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  • CLASSES

    Miscellaneous Antidepressants

    BOXED WARNING

    Children, suicidal ideation

    Safety and efficacy of trazodone for the treatment of depression have not been established in pediatric patients less than 18 years of age. A boxed warning in the product label describes the risk of suicidality and suicidal ideation in children, adolescent, and young adult patients receiving antidepressants. In a pooled analysis of placebo-controlled trials of antidepressants (n = 4,500 pediatrics and 77,000 adults), there was an increased risk for suicidal thoughts and behaviors in patients 24 years of age and younger receiving an antidepressant versus placebo, with considerable variation in the risk of suicidality among drugs. The difference in absolute risk of suicidal thoughts and behaviors across different indications was highest in those with major depression. The need for an antidepressant in children, adolescents, or young adults for any use must be weighed against the risk of suicidality; it is unknown if this risk extends to long-term use. All patients should be monitored for symptom worsening or suicidality, especially at treatment initiation or after dose changes. Caregivers and/or patients should immediately notify the prescriber of changes in behavior or suicidal ideation. A change to the treatment regimen or discontinuation of trazodone may be necessary in patients with emerging suicidality or worsening depression.

    DEA CLASS

    Rx

    DESCRIPTION

    Oral heterocyclic antidepressant with significant sedative actions; low incidence of cardiac side effect vs TCAs.

    COMMON BRAND NAMES

    Desyrel, Oleptro

    HOW SUPPLIED

    Desyrel/Trazodone/Trazodone Hydrochloride Oral Tab: 50mg, 100mg, 150mg, 300mg
    Oleptro Oral Tab ER: 150mg, 300mg

    DOSAGE & INDICATIONS

    For the treatment of major depression.
    Oral dosage (immediate release tablets)
    Adults

    Initially, 150 mg/day PO in divided doses, increase by 50 mg/day every 3 to 4 days as needed; however, slower titration schedules may be better tolerated. In general, elderly patients may require lower initial dosage and slower dose titration than younger adults. Maximum daily dosage is 400 mg/day PO for outpatients and 600 mg/day PO for inpatients. Maintenance therapy should be given at the lowest effective dosage.

    Adolescents†

    Data are limited; not considered a first-line agent for treatment of depression in this population. Initially, 25 mg PO once daily at bedtime, then may titrate every 3 to 4 days up to 100 to 150 mg/day, given in divided doses. Alternatively, weight-based dosing has been used: 1.5 to 2 mg/kg/day PO given in divided doses; if needed, gradually increase dose every 3 to 4 days. Max: 6 mg/kg/day PO, given in divided doses.

    Children† 6 to 12 years

    Data are limited; not considered a first-line agent for treatment of depression in this population. Weight-based dosing has been used: 1.5 to 2 mg/kg/day PO given in divided doses; if needed, gradually increase dose every 3 to 4 days. Max: 6 mg/kg/day PO, given in divided doses.

    Oral dosage (extended-release tablets)
    Adults

    Initially, 150 mg PO once daily on an empty stomach late in the evening, preferably at bedtime. Increase gradually by 75 mg/day PO every 3 days (i.e., may start 225 mg/day on Day 4 of therapy). Thereafter may adjust as tolerated and needed. Max: 375 mg/day PO. Once an adequate response has been achieved, dosage may be gradually reduced, with subsequent adjustment depending on therapeutic response.

    For the treatment of insomnia†.
    Oral dosage
    Adults

    25 mg to 150 mg PO at bedtime. Titration from a low initial dose (e.g., 25 to 50 mg) may increase tolerability. Guidelines suggest that there is insufficient or limited evidence for efficacy of trazodone for chronic insomnia. The American Academy of Sleep Medicine (AASM) guidelines recommend against trazodone for chronic insomnia based on a short-term controlled trial which evaluated 50 mg of trazodone and found no clinically significant improvement in sleep outcomes and significantly more side effects with trazodone (e.g., headache, daytime somnolence) than placebo; other studies were considered inadequate for assessment. The British Association for Psychopharmacology guidelines state that antidepressants may be considered for insomnia when there is a co-existing mood disorder and therapeutic doses are used. Findings from one large systematic review suggest there may be a small improvement in sleep quality during short-term use of low dose trazodone; however, further studies are needed to determine long-term safety and efficacy.[52062] [58830] [58831] [58836] [60017] [62207] [64074] [64075]

    For the maintenance treatment of alcohol dependence†.
    Oral dosage
    Adults

    50 to 100 mg PO once daily has been shown to decrease cravings for alcohol, depression and anxious symptoms in patients with alcohol dependence. Pharmacotherapy should be used as a part of a comprehensive management program that includes psychosocial support and treatment.

    For the treatment of panic disorder† or agoraphobia†.
    Oral dosage
    Adults

    Initially, 150 mg/day PO in divided doses, increase by 50 mg/day every 3 to 4 days as tolerated and needed. Trazodone 300 mg/day PO in divided doses has decreased symptoms of panic, phobia and anxiety in a small number of patients with panic disorder or agoraphobia. In comparison to imipramine and alprazolam, trazodone was not as effective in the treatment of panic attacks.

    For the treatment of generalized anxiety disorder (GAD)†.
    Oral dosage (immediate release tablets):
    Adults

    Initially, 150 mg/day PO in divided doses, increase by 50 mg/day every 3 to 4 days as needed; however, slower titration schedules may be better tolerated. In one study, the mean maximum daily effective dose was 255 mg/day. In general, elderly patients may require lower initial dosage and slower dose titration than younger adults. Max: 400 mg/day PO for outpatients or 600 mg/day PO for inpatients. Maintenance therapy should be given at the lowest effective dosage.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    For the immediate release tablets, 400 mg/day PO for outpatients and 600 mg/day PO for inpatients; for the extended-release tablets, 375 mg/day PO.

    Geriatric

    For the immediate release tablets, 400 mg/day PO for outpatients and 600 mg/day PO for inpatients; for the extended-release tablets, 375 mg/day PO.

    Adolescents

    Safety and efficacy have not been established; in clinical trials, doses off-label have not exceeded 150 mg/day PO.

    Children

    6 to 12 years: Safety and efficacy have not been established; off-label some references use a max of 6 mg/kg/day PO; in clinical trials, doses off-label have not exceeded 150 mg/day PO in adolescent patients.
    Less than 6 years: Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Patients with hepatic dysfunction may require dosage adjustment of trazodone based upon the severity of hepatic impairment as trazodone is extensively metabolized, however, no quantitative guidelines are available. Titrate according to patient response and tolerance; the manufacturer recommends caution since specific studies in hepatic dysfunction are not available.

    Renal Impairment

    CrCl 50 mL/minute: No dosage adjustment needed.
    CrCl less than 50 mL/minute: Specific guidelines are not available; no dosage adjustments are expected to be needed in initial dosage since less than 1% of a dose appears in the urine unchanged. Titrate according to patient response and tolerance; the manufacturer recommends caution since specific studies in renal dysfunction are not available.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Regular-release tablets:
    Administer shortly after a meal or light snack to decrease nausea. A fasting state may increase the incidence of lightheadedness or dizziness.
    If drowsiness occurs, a large portion of the dose may be administered at bedtime.
     
    Extended-release tablets:
    Administer orally at the same time every day in the late evening, preferably at bedtime, on an empty stomach.
    Do not crush or chew; swallow whole. Tablets may be broken in half along the score line.

    STORAGE

    Desyrel:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Oleptro:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Children, suicidal ideation

    Safety and efficacy of trazodone for the treatment of depression have not been established in pediatric patients less than 18 years of age. A boxed warning in the product label describes the risk of suicidality and suicidal ideation in children, adolescent, and young adult patients receiving antidepressants. In a pooled analysis of placebo-controlled trials of antidepressants (n = 4,500 pediatrics and 77,000 adults), there was an increased risk for suicidal thoughts and behaviors in patients 24 years of age and younger receiving an antidepressant versus placebo, with considerable variation in the risk of suicidality among drugs. The difference in absolute risk of suicidal thoughts and behaviors across different indications was highest in those with major depression. The need for an antidepressant in children, adolescents, or young adults for any use must be weighed against the risk of suicidality; it is unknown if this risk extends to long-term use. All patients should be monitored for symptom worsening or suicidality, especially at treatment initiation or after dose changes. Caregivers and/or patients should immediately notify the prescriber of changes in behavior or suicidal ideation. A change to the treatment regimen or discontinuation of trazodone may be necessary in patients with emerging suicidality or worsening depression.

    Bipolar disorder, mania

    All effective antidepressants can transform depression into mania or hypomania in predisposed individuals. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. If a patient develops manic symptoms, trazodone should be withheld and appropriate therapy initiated to treat the manic symptoms. Additionally, depression may be the presenting symptom of a mixed/manic episode of bipolar disorder. Patients should be adequately screened for bipolar disorder prior to initiating an antidepressant. Such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Patients with depression or comorbid depression in the setting of other psychiatric illness being 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. Caregivers should be advised to closely observe the patient on a daily basis and to communicate immediately with the prescriber the emergence of agitation, irritability, unusual changes in behavior, or suicidality. It should be noted that trazodone is not approved for use in treating bipolar depression.

    MAOI therapy

    Due to the risk for serotonin syndrome, it is recommended that trazodone not be used in combination with monoamine oxidase inhibitor therapy (MAOI therapy) or within 14 days of discontinuing treatment with an MAOI. Similarly, at least 14 days should be allowed after stopping trazodone before starting an MAOI. In addition to a risk for serotonin syndrome, limited animal data on the effects of combined use of serotonergic antidepressants and MAOIs suggest that these drugs may act synergistically to elevate blood pressure and evoke behavioral excitation. The development of a potentially life-threatening serotonin syndrome has been reported with antidepressants alone and may occur with trazodone treatment, but particularly with concomitant use of other serotoninergic drugs (e.g., SSRIs, SNRIs and triptans) and with drugs that impair metabolism of serotonin (including MAOIs, linezolid, or intravenous methylene blue), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Treatment with trazodone and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above reactions occur and supportive symptomatic treatment should be initiated. If concomitant treatment with trazodone and an SSRI, SNRI or a serotonin receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of trazodone with serotonin precursors (such as tryptophan) is not recommended.

    Acute myocardial infarction, alcoholism, bradycardia, cardiac arrhythmias, cardiac disease, coronary artery disease, dehydration, diabetes mellitus, females, heart failure, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, hypotension, hypovolemia, long QT syndrome, malnutrition, myocardial infarction, orthostatic hypotension, QT prolongation, syncope, thyroid disease

    Orthostatic hypotension and syncope can occur during treatment with trazodone; therefore, caution is advisable in patients with pre-existing hypotension. Conditions that may predispose patients to hypotension, such as hypovolemia and dehydration, should be corrected if possible before starting trazodone therapy. Lower doses may be required in patients at increased risk for hypotension or in patients taking antihypertensive agents. Trazodone is not recommended for use during the initial recovery phase following an acute myocardial infarction, and should be used cautiously in patients with cardiac disease. Trazodone can prolong the QT/QTc interval. There are postmarketing reports of isolated PVCs, ventricular couplets, and tachycardia with syncope. Torsade de pointes, a life-threatening arrhythmia, has also been reported. Some of these events have occurred at doses of 100 mg/day or less. Therefore, trazodone should be avoided in patients with risk factors for QT prolongation and in those receiving other drugs that increase the QT interval or that inhibit CYP3A4. Use trazodone with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, congenital long QT syndrome, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, elderly patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic dysfunction may also be at increased risk for QT prolongation.

    Coadministration with other CNS depressants, driving or operating machinery, ethanol ingestion

    Trazodone somnolence or sedation and may impair the mental and/or physical ability required for the performance of potentially hazardous tasks. Patients should be warned to use caution when driving or operating machinery until they know how trazodone will affect them. Trazodone may enhance the response to alcohol, barbiturates, and other CNS depressants; use with caution during coadministration with other CNS depressants. Ethanol ingestion should be limited or avoided.

    Hepatic disease

    Trazodone should be used with caution in patients with hepatic disease; trazodone has not been studied in patients with hepatic impairment. The drug is extensively metabolized in the liver.

    Renal failure, renal impairment

    Trazodone should be used with caution in patients with renal impairment. While less than 1% of an oral dose is excreted unchanged in the urine; trazodone's active metabolite and other metabolites are excreted primarily in the urine. Trazodone has not been studied in patients with renal impairment or renal failure.

    Hyponatremia

    Antidepressants may cause hyponatremia, which is frequently the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In some cases, serum sodium levels less than 110 mmol/L have been reported; however, the adverse effect appeared reversible upon discontinuation of the causative agent. Geriatric patients, those receiving diuretics or prone to dehydration, and those who are otherwise volume depleted (e.g., hypovolemia) appear to be at greatest risk. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of trazodone, as well as implementation of the appropriate medical interventions.

    Closed-angle glaucoma, increased intraocular pressure

    Caution is recommended when prescribing trazodone to patients with closed-angle glaucoma. The pupillary dilation that can occur with antidepressants may precipitate a closed-angle glaucoma attack in patients with anatomically narrow angles who do not have a patent iridectomy. An acute attack of closed-angle glaucoma is considered a medical emergency because the increased intraocular pressure is rapid and severe, and may quickly result in blindness if left untreated.

    Anticoagulant therapy, bleeding, thrombolytic therapy

    Monitor patients for signs and symptoms of bleeding. Postmarketing data have shown an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal (GI) bleeding. While no association between trazodone and bleeding events, in particular GI bleeding, was shown, platelet aggregation may be impaired by drugs that inhibit serotonin reuptake due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage). Concurrent use of aspirin, non-steroidal antiinflammatory drugs (NSAIDs), anticoagulant therapy, thrombolytic therapy, or other medications that enhance bleeding potential may increase this risk. Patients taking trazodone should be should be instructed to promptly report any bleeding events to the practitioner.

    Priapism

    Rare cases of priapism (painful erections greater than 6 hours in duration) were reported in men receiving trazodone. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Men who have an erection lasting greater than 6 hours, whether painful or not, should immediately discontinue the drug and seek emergency medical attention.

    Electroconvulsive therapy (ECT)

    There is limited experience with trazodone and electroconvulsive therapy (ECT). It is recommended to avoid concurrent use of these therapies.

    Abrupt discontinuation

    Abrupt discontinuation of trazodone should be avoided if possible. Withdrawal symptoms including anxiety, agitation and sleep disturbances, have been reported with trazodone. Clinical experience suggests that the dose should be gradually reduced before completely discontinuing the drug.

    Geriatric

    In general, clinical experience with trazodone has not identified differences in response to the drug in elderly vs. younger adult patients, but data are limited. Geriatric patients generally require a lower dosage of trazodone and are more susceptible to adverse reactions, such as sedation, orthostastic hypotension, or hyponatremia due to SIADH. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of antidepressants in residents of long-term care facilities (LTCFs). According to OBRA, the duration of therapy should be in accordance with pertinent literature for the condition being treated, including clinical practice guidelines. All residents being treated for depression with any antidepressant should be monitored closely for worsening of depression and/or suicidal behavior or thinking, especially during initiation of therapy and during dose changes. Antidepressants may cause dizziness, nausea, diarrhea, anxiety, nervousness, insomnia, somnolence, weight gain, anorexia, or increased appetite. Many of these effects can increase the risk for falls. Concurrent use of 2 or more antidepressants may increase the risk of side effects; in such cases there should be documentation of expected benefits that outweigh the associated risks and monitoring for any increase in side effects. Monitoring should consist of a review for continued need at least quarterly, and documentation of the rationale for continuation. When the drug is being used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt to taper the medication as outlined in the OBRA guidelines, unless a taper is clinically contraindicated. OBRA also regulates the use of sedative/hypnotics in residents of LTCFs. The OBRA guidelines provide criteria for use and tapering requirements for sedating antidepressants used as sedative/hypnotics, including trazodone.

    Pregnancy

    Although available studies cannot definitively establish the absence of risk, published prospective cohort studies, case series, and case reports over several decades with trazodone use in pregnant women have not identified any drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes. It should be noted that all available studies have methodological limitations, including small sample sizes and inconsistent comparator groups. A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. The women who discontinued antidepressants during pregnancy were more likey to experience a relapse of major depression than those who continued antidepressants. Consider the risk of untreated depression versus the potential for adverse fetal outcomes when discontinuing or changing treatment with trazodone during pregnancy and postpartum. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry.

    Breast-feeding

    The developmental and health benefits of breast-feeding should be considered along with the clinical need of the mother for trazodone and any potential adverse effects on the breastfed infant from trazodone or from the underlying maternal condition. Trazodone is excreted into breast milk; however, limited data from postmarketing reports have not identified trazodone-associated adverse effects on the breastfed child. There are no data regarding the effect of trazodone on milk production. Patients should advise their physician of their intention to breast-feed. Alternative therapy may be considered. A pooled analysis found that maternal use of sertraline, along with nortriptyline and paroxetine, usually produced undetectable or low drug concentrations in infant serum and, therefore, may be the preferred antidepressants in breast-feeding mothers.

    ADVERSE REACTIONS

    Severe

    ventricular tachycardia / Early / 0-7.0
    hearing loss / Delayed / 0-1.0
    visual impairment / Early / 1.0
    suicidal ideation / Delayed / Incidence not known
    cardiac arrest / Early / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    heart failure / Delayed / Incidence not known
    torsade de pointes / Rapid / Incidence not known
    bradycardia / Rapid / Incidence not known
    atrial fibrillation / Early / Incidence not known
    arrhythmia exacerbation / Early / Incidence not known
    tardive dyskinesia / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    respiratory arrest / Rapid / Incidence not known
    serotonin syndrome / Delayed / Incidence not known
    SIADH / Delayed / Incidence not known
    methemoglobinemia / Early / Incidence not known
    hemolytic anemia / Delayed / Incidence not known
    apnea / Delayed / Incidence not known

    Moderate

    blurred vision / Early / 5.0-14.7
    constipation / Delayed / 7.0-8.0
    hypotension / Rapid / 3.8-7.0
    palpitations / Early / 0-7.0
    confusion / Early / 1.0-5.7
    excitability / Early / 1.4-5.1
    hostility / Early / 1.3-3.5
    hypertension / Early / 1.3-2.1
    ejaculation dysfunction / Delayed / 1.5-1.5
    memory impairment / Delayed / 0-1.4
    impotence (erectile dysfunction) / Delayed / 0-1.0
    aphasia / Delayed / 0-1.0
    amnesia / Delayed / 0-1.0
    photophobia / Early / 0-1.0
    urinary incontinence / Early / 0-1.0
    edema / Delayed / 1.0
    dyspnea / Early / 1.0
    migraine / Early / 1.0
    mania / Early / Incidence not known
    akathisia / Delayed / Incidence not known
    priapism / Early / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    orthostatic hypotension / Delayed / Incidence not known
    premature ventricular contractions (PVCs) / Early / Incidence not known
    QT prolongation / Rapid / Incidence not known
    impaired cognition / Early / Incidence not known
    psychosis / Early / Incidence not known
    hallucinations / Early / Incidence not known
    ataxia / Delayed / Incidence not known
    psoriasis / Delayed / Incidence not known
    hyponatremia / Delayed / Incidence not known
    hematuria / Delayed / Incidence not known
    urinary retention / Early / Incidence not known
    jaundice / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    anemia / Delayed / Incidence not known

    Mild

    drowsiness / Early / 23.9-46.0
    xerostomia / Early / 14.8-33.8
    headache / Early / 9.9-33.0
    dizziness / Early / 19.7-28.0
    nausea / Early / 9.9-21.0
    fatigue / Early / 5.7-15.0
    vomiting / Early / 1.0-12.7
    insomnia / Early / 6.4-9.9
    diarrhea / Early / 0-9.0
    nasal congestion / Early / 2.8-5.7
    weight loss / Delayed / 0-5.7
    musculoskeletal pain / Early / 5.1-5.6
    nightmares / Early / 0-5.1
    tremor / Early / 0-5.1
    back pain / Delayed / 5.0-5.0
    syncope / Early / 2.8-4.5
    weight gain / Delayed / 1.4-4.5
    anorexia / Delayed / 3.5-3.5
    malaise / Early / 2.8-2.8
    libido decrease / Delayed / 1.3-1.5
    paresthesias / Delayed / 1.4-1.4
    tinnitus / Delayed / 0-1.4
    orgasm dysfunction / Delayed / 0-1.0
    hypoesthesia / Delayed / 0-1.0
    gastroesophageal reflux / Delayed / 0-1.0
    xerophthalmia / Early / 0-1.0
    ocular pain / Early / 0-1.0
    photosensitivity / Delayed / 0-1.0
    acne vulgaris / Delayed / 0-1.0
    hyperhidrosis / Delayed / 0-1.0
    vertigo / Early / 0-1.0
    bladder discomfort / Early / 0-1.0
    agitation / Early / 1.0
    myalgia / Early / 1.0
    abdominal pain / Early / 1.0
    dysgeusia / Early / 1.0
    night sweats / Early / 1.0
    urinary urgency / Early / 1.0
    anxiety / Delayed / Incidence not known
    restlessness / Early / Incidence not known
    irritability / Delayed / Incidence not known
    libido increase / Delayed / Incidence not known
    paranoia / Early / Incidence not known
    diplopia / Early / Incidence not known
    chills / Rapid / Incidence not known
    weakness / Early / Incidence not known
    flatulence / Early / Incidence not known
    flushing / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known
    rash / Early / Incidence not known
    pruritus / Rapid / Incidence not known
    alopecia / Delayed / Incidence not known
    hirsutism / Delayed / Incidence not known
    increased urinary frequency / Early / Incidence not known
    leukocytosis / Delayed / Incidence not known
    appetite stimulation / Delayed / Incidence not known
    menstrual irregularity / Delayed / Incidence not known
    breast enlargement / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abciximab: (Moderate) Platelet aggregation may be impaired by trazodone due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking trazodone concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) The combined use of trazodone and salicylates that affect hemostasis may elevate the risk for an upper GI bleed. Trazodone may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of salicylates. Additionally, salicylates impair the gastric mucosa defenses by inhibiting prostaglandin formation. It would be prudent for clinicians to monitor the patient's clinical status closely if trazodone is added to or removed from the regimen of a patient stabilized on salicylate therapy.
    Acetaminophen; Butalbital: (Major) Monitor for excessive sedation and somnolence during coadministration of trazodone and butalbital. Concurrent use may result in additive CNS depression.
    Acetaminophen; Butalbital; Caffeine: (Major) Monitor for excessive sedation and somnolence during coadministration of trazodone and butalbital. Concurrent use may result in additive CNS depression.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Avoid prescribing opioid cough medications in patients taking trazodone. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Major) Monitor for excessive sedation and somnolence during coadministration of trazodone and butalbital. Concurrent use may result in additive CNS depression.
    Acetaminophen; Caffeine; Dihydrocodeine: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Avoid prescribing opioid cough medications in patients taking trazodone. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. (Moderate) The combined use of trazodone and salicylates that affect hemostasis may elevate the risk for an upper GI bleed. Trazodone may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of salicylates. Additionally, salicylates impair the gastric mucosa defenses by inhibiting prostaglandin formation. It would be prudent for clinicians to monitor the patient's clinical status closely if trazodone is added to or removed from the regimen of a patient stabilized on salicylate therapy.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. (Moderate) The combined use of trazodone and salicylates that affect hemostasis may elevate the risk for an upper GI bleed. Trazodone may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of salicylates. Additionally, salicylates impair the gastric mucosa defenses by inhibiting prostaglandin formation. It would be prudent for clinicians to monitor the patient's clinical status closely if trazodone is added to or removed from the regimen of a patient stabilized on salicylate therapy.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Acetaminophen; Codeine: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Avoid prescribing opioid cough medications in patients taking trazodone. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Acetaminophen; Diphenhydramine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. A dose reduction of one or both drugs may be warranted.
    Acetaminophen; Hydrocodone: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Avoid prescribing opioid cough medications in patients taking trazodone. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Acetaminophen; Oxycodone: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Acetaminophen; Pentazocine: (Moderate) Concomitant use of pentazocine with other CNS depressants such as trazodone can potentiate respiratory depression and/or sedation. The central nervous system (CNS) effects of pentazocine and other CNS depressants are additive. Trazodone has significant potential for sedation. In addition, both agents may increase serotonin activity, which may increase the risk for serotonin-related side effects and in rare cases lead to serotonin syndrome.
    Acetaminophen; Propoxyphene: (Moderate) Concomitant use of propoxyphene with other CNS depressants such as trazodone can potentiate respiratory depression and/or sedation. The central nervous system (CNS) effects of propoxyphene and other CNS depressants are additive. Trazodone has significant potential for sedation. In addition, both agents may increase serotonin activity, which may increase the risk for serotonin-related side effects and in rare cases lead to serotonin syndrome.
    Acetaminophen; Tramadol: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Acetazolamide: (Moderate) Trazodone can lower the seizure threshold of anticonvulsants, although the overall risk is low at therapeutic doses. Patients may require increased concentrations of anticonvulsants to achieve equivalent effects if trazodone is added.
    Acrivastine; Pseudoephedrine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Alfentanil: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Alfuzosin: (Major) Trazodone should be avoided in combination with alfuzosin. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Based on electrophysiology studies performed by the manufacturer, alfuzosin has a slight effect to prolong the QT interval. The QT prolongation appeared less with alfuzosin 10 mg than with 40 mg. The manufacturer warns that the QT effect of alfuzosin should be considered prior to administering the drug to patients taking other medications known to prolong the QT interval.
    Alprazolam: (Major) Monitor for excessive sedation and somnolence during coadministration of trazodone and benzodiazepines. Concurrent use may result in additive CNS depression.
    Aminosalicylate sodium, Aminosalicylic acid: (Moderate) The combined use of trazodone and salicylates that affect hemostasis may elevate the risk for an upper GI bleed. Trazodone may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of salicylates. Additionally, salicylates impair the gastric mucosa defenses by inhibiting prostaglandin formation. It would be prudent for clinicians to monitor the patient's clinical status closely if trazodone is added to or removed from the regimen of a patient stabilized on salicylate therapy.
    Amiodarone: (Major) The manufacturer of trazodone recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Amiodarone, a Class III antiarrhythmic, is associated with a well-established risk of QT prolongation and TdP, although the frequency of TdP is less with amiodarone than with other Class III agents. At least one case of QT interval prolongation and torsade de pointes (TdP) has been documented during coadministration of trazodone and amiodarone. Theoretically, amiodarone could impair the metabolism of trazodone through inhibition of CYP3A4, thereby increasing the risk of trazodone-related adverse effects, including QT prolongation.
    Amitriptyline: (Moderate) Avoid coadministration of trazodone and tricyclic antidepressants (TCAs) due to the potential for QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported during treatment with trazodone. Tricyclic antidepressants have a possible risk for QT prolongation and TdP, particularly in overdose. In addition, concurrent use may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Amitriptyline; Chlordiazepoxide: (Major) Monitor for excessive sedation and somnolence during coadministration of trazodone and benzodiazepines. Concurrent use may result in additive CNS depression. (Moderate) Avoid coadministration of trazodone and tricyclic antidepressants (TCAs) due to the potential for QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported during treatment with trazodone. Tricyclic antidepressants have a possible risk for QT prolongation and TdP, particularly in overdose. In addition, concurrent use may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Amobarbital: (Major) Monitor for excessive sedation and somnolence during coadministration of trazodone and amobarbital. Concurrent use may result in additive CNS depression.
    Amoxapine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of amoxapine and trazodone. Concurrent use may result in additive CNS depression.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid coadministration of trazodone with clarithromycin due to the potential for increased trazodone exposure and associated adverse effects including QT prolongation. If concurrent use cannot be avoided, consider a reduced dose of trazodone based on tolerability. Trazodone is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of trazodone with clarithromycin due to the potential for increased trazodone exposure and associated adverse effects including QT prolongation. If concurrent use cannot be avoided, consider a reduced dose of trazodone based on tolerability. Trazodone is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone.
    Amphetamine: (Moderate) Coadministration of trazodone and amphetamines may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. The MAOI activity of amphetamines may also be of concern with trazodone. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Trazodone and the amphetamine should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Amphetamine; Dextroamphetamine: (Moderate) Coadministration of trazodone and amphetamines may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. The MAOI activity of amphetamines may also be of concern with trazodone. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Trazodone and the amphetamine should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Amphetamines: (Moderate) Coadministration of trazodone and amphetamines may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. The MAOI activity of amphetamines may also be of concern with trazodone. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Trazodone and the amphetamine should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Anagrelide: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include trazodone. In addition, platelet aggregation may be impaired by trazodone due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be instructed to monitor for signs and symptoms of bleeding while taking trazodone concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Angiotensin II receptor antagonists: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
    Angiotensin-converting enzyme inhibitors: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
    Anticoagulants: (Moderate) Patients should be instructed to monitor for signs and symptoms of bleeding while taking trazodone concurrently with anticoagulants and to promptly report any bleeding events to the practitioner. Serotonergic agents may increase the risk of bleeding when combined with anticoagulants via inhibition of serotonin uptake by platelets; however, the absolute risk is not known. It would be prudent for clinicians to monitor the INR and patient's clinical status closely if trazodone is added to or removed from the regimen of a patient stabilized on anticoagulant therapy.
    Apalutamide: (Moderate) Consider increasing the trazodone dose based on therapeutic response when coadministered with apalutamide. Concurrent use may decrease trazodone exposure. Trazodone is a CYP3A4 substrate; apalutamide is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers decreased the exposure of trazodone compared to the use of trazodone alone.
    Apomorphine: (Major) Apomorphine should be avoided in combination with trazodone. Limited data indicate that QT prolongation is possible with apomorphine administration; the change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines. In one study, a single mean dose of 5.2 mg (range 2-10 mg) prolonged the QT interval by about 3 msec. However, large increases (> 60 msecs from pre-dose) have occurred in two patients receiving 6 mg doses. Doses <= 6 mg SC are associated with minimal increases in QTc; doses > 6 mg SC do not provide additional clinical benefit and are not recommended. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Apomorphine also causes significant somnolence. Concomitant administration of apomorphine and CNS depressants, such as trazodone, could result in additive depressant effects. Careful monitoring is recommended during combined use of a CNS depressant and apomorphine. A dose reduction of one or both drugs may be warranted.
    Aprepitant, Fosaprepitant: (Major) Use caution if trazodone and aprepitant, fosaprepitant are used concurrently and monitor for an increase in trazodone-related adverse effects for several days after administration of a multi-day aprepitant regimen. Trazodone is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of trazodone. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Aripiprazole: (Major) QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    Arsenic Trioxide: (Major) If possible, drugs that are known to prolong the QT interval, such as trazodone, should be discontinued prior to initiating arsenic trioxide therapy. QT prolongation should be expected with the administration of arsenic trioxide. Torsade de pointes (TdP) and complete atrioventricular block have been reported. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of TdP. Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    Artemether; Lumefantrine: (Major) Avoid coadministration of trazodone and artemether; lumefantrine. The administration of artemether; lumefantrine is associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Consider ECG monitoring if trazodone must be used with or after artemether; lumefantrine treatment.
    Asenapine: (Major) Asenapine has been associated with QT prolongation. According to the manufacturer of asenapine, the drug should be avoided in combination with other agents also known to have this effect, such as trazodone. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. In addition, coadministration may increase adverse effects such as drowsiness, sedation, and dizziness.
    Aspirin, ASA: (Moderate) The combined use of trazodone and salicylates that affect hemostasis may elevate the risk for an upper GI bleed. Trazodone may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of salicylates. Additionally, salicylates impair the gastric mucosa defenses by inhibiting prostaglandin formation. It would be prudent for clinicians to monitor the patient's clinical status closely if trazodone is added to or removed from the regimen of a patient stabilized on salicylate therapy.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Monitor for excessive sedation and somnolence during coadministration of trazodone and butalbital. Concurrent use may result in additive CNS depression. (Moderate) The combined use of trazodone and salicylates that affect hemostasis may elevate the risk for an upper GI bleed. Trazodone may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of salicylates. Additionally, salicylates impair the gastric mucosa defenses by inhibiting prostaglandin formation. It would be prudent for clinicians to monitor the patient's clinical status closely if trazodone is added to or removed from the regimen of a patient stabilized on salicylate therapy.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Avoid prescribing opioid cough medications in patients taking trazodone. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Major) Monitor for excessive sedation and somnolence during coadministration of trazodone and butalbital. Concurrent use may result in additive CNS depression. (Moderate) The combined use of trazodone and salicylates that affect hemostasis may elevate the risk for an upper GI bleed. Trazodone may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of salicylates. Additionally, salicylates impair the gastric mucosa defenses by inhibiting prostaglandin formation. It would be prudent for clinicians to monitor the patient's clinical status closely if trazodone is added to or removed from the regimen of a patient stabilized on salicylate therapy.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Avoid prescribing opioid cough medications in patients taking trazodone. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Moderate) The combined use of trazodone and salicylates that affect hemostasis may elevate the risk for an upper GI bleed. Trazodone may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of salicylates. Additionally, salicylates impair the gastric mucosa defenses by inhibiting prostaglandin formation. It would be prudent for clinicians to monitor the patient's clinical status closely if trazodone is added to or removed from the regimen of a patient stabilized on salicylate therapy.
    Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) CNS depressants, such as skeletal muscle relaxants, should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. A dose reduction of one or both drugs may be warranted. (Moderate) The combined use of trazodone and salicylates that affect hemostasis may elevate the risk for an upper GI bleed. Trazodone may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of salicylates. Additionally, salicylates impair the gastric mucosa defenses by inhibiting prostaglandin formation. It would be prudent for clinicians to monitor the patient's clinical status closely if trazodone is added to or removed from the regimen of a patient stabilized on salicylate therapy.
    Aspirin, ASA; Carisoprodol: (Moderate) CNS depressants, such as carisoprodol, should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. A dose reduction of one or both drugs may be warranted. (Moderate) The combined use of trazodone and salicylates that affect hemostasis may elevate the risk for an upper GI bleed. Trazodone may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of salicylates. Additionally, salicylates impair the gastric mucosa defenses by inhibiting prostaglandin formation. It would be prudent for clinicians to monitor the patient's clinical status closely if trazodone is added to or removed from the regimen of a patient stabilized on salicylate therapy.
    Aspirin, ASA; Carisoprodol; Codeine: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Avoid prescribing opioid cough medications in patients taking trazodone. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Moderate) CNS depressants, such as carisoprodol, should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. A dose reduction of one or both drugs may be warranted. (Moderate) The combined use of trazodone and salicylates that affect hemostasis may elevate the risk for an upper GI bleed. Trazodone may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of salicylates. Additionally, salicylates impair the gastric mucosa defenses by inhibiting prostaglandin formation. It would be prudent for clinicians to monitor the patient's clinical status closely if trazodone is added to or removed from the regimen of a patient stabilized on salicylate therapy.
    Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) The combined use of trazodone and salicylates that affect hemostasis may elevate the risk for an upper GI bleed. Trazodone may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of salicylates. Additionally, salicylates impair the gastric mucosa defenses by inhibiting prostaglandin formation. It would be prudent for clinicians to monitor the patient's clinical status closely if trazodone is added to or removed from the regimen of a patient stabilized on salicylate therapy.
    Aspirin, ASA; Dipyridamole: (Moderate) Platelet aggregation may be impaired by trazodone due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking trazodone concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner. (Moderate) The combined use of trazodone and salicylates that affect hemostasis may elevate the risk for an upper GI bleed. Trazodone may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of salicylates. Additionally, salicylates impair the gastric mucosa defenses by inhibiting prostaglandin formation. It would be prudent for clinicians to monitor the patient's clinical status closely if trazodone is added to or removed from the regimen of a patient stabilized on salicylate therapy.
    Aspirin, ASA; Omeprazole: (Moderate) The combined use of trazodone and salicylates that affect hemostasis may elevate the risk for an upper GI bleed. Trazodone may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of salicylates. Additionally, salicylates impair the gastric mucosa defenses by inhibiting prostaglandin formation. It would be prudent for clinicians to monitor the patient's clinical status closely if trazodone is added to or removed from the regimen of a patient stabilized on salicylate therapy.
    Aspirin, ASA; Oxycodone: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Moderate) The combined use of trazodone and salicylates that affect hemostasis may elevate the risk for an upper GI bleed. Trazodone may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of salicylates. Additionally, salicylates impair the gastric mucosa defenses by inhibiting prostaglandin formation. It would be prudent for clinicians to monitor the patient's clinical status closely if trazodone is added to or removed from the regimen of a patient stabilized on salicylate therapy.
    Aspirin, ASA; Pravastatin: (Moderate) The combined use of trazodone and salicylates that affect hemostasis may elevate the risk for an upper GI bleed. Trazodone may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of salicylates. Additionally, salicylates impair the gastric mucosa defenses by inhibiting prostaglandin formation. It would be prudent for clinicians to monitor the patient's clinical status closely if trazodone is added to or removed from the regimen of a patient stabilized on salicylate therapy.
    Atazanavir: (Major) Avoid coadministration of trazodone with atazanavir due to the potential for increased trazodone exposure and associated adverse effects including QT prolongation. If concurrent use cannot be avoided, consider a reduced dose of trazodone based on tolerability. Trazodone is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone.
    Atazanavir; Cobicistat: (Major) Avoid coadministration of trazodone with atazanavir due to the potential for increased trazodone exposure and associated adverse effects including QT prolongation. If concurrent use cannot be avoided, consider a reduced dose of trazodone based on tolerability. Trazodone is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone. (Major) Avoid coadministration of trazodone with cobicistat due to the potential for increased trazodone exposure and associated adverse effects including QT prolongation. If concurrent use cannot be avoided, consider a reduced dose of trazodone based on tolerability. Trazodone is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone.
    Atomoxetine: (Major) QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. Atomoxetine is considered a drug with a possible risk of torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with atomoxetine include trazodone.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Severe) According to the manufacturer of trazodone, treatment initiation with trazodone is contraindicated in patients currently receiving intravenous methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than trazodone (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving trazodone and requiring urgent treatment with intravenous methylene blue, trazodone should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits of methylene blue outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Trazodone may be re-initiated 24 hours after the last dose of methylene blue. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and trazodone increases central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving serotonergic agents such as selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving intravenous methylene blue with other serotonergic psychiatric agents are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death. (Moderate) The combined use of trazodone and salicylates that affect hemostasis may elevate the risk for an upper GI bleed. Trazodone may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of salicylates. Additionally, salicylates impair the gastric mucosa defenses by inhibiting prostaglandin formation. It would be prudent for clinicians to monitor the patient's clinical status closely if trazodone is added to or removed from the regimen of a patient stabilized on salicylate therapy.
    Atropine; Difenoxin: (Moderate) Concurrent administration of diphenoxylate/difenoxin with trazodone can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    Atropine; Diphenoxylate: (Moderate) Concurrent administration of diphenoxylate/difenoxin with trazodone can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Monitor for excessive sedation and somnolence during coadministration of trazodone and phenobarbital. Concurrent use may result in additive CNS depression. Additionally, concurrent use may decrease trazodone exposure; adjust dose as needed based on therapeutic response. Trazodone is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers decreased the exposure of trazodone compared to the use of trazodone alone.
    Azelastine: (Moderate) CNS depressants, such as azelastine, should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Azelastine; Fluticasone: (Moderate) CNS depressants, such as azelastine, should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Azithromycin: (Major) Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval, such as azithromycin. There have been case reports of QT prolongation and torsade de pointes (TdP) with the use of azithromycin in post-marketing reports.
    Baclofen: (Moderate) CNS depressants, such as baclofen, should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. A dose reduction of one or both drugs may be warranted.
    Bedaquiline: (Major) Avoid coadministration of bedaquiline and trazodone. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Coadministration with other QT prolonging drugs may result in additive or synergistic prolongation of the QT interval. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Monitor for excessive sedation and somnolence during coadministration of trazodone and phenobarbital. Concurrent use may result in additive CNS depression. Additionally, concurrent use may decrease trazodone exposure; adjust dose as needed based on therapeutic response. Trazodone is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers decreased the exposure of trazodone compared to the use of trazodone alone.
    Belladonna; Opium: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Benzhydrocodone; Acetaminophen: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Benzodiazepines: (Major) Monitor for excessive sedation and somnolence during coadministration of trazodone and benzodiazepines. Concurrent use may result in additive CNS depression.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Severe) According to the manufacturer of trazodone, treatment initiation with trazodone is contraindicated in patients currently receiving intravenous methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than trazodone (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving trazodone and requiring urgent treatment with intravenous methylene blue, trazodone should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits of methylene blue outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Trazodone may be re-initiated 24 hours after the last dose of methylene blue. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and trazodone increases central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving serotonergic agents such as selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving intravenous methylene blue with other serotonergic psychiatric agents are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death. (Moderate) The combined use of trazodone and salicylates that affect hemostasis may elevate the risk for an upper GI bleed. Trazodone may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of salicylates. Additionally, salicylates impair the gastric mucosa defenses by inhibiting prostaglandin formation. It would be prudent for clinicians to monitor the patient's clinical status closely if trazodone is added to or removed from the regimen of a patient stabilized on salicylate therapy.
    Benzphetamine: (Moderate) Coadministration of trazodone and amphetamines may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. The MAOI activity of amphetamines may also be of concern with trazodone. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Trazodone and the amphetamine should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Beta-adrenergic blockers: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include trazodone.
    Bismuth Subsalicylate: (Moderate) The combined use of trazodone and salicylates that affect hemostasis may elevate the risk for an upper GI bleed. Trazodone may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of salicylates. Additionally, salicylates impair the gastric mucosa defenses by inhibiting prostaglandin formation. It would be prudent for clinicians to monitor the patient's clinical status closely if trazodone is added to or removed from the regimen of a patient stabilized on salicylate therapy.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include trazodone. (Moderate) The combined use of trazodone and salicylates that affect hemostasis may elevate the risk for an upper GI bleed. Trazodone may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of salicylates. Additionally, salicylates impair the gastric mucosa defenses by inhibiting prostaglandin formation. It would be prudent for clinicians to monitor the patient's clinical status closely if trazodone is added to or removed from the regimen of a patient stabilized on salicylate therapy.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering trazodone with boceprevir due to an increased potential for trazodone-related adverse event, such as dizziness, hypotension, and syncope. When used in combination, the plasma concentrations of trazodone were increased; thus, consider initiating trazodone at the lowest effective dose. If trazodone dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment.
    Bosentan: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
    Brexpiprazole: (Moderate) Due to the CNS effects of brexpiprazole, caution is advisable when brexpiprazole is given in combination with other centrally-acting medications including heterocyclic antidepressants.
    Brivaracetam: (Moderate) Trazodone can lower the seizure threshold of anticonvulsants, although the overall risk is low at therapeutic doses. Patients may require increased concentrations of anticonvulsants to achieve equivalent effects if trazodone is added. Finally, drowsiness may be additive between trazodone and other anticonvulsants.
    Brompheniramine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including amoxapine, maprotiline, mirtazapine or trazodone.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Brompheniramine; Guaifenesin; Hydrocodone: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Avoid prescribing opioid cough medications in patients taking trazodone. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Avoid prescribing opioid cough medications in patients taking trazodone. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Brompheniramine; Pseudoephedrine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Buprenorphine: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of trazodone and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsades de pointes (TdP). Trazodone has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as trazodone, has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected. Also, the risk of CNS depression is incresaed if these drugs are coadministered. Consider a dose reduction of one or both drugs. Sedation, coma, or respiratory depression may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Buprenorphine; Naloxone: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of trazodone and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsades de pointes (TdP). Trazodone has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as trazodone, has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected. Also, the risk of CNS depression is incresaed if these drugs are coadministered. Consider a dose reduction of one or both drugs. Sedation, coma, or respiratory depression may occur. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Buspirone: (Moderate) Coadministration of trazodone and buspirone may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue buspirone and trazodone and initiate symptomatic treatment if serotonin syndrome occurs.
    Butorphanol: (Moderate) Concomitant use of butorphanol with other CNS depressants, such as trazodone, can potentiate the effects of butorphanol on respiratory depression, CNS depression, and sedation.
    Calcium-channel blockers: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
    Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cannabidiol and trazodone. CNS depressants can potentiate the effects of cannabidiol.
    Capsaicin; Metaxalone: (Moderate) The sedative effects of metaxalone and other CNS depressants may be additive. Trazodone is associated with sedation and should be used with metaxalone with caution. Both drugs have also been associated with serotonin syndrome. Due to the potential for serotonin syndrome, caution is advised when metaxalone is co-administered with drugs that may affect the serotonergic neurotransmitter systems, such as trazodone. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, sertraline and concurrent serotonergic agents should be discontinued.
    Carbamazepine: (Moderate) Consider increasing the trazodone dose based on therapeutic response when coadministered with carbamazepine. Concurrent use may decrease trazodone exposure. Trazodone is a CYP3A4 substrate; carbamazepine is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers decreased the exposure of trazodone compared to the use of trazodone alone.
    Carbetapentane; Chlorpheniramine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including amoxapine, maprotiline, mirtazapine or trazodone.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including amoxapine, maprotiline, mirtazapine or trazodone.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. A dose reduction of one or both drugs may be warranted. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including amoxapine, maprotiline, mirtazapine or trazodone.
    Carbetapentane; Guaifenesin: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including amoxapine, maprotiline, mirtazapine or trazodone.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including amoxapine, maprotiline, mirtazapine or trazodone.
    Carbetapentane; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including amoxapine, maprotiline, mirtazapine or trazodone.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including amoxapine, maprotiline, mirtazapine or trazodone.
    Carbetapentane; Pseudoephedrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including amoxapine, maprotiline, mirtazapine or trazodone.
    Carbetapentane; Pyrilamine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including amoxapine, maprotiline, mirtazapine or trazodone.
    Carbinoxamine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Avoid prescribing opioid cough medications in patients taking trazodone. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Avoid prescribing opioid cough medications in patients taking trazodone. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Carbinoxamine; Phenylephrine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Carbinoxamine; Pseudoephedrine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Cariprazine: (Moderate) Due to the CNS effects of cariprazine, caution is advisable when cariprazine is given in combination with other centrally-acting medications including heterocyclic antidepressants.
    Carisoprodol: (Moderate) CNS depressants, such as carisoprodol, should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. A dose reduction of one or both drugs may be warranted.
    Ceritinib: (Major) Avoid coadministration of ceritinib with trazodone due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of trazodone may also be increased resulting in increase in treatment-related adverse reactions. Ceritinib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Trazodone is a CYP3A4 substrate that can also prolong the QT/QTc interval at therapeutic doses; in addition, there are postmarketing reports of TdP. Concomitant use may increase the risk for QT prolongation.
    Cetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with heterocyclic antidepressants should generally be avoided. Coadministration may increase the risk of anticholinergic and CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive anticholinergic effects, sedation, and somnolence.
    Cetirizine; Pseudoephedrine: (Moderate) Concurrent use of cetirizine/levocetirizine with heterocyclic antidepressants should generally be avoided. Coadministration may increase the risk of anticholinergic and CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive anticholinergic effects, sedation, and somnolence.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Chloramphenicol: (Major) Avoid coadministration of trazodone with chloramphenicol due to the potential for increased trazodone exposure and associated adverse effects including QT prolongation. If concurrent use cannot be avoided, consider a reduced dose of trazodone based on tolerability. Trazodone is a CYP3A4 substrate; chloramphenicol is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone.
    Chlorcyclizine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Chlordiazepoxide: (Major) Monitor for excessive sedation and somnolence during coadministration of trazodone and benzodiazepines. Concurrent use may result in additive CNS depression.
    Chlordiazepoxide; Clidinium: (Major) Monitor for excessive sedation and somnolence during coadministration of trazodone and benzodiazepines. Concurrent use may result in additive CNS depression.
    Chloroquine: (Major) The manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval, such as chloroquine. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of torsade de pointes (TdP). Chloroquine is associated with an increased risk of QT prolongation and TdP; fatalities have been reported. The risk of QT prolongation is increased with higher chloroquine doses.
    Chlorpheniramine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Chlorpheniramine; Codeine: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Avoid prescribing opioid cough medications in patients taking trazodone. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Chlorpheniramine; Dextromethorphan: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Avoid prescribing opioid cough medications in patients taking trazodone. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Avoid prescribing opioid cough medications in patients taking trazodone. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Avoid prescribing opioid cough medications in patients taking trazodone. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Chlorpheniramine; Hydrocodone: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Avoid prescribing opioid cough medications in patients taking trazodone. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Avoid prescribing opioid cough medications in patients taking trazodone. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Avoid prescribing opioid cough medications in patients taking trazodone. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Chlorpheniramine; Phenylephrine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Chlorpheniramine; Pseudoephedrine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Chlorpromazine: (Major) Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and torsade de pointes (TdP) and should be avoided in combination with trazodone. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of TdP. Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. In addition, CNS depressants, such as phenothiazines, should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Chlorthalidone; Clonidine: (Moderate) Clonidine may potentiate the CNS-depressive effects of other sedating drugs, such as trazodone. Trazodone may cause orthostatic hypotension or other effects on blood pressure that may be additive to clonidine. Monitor blood pressure to ensure blood pressure remains controlled.
    Chlorzoxazone: (Moderate) CNS depressants, such as skeletal muscle relaxants, should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. A dose reduction of one or both drugs may be warranted.
    Choline Salicylate; Magnesium Salicylate: (Moderate) The combined use of trazodone and salicylates that affect hemostasis may elevate the risk for an upper GI bleed. Trazodone may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of salicylates. Additionally, salicylates impair the gastric mucosa defenses by inhibiting prostaglandin formation. It would be prudent for clinicians to monitor the patient's clinical status closely if trazodone is added to or removed from the regimen of a patient stabilized on salicylate therapy.
    Cilostazol: (Moderate) Platelet aggregation may be impaired by trazodone due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking trazodone concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Ciprofloxacin: (Major) Coadministration of ciprofloxacin and trazodone should be avoided. Rare cases of QT prolongation and torsade de pointe (TdP) have been reported with ciprofloxacin during post-marketing surveillance. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    Cisapride: (Severe) QT prolongation and ventricular arrhythmias, including torsade de pointes (TdP) and death, have been reported with cisapride. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of TdP. Because of the potential for TdP, use of cisapride with trazodone is contraindicated.
    Citalopram: (Major) Avoid coadministration of trazodone and citalopram due to the potential for QT prolongation. If concurrent therapy is considered essential, ECG monitoring is recommended. Concurrent use also increases the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue citalopram and trazodone and initiate symptomatic treatment if serotonin syndrome occurs.
    Clarithromycin: (Major) Avoid coadministration of trazodone with clarithromycin due to the potential for increased trazodone exposure and associated adverse effects including QT prolongation. If concurrent use cannot be avoided, consider a reduced dose of trazodone based on tolerability. Trazodone is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone.
    Clemastine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Clofazimine: (Major) Avoid coadministration of clofazimine with trazodone due to the potential for additive QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients receiving clofazimine in combination with QT prolonging medications. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of TdP.
    Clomipramine: (Moderate) Avoid coadministration of trazodone and tricyclic antidepressants (TCAs) due to the potential for QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported during treatment with trazodone. Tricyclic antidepressants have a possible risk for QT prolongation and TdP, particularly in overdose. In addition, concurrent use may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Clonazepam: (Major) Monitor for excessive sedation and somnolence during coadministration of trazodone and benzodiazepines. Concurrent use may result in additive CNS depression.
    Clonidine: (Moderate) Clonidine may potentiate the CNS-depressive effects of other sedating drugs, such as trazodone. Trazodone may cause orthostatic hypotension or other effects on blood pressure that may be additive to clonidine. Monitor blood pressure to ensure blood pressure remains controlled.
    Clopidogrel: (Moderate) Platelet aggregation may be impaired by trazodone due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking trazodone concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Clorazepate: (Major) Monitor for excessive sedation and somnolence during coadministration of trazodone and benzodiazepines. Concurrent use may result in additive CNS depression.
    Clozapine: (Major) If possible, avoid the concomitant administration of clozapine and trazodone. Trazodone can prolong the QT/QTc interval at therapeutic doses, and the manufacturer recommends avoiding administration with other drugs that can prolong the QT interval, such as clozapine. Furthermore, the concomitant administration of trazodone and clozapine can cause additive depressant effects and possible respiratory depression or hypotension.
    Cobicistat: (Major) Avoid coadministration of trazodone with cobicistat due to the potential for increased trazodone exposure and associated adverse effects including QT prolongation. If concurrent use cannot be avoided, consider a reduced dose of trazodone based on tolerability. Trazodone is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone.
    Codeine: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Avoid prescribing opioid cough medications in patients taking trazodone. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Codeine; Guaifenesin: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Avoid prescribing opioid cough medications in patients taking trazodone. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Avoid prescribing opioid cough medications in patients taking trazodone. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Major) Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Promethazine has been reported to cause QT prolongation. Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may also occur when it is combined with other CNS depressants including trazodone.
    Codeine; Promethazine: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Avoid prescribing opioid cough medications in patients taking trazodone. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Major) Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Promethazine has been reported to cause QT prolongation. Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may also occur when it is combined with other CNS depressants including trazodone.
    COMT inhibitors: (Moderate) COMT inhibitors, such as entacapone and tolcapone, should be given cautiously with other agents that cause CNS depression, such as heterocyclic antidepressants, due to the possibility of additive sedation.
    Conivaptan: (Major) Avoid coadministration of trazodone with conivaptan due to the potential for increased trazodone exposure and associated adverse effects including QT prolongation. According to the manufacturer of conivaptan, treatment with CYP3A4 substrates, such as trazodone, may be initiated no sooner than 1 week after completion of conivaptan therapy. If concurrent use cannot be avoided, consider a reduced dose of trazodone based on tolerability. Trazodone is a CYP3A4 substrate; conivaptan is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone.
    Crizotinib: (Major) Avoid coadministration of crizotinib with trazodone due to the risk of QT prolongation and torsade de pointes (TdP). Crizotinib has been associated with concentration-dependent QT prolongation. Trazodone can also prolong the QT/QTc interval at therapeutic doses; in addition, there are postmarketing reports of TdP with trazodone use.
    Cyclizine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Cyclobenzaprine: (Moderate) Increased CNS depressant effects may be seen if cyclcobenzaprine and trazodone are administered concurrently.
    Cyproheptadine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Dantrolene: (Moderate) CNS depressants, such as skeletal muscle relaxants, should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. A dose reduction of one or both drugs may be warranted.
    Darunavir: (Major) Avoid coadministration of trazodone with darunavir due to the potential for increased trazodone exposure and associated adverse effects including QT prolongation. If concurrent use cannot be avoided, consider a reduced dose of trazodone based on tolerability. Trazodone is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone.
    Darunavir; Cobicistat: (Major) Avoid coadministration of trazodone with cobicistat due to the potential for increased trazodone exposure and associated adverse effects including QT prolongation. If concurrent use cannot be avoided, consider a reduced dose of trazodone based on tolerability. Trazodone is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone. (Major) Avoid coadministration of trazodone with darunavir due to the potential for increased trazodone exposure and associated adverse effects including QT prolongation. If concurrent use cannot be avoided, consider a reduced dose of trazodone based on tolerability. Trazodone is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of trazodone with cobicistat due to the potential for increased trazodone exposure and associated adverse effects including QT prolongation. If concurrent use cannot be avoided, consider a reduced dose of trazodone based on tolerability. Trazodone is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone. (Major) Avoid coadministration of trazodone with darunavir due to the potential for increased trazodone exposure and associated adverse effects including QT prolongation. If concurrent use cannot be avoided, consider a reduced dose of trazodone based on tolerability. Trazodone is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of trazodone with ritonavir due to the potential for increased trazodone exposure and associated adverse effects including QT prolongation. If concurrent use cannot be avoided, consider a reduced dose of trazodone based on tolerability. Trazodone is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone.
    Dasatinib: (Major) Avoid coadministration of trazodone and dasatinib due to the potential for QT prolongation and torsade de pointes (TdP). Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of TdP. In vitro studies have shown that dasatinib has the potential to prolong the QT interval.
    Degarelix: (Major) Degarelix can cause QT prolongation and should be avoided in combination with trazodone. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    Delavirdine: (Major) Avoid coadministration of trazodone with delavirdine due to the potential for increased trazodone exposure and associated adverse effects including QT prolongation. If concurrent use cannot be avoided, consider a reduced dose of trazodone based on tolerability. Trazodone is a CYP3A4 substrate; delavirdine is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone.
    Desflurane: (Major) Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Drugs with a known risk for QT prolongation and TdP include the halogenated anesthetics.
    Desipramine: (Moderate) Avoid coadministration of trazodone and tricyclic antidepressants (TCAs) due to the potential for QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported during treatment with trazodone. Tricyclic antidepressants have a possible risk for QT prolongation and TdP, particularly in overdose. In addition, concurrent use may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Desvenlafaxine: (Moderate) Coadministration of trazodone and desvenlafaxine may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue desvenlafaxine and trazodone and initiate symptomatic treatment if serotonin syndrome occurs.
    Deutetrabenazine: (Major) Avoid trazodone in patients receiving other drugs that increase the QT interval. Clinically relevant QTc prolongation may occur with deutetrabenazine. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of torsade de pointes (TdP). Additionally, concurrent use of deutetrabenazine and drugs that cause CNS depression, such as trazodone, may have additive effects and worsen drowsiness or sedation.
    Dexchlorpheniramine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Dextroamphetamine: (Moderate) Coadministration of trazodone and amphetamines may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. The MAOI activity of amphetamines may also be of concern with trazodone. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Trazodone and the amphetamine should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. A dose reduction of one or both drugs may be warranted.
    Dextromethorphan; Promethazine: (Major) Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Promethazine has been reported to cause QT prolongation. Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may also occur when it is combined with other CNS depressants including trazodone.
    Dextromethorphan; Quinidine: (Major) Avoid coadministration of quinidine and trazodone if possible due to a potential increase in risk of QT prolongation and torsade de pointes (TdP). Quinidine administration is associated with QT prolongation and TdP. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of TdP for trazodone. Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    Diazepam: (Major) Monitor for excessive sedation and somnolence during coadministration of trazodone and benzodiazepines. Concurrent use may result in additive CNS depression.
    Diazoxide: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
    Digoxin: (Moderate) Monitor digoxin concentrations before initiating concomitant trazodone and continually during therapy; decrease phenytoin dose as clinically necessary. Trazodone may increase digoxin concentrations.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Avoid prescribing opioid cough medications in patients taking trazodone. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Dimenhydrinate: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Diphenhydramine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. A dose reduction of one or both drugs may be warranted.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Avoid prescribing opioid cough medications in patients taking trazodone. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. A dose reduction of one or both drugs may be warranted.
    Diphenhydramine; Ibuprofen: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. A dose reduction of one or both drugs may be warranted.
    Diphenhydramine; Naproxen: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. A dose reduction of one or both drugs may be warranted.
    Diphenhydramine; Phenylephrine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. A dose reduction of one or both drugs may be warranted.
    Dipyridamole: (Moderate) Platelet aggregation may be impaired by trazodone due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking trazodone concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Disopyramide: (Major) Disopyramide administration is associated with QT prolongation and torsades de pointes (TdP) and should be avoided in combination with trazodone. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of TdP. Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    Dofetilide: (Major) Coadministration of dofetilide and trazodone is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of TdP.
    Dolasetron: (Major) Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval, such as dolasetron. Dolasetron has been associated with a dose-dependant prolongation in the QT, PR, and QRS intervals on an electrocardiogram. Use of dolasetron injection for the prevention of chemotherapy-induced nausea and vomiting is contraindicated because the risk of QT prolongation is higher with the doses required for this indication; when the injection is used at lower doses (i.e., those approved for post-operative nausea and vomiting) or when the oral formulation is used, the risk of QT prolongation is lower and caution is advised.
    Dolutegravir; Rilpivirine: (Major) Avoid coadministration of trazodone and rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    Donepezil: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include trazodone.
    Donepezil; Memantine: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include trazodone.
    Doxazosin: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
    Doxepin: (Moderate) Avoid coadministration of trazodone and tricyclic antidepressants (TCAs) due to the potential for QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported during treatment with trazodone. Tricyclic antidepressants have a possible risk for QT prolongation and TdP, particularly in overdose. In addition, concurrent use may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Doxylamine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Doxylamine; Pyridoxine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Dronabinol: (Moderate) CNS depressants, such as dronabinol, should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. A dose reduction of one or both drugs may be warranted.
    Dronedarone: (Severe) Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. The concomitant use of dronedarone with other drugs that prolong the QTc, such as trazodone, may induce Torsade de Pointes (TdP) and is contraindicated. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of TdP.
    Droperidol: (Major) Coadministration of droperidol and trazodone should be avoided. Droperidol administration is associated with an established risk for QT prolongation and torsades de pointes (TdP). In December 2001, the FDA issued a black box warning regarding the use of droperidol and its association with QT prolongation and potential for cardiac arrhythmias based on post-marketing surveillance data. According to the revised 2001 labeling for droperidol, any drug known to have potential to prolong the QT interval should not be coadministered with droperidol. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. In addition, CNS depressants, inlcluding droperidol, should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Duloxetine: (Moderate) Coadministration of trazodone and duloxetine may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue duloxetine and trazodone and initiate symptomatic treatment if serotonin syndrome occurs.
    Efavirenz: (Major) Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval, such as efavirenz. In addition, efavirenz may induce the CYP3A4 metabolism of trazodone; potentially reducing the efficacy of trazodone by decreasing its systemic exposure.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval, such as efavirenz. In addition, efavirenz may induce the CYP3A4 metabolism of trazodone; potentially reducing the efficacy of trazodone by decreasing its systemic exposure.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval, such as efavirenz. In addition, efavirenz may induce the CYP3A4 metabolism of trazodone; potentially reducing the efficacy of trazodone by decreasing its systemic exposure.
    Elbasvir; Grazoprevir: (Moderate) Administering trazodone with elbasvir; grazoprevir may result in elevated trazodone plasma concentrations. Trazodone is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Eliglustat: (Major) Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with eliglustat include trazodone.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of trazodone with cobicistat due to the potential for increased trazodone exposure and associated adverse effects including QT prolongation. If concurrent use cannot be avoided, consider a reduced dose of trazodone based on tolerability. Trazodone is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of trazodone with cobicistat due to the potential for increased trazodone exposure and associated adverse effects including QT prolongation. If concurrent use cannot be avoided, consider a reduced dose of trazodone based on tolerability. Trazodone is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Avoid coadministration of trazodone and rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Avoid coadministration of trazodone and rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    Encorafenib: (Major) Avoid coadministration of encorafenib and trazodone due to the potential for additive QT prolongation. Encorafenib is associated with dose-dependent prolongation of the QT interval. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of torsade de pointes (TdP).l
    Enflurane: (Major) Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Drugs with a known risk for QT prolongation and TdP include the halogenated anesthetics.
    Entrectinib: (Major) Avoid coadministration of entrectinib with trazodone due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of torsade de pointes (TdP).
    Enzalutamide: (Moderate) Consider increasing the trazodone dose based on therapeutic response when coadministered with enzalutamide. Concurrent use may decrease trazodone exposure. Trazodone is a CYP3A4 substrate; enzalutamide is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers decreased the exposure of trazodone compared to the use of trazodone alone.
    Eplerenone: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
    Epoprostenol: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
    Eptifibatide: (Moderate) Platelet aggregation may be impaired by trazodone due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking trazodone concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Eribulin: (Major) Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval, such as eribulin. Eribulin has been associated with QT prolongation. If eribulin and trazodone must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
    Erythromycin: (Major) The manufacturer of trazodone recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Erythromycin has a possible risk for QT prolongation and TdP. In addition, erythromycin could impair the metabolism of trazodone through inhibition of CYP3A4, thereby increasing the risk of trazodone-related adverse effects, including QT prolongation.
    Erythromycin; Sulfisoxazole: (Major) The manufacturer of trazodone recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Erythromycin has a possible risk for QT prolongation and TdP. In addition, erythromycin could impair the metabolism of trazodone through inhibition of CYP3A4, thereby increasing the risk of trazodone-related adverse effects, including QT prolongation.
    Escitalopram: (Major) Due to the risk of QT prolongation and torsade de pointes (TdP), the manufacturer of trazodone recommends avoiding use with other drugs that increase the QT interval. Escitalopram has been associated with a risk of QT prolongation and TdP. In addition, coadministration of trazodone and escitalopram may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue escitalopram and trazodone and initiate symptomatic treatment if serotonin syndrome occurs.
    Esketamine: (Major) Closely monitor patients receiving esketamine and trazodone for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
    Estazolam: (Major) Monitor for excessive sedation and somnolence during coadministration of trazodone and benzodiazepines. Concurrent use may result in additive CNS depression.
    Eszopiclone: (Moderate) Eszopiclone should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. If used together, a reduction in the dose of one or both drugs may be needed.
    Ethanol: (Moderate) Trazodone may enhance the response to alcohol and other CNS depressants. Trazodone can have significant sedative effects. The patient should be cautioned accordingly. In some studies, alcohol did not significantly alter the pharmacodynamic response to trazodone, but other individuals may have different responses.
    Ezogabine: (Major) Ezogabine has been associated with QT prolongation and should be avoided in combination with trazodone. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. In addition, due to the CNS effects of ezogabine, an enhanced CNS depressant effect may occur during concurrent use of other centrally-acting medications such as trazodone. Patients should be monitored for excessive somnolence during concurrent therapy with this agent.
    Fenoldopam: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
    Fentanyl: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Fingolimod: (Major) Coadministration of trazodone and fingolimod should be avoided. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of TdP. Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    Flecainide: (Major) Avoid coadministration of trazodone and flecainide. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or torsades de pointes (TdP); flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs which have the potential for QT prolongation may have an increased risk of developing proarrhythmias. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of TdP. Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    Flibanserin: (Moderate) The concomitant use of flibanserin with CNS depressants, such as trazodone, may increase the risk of CNS depression (e.g., dizziness, somnolence) compared to the use of flibanserin alone. Patients should avoid activities requiring full alertness (e.g., operating machinery or driving) until at least 6 hours after each dose and until they know how flibanserin affects them.
    Fluconazole: (Severe) The concurrent use of fluconazole with drugs that are associated with QT prolongation and are CYP3A4 substrates, such as trazodone, is contraindicated. Fluconazole has been associated with QT prolongation; QT prolongation and torsade de pointes (TdP) have been observed during trazodone treatment. Additionally, fluconazole has been associated with prolongation of the QT interval as well as rare cases of TdP; avoid use with other drugs that may prolong the QT interval and are metabolized through CYP3A4, such as trazodone.
    Fluoxetine: (Major) Due to the risk of QT prolongation and torsade de pointes (TdP), the manufacturer of trazodone recommends avoiding use with other drugs that increase the QT interval. Fluoxetine has been associated with a risk of QT prolongation and TdP. In addition, coadministration of trazodone and fluoxetine may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue fluoxetine and trazodone and initiate symptomatic treatment if serotonin syndrome occurs.
    Fluoxetine; Olanzapine: (Major) Avoid coadministration of trazodone and olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Trazodone can also cause CNS depression and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. (Major) Due to the risk of QT prolongation and torsade de pointes (TdP), the manufacturer of trazodone recommends avoiding use with other drugs that increase the QT interval. Fluoxetine has been associated with a risk of QT prolongation and TdP. In addition, coadministration of trazodone and fluoxetine may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue fluoxetine and trazodone and initiate symptomatic treatment if serotonin syndrome occurs.
    Fluphenazine: (Minor) Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Theoretically, the risk of QT prolongation may be increased if coadministered with drugs with a possible risk for QT prolongation, such as trazodone. In addition, phenothiazines can potentiate the CNS-depressant action of other drugs such as trazodone. Clinicians should note that additive CNS effects (e.g., oversedation, respiratory depression, and hypotension) may occur if fluphenazine is administered concomitantly with trazodone.
    Flurazepam: (Major) Monitor for excessive sedation and somnolence during coadministration of trazodone and benzodiazepines. Concurrent use may result in additive CNS depression.
    Fluvoxamine: (Major) Due to the risk of QT prolongation and torsade de pointes (TdP), the manufacturer of trazodone recommends avoiding use with other drugs that increase the QT interval. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. In addition, coadministration of trazodone and fluvoxamine may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue fluvoxamine and trazodone and initiate symptomatic treatment if serotonin syndrome occurs.
    Fosamprenavir: (Major) Avoid coadministration of trazodone with fosamprenavir due to the potential for increased trazodone exposure and associated adverse effects including QT prolongation. If concurrent use cannot be avoided, consider a reduced dose of trazodone based on tolerability. Trazodone is a CYP3A4 substrate; fosamprenavir is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone.
    Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as trazodone. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of TdP with trazodone. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
    Fosphenytoin: (Moderate) Consider increasing the trazodone dose based on therapeutic response when coadministered with fosphenytoin. Concurrent use may decrease trazodone exposure. Additionally, trazodone may increase phenytoin concentrations. Monitor phenytoin concentrations before initiating concomitant trazodone and continually during therapy; decrease fosphenytoin dose as clinically necessary. Trazodone is a CYP3A4 substrate; fosphenytoin is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers decreased the exposure of trazodone compared to the use of trazodone alone.
    Gabapentin: (Major) Initiate gabapentin at the lowest recommended dose and monitor patients for symptoms of sedation and somnolence during coadministration of gabapentin and trazodone. Concomitant use of gabapentin with trazodone may cause additive CNS depression. Educate patients about the risks and symptoms of excessive CNS depression.
    Gemifloxacin: (Major) Avoid coadministration of gemifloxacin and trazodone. Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5-10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    Gemtuzumab Ozogamicin: (Major) Avoid coadministration of gemtuzumab ozogamicin with trazodone due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab ozogamicin, it has been reported with other drugs that contain calicheamicin. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of TdP.
    Gilteritinib: (Major) Avoid concomitant use of trazodone with gilteritinib due to the potential for additive QT prolongation. Gilteritinib has been associated with QT prolongation. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of torsade de pointes (TdP).
    Ginkgo, Ginkgo biloba: (Major) A case report of a potential interaction between trazodone and ginkgo biloba has been described in a patient with dementia. The interaction purportedly led to oversedation requiring medical intervention. The mechanism is uncertain. Clinically, the flavonoids of ginkgo do not usually produce significant sedative effects. However, the addition of trazodone may have enhanced activity of the ginkgo flavonoids on GABA in the CNS. Use trazodone with caution in any patient taking ginkgo biloba.
    Glasdegib: (Major) Avoid coadministration of glasdegib with trazodone due to the potential for additive QT prolongation. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of torsade de pointes (TdP).
    Goserelin: (Major) Avoid coadministration of trazodone with goserelin due to the risk of QT prolongation. Trazodone can prolong the QT/QTc interval at therapeutic doses; in addition, there are postmarketing reports of torsade de pointes (TdP). Androgen deprivation therapy (i.e., goserelin) may prolong the QT/QTc interval.
    Granisetron: (Major) Because trazodone can prolong the QT/QTc interval at therapeutic doses and there are postmarketing reports of torsade de pointes (TdP), the manufacturer of trazodone recommends avoiding use in patients receiving other drugs that increase the QT interval, such as granisetron. In addition, coadministration of trazodone and granisetron may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue granisetron and trazodone and initiate symptomatic treatment if serotonin syndrome occurs.
    Grapefruit juice: (Major) Advise patients to avoid coadministration of trazodone with grapefruit juice due to the potential for increased trazodone exposure and associated adverse effects including QT prolongation. Trazodone is a CYP3A4 substrate; grapefruit juice is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone.
    Guaifenesin; Hydrocodone: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Avoid prescribing opioid cough medications in patients taking trazodone. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Avoid prescribing opioid cough medications in patients taking trazodone. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Guanfacine: (Moderate) Guanfacine may potentiate the CNS-depressive effects of other sedating drugs, such as trazodone. Monitor blood pressure to ensure blood pressure remains controlled.
    Halogenated Anesthetics: (Major) Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Drugs with a known risk for QT prolongation and TdP include the halogenated anesthetics.
    Haloperidol: (Major) Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Haloperidol has a possible risk for QT prolongation and TdP. Myoclonus, which responded to a serotonin antagonist, was reported in a patient taking trazodone with buspirone and haloperidol.
    Halothane: (Major) Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Drugs with a known risk for QT prolongation and TdP include the halogenated anesthetics.
    Histrelin: (Major) Avoid coadministration of trazodone with histrelin due to the risk of QT prolongation. Trazodone can prolong the QT/QTc interval at therapeutic doses; in addition, there are postmarketing reports of torsade de pointes (TdP). Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
    Homatropine; Hydrocodone: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Avoid prescribing opioid cough medications in patients taking trazodone. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Hydralazine: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
    Hydralazine; Isosorbide Dinitrate, ISDN: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
    Hydrocodone: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Avoid prescribing opioid cough medications in patients taking trazodone. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Hydrocodone; Ibuprofen: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Avoid prescribing opioid cough medications in patients taking trazodone. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Hydrocodone; Phenylephrine: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Avoid prescribing opioid cough medications in patients taking trazodone. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Hydrocodone; Potassium Guaiacolsulfonate: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Avoid prescribing opioid cough medications in patients taking trazodone. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Avoid prescribing opioid cough medications in patients taking trazodone. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Hydrocodone; Pseudoephedrine: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Avoid prescribing opioid cough medications in patients taking trazodone. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Hydromorphone: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Hydroxychloroquine: (Major) Avoid coadministration of hydroxychloroquine and trazodone. Hydroxychloroquine increases the QT interval and should not be administered with other drugs known to prolong the QT interval. Ventricular arrhythmias and torsade de pointes (TdP) have been reported with the use of hydroxychloroquine. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of TdP with trazodone.
    Hydroxyzine: (Major) Avoid coadministration of hydroxyzine and trazodone due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). In addition, because hydroxyzine causes pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including trazodone. Postmarketing data indicate that hydroxyzine causes QT prolongation and TdP. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of TdP.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Severe) According to the manufacturer of trazodone, treatment initiation with trazodone is contraindicated in patients currently receiving intravenous methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than trazodone (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving trazodone and requiring urgent treatment with intravenous methylene blue, trazodone should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits of methylene blue outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Trazodone may be re-initiated 24 hours after the last dose of methylene blue. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and trazodone increases central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving serotonergic agents such as selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving intravenous methylene blue with other serotonergic psychiatric agents are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death. (Moderate) The combined use of trazodone and salicylates that affect hemostasis may elevate the risk for an upper GI bleed. Trazodone may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of salicylates. Additionally, salicylates impair the gastric mucosa defenses by inhibiting prostaglandin formation. It would be prudent for clinicians to monitor the patient's clinical status closely if trazodone is added to or removed from the regimen of a patient stabilized on salicylate therapy.
    Ibuprofen; Oxycodone: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Ibutilide: (Major) Avoid coadministration of trazodone and ibutilide. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Ibutilide administration can cause QT prolongation and TdP; proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval.
    Idelalisib: (Major) Avoid coadministration of trazodone with idelalisib due to the potential for increased trazodone exposure and associated adverse effects including QT prolongation. If concurrent use cannot be avoided, consider a reduced dose of trazodone based on tolerability. Trazodone is a CYP3A4 substrate; idelalisib is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone.
    Iloperidone: (Major) Avoid coadministration of iloperidone and trazodone. Iloperidone has been associated with QT prolongation; however, torsade de pointes (TdP) has not been reported. According to the manufacturer, since iloperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. In addition, coadministration increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
    Iloprost: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
    Imipramine: (Moderate) Avoid coadministration of trazodone and tricyclic antidepressants (TCAs) due to the potential for QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported during treatment with trazodone. Tricyclic antidepressants have a possible risk for QT prolongation and TdP, particularly in overdose. In addition, concurrent use may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Indinavir: (Major) Avoid coadministration of trazodone with indinavir due to the potential for increased trazodone exposure and associated adverse effects including QT prolongation. If concurrent use cannot be avoided, consider a reduced dose of trazodone based on tolerability. Trazodone is a CYP3A4 substrate; indinavir is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with trazodone due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of TdP.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with trazodone may result in increased serum concentrations of trazodone. Trazodone is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isocarboxazid: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with trazodone or within 14 days of discontinuing treatment with trazodone. Conversely, trazodone should not be initiated within 14 days of stopping an MAOI. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Isoflurane: (Major) Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Drugs with a known risk for QT prolongation and TdP include the halogenated anesthetics.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Consider increasing the trazodone dose based on therapeutic response when coadministered with rifampin. Concurrent use may decrease trazodone exposure. Trazodone is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers decreased the exposure of trazodone compared to the use of trazodone alone.
    Isoniazid, INH; Rifampin: (Moderate) Consider increasing the trazodone dose based on therapeutic response when coadministered with rifampin. Concurrent use may decrease trazodone exposure. Trazodone is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers decreased the exposure of trazodone compared to the use of trazodone alone.
    Itraconazole: (Major) Avoid coadministration of itraconazole with trazodone due to the potential for additive effects on the QT interval; increased exposure to trazodone may also occur. Both trazodone and itraconazole are associated with QT prolongation; there are also postmarketing reports of torsade de pointes (TdP) with trazodone. In addition, coadministration of itraconazole (a potent CYP3A4 inhibitor) with trazodone (a CYP3A4 substrate) may result in elevated trazodone plasma concentrations and an increased risk for adverse events, including QT prolongation. Consider decreasing the dose of trazodone during coadministration with itraconazole. If itraconazole therapy is stopped, it may be prudent to continue close monitoring for up to 2 weeks after discontinuing itraconazole. Once discontinued, the plasma concentration of itraconazole decreases to almost undetectable concentrations within 7 to 14 days. The decline in plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with trazodone due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of torsade de pointes (TdP).
    Ketoconazole: (Major) Avoid coadministration of trazodone and ketoconazole due to the potential for additive effects on the QT interval; increased exposure to trazodone may also occur. Both trazodone and ketoconazole are associated with QT prolongation; there are also postmarketing reports of torsade de pointes (TdP) with trazodone. In addition, concurrent use may lead to substantial increases in trazodone plasma concentrations, further increasing the risk for adverse effects. If trazodone must be used with a potent CYP3A4 inhibitor, such as ketoconazole, a lower dose of trazodone should be considered.
    Lapatinib: (Major) Avoid coadministration of trazodone with lapatinib due to the risk of QT prolongation. Trazodone can prolong the QT/QTc interval at therapeutic doses; in addition, there are postmarketing reports of torsade de pointes (TdP). Lapatinib has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience with lapatinib.
    Lefamulin: (Major) Avoid coadministration of lefamulin with trazodone as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of torsade de pointes (TdP).
    Lenvatinib: (Major) Avoid coadministration of lenvatinib with trazodone due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Trazodone can also prolong the QT/QTc interval at therapeutic doses; in addition, there are postmarketing reports of torsade de pointes (TdP).
    Letermovir: (Moderate) An increase in the plasma concentration of trazodone may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, consider reducing the trazodone dose based on tolerability and monitor for cardiac arrhythmias or other trazodone toxicities because the magnitude of this interaction may be amplified. Trazodone is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
    Leuprolide: (Major) Avoid coadministration of trazodone with leuprolide due to the risk of QT prolongation. Trazodone can prolong the QT/QTc interval at therapeutic doses; in addition, there are postmarketing reports of torsade de pointes (TdP). Androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval.
    Leuprolide; Norethindrone: (Major) Avoid coadministration of trazodone with leuprolide due to the risk of QT prolongation. Trazodone can prolong the QT/QTc interval at therapeutic doses; in addition, there are postmarketing reports of torsade de pointes (TdP). Androgen deprivation therapy (i.e., leuprolide) may prolong the QT/QTc interval.
    Levocetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with heterocyclic antidepressants should generally be avoided. Coadministration may increase the risk of anticholinergic and CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive anticholinergic effects, sedation, and somnolence.
    Levofloxacin: (Major) Avoid coadministration of trazodone and levofloxacin. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Levofloxacin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia. Rare cases of TdP have been spontaneously reported during postmarketing surveillance in patients receiving levofloxacin. According to the manufacturer, levofloxacin should be avoided in patients taking drugs that can result in prolongation of the QT interval.
    Levomilnacipran: (Moderate) Coadministration of trazodone and levomilnacipran may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue levomilnacipran and trazodone and initiate symptomatic treatment if serotonin syndrome occurs.
    Levorphanol: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Reduce the initial dose of levorphanol by approximately 50% or more. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Linezolid: (Severe) Concurrent use of linezolid and trazodone is contraindicated due to an increased risk of serotonin syndrome. Trazodone is a serotonergic antidepressant and linezolid is a nonselective inhibitor of monoamine oxidase which increases central serotonin levels. If urgent psychiatric treatment is required, interventions other than trazodone (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving trazodone and requiring urgent treatment with linezolid, trazodone should be discontinued immediately and linezolid therapy initiated only if acceptable alternatives are not available and the potential benefits of linezolid outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid, whichever comes first. Trazodone may be resumed 24 hours after the last dose of linezolid.
    Lisdexamfetamine: (Moderate) Coadministration of trazodone and amphetamines may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. The MAOI activity of amphetamines may also be of concern with trazodone. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Trazodone and the amphetamine should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Lithium: (Major) Due to the risk of QT prolongation and torsade de pointes (TdP), the manufacturer of trazodone recommends avoiding use with other drugs that increase the QT interval. Lithium has been associated with a risk of QT prolongation. In addition, coadministration of trazodone and lithium may increase the risk of serotonin syndrome. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue lithium and trazodone and initiate symptomatic treatment if serotonin syndrome occurs.
    Lofexidine: (Major) Avoid coadministration of lofexidine with trazodone due to the potential for additive QT prolongation and torsade de pointes (TdP). Monitor ECG if coadministration cannot be avoided. Additionally, monitor for excessive hypotension and sedation during coadministration as lofexidine can potentiate the effects of CNS depressants. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of TdP.
    Long-acting beta-agonists: (Moderate) Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Coadministration with other drugs known to prolong the QT interval may potentiate the action of beta-agonists on the cardiovascular system.
    Loop diuretics: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
    Loperamide: (Major) At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Trazodone also prolongs the QT/QTc interval at therapeutic doses, and reports of TdP have occurred during post-marketing surveillance. The manufacturer of trazodone recommends avoiding trazodone in patients taking other drugs that prolong the QT interval.
    Loperamide; Simethicone: (Major) At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Trazodone also prolongs the QT/QTc interval at therapeutic doses, and reports of TdP have occurred during post-marketing surveillance. The manufacturer of trazodone recommends avoiding trazodone in patients taking other drugs that prolong the QT interval.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of trazodone and lopinavir; ritonavir due to the potential for additive effects on the QT interval; increased exposure to trazodone may also occur. Both trazodone and lopinavir; ritonavir are associated with QT prolongation; there are also postmarketing reports of torsade de pointes with trazodone. In addition, concurrent use may lead to substantial increases in trazodone plasma concentrations, further increasing the risk for adverse effects. If trazodone must be used with a potent CYP3A4 inhibitor, such as lopinavir; ritonavir, a lower dose of trazodone should be considered. (Major) Avoid coadministration of trazodone with ritonavir due to the potential for increased trazodone exposure and associated adverse effects including QT prolongation. If concurrent use cannot be avoided, consider a reduced dose of trazodone based on tolerability. Trazodone is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone.
    Lorazepam: (Major) Monitor for excessive sedation and somnolence during coadministration of trazodone and benzodiazepines. Concurrent use may result in additive CNS depression.
    Lumacaftor; Ivacaftor: (Moderate) Consider increasing the trazodone dose based on therapeutic response when coadministered with lumacaftor; ivacaftor. Concurrent use may decrease trazodone exposure. Trazodone is a CYP3A4 substrate; lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers decreased the exposure of trazodone compared to the use of trazodone alone.
    Lumateperone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lumateperone and trazodone. Concurrent use may result in additive CNS depression.
    Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as trazodone. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of torsade de pointes (TdP) with trazodone therapy.
    Magnesium Salicylate: (Moderate) The combined use of trazodone and salicylates that affect hemostasis may elevate the risk for an upper GI bleed. Trazodone may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of salicylates. Additionally, salicylates impair the gastric mucosa defenses by inhibiting prostaglandin formation. It would be prudent for clinicians to monitor the patient's clinical status closely if trazodone is added to or removed from the regimen of a patient stabilized on salicylate therapy.
    Magnesium Salts: (Minor) Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as heterocyclic antidepressants. Caution should be exercised when using these agents concurrently.
    Maprotiline: (Major) Avoid coadministration of trazodone and maprotiline. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Meclizine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Mefloquine: (Major) Avoid coadministration of trazodone and mefloquine. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    Meperidine: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Meperidine; Promethazine: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome. (Major) Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Promethazine has been reported to cause QT prolongation. Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may also occur when it is combined with other CNS depressants including trazodone.
    Meprobamate: (Moderate) Meprobamate should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. If used together, a reduction in the dose of one or both drugs may be needed.
    Mesoridazine: (Severe) Mesoridazine is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Mesoridazine is considered contraindicated for use along with agents that, when combined with a phenothiazine, may prolong the QT interval and increase the risk of TdP, and/or cause orthostatic hypotension. Because of the potential for TdP, the co-use of trazodone is contraindicated. Trazodone can prolong the QT/QTc interval at therapeutic doses and there are post-marketing reports of torsade de pointes (TdP).
    Metaxalone: (Moderate) The sedative effects of metaxalone and other CNS depressants may be additive. Trazodone is associated with sedation and should be used with metaxalone with caution. Both drugs have also been associated with serotonin syndrome. Due to the potential for serotonin syndrome, caution is advised when metaxalone is co-administered with drugs that may affect the serotonergic neurotransmitter systems, such as trazodone. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, sertraline and concurrent serotonergic agents should be discontinued.
    Methadone: (Major) Avoid coadministration of trazodone and methadone due to an additive risk of QT prolongation. Concomitant use of opioid agonists with trazodone may also cause serotonin syndrome and excessive sedation and somnolence. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of serotonin syndrome and excessive CNS depression. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of torsade de pointes (TdP). Methadone is associated with an increased risk for QT prolongation and torsade de pointes (TdP), especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.
    Methamphetamine: (Moderate) Coadministration of trazodone and amphetamines may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. The MAOI activity of amphetamines may also be of concern with trazodone. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Trazodone and the amphetamine should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Severe) According to the manufacturer of trazodone, treatment initiation with trazodone is contraindicated in patients currently receiving intravenous methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than trazodone (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving trazodone and requiring urgent treatment with intravenous methylene blue, trazodone should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits of methylene blue outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Trazodone may be re-initiated 24 hours after the last dose of methylene blue. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and trazodone increases central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving serotonergic agents such as selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving intravenous methylene blue with other serotonergic psychiatric agents are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
    Methohexital: (Major) Monitor for excessive sedation and somnolence during coadministration of trazodone and methohexital. Concurrent use may result in additive CNS depression.
    Methylene Blue: (Severe) According to the manufacturer of trazodone, treatment initiation with trazodone is contraindicated in patients currently receiving intravenous methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than trazodone (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving trazodone and requiring urgent treatment with intravenous methylene blue, trazodone should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits of methylene blue outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Trazodone may be re-initiated 24 hours after the last dose of methylene blue. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and trazodone increases central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving serotonergic agents such as selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving intravenous methylene blue with other serotonergic psychiatric agents are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death.
    Metronidazole: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include trazodone.
    Metyrapone: (Moderate) Metyrapone may cause dizziness and/or drowsiness. Other drugs that may also cause drowsiness, such as trazodone, should be used with caution. Additive drowsiness and/or dizziness is possible.
    Midazolam: (Major) Monitor for excessive sedation and somnolence during coadministration of trazodone and benzodiazepines. Concurrent use may result in additive CNS depression.
    Midostaurin: (Major) Avoid the concomitant use of midostaurin and trazodone; both drugs have been reported to increase the QT interval. If coadministration cannot be avoided, consider electrocardiogram monitoring. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of torsade de pointes.
    Mifepristone: (Major) Avoid coadministration of trazodone and mifepristone due to the potential for additive effects on the QT interval; increased exposure to trazodone may also occur. Both trazodone and mifepristone are associated with QT prolongation; there are also postmarketing reports of torsade de pointes with trazodone. In addition, concurrent use may lead to substantial increases in trazodone plasma concentrations, further increasing the risk for adverse effects. If trazodone must be used with a potent CYP3A4 inhibitor, such as mifepristone, a lower dose of trazodone should be considered.
    Milnacipran: (Moderate) Coadministration of trazodone and milnacipran may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue milnacipran and trazodone and initiate symptomatic treatment if serotonin syndrome occurs.
    Minocycline: (Minor) Injectable minocycline contains magnesium sulfate heptahydrate. Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as heterocyclic antidepressants (i.e., amoxapine, maprotiline, mirtazapine, and trazodone). Caution should be exercised when using these agents concurrently.
    Minoxidil: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
    Mirtazapine: (Major) Due to the risk of QT prolongation and torsade de pointes (TdP), the manufacturer of trazodone recommends avoiding use with other drugs that increase the QT interval. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during use of mirtazapine, primarily after overdose or in patients with risk factors for QT prolongation (e.g., concurrent use of other medications associated with QT prolongation). Coadministration of trazodone and mirtazapine may also increase the risk of serotonin syndrome. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue mirtazapine and trazodone and initiate symptomatic treatment if serotonin syndrome occurs.
    Mitotane: (Moderate) Consider increasing the trazodone dose based on therapeutic response when coadministered with mitotane. Concurrent use may decrease trazodone exposure. Trazodone is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers decreased the exposure of trazodone compared to the use of trazodone alone.
    Molindone: (Moderate) Molindone may cause central nervous system (CNS) depression thereby having additive effects with other drugs that can cause CNS depression such as trazodone. Caution is advisable during concurrent use.
    Monoamine oxidase inhibitors: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with trazodone or within 14 days of discontinuing treatment with trazodone. Conversely, trazodone should not be initiated within 14 days of stopping an MAOI. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Morphine: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. For extended-release morphine tablets, start with 15 mg every 12 hours. Morphine; naltrexone should be initiated at 1/3 to 1/2 the recommended starting dosage. Educate patients about the risks and symptoms of excessive CNS depression.
    Morphine; Naltrexone: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. For extended-release morphine tablets, start with 15 mg every 12 hours. Morphine; naltrexone should be initiated at 1/3 to 1/2 the recommended starting dosage. Educate patients about the risks and symptoms of excessive CNS depression.
    Moxifloxacin: (Major) Avoid coadministration of trazodone and moxifloxacin. Prolongation of the QT interval has been reported with administration of moxifloxacin. Post-marketing surveillance has identified very rare cases of ventricular arrhythmias including torsade de pointes (TdP), usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin, therefore the recommended dose or infusion rate should not be exceeded. According to the manufacturer, moxifloxacin should be avoided in patients taking drugs that can result in prolongation of the QT interval. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of TdP. Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    Nabilone: (Moderate) Nabilone or other CNS depressants should be combined cautiously with heterocyclic antidepressants because they could cause additive depressant effects and possible respiratory depression or hypotension.
    Nalbuphine: (Moderate) CNS depressants, such as nalbuphine, should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Nefazodone: (Moderate) Coadministration of trazodone and nefazodone may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue nefazodone and trazodone and initiate symptomatic treatment if serotonin syndrome occurs.
    Nelfinavir: (Major) Avoid coadministration of trazodone with nelfinavir due to the potential for increased trazodone exposure and associated adverse effects including QT prolongation. If concurrent use cannot be avoided, consider a reduced dose of trazodone based on tolerability. Trazodone is a CYP3A4 substrate; nelfinavir is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone.
    Netupitant, Fosnetupitant; Palonosetron: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as trazodone. The plasma concentrations of trazodone can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days.
    Nilotinib: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval. Trazodone can prolong the QT interval at therapeutic doses, and torsade de pointes (TdP) has been reported with post-marketing use. Additionally, nilotinib is a moderate CYP3A4 inhibitor and trazodone is a CYP3A4 substrate; administering these drugs together may result in increased trazodone levels. If the use of trazodone is required, hold nilotinib therapy. If the use of nilotinib and trazodone cannot be avoided, a trazodone dose reduction may be necessary; close monitoring of the QT interval is recommended.
    Nitroglycerin: (Minor) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as antidepressants. Patients should be monitored more closely for hypotension if nitroglycerin is used concurrently with antidepressants.
    Nitroprusside: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
    Nonsteroidal antiinflammatory drugs: (Moderate) Platelet aggregation may be impaired by trazodone due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving nonsteroidal antiinflammatory drugs (NSAIDs). Patients should be instructed to monitor for signs and symptoms of bleeding while taking trazodone concurrently with medications that impair platelet function and to promptly report any bleeding events to the practitioner.
    Norfloxacin: (Major) Avoid coadministration of norfloxacin and trazodone. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Quinolones have been associated with a risk of QT prolongation and TdP. Although extremely rare, torsade de pointes has been reported during post-marketing surveillance of norfloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Nortriptyline: (Moderate) Avoid coadministration of trazodone and tricyclic antidepressants (TCAs) due to the potential for QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported during treatment with trazodone. Tricyclic antidepressants have a possible risk for QT prolongation and TdP, particularly in overdose. In addition, concurrent use may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Octreotide: (Major) Avoid coadministration of octreotide and trazodone. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy warranting more cautious monitoring during octreotide administration in higher risk patients with cardiac disease. Since bradycardia is a risk factor for development of TdP, the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    Ofloxacin: (Major) Avoid coadministration of trazodone and ofloxacin. Some quinolones, including ofloxacin, have been associated with QT prolongation and infrequent cases of arrhythmia. Post-marketing surveillance for ofloxacin has identified very rare cases of torsades de pointes (TdP). Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of TdP. Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    Olanzapine: (Major) Avoid coadministration of trazodone and olanzapine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval in rare instances. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Trazodone can also cause CNS depression and if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of trazodone with ritonavir due to the potential for increased trazodone exposure and associated adverse effects including QT prolongation. If concurrent use cannot be avoided, consider a reduced dose of trazodone based on tolerability. Trazodone is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone.
    Ondansetron: (Major) Avoid coadministration due to the potential for QT prolongation. If ondansetron and trazodone must be coadministered, ECG monitoring is recommended. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of TdP.
    Oritavancin: (Moderate) Trazodone is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of trazodone may be reduced if these drugs are administered concurrently.
    Orphenadrine: (Moderate) CNS depressants, such as skeletal muscle relaxants, should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. A dose reduction of one or both drugs may be warranted.
    Osimertinib: (Major) Avoid coadministration of trazodone with osimertinib due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is necessary, periodically monitor ECGs and electrolytes; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Trazodone can prolong the QT/QTc interval at therapeutic doses; in addition, there are postmarketing reports of TdP. Concentration-dependent QTc prolongation has also occurred during clinical trials of osimertinib.
    Oxaliplatin: (Major) Avoid coadministration of trazodone with oxaliplatin due to the additive risk of QT prolongation. Trazodone can prolong the QT/QTc interval at therapeutic doses; in addition, there are postmarketing reports of torsade de pointes (TdP). QT prolongation and ventricular arrhythmias including fatal TdP have also been reported with oxaliplatin use in postmarketing experience.
    Oxazepam: (Major) Monitor for excessive sedation and somnolence during coadministration of trazodone and benzodiazepines. Concurrent use may result in additive CNS depression.
    Oxycodone: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Oxymorphone: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Reduce the initial oxymorphone dosage by 1/3 to 1/2. Educate patients about the risks and symptoms of excessive CNS depression.
    Paliperidone: (Major) Avoid coadministration of trazodone and paliperidone if possible. Trazodone can prolong the QT/QTc interval at therapeutic doses and there are postmarketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer of paliperidone, the drug should be avoided in combination with other agents also known to have this effect. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential. Concurrent use can also result in additive adverse effects such as drowsiness and dizziness.
    Panobinostat: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include trazodone.
    Paroxetine: (Moderate) Coadministration of trazodone and paroxetine may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue paroxetine and trazodone and initiate symptomatic treatment if serotonin syndrome occurs.
    Pasireotide: (Major) Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Drugs with a possible risk for QT prolongation and TdP include pasireotide.
    Pazopanib: (Major) Avoid coadministration of trazodone and pazopanib. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Pazopanib has been reported to prolong the QT interval. If pazopanib and the other drug must be continued, closely monitor the patient for QT interval prolongation. Pazopanib is also a weak inhibitor of CYP3A4. Coadministration of pazopanib and trazodone, a CYP3A4 substrate, may cause an increase in systemic concentrations of trazodone.
    Pentamidine: (Major) Pentamidine has been associated with QT prolongation and should be avoided in combination with trazodone. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    Pentazocine: (Moderate) Concomitant use of pentazocine with other CNS depressants such as trazodone can potentiate respiratory depression and/or sedation. The central nervous system (CNS) effects of pentazocine and other CNS depressants are additive. Trazodone has significant potential for sedation. In addition, both agents may increase serotonin activity, which may increase the risk for serotonin-related side effects and in rare cases lead to serotonin syndrome.
    Pentazocine; Naloxone: (Moderate) Concomitant use of pentazocine with other CNS depressants such as trazodone can potentiate respiratory depression and/or sedation. The central nervous system (CNS) effects of pentazocine and other CNS depressants are additive. Trazodone has significant potential for sedation. In addition, both agents may increase serotonin activity, which may increase the risk for serotonin-related side effects and in rare cases lead to serotonin syndrome.
    Pentobarbital: (Major) Monitor for excessive sedation and somnolence during coadministration of trazodone and pentobarbital. Concurrent use may result in additive CNS depression.
    Perphenazine: (Minor) Perphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Theoretically, the risk of QT prolongation may be increased if coadministered with drugs with a possible risk for QT prolongation, such as trazodone. In addition, phenothiazines can potentiate the CNS-depressant action of other drugs such as trazodone. Clinicians should note that additive CNS effects (e.g., oversedation, respiratory depression, and hypotension) may occur if perphenazine is administered concomitantly with trazodone.
    Perphenazine; Amitriptyline: (Moderate) Avoid coadministration of trazodone and tricyclic antidepressants (TCAs) due to the potential for QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported during treatment with trazodone. Tricyclic antidepressants have a possible risk for QT prolongation and TdP, particularly in overdose. In addition, concurrent use may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Minor) Perphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Theoretically, the risk of QT prolongation may be increased if coadministered with drugs with a possible risk for QT prolongation, such as trazodone. In addition, phenothiazines can potentiate the CNS-depressant action of other drugs such as trazodone. Clinicians should note that additive CNS effects (e.g., oversedation, respiratory depression, and hypotension) may occur if perphenazine is administered concomitantly with trazodone.
    Phenelzine: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with trazodone or within 14 days of discontinuing treatment with trazodone. Conversely, trazodone should not be initiated within 14 days of stopping an MAOI. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Phenobarbital: (Major) Monitor for excessive sedation and somnolence during coadministration of trazodone and phenobarbital. Concurrent use may result in additive CNS depression. Additionally, concurrent use may decrease trazodone exposure; adjust dose as needed based on therapeutic response. Trazodone is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers decreased the exposure of trazodone compared to the use of trazodone alone.
    Phenoxybenzamine: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
    Phentolamine: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
    Phenylephrine; Promethazine: (Major) Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Promethazine has been reported to cause QT prolongation. Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may also occur when it is combined with other CNS depressants including trazodone.
    Phenytoin: (Moderate) Consider increasing the trazodone dose based on therapeutic response when coadministered with phenytoin. Concurrent use may decrease trazodone exposure. Additionally, trazodone may increase phenytoin concentrations. Monitor phenytoin concentrations before initiating concomitant trazodone and continually during therapy; decrease phenytoin dose as clinically necessary. Trazodone is a CYP3A4 substrate; phenytoin is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers decreased the exposure of trazodone compared to the use of trazodone alone.
    Pimavanserin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as trazodone. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Coadministration may increase the risk for QT prolongation.
    Pimozide: (Severe) Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of TdP. Therefore, because of the potential for TdP, use coadministration is contraindicated.
    Pitolisant: (Major) Avoid coadministration of pitolisant with trazodone as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of torsade de pointes (TdP).
    Posaconazole: (Severe) The concurrent use of posaconazole and trazodone is contraindicated due to the risk of life threatening arrhythmias such as torsades de pointes (TdP). Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of trazodone. These drugs used in combination may result in elevated trazodone plasma concentrations, causing an increased risk for trazodone-related adverse events, such as QT prolongation. Additionally, posaconazole has been associated with prolongation of the QT interval as well as rare cases of TdP; avoid use with other drugs that may prolong the QT interval and are metabolized through CYP3A4, such as trazodone.
    Potassium-sparing diuretics: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
    Prasugrel: (Moderate) Platelet aggregation may be impaired by trazodone due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking trazodone concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Prazosin: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
    Pregabalin: (Major) Initiate pregabalin at the lowest recommended dose and monitor patients for symptoms of sedation and somnolence during coadministration of pregabalin and trazodone. Concomitant use of pregabalin with trazodone may cause additive CNS depression. Educate patients about the risks and symptoms of excessive CNS depression.
    Primaquine: (Major) Due to the potential for QT interval prolongation with primaquine, caution is advised with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with primaquine include trazodone.
    Primidone: (Major) Monitor for excessive sedation and somnolence during coadministration of trazodone and primidone. Concurrent use may result in additive CNS depression. Additionally, concurrent use may decrease trazodone exposure; adjust dose as needed based on therapeutic response. Trazodone is a CYP3A4 substrate; primidone is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers decreased the exposure of trazodone compared to the use of trazodone alone.
    Procainamide: (Major) Procainamide is associated with a well-established risk of QT prolongation and torsades de pointes (TdP) and should be avoided in combination with trazodone. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of TdP. Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    Procarbazine: (Moderate) Coadministration of trazodone and procarbazine may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue procarbazine and trazodone and initiate symptomatic treatment if serotonin syndrome occurs.
    Prochlorperazine: (Minor) Prochlorperazine, a phenothiazine, is associated with a possible risk for QT prolongation. Theoretically, the risk of QT prolongation may be increased if coadministered with drugs with a possible risk for QT prolongation, such as trazodone. In addition, phenothiazines can potentiate the CNS-depressant action of other drugs such as trazodone. Clinicians should note that additive CNS effects (e.g., oversedation, respiratory depression, and hypotension) may occur if prochlorperazine is administered concomitantly with trazodone.
    Promethazine: (Major) Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Promethazine has been reported to cause QT prolongation. Because promethazine causes pronounced sedation, an enhanced CNS depressant effect or additive drowsiness may also occur when it is combined with other CNS depressants including trazodone.
    Propafenone: (Major) Avoid coadministration of trazodone and propafenone. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of TdP.
    Propoxyphene: (Moderate) Concomitant use of propoxyphene with other CNS depressants such as trazodone can potentiate respiratory depression and/or sedation. The central nervous system (CNS) effects of propoxyphene and other CNS depressants are additive. Trazodone has significant potential for sedation. In addition, both agents may increase serotonin activity, which may increase the risk for serotonin-related side effects and in rare cases lead to serotonin syndrome.
    Protriptyline: (Moderate) Avoid coadministration of trazodone and tricyclic antidepressants (TCAs) due to the potential for QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported during treatment with trazodone. Tricyclic antidepressants have a possible risk for QT prolongation and TdP, particularly in overdose. In addition, concurrent use may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Quazepam: (Major) Monitor for excessive sedation and somnolence during coadministration of trazodone and benzodiazepines. Concurrent use may result in additive CNS depression.
    Quetiapine: (Major) Avoid coadministration of trazodone and quetiapine. Limited data, including some case reports, suggest that quetiapine may be associated with a significant prolongation of the QTc interval in rare instances. According to the manufacturer, use of quetiapine should be avoided in combination with drugs known to increase the QT interval. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of TdP. Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    Quinidine: (Major) Avoid coadministration of quinidine and trazodone if possible due to a potential increase in risk of QT prolongation and torsade de pointes (TdP). Quinidine administration is associated with QT prolongation and TdP. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of TdP for trazodone. Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    Ramelteon: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS depressant effects, including possible respiratory depression or hypotension. A dose reduction of one or both drugs may be warranted.
    Ranolazine: (Major) The manufacturer of trazodone recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP).Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval.The mean increase in QTc is about 6 milliseconds, measured at the Tmax of the maximum dosage (1000 mg PO twice daily). However, in 5% of the population studied, increases in the QTc of at least 15 milliseconds have been reported. In addition, ranolazine could impair the metabolism of trazodone through inhibition of CYP3A, thereby increasing the risk of trazodone-related adverse effects, including QT prolongation.
    Rasagiline: (Major) The manufacturer of rasagiline recommends against concurrent use with antidepressants, including trazodone, or use of an antidepressant within 14 days of discontinuing rasagiline since serotonin syndrome has been reported in patients treated with antidepressants and rasagiline. If coadministration is necessary, inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue rasagiline and trazodone and initiate symptomatic treatment if serotonin syndrome occurs.
    Remifentanil: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Reserpine: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
    Ribociclib: (Major) Avoid coadministration of ribociclib with trazodone due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of trazodone may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Trazodone is a CYP3A4 substrate that can also prolong the QT/QTc interval at therapeutic doses; in addition, there are postmarketing reports of TdP. Concomitant use may increase the risk for QT prolongation.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with trazodone due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of trazodone may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Trazodone is a CYP3A4 substrate that can also prolong the QT/QTc interval at therapeutic doses; in addition, there are postmarketing reports of TdP. Concomitant use may increase the risk for QT prolongation.
    Rifampin: (Moderate) Consider increasing the trazodone dose based on therapeutic response when coadministered with rifampin. Concurrent use may decrease trazodone exposure. Trazodone is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers decreased the exposure of trazodone compared to the use of trazodone alone.
    Rilpivirine: (Major) Avoid coadministration of trazodone and rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    Risperidone: (Major) Avoid coadministration of trazodone and risperidone. Risperidone has been associated with a possible risk for QT prolongation and/or torsade de pointes; however, data are currently lacking to establish causality in association with torsades de pointes (TdP). Reports of QT prolongation and torsades de pointes during risperidone therapy are noted by the manufacturer, primarily in the overdosage setting. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of TdP. Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    Ritonavir: (Major) Avoid coadministration of trazodone with ritonavir due to the potential for increased trazodone exposure and associated adverse effects including QT prolongation. If concurrent use cannot be avoided, consider a reduced dose of trazodone based on tolerability. Trazodone is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone.
    Romidepsin: (Major) Romidepsin has been reported to prolong the QT interval and should be avoided in combination with trazodone. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. If romidepsin must be coadministered with trazodone, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Safinamide: (Severe) Safinamide is contraindicated for use with trazodone due to the risk of serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. At least 14 days should elapse between the discontinuation of safinamide and the initiation of trazodone.
    Salicylates: (Moderate) The combined use of trazodone and salicylates that affect hemostasis may elevate the risk for an upper GI bleed. Trazodone may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of salicylates. Additionally, salicylates impair the gastric mucosa defenses by inhibiting prostaglandin formation. It would be prudent for clinicians to monitor the patient's clinical status closely if trazodone is added to or removed from the regimen of a patient stabilized on salicylate therapy.
    Salsalate: (Moderate) The combined use of trazodone and salicylates that affect hemostasis may elevate the risk for an upper GI bleed. Trazodone may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of salicylates. Additionally, salicylates impair the gastric mucosa defenses by inhibiting prostaglandin formation. It would be prudent for clinicians to monitor the patient's clinical status closely if trazodone is added to or removed from the regimen of a patient stabilized on salicylate therapy.
    Saquinavir: (Severe) The concurrent use of trazodone and saquinavir boosted with ritonavir is contraindicated due to the risk of life threatening cardiac arrythmias. Saquinavir boosted with ritonavir is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of trazodone. These drugs used together may result in large increases in trazodone serum concentrations, which could cause adverse events such as nausea, dizziness, hypotension, syncope, and cardiac arrhythmias.
    Secobarbital: (Major) Monitor for excessive sedation and somnolence during coadministration of trazodone and secobarbital. Concurrent use may result in additive CNS depression.
    Selegiline: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with trazodone or within 14 days of discontinuing treatment with trazodone. Conversely, trazodone should not be initiated within 14 days of stopping an MAOI. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Serotonin-Receptor Agonists: (Moderate) Coadministration of trazodone and serotonin-receptor agonists may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue the serotonin-receptor agonist and trazodone and initiate symptomatic treatment if serotonin syndrome occurs.
    Sertraline: (Major) Avoid coadministration of trazodone with sertraline due to the risk for additive QT prolongation and torsade de pointes (TdP); the risk of serotonin syndrome is also increased. Trazodone can prolong the QT/QTc interval at therapeutic doses and there are postmarketing reports of TdP. QTc prolongation and TdP have been reported during postmarketing use of sertraline; most cases had confounding risk factors. The risk of sertraline-induced QT prolongation is generally considered to be low in clinical practice. Its effect on QTc interval is minimal (typically less than 5 msec), and the drug has been used safely in patients with cardiac disease (e.g., recent myocardial infarction, unstable angina, chronic heart failure). In addition, serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Sevoflurane: (Major) Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Drugs with a known risk for QT prolongation and TdP include the halogenated anesthetics.
    Short-acting beta-agonists: (Minor) Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia. Coadministration with other drugs known to prolong the QT interval may potentiate the action of beta-agonists on the cardiovascular system.
    Sibutramine: (Moderate) Coadministration of trazodone and sibutramine may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue sibutramine and trazodone and initiate symptomatic treatment if serotonin syndrome occurs.
    Simeprevir: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of trazodone, which is a CYP3A4 substrate. Monitor patients for adverse effects of trazodone, such as QT prolongation and drowsiness/sedation.
    Siponimod: (Major) Avoid coadministration of siponimod and trazodone due to the potential for additive QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of torsade de pointes.
    Solifenacin: (Major) Avoid coadministration of trazodone and solifenacin. Solifenacin has been associated with dose-dependent prolongation of the QT interval. Torsades de pointes (TdP) has been reported with post-marketing use, although causality was not determined. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of TdP. Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    Sorafenib: (Major) Avoid coadministration of trazodone with sorafenib due to the risk of QT prolongation. Trazodone can prolong the QT/QTc interval at therapeutic doses; in addition, there are postmarketing reports of torsade de pointes (TdP). Sorafenib has also been associated with QT prolongation.
    Sotalol: (Major) Sotalol administration is associated with QT prolongation and torsades de pointes (TdP). Proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    St. John's Wort, Hypericum perforatum: (Moderate) Coadministration of trazodone and St. John's Wort may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue St. John's Wort and trazodone and initiate symptomatic treatment if serotonin syndrome occurs.
    Sufentanil: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Sunitinib: (Major) Avoid coadministration of trazodone in patients receiving other drugs that increase the QT interval, such as sunitinib. Trazodone can prolong the QT/QTc interval at therapeutic doses; in addition, there are postmarketing reports of torsade de pointes (TdP). Sunitinib can also cause dose-dependent QT prolongation, which may increase the risk for ventricular arrhythmias, including TdP.
    Suvorexant: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases.
    Tacrolimus: (Major) Tacrolimus causes QT prolongation and should be avoided in combination with trazodone. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    Tamoxifen: (Major) Avoid coadministration of tamoxifen with trazodone due to an increased risk of QT prolongation and torsade de pointes (TdP). Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of TdP.
    Tapentadol: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Tasimelteon: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS depressant effects, including possible respiratory depression or hypotension. A dose reduction of one or both drugs may be warranted.
    Tedizolid: (Minor) Caution is warranted with the concurrent use of tedizolid and trazodone. Tedizolid is an antibiotic that is also a weak reversible, non-selective inhibitor of MAO. Since monoamine oxidase type A deaminates serotonin, administration of a non-selective MAO inhibitor concurrently with trazodone can lead to serious reactions including serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering trazodone with telaprevir due to an increased potential for trazodone-related adverse event, such as nausea, dizziness, hypotension, and syncope. When used in combination, the plasma concentrations of trazodone were increased; thus, consider initiating trazodone at the lowest effective dose. If trazodone dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment.
    Telavancin: (Major) Telavancin has been associated with QT prolongation and should be avoided in combination with trazodone. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    Telithromycin: (Major) Avoid coadministration of trazodone and telithromycin due to the potential for additive effects on the QT interval; increased exposure to trazodone may also occur. Both trazodone and telithromycin are associated with QT prolongation; there are also postmarketing reports of torsade de pointes with trazodone. In addition, concurrent use may lead to substantial increases in trazodone plasma concentrations, further increasing the risk for adverse effects. If trazodone must be used with a potent CYP3A4 inhibitor, such as telithromycin, a lower dose of trazodone should be considered.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and trazodone is necessary, as the systemic exposure of trazodone may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of trazodone; consider increasing the dose of trazodone if necessary. Trazodone is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Temazepam: (Major) Monitor for excessive sedation and somnolence during coadministration of trazodone and benzodiazepines. Concurrent use may result in additive CNS depression.
    Terazosin: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
    Tetrabenazine: (Major) Avoid coadministration of trazodone and tetrabenazine. Tetrabenazine causes a small increase in the corrected QT interval (QTc). The manufacturer recommends avoiding concurrent use of tetrabenazine with other drugs known to prolong QTc. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. In addition, additive effects are possible when tetrabenazine is combined with other drugs that cause CNS depression. Concurrent use of tetrabenazine and drugs that can cause CNS depression, such as trazodone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
    Thalidomide: (Major) The use of CNS depressants, such as trazodone, concomitantly with thalidomide may cause an additive sedative effect and should be avoided. Thalidomide frequently causes drowsiness and somnolence. Dose reductions may be required. Patients should be instructed to avoid situations where drowsiness may be a problem and not to take other medications that may cause drowsiness without adequate medical advice. Advise patients as to the possible impairment of mental and/or physical abilities required for the performance of hazardous tasks, such as driving a car or operating other complex or dangerous machinery.
    Thiazide diuretics: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
    Thioridazine: (Severe) Thioridazine, a phenothiazine, is associated with an established risk of QT prolongation and torsade de pointes (TdP) and is contraindicated for use with other drugs that are known to prolong the QT interval, such as trazodone. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of TdP occurring with trazodone.
    Thiothixene: (Moderate) Thiothixene can potentiate the CNS-depressant action of other drugs such as trazodone. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
    Thrombolytic Agents: (Moderate) Platelet aggregation may be impaired by trazodone due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with trazodone.
    Ticagrelor: (Moderate) Platelet aggregation may be impaired by trazodone due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking trazodone concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Ticlopidine: (Moderate) Platelet aggregation may be impaired by trazodone due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking trazodone concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Tipranavir: (Major) Avoid coadministration of trazodone with tipranavir due to the potential for increased trazodone exposure and associated adverse effects including QT prolongation. If concurrent use cannot be avoided, consider a reduced dose of trazodone based on tolerability. Trazodone is a CYP3A4 substrate; tipranavir is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone.
    Tolterodine: (Major) Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers and should be avoided in combination with trazodone. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    Toremifene: (Major) Avoid coadministration of trazodone with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Trazodone can also prolong the QT/QTc interval at therapeutic doses; in addition, there are postmarketing reports of torsade de pointes (TdP).
    Tramadol: (Major) Concomitant use of opioid agonists with trazodone may cause excessive sedation, somnolence, and increased risk of serotonin syndrome. Limit the use of opioid pain medications with trazodone to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and serotonin syndrome.
    Tranylcypromine: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with trazodone or within 14 days of discontinuing treatment with trazodone. Conversely, trazodone should not be initiated within 14 days of stopping an MAOI. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Treprostinil: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
    Triazolam: (Major) Monitor for excessive sedation and somnolence during coadministration of trazodone and benzodiazepines. Concurrent use may result in additive CNS depression.
    Tricyclic antidepressants: (Moderate) Avoid coadministration of trazodone and tricyclic antidepressants (TCAs) due to the potential for QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported during treatment with trazodone. Tricyclic antidepressants have a possible risk for QT prolongation and TdP, particularly in overdose. In addition, concurrent use may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Trifluoperazine: (Minor) Trifluoperazine, a phenothiazine, is associated with a possible risk for QT prolongation. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval; if the drugs must be used together, use with caution. In addition, phenothiazines should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Trimipramine: (Moderate) Avoid coadministration of trazodone and tricyclic antidepressants (TCAs) due to the potential for QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported during treatment with trazodone. Tricyclic antidepressants have a possible risk for QT prolongation and TdP, particularly in overdose. In addition, concurrent use may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Triprolidine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Triptorelin: (Major) Avoid coadministration of trazodone with triptorelin due to the risk of QT prolongation. Trazodone can prolong the QT/QTc interval at therapeutic doses; in addition, there are postmarketing reports of torsade de pointes (TdP). Androgen deprivation therapy (i.e., triptorelin) may prolong the QT/QTc interval.
    Valerian, Valeriana officinalis: (Moderate) The German Commission E and other groups warn that any substances that act on the CNS, including psychopharmacologic agents, may interact with valerian, Valeriana officinalis. These interactions are probably pharmacodynamic in nature, or result from additive mechanisms of action.
    Vandetanib: (Major) Avoid coadministration of vandetanib with trazodone due to an increased risk of QT prolongation and torsade de pointes (TdP). Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Trazodone can also prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of TdP.
    Vardenafil: (Major) Avoid coadministration of vardenafil and trazodone. Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produce an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). When vardenafil (10 mg) was given with gatifloxacin (400 mg), an additive effect on the QT interval was observed. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    Vemurafenib: (Major) Avoid coadministration of trazodone and vemurafenib. If vemurafenib and trazodone must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Vemurafenib has been associated with QT prolongation. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP).
    Venlafaxine: (Major) Due to the risk of QT prolongation and torsade de pointes (TdP), the manufacturer of trazodone recommends avoiding trazodone in patients receiving other drugs that cause QT prolongation and TdP. Venlafaxine has a possible risk for QT prolongation and TdP. In addition, coadministration of trazodone and venlafaxine may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue venlafaxine and trazodone and initiate symptomatic treatment if serotonin syndrome occurs.
    Vilazodone: (Moderate) Coadministration of trazodone and vilazodone may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue vilazodone and trazodone and initiate symptomatic treatment if serotonin syndrome occurs.
    Voriconazole: (Major) Avoid coadministration of voriconazole with trazodone due to the potential for additive effects on the QT interval; increased exposure to trazodone may also occur. Both drugs are associated with QT prolongation; there are also postmarketing reports of torsade de pointes (TdP) with trazodone. Voriconazole has also been associated with rare cases of torsades de pointes, cardiac arrest, and sudden death. In addition, coadministration of voriconazole (a strong CYP3A4 inhibitor) with trazodone (a CYP3A4 substrate) may result in elevated trazodone plasma concentrations and an increased risk for adverse events, including QT prolongation. If these drugs are given together, consider decreasing the dose of trazodone and closely monitor for prolongation of the QT interval. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
    Vorinostat: (Major) Avoid coadministration of trazodone and vorinostat. Vorinostat therapy is associated with a risk of QT prolongation. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    Vortioxetine: (Moderate) Coadministration of trazodone and vortioxetine may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue vortioxetine and trazodone and initiate symptomatic treatment if serotonin syndrome occurs.
    Zaleplon: (Moderate) In premarketing studies, zaleplon potentiated the CNS effects of ethanol, imipramine, and thioridazine for at least 2 to 4 hours. Other drugs that may have additive CNS effects with zaleplon but have not been studied include trazodone. If used together, a reduction in the dose of one or both drugs may be needed.
    Ziconotide: (Moderate) Trazodone is a CNS depressant medication that may increase drowsiness, dizziness, and confusion that are associated with ziconotide.
    Ziprasidone: (Major) Concomitant use of ziprasidone and trazodone should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of TdP. Therefore, the manufacturer of trazodone recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    Zolpidem: (Moderate) Zolpidem should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. If used together, a reduction in the dose of one or both drugs may be needed. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.

    PREGNANCY AND LACTATION

    Pregnancy

    Although available studies cannot definitively establish the absence of risk, published prospective cohort studies, case series, and case reports over several decades with trazodone use in pregnant women have not identified any drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes. It should be noted that all available studies have methodological limitations, including small sample sizes and inconsistent comparator groups. A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. The women who discontinued antidepressants during pregnancy were more likey to experience a relapse of major depression than those who continued antidepressants. Consider the risk of untreated depression versus the potential for adverse fetal outcomes when discontinuing or changing treatment with trazodone during pregnancy and postpartum. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry.

    The developmental and health benefits of breast-feeding should be considered along with the clinical need of the mother for trazodone and any potential adverse effects on the breastfed infant from trazodone or from the underlying maternal condition. Trazodone is excreted into breast milk; however, limited data from postmarketing reports have not identified trazodone-associated adverse effects on the breastfed child. There are no data regarding the effect of trazodone on milk production. Patients should advise their physician of their intention to breast-feed. Alternative therapy may be considered. A pooled analysis found that maternal use of sertraline, along with nortriptyline and paroxetine, usually produced undetectable or low drug concentrations in infant serum and, therefore, may be the preferred antidepressants in breast-feeding mothers.

    MECHANISM OF ACTION

    Mechanism of Action: Similar to fluoxetine, trazodone inhibits the reuptake of serotonin, although trazodone is less potent than fluoxetine in this regard. Trazodone appears to act as a serotonin agonist at higher doses (6—8 mg/kg), yet appears to antagonize serotonin at low doses (0.05—1 mg/kg). Antidepressant activity is believed to be produced by blocking the reuptake of serotonin at the presynaptic neuronal membrane. Long-term therapy also can affect postsynaptic neuronal receptor binding sites. Trazodone has no influence on the reuptake of norepinephrine or dopamine within the CNS. There is some evidence in animals that norepinephrine release is enhanced by trazodone. Trazodone does not inhibit monoamine oxidase.Anticholinergic activity is lower with trazodone than with the tricyclic antidepressants. It has a sedative effect, which is believed to be produced by the alpha-adrenergic blocking action and modest histamine blockade. Total sleep time is increased, but unlike the tricyclics, trazodone does not affect stage 4 sleep. Trazodone has weak skeletal muscle-relaxant activity and no anticonvulsant activity. Unlike the tricyclics, trazodone has no direct quinidine-like action on the cardiovascular system. Hypotension may be a result of lowered arterial blood pressure caused by the blocking of pressor response to norepinephrine. Trazodone may affect the endocrine system, but results are inconclusive.

    PHARMACOKINETICS

    Trazodone is administered orally. The drug is highly protein bound (89% to 95%). Distribution occurs without selective localization into any tissue. In vitro studies in human liver microsomes show that trazodone undergoes oxidation to an active metabolite, m-chlorophenylpiperazine (mCPP), by CYP3A4. Other metabolic pathways have not been well described. The mean terminal half-life is about 10 hours. Less than 1% of an oral dose is excreted unchanged in the urine. Elimination is mainly through the urine, with about 70% to 75% of a dose being excreted, mainly as metabolites, within 72 hours.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4
    Trazodone is extensively metabolized in the liver, primarily by CYP3A4. Concurrent use of CYP3A4 inhibitors may necessitate lower dose of trazodone and concurrent use of CYP3A4 inducers may necessitate higher doses of trazodone. Use of potent CYP3A4 inhibitors may increase the risk of trazodone-associated cardiac arrhythmias.

    Oral Route

    Trazodone is well absorbed after oral administration. Food affects absorption. When taken with or shortly after a meal, there may be an increase in the amount of drug absorbed, a decrease in peak plasma concentrations, and a delay in the time taken to reach peak concentrations. Peak levels are achieved 1 hour after dosing in the fasting state and 2 hours after dosing with food following administration of the immediate-release formulation. When the extended-release tablets are taken shortly after ingestion of a high-fat meal, Cmax increases by about 86% compared to administration under fasting conditions. However, Tmax is not significantly affected by food.