choosing the switch strategy, consider the risk of discontinuation symptoms, potential for drug interactions, other antidepressant properties (eg, half-life, adverse effects, and pharmacodynamics), and the degree of symptom control desired (Hirsch 2018b; Ogle 2013; WFSBP [Bauer 2013]).

Switching to or from an MAOI:

Allow 14 days to elapse between discontinuing an MAOI and initiation of trazodone.

Allow 14 days to elapse between discontinuing trazodone and initiation of an MAOI.

Dosing: Geriatric

Major depressive disorder (unipolar) (alternative agent):

Immediate release: Oral: Initial: 25 to 50 mg at bedtime; may increase in increments of 25 to 50 mg/day every 3 days for inpatients and weekly for outpatients, if tolerated; usual dose: 75 to 150 mg/day

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

Discontinuation of therapy: Refer to adult dosing.

Switching antidepressants: Refer to adult dosing.

Dosing: Pediatric

Insomnia; sleep disturbances (in children with comorbid psychiatric disorders): Limited data available; frequently used clinically in children with comorbid psychiatric disorders (eg, mood disorder, anxiety disorder, developmental delay with ADHD) (Owens 2010): Oral: Immediate release formulation:

Children 18 months to 5 years: Dosing based on a subset of a pediatric trial which included young children (n=16; range: 20 months to 5 years) with opsoclonus-myoclonus syndrome and used fixed doses (see below); however, the median overall dose (n=19) reported was 2.6 mg/kg/day (range: 1.2 to 6.9 mg/kg/day) (Pranzatelli 2005)

Children 18 months to <3 years: Initial: 25 mg/dose at bedtime; may increase dose at 2-week intervals in 25 mg increments; maximum dose: 100 mg/dose

Children 3 to 5 years: Initial 50 mg/dose at bedtime; may increase dose at 2-week intervals in 25 mg increments; maximum dose: 150 mg/dose

Children >5 years and Adolescents: Initial: 0.75 to 1 mg/kg/dose or 25 to 50 mg at bedtime; reported range: 0.5 to 2 mg/kg/day (do not to exceed adult dosing: 200 mg/day); reported trials conducted in pediatric patients with comorbid psychiatric disorders (eg, ADHD, autism, developmental delay), or sleep bruxism (Hollway 2011; Kratochvil 2005); when used for palliative care, multiple daily dosing may be necessary; 25 to 50 mg/dose increase gradually to twice or three times daily as needed (do not exceed adult dosing)

Migraine, prophylaxis: Limited data available: Efficacy results variable: Children and Adolescents ≥7 years: Oral: Immediate release formulation: 1 mg/kg/day in 3 divided doses; maximum dose: 150 mg/dose (Battistella 1993; Damen 2005; Lewis 2004)

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 reemerging 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.

Administration

Oral:

Immediate-release tablet: Administer shortly after a meal or light snack; swallow whole or as a half tablet by breaking along the score line.

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 20ºC to 25ºC (68ºF to 77ºF); excursions permitted between 15ºC to 30ºC (59ºF to 86ºF). Protect from light.

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

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

Alizapride: May enhance the CNS depressant effect of CNS Depressants. 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 Serotonin Reuptake Inhibitor/Antagonists. Specifically, this may be manifest as symptoms consistent with serotonin syndrome or neuroleptic malignant syndrome. Serotonin Reuptake Inhibitor/Antagonists may enhance the hypotensive effect of Antipsychotic Agents (Phenothiazines). Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Monitor therapy

Brexanolone: Serotonin Reuptake Inhibitor/Antagonists may enhance the CNS depressant effect of Brexanolone. Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

BusPIRone: May enhance the serotonergic effect of Serotonin Reuptake Inhibitor/Antagonists. 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

Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

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

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

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

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). 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 (High risk with Inhibitors). Monitor therapy

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

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). 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

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Consider therapy modification

Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). 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

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Esketamine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. 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 (High risk with Inhibitors). Monitor therapy

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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 (High risk with Inhibitors). Avoid combination

Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Monitor therapy

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Linezolid: May enhance the serotonergic effect of TraZODone. This could result in serotonin syndrome. Management: Consider alternatives to this combination whenever possible, and discontinue trazodone prior to administration of linezolid. Waiting at least 2 weeks after trazodone discontinuation to initiate linezolid should minimize the interaction risk. Consider therapy modification

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Monitor therapy

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

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

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

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

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

Methylphenidate: May enhance the adverse/toxic effect of Serotonin Modulators. Specifically, the risk of serotonin syndrome or serotonin toxicity may be increased. Monitor therapy

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

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mirtazapine: CNS Depressants may enhance the CNS depressant effect of Mirtazapine. Monitor therapy

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

Monoamine Oxidase Inhibitors: May enhance the adverse/toxic effect of Serotonin Reuptake Inhibitor/Antagonists. 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

Nabilone: May enhance the CNS depressant effect of CNS Depressants. 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 (High risk with Inhibitors). Monitor therapy

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

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

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Monitor therapy

Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Consider therapy modification

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. 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

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

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

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the serotonergic effect of Serotonin Reuptake Inhibitor/Antagonists. 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 (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). 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 (High risk with Inhibitors). 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

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

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

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Tetrahydrocannabinol and Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

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 (High risk with Inducers). Monitor therapy

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. 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

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Test Interactions

May interfere with urine detection of amphetamine/methamphetamine (false-positive) (Brahm 2010).

Adverse Reactions

>10%:

Central nervous system: Drowsiness (24% to 41%), dizziness (20% to 28%), headache (10% to 20%), nervousness (15%), fatigue (6% to 11%)

Gastrointestinal: Xerostomia (15% to 34%), nausea and vomiting (10% to 13%)

Ophthalmic: Blurred vision (6% to 15%)

1% to 10%:

Cardiovascular: Hypotension (4% to 7%), syncope (3% to 5%), palpitations (<2%), sinus bradycardia (<2%), tachycardia (<2%; may include syncope)

Central nervous system: Confusion (5%), ataxia (2% to 5%), heavy headedness (3%), malaise (3%), lack of concentration (1% to 3%), disorientation (2%), akathisia (<2%), chest pain (<2%), delusions (<2%), hallucination (<2%), hypomania (<2%), memory impairment (<2%), numbness (<2%), paresthesia (<2%), speech disturbance (<2%)

Endocrine & metabolic: Weight loss (6%), weight gain (1% to 5%), change in menstrual flow (<2%), increased libido (<2%)

Gastrointestinal: Constipation (7% to 8%), gastrointestinal disease (6%), diarrhea (5%), flatulence (<2%), increased appetite (<2%), sialorrhea (<2%)

Genitourinary: Early menses (<2%), hematuria (<2%), impotence (<2%), retrograde ejaculation (<2%), urinary frequency (<2%), urinary hesitancy (<2%)

Hematologic & oncologic: Anemia (<2%)

Hypersensitivity: Angioedema (3% to 7%), hypersensitivity reaction (<2%)

Neuromuscular & skeletal: Myalgia (5% to 6%), tremor (3% to 5%), muscle twitching (<2%)

Ophthalmic: Asthenopia (≤3%), eye pruritus (≤3%), eye redness (≤3%)

Respiratory: Nasal congestion (≤6%), paranasal sinus congestion (≤6%), dyspnea (<2%)

Frequency not defined:

Cardiovascular: Hypertension, ventricular premature contractions

Central nervous system: Suicidal ideation, suicidal tendencies

<1%, postmarketing, and/or case reports: Abnormal dreams, agitation, alopecia, anxiety, aphasia, apnea, asthenia, atrial fibrillation, bradycardia, breast engorgement, breast hypertrophy, cardiac arrhythmia, cardiac conduction disturbance, cardiac failure, cerebrovascular accident, chills, cholestasis, diplopia, edema, esophageal achalasia, extrapyramidal reaction, female sexual disorder (clitorism), hemolytic anemia, hirsutism, hyperbilirubinemia, increased amylase, insomnia, jaundice, lactation, leukocytosis, leukonychia, liver enzyme disorder, methemoglobinemia, myocardial infarction, orthostatic hypotension, paranoia, priapism, prolonged QT interval on ECG, pruritus, psoriasis, psychosis, SIADH, skin rash, stupor, tardive dyskinesia, tonic clonic epilepsy, torsades de pointes, urinary incontinence, urinary retention, urticaria, vasodilatation, ventricular ectopy, ventricular tachycardia, vertigo

ALERT: U.S. Boxed Warning

Suicidal thoughts and behaviors:

Antidepressants increase the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors. Trazodone is not approved for use in pediatric patients.

Warnings/Precautions

Major psychiatric warnings:

• Suicidal thinking/behavior: [US Boxed Warning]: Antidepressants increase the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies; 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 all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors, 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 health care provider. A medication guide concerning the use of antidepressants should be dispensed with each prescription. Trazodone is not FDA approved for use in pediatric patients.

• 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 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 health care 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.

• Cardiac arrhythmias: Although the risk of conduction abnormalities is low relative to other antidepressants, QT prolongation (with or without torsades de pointes) and ventricular tachycardia have been observed with the use of trazodone (reports limited to immediate-release formulation); use with caution in patients with preexisting cardiac disease (including previous MI, stroke, tachycardia, or conduction abnormalities). Other arrhythmias reported include isolated PVCs, ventricular couplets, and tachycardia with syncope. Concurrent use of CYP3A4 inhibitors may increase the risk of QT prolongation or other cardiac arrhythmia. Not recommended for use in a patient during the acute recovery phase of MI.

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).

• 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).

• 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:

• 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 (Hill 2015).

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.

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.

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); signs/symptoms of serotonin syndrome; signs/symptoms of hypotension or orthostasis

Pregnancy Considerations

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.

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, abdominal pain, nausea, vomiting, anxiety, tremors, loss of strength and energy, muscle pain, rhinorrhea, weight gain, or weight loss. Have patient report immediately to prescriber signs of depression (suicidal ideation, anxiety, emotional instability, confusion), signs of low sodium (headache, difficulty focusing, memory impairment, confusion, weakness, seizures, or change in balance), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), irritability, panic attacks, agitation, mood changes, severe headache, edema, tachycardia, abnormal heartbeat, confusion, vision changes, eye pain, eye redness, eye edema, severe dizziness, passing out, priapism, or signs of serotonin syndrome (dizziness, severe headache, agitation, hallucinations, tachycardia, abnormal heartbeat, 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 health care 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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