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    Miscellaneous Antidepressants

    BOXED WARNING

    Children, suicidal ideation

    Trazodone is not FDA approved for the treatment of depression in children. In October 2004, the FDA directed manufacturers of all antidepressants to include a boxed warning detailing the risk of suicide in children. A causal role has been established for antidepressants in inducing suicidality in pediatric patients. The risk of suicidality for these drugs was identified in a pooled analysis of 24 placebo-controlled trials (n = 4400) lasting up to 16 weeks in pediatric patients with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. The analysis showed a greater risk of suicidality during the first few months of treatment in those receiving antidepressants (SSRIs and others). The average risk of such events on drug was 4% and 2% for placebo; however, no suicides occurred in these trials. Pooled analysis of short-term clinical trials during early phase treatment with SSRIs and other antidepressants in young adults (18 to 24 years) also showed an increased risk of suicidal thinking and behavior. The clinical need for an antidepressant in children or young adults for any use must be weighed against the risk of increased suicidality; patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior, particularly within the first few months of starting therapy or at the time of dose increase or decrease; such observation would generally include at least weekly face-to-face contact with patients during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks; additional contact by telephone may be appropriate between visits. It is unknown if the suicidality risk in children and young adults extends to longer-term therapy (i.e., beyond several months). The possibility of a suicide attempt is inherent in patients with depressive symptoms, whether these occur in primary depression or in association with another primary disorder such as OCD. All patients with a history of suicidal ideation or behaviors and those with a prominence of suicidal ideation prior to treatment are considered at an increased risk for suicidal ideation or attempts, and should be closely monitored during treatment with trazodone. In patients who exhibit changes in symptoms, worsening of depression or suicidality, a decision should be made to change or discontinue treatment. If discontinuing, medication should be tapered as rapidly as possible, but with recognition that abruptly discontinuing treatment can also cause adverse symptoms. All antidepressants should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose.

    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.

    Children† and Adolescents† 6 years and older

    Data are limited. Initially, 1.5 to 2 mg/kg/day PO in divided doses, increase gradually at 3 or 4 day intervals, as tolerated or needed. Max: 6 mg/kg/day PO in divided doses or not to exceed 400 mg/day PO, whichever is less.

    Oral dosage (extended-release tablets)
    Adults

    Initially, 150 mg PO once daily late in the evening, preferably at bedtime; give on an empty stomach. Increase gradually by 75 mg/day PO at 3 day intervals, as tolerated or needed. Max: 375 mg/day PO.

    For the treatment of insomnia†.
    Oral dosage
    Adults

    Doses up to 100 mg (range 25 mg to 100 mg) PO at bedtime have commonly been evaluated in clinical trials. In clinical use, initiate at 25 or 50 mg PO at bedtime and titrate upward if needed within this range according to efficacy and as tolerated. Efficacy of low-dose trazodone as a sleep aid has been shown most consistently in secondary insomnia due to depression; few trials have evaluated trazodone for efficacy in primary insomnia. More placebo-controlled studies of subjective and objective effects are needed to determine whether trazodone has efficacy in the treatment of insomnia without major depression. The American Academy of Sleep Medicine guidelines recommend use of low-dose trazodone as a second-line treatment option for secondary insomnia when treating concurrent depression or anxiety. The drug is a third-line agent in cases of first- and second-line treatment failures (e.g., melatonin-receptor agonists, benzodiazepine-receptor agonists such as zolpidem, temazepam) in chronic primary insomnia. One study suggests trazodone use for insomnia is associated impairment of short-term memory, verbal learning, or motor skills, which necessitates caution. Long-term safety and efficacy have not been adequately evaluated.

    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.

    Elderly

    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; however, 6 mg/kg/day PO, not to exceed 400 mg/day PO has been used off-label.

    Children

    6—18 years: Safety and efficacy have not been established; however, 6 mg/kg/day PO, not to exceed 400 mg/day PO has been used off-label.
    < 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, however, no quantitative guidelines are available.

    Renal Impairment

    CrCl >= 50 ml/min: No dosage adjustment needed.
    CrCl < 50 ml/min: Specific guidelines are not available; no dosage adjustments are expected to be needed in initial dosage. Titrate according to patient response and tolerance.

    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 between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Oleptro:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    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, thyroid disease

    Trazodone can prolong the QT/QTc interval. In addition, there are post-market reports of torsade de pointes (TdP), a life-threatening arrhythmia, during use of the immediate-release form of trazodone. Some cases 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. 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. 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. Trazodone is not recommended for use during the initial recovery phase following an acute myocardial infarction.

    Hepatic disease

    Trazodone should be used with caution in patients with hepatic disease because the drug could accumulate and adverse reactions could increase.

    Renal impairment

    Trazodone and its metabolites are excreted primarily in the urine and should be used with caution in patients with renal impairment because of possible reduced excretion and increased effects of the drug.

    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.

    Children, suicidal ideation

    Trazodone is not FDA approved for the treatment of depression in children. In October 2004, the FDA directed manufacturers of all antidepressants to include a boxed warning detailing the risk of suicide in children. A causal role has been established for antidepressants in inducing suicidality in pediatric patients. The risk of suicidality for these drugs was identified in a pooled analysis of 24 placebo-controlled trials (n = 4400) lasting up to 16 weeks in pediatric patients with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. The analysis showed a greater risk of suicidality during the first few months of treatment in those receiving antidepressants (SSRIs and others). The average risk of such events on drug was 4% and 2% for placebo; however, no suicides occurred in these trials. Pooled analysis of short-term clinical trials during early phase treatment with SSRIs and other antidepressants in young adults (18 to 24 years) also showed an increased risk of suicidal thinking and behavior. The clinical need for an antidepressant in children or young adults for any use must be weighed against the risk of increased suicidality; patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior, particularly within the first few months of starting therapy or at the time of dose increase or decrease; such observation would generally include at least weekly face-to-face contact with patients during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks; additional contact by telephone may be appropriate between visits. It is unknown if the suicidality risk in children and young adults extends to longer-term therapy (i.e., beyond several months). The possibility of a suicide attempt is inherent in patients with depressive symptoms, whether these occur in primary depression or in association with another primary disorder such as OCD. All patients with a history of suicidal ideation or behaviors and those with a prominence of suicidal ideation prior to treatment are considered at an increased risk for suicidal ideation or attempts, and should be closely monitored during treatment with trazodone. In patients who exhibit changes in symptoms, worsening of depression or suicidality, a decision should be made to change or discontinue treatment. If discontinuing, medication should be tapered as rapidly as possible, but with recognition that abruptly discontinuing treatment can also cause adverse symptoms. All antidepressants should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose.

    Geriatric

    Geriatric patients generally require a lower dosage and are more susceptible to adverse reactions. If an elderly patient is unable to take an SSRI or SNRI antidepressant, trazodone may be preferred over a tricyclic antidepressant because of the lower incidence of cardiac effects. Trazodone may cause low plasma sodium concentrations and syndrome of inappropriate antidiuretic hormone secretion (SIADH); elderly patients appear to be at greater risk. 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.

    Driving or operating machinery

    Patients should be warned to use caution when driving or operating machinery until they know how trazodone will affect them.

    Pregnancy

    Trazodone is classified as FDA pregnancy risk category C. Animal studies have shown congenital anomalies and other fetal adverse effects at doses ranging from 15—50 times the maximum human dose. Animal data is not always predictive of human response and adequate studies have not been done in humans; benefits versus risks should be considered.

    Electroconvulsive therapy (ECT)

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

    MAOI therapy

    Use caution in combining trazodone with MAOI therapy (see Drug Interactions).

    Breast-feeding

    According to the manufacturer, caution should be exercised when administering trazodone to a breast-feeding woman. Trazodone is excreted into the breast milk. Although no problems have been documented during breast-feeding, the benefits and risks should be taken into account. The American Academy of Pediatrics has suggested that antidepressant use, including trazodone, during breast-feeding may be of concern. Consider the benefits of breast-feeding, the risk of potential drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding baby experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Anticoagulant therapy, bleeding, thrombolytic therapy

    Monitor patients for signs and symptoms of bleeding. 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 anticoagulant therapy, thrombolytic therapy, or other medications that enhance bleeding potential may increase this risk (see Drug Interactions). While no association between trazodone and bleeding events was shown, patients taking trazodone should be should be instructed to promptly report any bleeding events to the practitioner.

    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.

    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.

    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
    irritability / Delayed / Incidence not known
    anxiety / 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 (unspecified) / 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: (Moderate) Heterocyclic antidepressants can increase CNS and/or respiratory depression, dizziness, and may also lower the seizure threshold, leading to pharmacodynamic interactions with barbiturate sedatives and anticonvulsants. Psychomotor impairment may be increased.
    Acetaminophen; Butalbital; Caffeine: (Moderate) Heterocyclic antidepressants can increase CNS and/or respiratory depression, dizziness, and may also lower the seizure threshold, leading to pharmacodynamic interactions with barbiturate sedatives and anticonvulsants. Psychomotor impairment may be increased.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) CNS depressants such as opiate agonists should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. If concurrent use of codeine and another CNS depressant is imperative, reduce the dose of one or both drugs. (Moderate) Heterocyclic antidepressants can increase CNS and/or respiratory depression, dizziness, and may also lower the seizure threshold, leading to pharmacodynamic interactions with barbiturate sedatives and anticonvulsants. Psychomotor impairment may be increased.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) CNS depressants such as opiate agonists should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. The dose of one or both drugs should be reduced.
    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: (Moderate) CNS depressants such as opiate agonists should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. If concurrent use of codeine and another CNS depressant is imperative, reduce the dose of one or both drugs.
    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; 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: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include trazodone.
    Acetaminophen; Oxycodone: (Moderate) Concomitant use of oxycodone with other CNS depressants, such as trazodone, can lead to additive respiratory depression, hypotension, profound sedation, or coma. Prior to concurrent use of oxycodone 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. Consider the patient's use of alcohol or illicit drugs. Oxycodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate oxycodone at one-third to one-half the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    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) Due to the risk of serotonin syndrome, concurrent use of trazodone and other serotonergic medications, such as tramadol, should be avoided if possible. If concomitant use is clinically warranted, patients should be informed of the increased risk of serotonin syndrome, particularly during treatment initiation and during dose increases. 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. Treatment with trazodone and any concomitant serotonergic agents should be discontinued immediately if signs and symptoms of serotonin syndrome occur, and supportive symptomatic treatment should be initiated.
    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: (Moderate) Concomitant use of alfentanil with other CNS depressants can potentiate the effects of alfentanil on respiration, alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    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: (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.
    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: (Major) Due to the risk of serotonin syndrome, concurrent use of trazodone and other serotonergic medications, such as tricyclic antidepressants, should be avoided if possible. If concomitant use is clinically warranted, patients should be informed of the increased risk of serotonin syndrome, particularly during treatment initiation and during dose increases. 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. Treatment with trazodone and any concomitant serotonergic agents should be discontinued immediately if signs and symptoms of serotonin syndrome occur, and supportive symptomatic treatment should be initiated. In addition, the manufacturer of trazodone recommends avoiding trazodone in patients receiving other drugs that increase the QT interval due to reports of QT prolongation and torsade de pointes (TdP) during treatment with trazodone. Tricyclic antidepressants have a possible risk for QT prolongation and TdP, particularly in overdose.
    Amitriptyline; Chlordiazepoxide: (Major) Due to the risk of serotonin syndrome, concurrent use of trazodone and other serotonergic medications, such as tricyclic antidepressants, should be avoided if possible. If concomitant use is clinically warranted, patients should be informed of the increased risk of serotonin syndrome, particularly during treatment initiation and during dose increases. 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. Treatment with trazodone and any concomitant serotonergic agents should be discontinued immediately if signs and symptoms of serotonin syndrome occur, and supportive symptomatic treatment should be initiated. In addition, the manufacturer of trazodone recommends avoiding trazodone in patients receiving other drugs that increase the QT interval due to reports of QT prolongation and torsade de pointes (TdP) during treatment with trazodone. Tricyclic antidepressants have a possible risk for QT prolongation and TdP, particularly in overdose. (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.
    Amobarbital: (Moderate) Heterocyclic antidepressants can increase CNS and/or respiratory depression, dizziness, and may also lower the seizure threshold, leading to pharmacodynamic interactions with barbiturate sedatives and anticonvulsants. Psychomotor impairment may be increased.
    Amoxapine: (Moderate) Trazodone inhibits serotonin reuptake, although, it is less potent than other serotonin reuptake inhibitors in this regard. Amoxapine augments the activity of norepinephrine and serotonin. Because of the similarity in mechanism of action, patients receiving amoxapine and trazodone together should be monitored for effects related to excessive serotonergic stimulation (e.g., serotonin syndrome), as well as additive effects like sedation. 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.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Coadministration of clarithromycin and trazodone should be avoided. Clarithromycin is associated with an established risk for QT prolongation and 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.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Coadministration of clarithromycin and trazodone should be avoided. Clarithromycin is associated with an established risk for QT prolongation and 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.
    Amphetamine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering trazodone with other drugs that have serotonergic properties such as amphetamines. 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. The MAOI activity of amphetamines may also be of concern with trazodone. The safe and effective use of trazodone with amphetamines has not been established; however, this combination has been used clinically. Further study is needed to fully elucidate the severity and frequency of adverse effects that may occur from concomitant administration of amphetamines and trazodone. Patients receiving trazodone and an amphetamine should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. Trazodone and the amphetamine should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Amphetamine; Dextroamphetamine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering trazodone with other drugs that have serotonergic properties such as amphetamines. 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. The MAOI activity of amphetamines may also be of concern with trazodone. The safe and effective use of trazodone with amphetamines has not been established; however, this combination has been used clinically. Further study is needed to fully elucidate the severity and frequency of adverse effects that may occur from concomitant administration of amphetamines and trazodone. Patients receiving trazodone and an amphetamine should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. Trazodone and the amphetamine should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Amphetamines: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering trazodone with other drugs that have serotonergic properties such as amphetamines. 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. The MAOI activity of amphetamines may also be of concern with trazodone. The safe and effective use of trazodone with amphetamines has not been established; however, this combination has been used clinically. Further study is needed to fully elucidate the severity and frequency of adverse effects that may occur from concomitant administration of amphetamines and trazodone. Patients receiving trazodone and an amphetamine should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. 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.
    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: (Moderate) Heterocyclic antidepressants can increase CNS and/or respiratory depression, dizziness, and may also lower the seizure threshold, leading to pharmacodynamic interactions with barbiturate sedatives and anticonvulsants. Psychomotor impairment may be increased. (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: (Moderate) CNS depressants such as opiate agonists should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. If concurrent use of codeine and another CNS depressant is imperative, reduce the dose of one or both drugs. (Moderate) Heterocyclic antidepressants can increase CNS and/or respiratory depression, dizziness, and may also lower the seizure threshold, leading to pharmacodynamic interactions with barbiturate sedatives and anticonvulsants. Psychomotor impairment may be increased. (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: (Moderate) CNS depressants such as opiate agonists should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. The dose of one or both drugs should be reduced. (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: (Moderate) CNS depressants such as opiate agonists should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. If concurrent use of codeine and another CNS depressant is imperative, reduce the dose of one or both drugs. (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; 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: (Moderate) Concomitant use of oxycodone with other CNS depressants, such as trazodone, can lead to additive respiratory depression, hypotension, profound sedation, or coma. Prior to concurrent use of oxycodone 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. Consider the patient's use of alcohol or illicit drugs. Oxycodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate oxycodone at one-third to one-half the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory 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; 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: (Moderate) Concomitant administration of atazanavir, with or without ritonavir, and trazodone may increase plasma concentrations of trazodone. When coadministered, adverse events including nausea, dizziness, hypotension, and syncope have been observed. Use trazodone cautiously with CYP3A4 inhibitors such as atazanavir; a lower dose of trazodone should be considered.
    Atazanavir; Cobicistat: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of trazodone and cobicistat. Concurrent use may result in elevated trazodone plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is an inhibitor of CYP3A4 and CYP2D6, two isoenzymes 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. (Moderate) Concomitant administration of atazanavir, with or without ritonavir, and trazodone may increase plasma concentrations of trazodone. When coadministered, adverse events including nausea, dizziness, hypotension, and syncope have been observed. Use trazodone cautiously with CYP3A4 inhibitors such as atazanavir; a lower dose of trazodone should be considered.
    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: (Moderate) Heterocyclic antidepressants can increase CNS and/or respiratory depression, dizziness, and may also lower the seizure threshold, leading to pharmacodynamic interactions with barbiturate sedatives and anticonvulsants. Psychomotor impairment may be increased.
    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.
    Barbiturates: (Moderate) Heterocyclic antidepressants can increase CNS and/or respiratory depression, dizziness, and may also lower the seizure threshold, leading to pharmacodynamic interactions with barbiturate sedatives and anticonvulsants. Psychomotor impairment may be increased.
    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: (Moderate) Heterocyclic antidepressants can increase CNS and/or respiratory depression, dizziness, and may also lower the seizure threshold, leading to pharmacodynamic interactions with barbiturate sedatives and anticonvulsants. Psychomotor impairment may be increased.
    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: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering trazodone with other drugs that have serotonergic properties such as amphetamines. 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. The MAOI activity of amphetamines may also be of concern with trazodone. The safe and effective use of trazodone with amphetamines has not been established; however, this combination has been used clinically. Further study is needed to fully elucidate the severity and frequency of adverse effects that may occur from concomitant administration of amphetamines and trazodone. Patients receiving trazodone and an amphetamine should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. 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.
    Brigatinib: (Moderate) Monitor for decreased efficacy of trazodone if coadministration with brigatinib is necessary. Trazodone is a CYP3A substrate and brigatinib induces CYP3A in vitro; plasma concentrations of trazodone may decrease.
    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: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include trazodone.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include trazodone.
    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: (Major) Due to the risk of serotonin syndrome, concurrent use of trazodone and other serotonergic medications, such as buspirone, should be avoided if possible. If concomitant use is clinically warranted, patients should be informed of the increased risk of serotonin syndrome, particularly during treatment initiation and during dose increases. 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. Treatment with trazodone and any concomitant serotonergic agents should be discontinued immediately if signs and symptoms of serotonin syndrome occur, and supportive symptomatic treatment should be initiated. Myoclonus, which responded to a serotonin antagonist, was reported in a patient taking trazodone with buspirone and a dopamine antagonist.
    Butabarbital: (Moderate) Heterocyclic antidepressants can increase CNS and/or respiratory depression, dizziness, and may also lower the seizure threshold, leading to pharmacodynamic interactions with barbiturate sedatives and anticonvulsants. Psychomotor impairment may be increased.
    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.
    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) Carbamazepine has been found to reduce plasma concentrations of trazodone when coadministered. Patients should be closely monitored, as an increased dose of trazodone may be needed when these drugs are coadministered. Trazodone, in turn, can lower the seizure threshold of anticonvulsants. Patients may require increased concentrations of anticonvulsants to achieve equivalent effects if trazodone is added. Finally, drowsiness may be additive between trazodone and anticonvulsants.
    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: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include trazodone.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include trazodone.
    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.
    Central-acting adrenergic agents: (Major) Cyclic antidepressants can interfere with the therapeutic antihypertensive effect of clonidine. Since guanabenz acts similarly to clonidine, it, too, may be affected by cyclic antidepressants. Limited data suggest that a clinically significant interaction occurs between trazodone and clonidine. Until more data are available, a similar interaction should be expected between trazodone and guanabenz or guanfacine. In general, due to additive hypotensive effects, patients receiving other antihypertensive agents concurrently with trazodone may experience hypotension, which could cause dizziness or faintness. Decreased dosage of the antihypertensive agent may be required in some patients.
    Ceritinib: (Major) Avoid coadministration of ceritinib with trazodone due to increased trazodone exposure and the risk of QT prolongation. If coadministration is unavoidable, periodically monitor electrolytes and ECGs; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib is a CYP3A4 inhibitor that causes concentration-dependent prolongation of the QT interval. Trazodone is primarily metabolized by CYP3A4 and is also associated with QT /QTc prolongation at therapeutic doses; additionally, there are postmarketing reports of torsade de pointes (TdP) with trazodone administration.
    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.
    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: (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.
    Chlordiazepoxide; Clidinium: (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.
    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: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. (Moderate) CNS depressants such as opiate agonists should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. If concurrent use of codeine and another CNS depressant is imperative, reduce the dose of one or both drugs.
    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: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. (Moderate) CNS depressants such as opiate agonists should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. The dose of one or both drugs should be reduced.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. (Moderate) CNS depressants such as opiate agonists should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. The dose of one or both drugs should be reduced.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include trazodone.
    Chlorpheniramine; Hydrocodone: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include trazodone.
    Chlorpheniramine; Hydrocodone; 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) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include trazodone.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include trazodone.
    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: (Major) Cyclic antidepressants can interfere with the therapeutic antihypertensive effect of clonidine. Since guanabenz acts similarly to clonidine, it, too, may be affected by cyclic antidepressants. Limited data suggest that a clinically significant interaction occurs between trazodone and clonidine. Until more data are available, a similar interaction should be expected between trazodone and guanabenz or guanfacine. In general, due to additive hypotensive effects, patients receiving other antihypertensive agents concurrently with trazodone may experience hypotension, which could cause dizziness or faintness. Decreased dosage of the antihypertensive agent may be required in some patients.
    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.
    Cinacalcet: (Moderate) Monitor for increased trazodone-related adverse effects if coadministered with cinacalcet due to the potential for increased exposure to the active metabolite of trazodone, meto-chlorophenylpiperazine (mCPP). Accumulation of mCPP has been reported to increase dysphoria, anxiety, and agitation. Cinacalcet is a strong CYP2D6 inhibitor; the active metabolite of trazodone, meto-chlorophenylpiperazine (mCPP), is metabolized by CYP2D6.
    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) Due to the risk of serotonin syndrome, concurrent use of trazodone and other serotonergic medications, such as selective serotonin reuptake inhibitors (SSRIs), should be avoided if possible. If concomitant use is clinically warranted, patients should be informed of the increased risk of serotonin syndrome, particularly during treatment initiation and during dose increases. 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. Treatment with trazodone and any concomitant serotonergic agents should be discontinued immediately if signs and symptoms of serotonin syndrome occur, and supportive symptomatic treatment should be initiated. Both trazodone and citalopram may additionally cause QT prolongation. The manufacturers of both trazodone and citalopram recommend avoiding use with other drugs that increase the QT interval.
    Clarithromycin: (Major) Coadministration of clarithromycin and trazodone should be avoided. Clarithromycin is associated with an established risk for QT prolongation and 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.
    Clemastine: (Moderate) CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Clomipramine: (Major) Due to the risk of serotonin syndrome, concurrent use of trazodone and other serotonergic medications, such as tricyclic antidepressants, should be avoided if possible. If concomitant use is clinically warranted, patients should be informed of the increased risk of serotonin syndrome, particularly during treatment initiation and during dose increases. 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. Treatment with trazodone and any concomitant serotonergic agents should be discontinued immediately if signs and symptoms of serotonin syndrome occur, and supportive symptomatic treatment should be initiated. In addition, the manufacturer of trazodone recommends avoiding trazodone in patients receiving other drugs that increase the QT interval due to reports of QT prolongation and torsade de pointes (TdP) during treatment with trazodone. Tricyclic antidepressants have a possible risk for QT prolongation and TdP, particularly in overdose.
    Clonazepam: (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.
    Clonidine: (Major) Cyclic antidepressants can interfere with the therapeutic antihypertensive effect of clonidine. Since guanabenz acts similarly to clonidine, it, too, may be affected by cyclic antidepressants. Limited data suggest that a clinically significant interaction occurs between trazodone and clonidine. Until more data are available, a similar interaction should be expected between trazodone and guanabenz or guanfacine. In general, due to additive hypotensive effects, patients receiving other antihypertensive agents concurrently with trazodone may experience hypotension, which could cause dizziness or faintness. Decreased dosage of the antihypertensive agent may be required in some patients.
    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: (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.
    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: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of trazodone and cobicistat. Concurrent use may result in elevated trazodone plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is an inhibitor of CYP3A4 and CYP2D6, two isoenzymes 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.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of trazodone and cobicistat. Concurrent use may result in elevated trazodone plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is an inhibitor of CYP3A4 and CYP2D6, two isoenzymes 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.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of trazodone and cobicistat. Concurrent use may result in elevated trazodone plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is an inhibitor of CYP3A4 and CYP2D6, two isoenzymes 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.
    Codeine: (Moderate) CNS depressants such as opiate agonists should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. If concurrent use of codeine and another CNS depressant is imperative, reduce the dose of one or both drugs.
    Codeine; Guaifenesin: (Moderate) CNS depressants such as opiate agonists should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. If concurrent use of codeine and another CNS depressant is imperative, reduce the dose of one or both drugs.
    Codeine; 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. (Moderate) CNS depressants such as opiate agonists should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. If concurrent use of codeine and another CNS depressant is imperative, reduce the dose of one or both drugs.
    Codeine; 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. (Moderate) CNS depressants such as opiate agonists should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. If concurrent use of codeine and another CNS depressant is imperative, reduce the dose of one or both drugs.
    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) Concomitant use of conivaptan and trazodone, a CYP3A4 substrate, should be avoided. Conivaptan is a potent inhibitor of CYP3A4 and may increase plasma concentrations of drugs that are primarily metabolized by CYP3A4. 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.
    Crizotinib: (Major) According to the manufacturer of trazodone, coadministration with other drugs that increase the QT interval, such as crizotinib, should be avoided. If coadministration cannot be avoided, monitor ECGs and electrolytes. Trazodone can prolong the QT/QTc interval at therapeutic doses; in addition, there are postmarketing reports of torsade de pointes (TdP). Crizotinib has been associated with concentration-dependent QT prolongation.
    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: (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). Cyclobenzaprine is structurally similar to tricyclic antidepressants. Tricyclic antidepressants have been reported to prolong the QT interval, especially when given in excessive doses (or in overdosage settings). Cyclobenzaprine is associated with a possible risk of QT prolongation and torsades de pointes (TdP), particularly in the event of acute overdose. In addition, many skeletal muscle relaxants, including cyclobenzaprine, produce CNS depressant effects which can be additive with trazodone.
    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: (Moderate) Coadministration of trazodone and CYP3A inhibitors, such as darunavir, may result in increased trazodone plasma concentrations. If trazodone is used with CYP3A inhibitors, the combination should be used with caution and a lower dose of trazodone should be considered. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone with the CYP3A4 inhibitor ritonavir.
    Darunavir; Cobicistat: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of trazodone and cobicistat. Concurrent use may result in elevated trazodone plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is an inhibitor of CYP3A4 and CYP2D6, two isoenzymes 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. (Moderate) Coadministration of trazodone and CYP3A inhibitors, such as darunavir, may result in increased trazodone plasma concentrations. If trazodone is used with CYP3A inhibitors, the combination should be used with caution and a lower dose of trazodone should be considered. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone with the CYP3A4 inhibitor ritonavir.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (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). Ritonavir has a possible risk for QT prolongation and TdP. In addition, ritonavir may decrease the hepatic CYP metabolism of trazodone, resulting in increased trazodone concentrations. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir.
    Dasatinib: (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 dasatinib. In vitro studies have shown that dasatinib has the potential to prolong cardiac ventricular repolarization (prolong QT interval).
    Daunorubicin: (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). Acute cardiotoxicity can occur during administration of daunorubicin, doxorubicin, epirubicin, or idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    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: (Moderate) Delavirdine is a potent inhibitor of CYP2D6 and might decrease the metabolism of trazodone, leading to increased concentrations and risk of adverse reactions.
    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: (Major) Due to the risk of serotonin syndrome, concurrent use of trazodone and other serotonergic medications, such as tricyclic antidepressants, should be avoided if possible. If concomitant use is clinically warranted, patients should be informed of the increased risk of serotonin syndrome, particularly during treatment initiation and during dose increases. 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. Treatment with trazodone and any concomitant serotonergic agents should be discontinued immediately if signs and symptoms of serotonin syndrome occur, and supportive symptomatic treatment should be initiated. In addition, the manufacturer of trazodone recommends avoiding trazodone in patients receiving other drugs that increase the QT interval due to reports of QT prolongation and torsade de pointes (TdP) during treatment with trazodone. Tricyclic antidepressants have a possible risk for QT prolongation and TdP, particularly in overdose.
    Desvenlafaxine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as trazodone and desvenlafaxine. 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 occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Deutetrabenazine: (Major) Avoid coadministration of deutetrabenazine with trazodone. Clinically relevant QT 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: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering trazodone with other drugs that have serotonergic properties such as amphetamines. 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. The MAOI activity of amphetamines may also be of concern with trazodone. The safe and effective use of trazodone with amphetamines has not been established; however, this combination has been used clinically. Further study is needed to fully elucidate the severity and frequency of adverse effects that may occur from concomitant administration of amphetamines and trazodone. Patients receiving trazodone and an amphetamine should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. 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: (Severe) Quinidine administration is associated with QT prolongation and torsades de pointes (TdP). Quinidine inhibits CYP2D6 and has QT-prolonging actions; quinidine is contraindicated with other drugs that prolong the QT interval and are metabolized by CYP2D6 as the effects on the QT interval may be increased during concurrent use of these agents. Drugs that prolong the QT and are substrates for CYP2D6 that are contraindicated with quinidine include trazodone.
    Diazepam: (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.
    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) Increased serum digoxin levels have been reported in patients taking trazodone and digoxin concomitantly. The clinical significance of this interaction is not known.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) CNS depressants such as opiate agonists should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. The dose of one or both drugs should be reduced.
    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: (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) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include trazodone.
    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: (Severe) Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Because of the potential for TdP, use of dofetilide with trazodone is contraindicated.
    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.
    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: (Major) Due to the risk of serotonin syndrome, concurrent use of trazodone and other serotonergic medications, such as tricyclic antidepressants, should be avoided if possible. If concomitant use is clinically warranted, patients should be informed of the increased risk of serotonin syndrome, particularly during treatment initiation and during dose increases. 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. Treatment with trazodone and any concomitant serotonergic agents should be discontinued immediately if signs and symptoms of serotonin syndrome occur, and supportive symptomatic treatment should be initiated. In addition, the manufacturer of trazodone recommends avoiding trazodone in patients receiving other drugs that increase the QT interval due to reports of QT prolongation and torsade de pointes (TdP) during treatment with trazodone. Tricyclic antidepressants have a possible risk for QT prolongation and TdP, particularly in overdose.
    Doxorubicin: (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). Acute cardiotoxicity can occur during administration of daunorubicin, doxorubicin, epirubicin, or idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    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, THC: (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: (Major) Coadministration may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with SNRIs, including duloxetine, both when taken alone, but especially when coadministered with other serotonergic agents. Trazodone blocks the reuptake of serotonin at the presynaptic neuronal membrane. 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. Patients should be informed of the possible increased risk of serotonin syndrome. If serotonin syndrome occurs, duloxetine and the concomitant serotonergic agent should be discontinued and symptomatic treatment should be initiated. Because psychoactive drugs may have additive CNS effects, be alert for drowsiness or other CNS complaints.
    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.
    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.
    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.
    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.
    Epirubicin: (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). Acute cardiotoxicity can occur during administration of daunorubicin, doxorubicin, epirubicin, or idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    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) Coadministration should be avoided due to the potential for serotonin syndrome and QT prolongation. One case report is noted of the serotonin syndrome developing in a patient on trazodone (as well as nefazodone) after the addition of paroxetine. If concomitant use is clinically warranted, patients should be informed of the increased risk of serotonin syndrome, particularly during treatment initiation and during dose increases. 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. Treatment with trazodone and any concomitant serotonergic agents should be discontinued immediately if signs and symptoms of serotonin syndrome occur, and supportive symptomatic treatment should be initiated. In addition, due to the risk of QT prolongation and torsade de pointes (TdP), the manufacturers of both trazodone and citalopram recommend avoiding use with other drugs that increase the QT interval.
    Eslicarbazepine: (Moderate) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Eslicarbazepine is chemically related to carbamazepine. Carbamazepine 400 mg/day has been found to reduce plasma concentrations of trazodone by 76% when coadministered. Plasma concentrations of meta-chlorophenylpiperazine (mCPP), the metabolite of trazodone, were reduced by 60%. Patients should be closely monitored, as an increased dose of trazodone may be needed when coadministered with eslicarbazepine. Trazodone, in turn, can lower the seizure threshold of anticonvulsants. Patients may require increased concentrations of anticonvulsants to achieve equivalent effects if trazodone is added. Finally, drowsiness may be additive between trazodone and anticonvulsants.
    Estazolam: (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.
    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: (Major) Alcohol is associated with CNS depression. The combined use of alcohol and CNS depressants can lead to additive CNS depression, which could be dangerous in tasks requiring mental alertness and fatal in overdose. Alcohol taken with other CNS depressants can lead to additive respiratory depression, hypotension, profound sedation, or coma. Consider the patient's use of alcohol or illicit drugs when prescribing CNS depressant medications. In many cases, the patient should receive a lower dose of the CNS depressant initially if the patient is not likely to be compliant with avoiding alcohol.
    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.
    Felbamate: (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.
    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) Due to the risk of serotonin syndrome, concurrent use of trazodone and other serotonergic medications, such as fentanyl, should be avoided if possible. If concomitant use is clinically warranted, patients should be informed of the increased risk of serotonin syndrome, particularly during treatment initiation and during dose increases. 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. Treatment with trazodone and any concomitant serotonergic agents should be discontinued immediately if signs and symptoms of serotonin syndrome occur, and supportive symptomatic treatment should be initiated. In addition, CNS depressants such as opiate agonists should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    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.
    Flumazenil: (Major) The use of flumazenil to treat overdosage of mixtures of drugs should be undertaken with caution. Treatment with flumazenil can result in convulsions and cardiac dysrhythmias induced by drugs such as cyclic antidepressants.
    Fluoxetine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fluoxetine with other drugs that have serotonergic properties 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. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, fluoxetine and concurrent serotonergic agents should be discontinued. In addition, because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Trazodone is associated with a possible risk of QT prolongation and TdP.
    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) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fluoxetine with other drugs that have serotonergic properties 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. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, fluoxetine and concurrent serotonergic agents should be discontinued. In addition, because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Trazodone is associated with a possible risk of QT prolongation and TdP.
    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: (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.
    Fluvoxamine: (Major) Concurrent use of trazodone and fluvoxamine should be avoided if possible. If use together is clinically warranted, patients should be informed of the increased risk of serotonin syndrome, particularly during treatment initiation and during dose increases. Trazodone blocks the reuptake of serotonin at the presynaptic neuronal membrane. Serotonin syndrome has been reported with SSRIs, including fluvoxamine, both when taken alone, but especially when co-administered with other serotonergic agents. One case report is noted of the serotonin syndrome developing in a patient on trazodone (as well as nefazodone) after the addition of paroxetine. 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. Treatment with fluvoxamine and any concomitant serotonergic agents should be discontinued immediately if signs and symptoms of serotonin syndrome occur, and supportive symptomatic treatment should be initiated.
    Fosamprenavir: (Major) Concomitant administration of fosamprenavir, with or without ritonavir, and trazodone may increase plasma concentrations of trazodone. When amprenavir and trazodone were coadministered, adverse events including nausea, dizziness, hypotension, and syncope have been observed. Use trazodone cautiously with CYP3A4 inhibitors such as fosamprenavir; a lower dose of trazodone should be considered.
    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.
    Gabapentin: (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.
    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.
    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.
    Goserelin: (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 goserelin. Androgen deprivation therapy (e.g., goserelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Granisetron: (Major) Avoid coadministration of granisetron and trazodone. Granisetron has been associated with QT prolongation. According to the manufacturer, use of granisetron in patients concurrently treated with drugs known to prolong the QT interval and/or are arrhythmogenic, may result in clinical consequences. Trazodone can prolong the QT/QTc interval at therapeutic doses. 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, because of the potential risk and severity of serotonin syndrome, use caution when administering granisetron with other drugs that have serotonergic properties 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, discontinue granisetron and concurrent serotonergic agents and initiate appropriate medical treatment.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include trazodone.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include trazodone.
    Guanabenz: (Major) Cyclic antidepressants can interfere with the therapeutic antihypertensive effect of clonidine. Since guanabenz acts similarly to clonidine, it, too, may be affected by cyclic antidepressants. Limited data suggest that a clinically significant interaction occurs between trazodone and clonidine. Until more data are available, a similar interaction should be expected between trazodone and guanabenz or guanfacine. In general, due to additive hypotensive effects, patients receiving other antihypertensive agents concurrently with trazodone may experience hypotension, which could cause dizziness or faintness. Decreased dosage of the antihypertensive agent may be required in some patients.
    Guanfacine: (Major) Cyclic antidepressants can interfere with the therapeutic antihypertensive effect of clonidine. Since guanabenz acts similarly to clonidine, it, too, may be affected by cyclic antidepressants. Limited data suggest that a clinically significant interaction occurs between trazodone and clonidine. Until more data are available, a similar interaction should be expected between trazodone and guanabenz or guanfacine. In general, due to additive hypotensive effects, patients receiving other antihypertensive agents concurrently with trazodone may experience hypotension, which could cause dizziness or faintness. Decreased dosage of the antihypertensive agent may be required in some patients.
    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.
    Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include trazodone.
    Hydantoins: (Moderate) Hydantoins may induce hepatic microsomal enzymes and may increase the metabolism of trazodone. Trazodone, in turn, may increase serum hydantoin levels. In addition, trazodone can lower the seizure threshold. Finally, drowsiness may be additive between trazodone, fosphenytoin, phenytoin or other anticonvulsants.
    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.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Major) Cyclic antidepressants can interfere with the therapeutic antihypertensive effect of clonidine. Since guanabenz acts similarly to clonidine, it, too, may be affected by cyclic antidepressants. Limited data suggest that a clinically significant interaction occurs between trazodone and clonidine. Until more data are available, a similar interaction should be expected between trazodone and guanabenz or guanfacine. In general, due to additive hypotensive effects, patients receiving other antihypertensive agents concurrently with trazodone may experience hypotension, which could cause dizziness or faintness. Decreased dosage of the antihypertensive agent may be required in some patients.
    Hydrocodone: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include trazodone.
    Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include trazodone.
    Hydrocodone; Phenylephrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include trazodone.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include trazodone.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include trazodone.
    Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone 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. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include trazodone.
    Hydromorphone: (Moderate) Concomitant use of hydromorphone with other central nervous system (CNS) depressants can potentiate the effects of hydromorphone and may lead to additive CNS or respiratory depression, profound sedation, or coma. Examples of drugs associated with CNS depression include trazodone. Prior to concurrent use of hydromorphone 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. Consider the patient's use of alcohol or illicit drugs. If hydromorphone is used concurrently with a CNS depressant, a reduced dosage of hydromorphone and/or the CNS depressant is recommended; start with one-third to one-half of the estimated hydromorphone starting dose when using hydromorphone extended-release tablets. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    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) Post-marketing data indicate that hydroxyzine causes QT prolongation and Torsade de Pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with hydroxyzine include trazodone. In addition, because hydroxyzine causes pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including trazodone.
    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: (Moderate) Concomitant use of oxycodone with other CNS depressants, such as trazodone, can lead to additive respiratory depression, hypotension, profound sedation, or coma. Prior to concurrent use of oxycodone 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. Consider the patient's use of alcohol or illicit drugs. Oxycodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate oxycodone at one-third to one-half the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    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.
    Idarubicin: (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). Acute cardiotoxicity can occur during administration of daunorubicin, doxorubicin, epirubicin, or idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with trazodone, a CYP3A substrate, as trazodone toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    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: (Major) Due to the risk of serotonin syndrome, concurrent use of trazodone and other serotonergic medications, such as tricyclic antidepressants, should be avoided if possible. If concomitant use is clinically warranted, patients should be informed of the increased risk of serotonin syndrome, particularly during treatment initiation and during dose increases. 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. Treatment with trazodone and any concomitant serotonergic agents should be discontinued immediately if signs and symptoms of serotonin syndrome occur, and supportive symptomatic treatment should be initiated. In addition, the manufacturer of trazodone recommends avoiding trazodone in patients receiving other drugs that increase the QT interval due to reports of QT prolongation and torsade de pointes (TdP) during treatment with trazodone. Tricyclic antidepressants have a possible risk for QT prolongation and TdP, particularly in overdose.
    Indinavir: (Major) It is likely that indinavir, a CYP3A4 inhibitor, may lead to substantial increases in trazodone plasma concentrations, with the potential for adverse effects. If trazodone is used with a potent CYP3A4 inhibitor, a lower dose of trazodone should be considered
    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 heterocyclic antidepressants (e.g., trazodone, mirtazapine, amoxapine, maptrotiline) or within 14 days of discontinuing treatment with a heterocyclic antidepressant. Conversely, heterocyclic antidepressants should not be initiated within 14 days of stopping an MAOI. The manufacturer of rasagiline does not contraindicate the combination but recommends avoiding use of antidepressants with rasagiline or within 14 days of discontinuing rasagiline. 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 syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    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.
    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.
    Ivacaftor: (Minor) Use caution when administering ivacaftor and trazodone concurrently. Ivacaftor is an inhibitor of CYP3A and trazodone is partially metabolized by CYP3A. Co-administration can theoretically increase trazodone exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Kava Kava, Piper methysticum: (Moderate) The German Commission E and other groups warn that any substances that act on the CNS, including trazodone, may interact with the phytomedicinal kava kava, Piper methysticum. These interactions are probably pharmacodynamic in nature, or result from additive mechanisms of action.
    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.
    Lacosamide: (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. Drowsiness may be additive between trazodone and other anticonvulsants.
    Lamotrigine: (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.
    Lapatinib: (Major) Avoid coadministration of lapatinib and trazodone. Lapatinib can prolong the QT interval. Lapatinib should be administered with caution to patients who have or may develop prolongation of QTc such as patients taking anti-arrhythmic medicines or other medicinal products that lead to 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.
    Lenvatinib: (Major) Trazodone should be used cautiously and with close monitoring with lenvatinib. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). QT prolongation was reported in patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) in a double-blind, randomized, placebo-controlled clinical trial after receiving lenvatinib daily at the recommended dose; the QT/QTc interval was not prolonged, however, after a single 32 mg dose (1.3 times the recommended daily dose) in healthy subjects.
    Leuprolide: (Major) Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with leuprolide include trazodone.
    Leuprolide; Norethindrone: (Major) Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with leuprolide include trazodone.
    Levetiracetam: (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.
    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: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties 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, levomilnacipran and trazodone should be discontinued.
    Levorphanol: (Moderate) Concomitant use of levorphanol with other CNS depressants such as trazodone can potentiate the effects of levorphanol on respiration, blood pressure, and alertness. Severe hypotension, respiratory depression, profound sedation, or coma may occur. Prior to concurrent use of levorphanol 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. Consider the patient's use of alcohol or illicit drugs. When concomitant treatment with levorphanol with another CNS depressant is necessary, reduce the dose of 1 or both drugs. The initial dose of levorphanol should be reduced by approximately 50% or more when levorphanol is used with another drug that may depress respiration.
    Linezolid: (Severe) Treatment initiation with heterocyclic antidepressants (e.g., trazodone, amoxapine, maprotiline, mirtazapine) is contraindicated in patients currently receiving linezolid due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than these antidepressants (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving these antidepressants and requiring urgent treatment with linezolid, the antidepressant 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. The antidepressant may be re-initiated 24 hours after the last dose of linezolid
    Lisdexamfetamine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering trazodone with other drugs that have serotonergic properties such as amphetamines. 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. The MAOI activity of amphetamines may also be of concern with trazodone. The safe and effective use of trazodone with amphetamines has not been established; however, this combination has been used clinically. Further study is needed to fully elucidate the severity and frequency of adverse effects that may occur from concomitant administration of amphetamines and trazodone. Patients receiving trazodone and an amphetamine should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. 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 serotonin syndrome, concurrent use of trazodone and other serotonergic medications, such as lithium, should be avoided if possible. If concomitant use is clinically warranted, patients should be informed of the increased risk of serotonin syndrome, particularly during treatment initiation and during dose increases. 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. Treatment with trazodone and any concomitant serotonergic agents should be discontinued immediately if signs and symptoms of serotonin syndrome occur, and supportive symptomatic treatment should be initiated. Additionally, both trazodone and lithium have been associated with QT prolongation. If use together is not avoidable, close monitoring is advised.
    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) 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). Lopinavir; ritonavir has a possible risk for QT prolongation and TdP. In addition, ritonavir may decrease the hepatic CYP metabolism of trazodone, resulting in increased trazodone concentrations. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. (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). Ritonavir has a possible risk for QT prolongation and TdP. In addition, ritonavir may decrease the hepatic CYP metabolism of trazodone, resulting in increased trazodone concentrations. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir.
    Lorazepam: (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. CNS depressants should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may reduce the efficacy of trazodone by decreasing its systemic exposure. If used together, monitor patients closely for efficacy; a trazodone dosage adjustment may be required to obtain the desired therapeutic effect. Trazodone is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Coadministration of trazodone and carbamazepine, another strong CYP3A inducer, resulted in a 76% and 60% reduction in the plasma concentrations of trazodone and its active metabolite chlorophenylpiperazine, respectively.
    Lumacaftor; Ivacaftor: (Minor) Use caution when administering ivacaftor and trazodone concurrently. Ivacaftor is an inhibitor of CYP3A and trazodone is partially metabolized by CYP3A. Co-administration can theoretically increase trazodone exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    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.
    Magnesium Sulfate; Potassium Sulfate; Sodium Sulfate: (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: (Moderate) CNS depressants such as opiate agonists should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. Meperidine should be used with great caution and at a reduced dosage if used concurrently with a CNS depressant.
    Meperidine; 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. (Moderate) CNS depressants such as opiate agonists should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension. Meperidine should be used with great caution and at a reduced dosage if used concurrently with a CNS depressant.
    Mephobarbital: (Moderate) Heterocyclic antidepressants can increase CNS and/or respiratory depression, dizziness, and may also lower the seizure threshold, leading to pharmacodynamic interactions with barbiturate sedatives and anticonvulsants. Psychomotor impairment may be increased.
    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) Due to the risk of serotonin syndrome and the potential for QT prolongation and torsade de pointes (TdP), concurrent use of trazodone and other serotonergic medications, such as fentanyl, should be avoided if possible. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Methadone is considered to be associated with an increased risk for QT prolongation and torsades de pointes (TdP), especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day). Laboratory studies, both in vivo and in vitro, have demonstrated that methadone inhibits cardiac potassium channels and prolongs the QT interval. 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. If concomitant use is clinically warranted, patients should be informed of the increased risk of QT prolongation and serotonin syndrome, particularly during treatment initiation and during dose increases. 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. Treatment with trazodone and any concomitant serotonergic agents should be discontinued immediately if signs and symptoms of serotonin syndrome occur, and supportive symptomatic treatment should be initiated. In addition, CNS depressants such as opiate agonists should be used cautiously in patients receiving trazodone because of additive CNS-depressant effects, including possible respiratory depression or hypotension.
    Methamphetamine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering trazodone with other drugs that have serotonergic properties such as amphetamines. 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. The MAOI activity of amphetamines may also be of concern with trazodone. The safe and effective use of trazodone with amphetamines has not been established; however, this combination has been used clinically. Further study is needed to fully elucidate the severity and frequency of adverse effects that may occur from concomitant administration of amphetamines and trazodone. Patients receiving trazodone and an amphetamine should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. 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: (Moderate) Heterocyclic antidepressants can increase CNS and/or respiratory depression, dizziness, and may also lower the seizure threshold, leading to pharmacodynamic interactions with barbiturate sedatives and anticonvulsants. Psychomotor impairment may be increased.
    Methyldopa: (Major) Cyclic antidepressants can interfere with the therapeutic antihypertensive effect of clonidine. Since guanabenz acts similarly to clonidine, it, too, may be affected by cyclic antidepressants. Limited data suggest that a clinically significant interaction occurs between trazodone and clonidine. Until more data are available, a similar interaction should be expected between trazodone and guanabenz or guanfacine. In general, due to additive hypotensive effects, patients receiving other antihypertensive agents concurrently with trazodone may experience hypotension, which could cause dizziness or faintness. Decreased dosage of the antihypertensive agent may be required in some patients.
    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: (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.
    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, RU-486: (Major) Avoid coadministration of trazodone and mifepristone. 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. Mifepristone has been associated with dose-dependent prolongation of the QT interval. There is no experience with high exposure or concomitant use with other QT prolonging drugs. To minimize the risk of QT prolongation, the lowest effective dose should always be used.
    Milnacipran: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering levomilnacipran with other drugs that have serotonergic properties 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, levomilnacipran and concurrent serotonergic agents should be discontinued.
    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) Concomitant use of mirtazapine and trazodone may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes. Because trazodone can prolong the QT/QTc interval at therapeutic doses and there are postmarketing reports of TdP, the manufacturer recommends avoiding trazodone in patients receiving 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). Both mirtazapine and trazodone have central serotonin-enhancing effects; serotonin syndrome is possible. 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 serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Mitotane: (Major) Use caution if mitotane and trazodone are used concomitantly, and monitor for decreased efficacy of trazodone and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and trazodone is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of trazodone. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with trazodone.
    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 heterocyclic antidepressants (e.g., trazodone, mirtazapine, amoxapine, maptrotiline) or within 14 days of discontinuing treatment with a heterocyclic antidepressant. Conversely, heterocyclic antidepressants should not be initiated within 14 days of stopping an MAOI. The manufacturer of rasagiline does not contraindicate the combination but recommends avoiding use of antidepressants with rasagiline or within 14 days of discontinuing rasagiline. 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 syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Morphine: (Major) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include trazodone. Prior to concurrent use of morphine 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. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression. In addition, because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering drugs with serotonergic properties such as morphine and trazodone. 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 and trazodone should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Morphine; Naltrexone: (Major) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include trazodone. Prior to concurrent use of morphine 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. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours, extended-release capsules). Monitor patients for sedation and respiratory depression. In addition, because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering drugs with serotonergic properties such as morphine and trazodone. 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 and trazodone should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    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: (Major) Due to the risk of serotonin syndrome, concurrent use of trazodone and other serotonergic medications, such as nefazodone, should be avoided if possible. One case report is noted of the serotonin syndrome developing in a patient on trazodone (as well as nefazodone) after the addition of paroxetine. If concomitant use is clinically warranted, patients should be informed of the increased risk of serotonin syndrome, particularly during treatment initiation and during dose increases. 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. Treatment with trazodone and any concomitant serotonergic agents should be discontinued immediately if signs and symptoms of serotonin syndrome occur, and supportive symptomatic treatment should be initiated.
    Nelfinavir: (Major) Coadminister trazodone and CYP3A4 inhibitors such as nelfinavir with caution and consider a lower dose of trazodone. Nelfinavir may inhibit CYP3A4 metabolism of trazodone, resulting in increased trazodone plasma concentrations. Post-marketing reports of nausea, dizziness, hypotension, and syncope have been observed with the coadministration of trazodone and ritonavir. Similar results are expected with nelfinavir.
    Netupitant; 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: (Major) Due to the risk of serotonin syndrome, concurrent use of trazodone and other serotonergic medications, such as tricyclic antidepressants, should be avoided if possible. If concomitant use is clinically warranted, patients should be informed of the increased risk of serotonin syndrome, particularly during treatment initiation and during dose increases. 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. Treatment with trazodone and any concomitant serotonergic agents should be discontinued immediately if signs and symptoms of serotonin syndrome occur, and supportive symptomatic treatment should be initiated. In addition, the manufacturer of trazodone recommends avoiding trazodone in patients receiving other drugs that increase the QT interval due to reports of QT prolongation and torsade de pointes (TdP) during treatment with trazodone. Tricyclic antidepressants have a possible risk for QT prolongation and TdP, particularly in overdose.
    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) 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). Ritonavir has a possible risk for QT prolongation and TdP. In addition, ritonavir may decrease the hepatic CYP metabolism of trazodone, resulting in increased trazodone concentrations. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir.
    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 coadministration cannot be avoided, periodically monitor ECGs and electrolytes. Trazodone can prolong the QT/QTc interval at therapeutic doses; in addition, there are postmarketing reports of TdP. Concentration-dependent QTc prolongation has also been suggested at the recommended dosing of osimertinib in a pharmacokinetic/pharmacodynamic analysis. Concomitant use may increase the risk of QT prolongation.
    Oxaliplatin: (Major) Oxaliplatin 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). QT prolongation and ventricular arrhythmias including fatal TdP have been reported with oxaliplatin use in post-marketing experience. Coadministration may result in additive effects on the QT interval.
    Oxazepam: (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.
    Oxcarbazepine: (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.
    Oxycodone: (Moderate) Concomitant use of oxycodone with other CNS depressants, such as trazodone, can lead to additive respiratory depression, hypotension, profound sedation, or coma. Prior to concurrent use of oxycodone 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. Consider the patient's use of alcohol or illicit drugs. Oxycodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate oxycodone at one-third to one-half the usual dosage in patients that are concurrently receiving another CNS depressant. Also, consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression.
    Oxymorphone: (Moderate) Concomitant use of oxymorphone with other CNS depressants may produce additive CNS depressant effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur; examples of other CNS depressants include trazodone. Prior to concurrent use of oxymorphone 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. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with oxymorphone, a reduced dosage of oxymorphone (1/3 to 1/2 of the usual dose) and/or the CNS depressant is recommended. If the extended-release oxymorphone tablets are used concurrently with a CNS depressant, it is recommended to use an initial dosage of 5 mg PO every 12 hours. Monitor for sedation or respiratory depression.
    Paliperidone: (Major) Avoid coadministration of trazodone and paliperidone. 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. Paliperidone has been associated with QT prolongation; however, torsade de pointes (TdP) has not been reported. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect. However, if coadministration is considered necessary by the practitioner, and the patient has known risk factors for cardiac disease or arrhythmia, then close monitoring is essential. Coadministration can also increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, 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: (Major) Due to the risk of serotonin syndrome, concurrent use of trazodone and other serotonergic medications, such as selective serotonin reuptake inhibitors (SSRIs), should be avoided if possible. If concomitant use is clinically warranted, patients should be informed of the increased risk of serotonin syndrome, particularly during treatment initiation and during dose increases. 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. Treatment with trazodone and any concomitant serotonergic agents should be discontinued immediately if signs and symptoms of serotonin syndrome occur, and supportive symptomatic treatment should be initiated.
    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: (Moderate) Heterocyclic antidepressants can increase CNS and/or respiratory depression, dizziness, and may also lower the seizure threshold, leading to pharmacodynamic interactions with barbiturate sedatives and anticonvulsants. Psychomotor impairment may be increased.
    Perampanel: (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. Drowsiness may be additive between trazodone and other anticonvulsants.
    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: (Major) Due to the risk of serotonin syndrome, concurrent use of trazodone and other serotonergic medications, such as tricyclic antidepressants, should be avoided if possible. If concomitant use is clinically warranted, patients should be informed of the increased risk of serotonin syndrome, particularly during treatment initiation and during dose increases. 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. Treatment with trazodone and any concomitant serotonergic agents should be discontinued immediately if signs and symptoms of serotonin syndrome occur, and supportive symptomatic treatment should be initiated. In addition, the manufacturer of trazodone recommends avoiding trazodone in patients receiving other drugs that increase the QT interval due to reports of QT prolongation and torsade de pointes (TdP) during treatment with trazodone. Tricyclic antidepressants have a possible risk for QT prolongation and TdP, particularly in overdose. (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 heterocyclic antidepressants (e.g., trazodone, mirtazapine, amoxapine, maptrotiline) or within 14 days of discontinuing treatment with a heterocyclic antidepressant. Conversely, heterocyclic antidepressants should not be initiated within 14 days of stopping an MAOI. The manufacturer of rasagiline does not contraindicate the combination but recommends avoiding use of antidepressants with rasagiline or within 14 days of discontinuing rasagiline. 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 syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Phenobarbital: (Moderate) Heterocyclic antidepressants can increase CNS and/or respiratory depression, dizziness, and may also lower the seizure threshold, leading to pharmacodynamic interactions with barbiturate sedatives and anticonvulsants. Psychomotor impairment may be increased.
    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.
    Phentermine; Topiramate: (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.
    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.
    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.
    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: (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. Drowsiness may be additive between trazodone and other anticonvulsants.
    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: (Moderate) Heterocyclic antidepressants can increase CNS and/or respiratory depression, dizziness, and may also lower the seizure threshold, leading to pharmacodynamic interactions with barbiturate sedatives and anticonvulsants. Psychomotor impairment may be increased.
    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: (Major) Due to the risk of serotonin syndrome, concurrent use of trazodone and medications with MAO-like activity, such as procarbazine, should be avoided if possible. 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 syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    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. Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. In addition, in vitro studies support that propafenone inhibits CYP2D6. Coadministration of propafenone with trazodone, a CYP2D6 substrate, may theoretically increase concentrations of trazodone.
    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: (Major) Due to the risk of serotonin syndrome, concurrent use of trazodone and other serotonergic medications, such as tricyclic antidepressants, should be avoided if possible. If concomitant use is clinically warranted, patients should be informed of the increased risk of serotonin syndrome, particularly during treatment initiation and during dose increases. 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. Treatment with trazodone and any concomitant serotonergic agents should be discontinued immediately if signs and symptoms of serotonin syndrome occur, and supportive symptomatic treatment should be initiated. In addition, the manufacturer of trazodone recommends avoiding trazodone in patients receiving other drugs that increase the QT interval due to reports of QT prolongation and torsade de pointes (TdP) during treatment with trazodone. Tricyclic antidepressants have a possible risk for QT prolongation and TdP, particularly in overdose.
    Quazepam: (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.
    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: (Severe) Quinidine administration is associated with QT prolongation and torsades de pointes (TdP). Quinidine inhibits CYP2D6 and has QT-prolonging actions; quinidine is contraindicated with other drugs that prolong the QT interval and are metabolized by CYP2D6 as the effects on the QT interval may be increased during concurrent use of these agents. Drugs that prolong the QT and are substrates for CYP2D6 that are contraindicated with quinidine include trazodone.
    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) 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. The manufacturer of rasagiline does not contraindicate the combination but recommends avoiding use of antidepressants with rasagiline or within 14 days of discontinuing rasagiline. 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 syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Regadenoson: (Major) Regadenoson 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.
    Remifentanil: (Moderate) Concomitant use of trazadone and remifentanil increases the risk serotonin syndrome and can potentiate the effects of remifentanil on respiration, sedation, and hypotension. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected or significant adverse events occur.
    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 has been shown to prolong the QT interval in a concentration-dependent manner. Trazodone can 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 is also a moderate CYP3A4 inhibitor and trazodone is a CYP3A4 substrate.
    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 has been shown to prolong the QT interval in a concentration-dependent manner. Trazodone can 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 is also a moderate CYP3A4 inhibitor and trazodone is a CYP3A4 substrate.
    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) 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). Ritonavir has a possible risk for QT prolongation and TdP. In addition, ritonavir may decrease the hepatic CYP metabolism of trazodone, resulting in increased trazodone concentrations. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir.
    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.
    Rufinamide: (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. Drowsiness may be additive between trazodone and other anticonvulsants.
    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: (Moderate) Heterocyclic antidepressants can increase CNS and/or respiratory depression, dizziness, and may also lower the seizure threshold, leading to pharmacodynamic interactions with barbiturate sedatives and anticonvulsants. Psychomotor impairment may be increased.
    Selegiline: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with heterocyclic antidepressants (e.g., trazodone, mirtazapine, amoxapine, maptrotiline) or within 14 days of discontinuing treatment with a heterocyclic antidepressant. Conversely, heterocyclic antidepressants should not be initiated within 14 days of stopping an MAOI. The manufacturer of rasagiline does not contraindicate the combination but recommends avoiding use of antidepressants with rasagiline or within 14 days of discontinuing rasagiline. 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 syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Serotonin-Receptor Agonists: (Major) Avoid coadministration of medications which potentiate serotonin neurotransmission, such as serotonin-receptor agonists and heterocyclic antidepressants, since it could result in 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.
    Sertraline: (Major) Because both sertraline and trazodone are associated with a possible risk of QT prolongation and Torsade de Pointes (TdP), the combination should be used cautiously and with close monitoring. In addition, because of the potential risk and severity of serotonin syndrome, caution should be observed when administering sertraline with other drugs that have serotonergic properties 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. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, sertraline and concurrent serotonergic agents should be discontinued.
    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: (Major) Sibutramine is a serotonin reuptake inhibitor. Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering sibutramine with drugs that have serotonergic properties 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. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    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.
    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 and sorafenib. If sorafenib and trazodone must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Sorafenib 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). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval.
    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: (Major) Due to the risk of serotonin syndrome, concurrent use of trazodone and other serotonergic medications, such as St. John's Wort, hypericum perforatum, should be avoided if possible. If concomitant use is clinically warranted, patients should be informed of the increased risk of serotonin syndrome, particularly during treatment initiation and during dose increases. 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. Treatment with trazodone and any concomitant serotonergic agents should be discontinued immediately if signs and symptoms of serotonin syndrome occur, and supportive symptomatic treatment should be initiated.
    Succinimides: (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.
    Sufentanil: (Moderate) Concomitant use of sufentanil with other central nervous system (CNS) depressants can potentiate sufentanil-induced CNS (e.g., respiratory depression) and cardiovascular effects and the duration of these effects. Dose reduction of sufentanil and/or the concurrent CNS depressant is recommended.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Major) QT prolongation resulting in ventricular tachycardia and torsade de pointes (TdP) have been reported during post-marketing use of sulfamethoxazole; trimethoprim. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with sulfamethoxazole; trimethoprim include trazodone.
    Sunitinib: (Major) Sunitinib can 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.
    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) Because of the potential risk and severity of serotonin syndrome, caution is advised when administering tapentadol and trazodone concurrently. Cases of life-threatening serotonin syndrome have been reported with the concurrent use of tapentadol and serotonergic drugs. This may occur within therapeutic dose ranges. 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. Additive CNS depressant effects that may lead to severe hypotension, profound sedation, coma, or respiratory depression are also possible. Prior to concurrent use of tapentadol 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. Consider the patient's use of alcohol or illicit drugs. If trazodone is used concurrently with tapentadol, a reduced dosage of tapentadol and/or trazodone is recommended. If the extended-release tapentadol tablets are used concurrently with a CNS depressant, it is recommended to use an initial tapentadol dose of 50 mg PO every 12 hours. Monitor patients for sedation and respiratory depression.
    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) 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). Telithromycin has a possible risk for QT prolongation and TdP. In addition, telithromycin could impair the metabolism of trazodone through inhibition of CYP3A4, thereby increasing the risk of trazodone-related adverse effects, including QT prolongation.
    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: (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.
    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) Avoid the concomitant use of thalidomide with other central nervous system depressants such as trazodone due to the potential for additive sedative effects.
    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.
    Thiopental: (Moderate) Heterocyclic antidepressants can increase CNS and/or respiratory depression, dizziness, and may also lower the seizure threshold, leading to pharmacodynamic interactions with barbiturate sedatives and anticonvulsants. Psychomotor impairment may be increased.
    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.
    Tiagabine: (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.
    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) Coadministration of tipranavir boosted with ritonavir and trazodone may result in elevated trazodone plasma concentrations. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A inhibitor such as tipranavir (in the FDA approved dosage regimen), the combination should be used with caution and a lower dose of trazodone should be considered.
    Tizanidine: (Major) Avoid coadministration of tizanidine and trazodone. Tizanidine administration may result in 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.
    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.
    Topiramate: (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.
    Toremifene: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner 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.
    Tramadol: (Major) Due to the risk of serotonin syndrome, concurrent use of trazodone and other serotonergic medications, such as tramadol, should be avoided if possible. If concomitant use is clinically warranted, patients should be informed of the increased risk of serotonin syndrome, particularly during treatment initiation and during dose increases. 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. Treatment with trazodone and any concomitant serotonergic agents should be discontinued immediately if signs and symptoms of serotonin syndrome occur, and supportive symptomatic treatment should be initiated.
    Tranylcypromine: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with heterocyclic antidepressants (e.g., trazodone, mirtazapine, amoxapine, maptrotiline) or within 14 days of discontinuing treatment with a heterocyclic antidepressant. Conversely, heterocyclic antidepressants should not be initiated within 14 days of stopping an MAOI. The manufacturer of rasagiline does not contraindicate the combination but recommends avoiding use of antidepressants with rasagiline or within 14 days of discontinuing rasagiline. 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 syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    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: (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.
    Tricyclic antidepressants: (Major) Due to the risk of serotonin syndrome, concurrent use of trazodone and other serotonergic medications, such as tricyclic antidepressants, should be avoided if possible. If concomitant use is clinically warranted, patients should be informed of the increased risk of serotonin syndrome, particularly during treatment initiation and during dose increases. 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. Treatment with trazodone and any concomitant serotonergic agents should be discontinued immediately if signs and symptoms of serotonin syndrome occur, and supportive symptomatic treatment should be initiated. In addition, the manufacturer of trazodone recommends avoiding trazodone in patients receiving other drugs that increase the QT interval due to reports of QT prolongation and torsade de pointes (TdP) during treatment with trazodone. Tricyclic antidepressants have a possible risk for QT prolongation and TdP, particularly in overdose.
    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: (Major) Due to the risk of serotonin syndrome, concurrent use of trazodone and other serotonergic medications, such as tricyclic antidepressants, should be avoided if possible. If concomitant use is clinically warranted, patients should be informed of the increased risk of serotonin syndrome, particularly during treatment initiation and during dose increases. 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. Treatment with trazodone and any concomitant serotonergic agents should be discontinued immediately if signs and symptoms of serotonin syndrome occur, and supportive symptomatic treatment should be initiated. In addition, the manufacturer of trazodone recommends avoiding trazodone in patients receiving other drugs that increase the QT interval due to reports of QT prolongation and torsade de pointes (TdP) during treatment with trazodone. Tricyclic antidepressants have a possible risk for QT prolongation and TdP, particularly in overdose.
    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) Androgen deprivation therapy (e.g., triptorelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with triptorelin include trazodone.
    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.
    Valproic Acid, Divalproex Sodium: (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.
    Vandetanib: (Major) The manufacturer of vandetanib recommends avoiding coadministration with other drugs that prolong the QT interval 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 prolong the QT/QTc interval at therapeutic doses. In addition, there are postmarketing reports of TdP. If coadministration is necessary, an ECG is needed, as well as more frequent monitoring of the QT interval. If QTcF is greater than 500 msec, interrupt vandetanib dosing until the QTcF is less than 450 msec; then, vandetanib may be resumed at a reduced dose.
    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). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. In addition, concomitant use of vemurafenib and trazodone may result in altered concentrations of trazodone. Vemurafenib is a weak inhibitor of CYP2D6 and an inducer of CYP3A4. Trazodone is a substrate of CYP2D6 and CYP3A4.
    Venlafaxine: (Major) Due to the risk of serotonin syndrome, concurrent use of trazodone and venlafaxine, should be avoided if possible. If concomitant use is clinically warranted, patients should be informed of the increased risk of serotonin syndrome, particularly during treatment initiation and during dose increases. 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. Treatment with trazodone and any concomitant serotonergic agents should be discontinued immediately if signs and symptoms of serotonin syndrome occur, and supportive symptomatic treatment should be initiated. Tthe manufacturer of trazodone recommends avoiding trazodone in patients receiving other drugs that increase the QT interval due to reports of QT prolongation and torsade de pointes (TdP) during treatment with trazodone. Venlafaxine has a possible risk for QT prolongation and TdP.
    Vigabatrin: (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. Vigabatrin may cause somnolence and fatigue. Drugs that can cause CNS depression, if used concomitantly with vigabatrin, may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when vigabatrin is given with trazodone.
    Vilazodone: (Major) In general, avoid use together when possible due to duplication/similarity of therapeutic actions and the potential for additive side effects. Additive sedation and serotonin-related side effects may occur. Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering vilazodone with other drugs that have serotonergic properties 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 concomitant treatment with trazodone and vilazodone is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. If serotonin syndrome is suspected, all serotonergic agents should be discontinued and the appropriate supportive and symptomatic therapy instituted.
    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 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: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering vortioxetine with other drugs that have serotonergic properties 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. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving trazodone in combination with vortioxetine should be monitored for the emergence of serotonin syndrome or other adverse effects. If serotonin syndrome is suspected, vortioxetine and concurrent serotonergic agents should be discontinued.
    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: (Severe) Ziprasidone has been associated with a possible risk for QT prolongation and/or torsades de pointes. According to the manufacturer of ziprasidone, the drug is contraindicated with any drug that lists QT prolongation as a pharmacodynamic effect when this effect has been described within the contraindications or bolded or boxed warnings of the official labeling for such drugs. Therefore, concurrent use of ziprasidone and trazodone is contraindicated. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of TdP.
    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.
    Zonisamide: (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.

    PREGNANCY AND LACTATION

    Pregnancy

    Trazodone is classified as FDA pregnancy risk category C. Animal studies have shown congenital anomalies and other fetal adverse effects at doses ranging from 15—50 times the maximum human dose. Animal data is not always predictive of human response and adequate studies have not been done in humans; benefits versus risks should be considered.

    According to the manufacturer, caution should be exercised when administering trazodone to a breast-feeding woman. Trazodone is excreted into the breast milk. Although no problems have been documented during breast-feeding, the benefits and risks should be taken into account. The American Academy of Pediatrics has suggested that antidepressant use, including trazodone, during breast-feeding may be of concern. Consider the benefits of breast-feeding, the risk of potential drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding baby experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    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.