TRAZODONE Drug Interactions: What You Need to Know

INTERACTIONS

• CNS Depressants: Trazodone hydrochloride may enhance effects of alcohol, barbiturates, or other CNS depressants ( 7 ).
• CYP3A4 Inhibitors: Consider trazodone hydrochloride tablets dose reduction based on tolerability ( 2.5 , 7 ).
• CYP3A4 Inducers: Increase in trazodone hydrochloride tablets dosage may be necessary ( 2.5 , 7 ).
• Digoxin or Phenytoin: Monitor for increased digoxin or phenytoin serum levels ( 7 ).
• Warfarin: Monitor for increased or decreased prothrombin time ( 7 ).

7.1 Drugs Having Clinically Important Interactions with Trazodone Hydrochloride Table 3: Clinically Important Drug Interactions with Trazodone Hydrochloride Monoamine Oxidase Inhibitors (MAOIs)

Clinical

Impact: The concomitant use of MAOIs and serotonergic drugs including trazodone hydrochloride increases the risk of serotonin syndrome. Intervention: Trazodone hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Contraindications ( 4 ), Dosage and Administration ( 2.3 , 2.4 ), and Warnings and Precautions ( 5.2 )]. Examples: isocarboxazid, moclobemide, phenelzine, selegiline, tranylcypromine Other Serotonergic Drugs Clinical Impact: The concomitant use of serotonergic drugs including trazodone hydrochloride and other serotonergic drugs increases the risk of serotonin syndrome. Intervention: Monitor patients for signs and symptoms of serotonin syndrome, particularly during trazodone hydrochloride initiation. If serotonin syndrome occurs, consider discontinuation of trazodone hydrochloride and/or concomitant serotonergic drugs [see Warnings and Precautions ( 5.2 )]. Examples: triptans, antidepressants (tricyclic and serotonin uptake inhibitors), fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort Antiplatelet Agents and Anticoagulants Clinical Impact: Serotonin release by platelets plays an important role in hemostasis. The concurrent use of an antiplatelet agent or anticoagulant with trazodone hydrochloride may potentiate the risk of bleeding. Intervention: Inform patients of the increased risk of bleeding with the concomitant use of trazodone hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio (INR) when initiating or discontinuing trazodone hydrochloride [see Warnings and Precautions ( 5.5 )]. Examples: warfarin, rivaroxaban, dabigatran, clopidogrel Strong CYP3A4 Inhibitors Clinical Impact: The concomitant use of trazodone hydrochloride and strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone hydrochloride alone. Intervention: If trazodone hydrochloride is used with a potent CYP3A4 inhibitor, the risk of adverse reactions, including cardiac arrhythmias, may be increased and a lower dose of trazodone hydrochloride should be considered [see Dosage and Administration ( 2.5 ), Warnings and Precautions ( 5.3 )]. Examples: itraconazole, ketoconazole, clarithromycin, indinavir Strong CYP3A4 Inducers Clinical Impact: The concomitant use of trazodone hydrochloride and strong CYP3A4 inducers decreased the exposure of trazodone compared to the use of trazodone hydrochloride alone. Intervention: Patients should be closely monitored to see if there is a need for an increased dose of trazodone hydrochloride when taking CYP3A4 inducers [see Dosage and Administration ( 2.5 )]. Examples: rifampin, carbamazepine, phenytoin, St. John’s wort Digoxin and Phenytoin Clinical Impact: Digoxin and phenytoin are narrow therapeutic index drugs. Concomitant use of trazodone hydrochloride can increase digoxin or phenytoin concentrations. Intervention: Measure serum digoxin or phenytoin concentrations before initiating concomitant use of trazodone hydrochloride. Continue monitoring and reduce digoxin or phenytoin dose as necessary. Examples: digoxin, phenytoin Central Nervous System (CNS)

Depressants Clinical

Impact: Trazodone hydrochloride may enhance the response CNS depressants. Intervention: Patients should be counseled that trazodone hydrochloride may enhance the response to alcohol, barbiturates, and other CNS depressants. Examples: alcohol, barbiturates QT Interval Prolongation Clinical Impact: Concomitant use of drugs that prolong the QT interval may add to the QT effects of trazodone hydrochloride and increase the risk of cardiac arrhythmia. Intervention: Avoid the use of trazodone hydrochloride tablets in combination with other drugs known to prolong QTc [see Warnings and Precautions ( 5.3 )]. Examples: Class 1A antiarrhythmics: quinidine, procainamide, disopyramide; Class 3 antiarrhythmics: amiodarone, sotalol; Antipsychotics: ziprasidone, chlorpromazine, thioridazine; Antibiotics: gatifloxacin

7.1 Drugs Having Clinically Important Interactions with Trazodone Hydrochloride Table 3: Clinically Important Drug Interactions with Trazodone Hydrochloride Monoamine Oxidase Inhibitors (MAOIs)

Clinical

Impact: The concomitant use of MAOIs and serotonergic drugs including trazodone hydrochloride increases the risk of serotonin syndrome. Intervention: Trazodone hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Contraindications ( 4 ), Dosage and Administration ( 2.3 , 2.4 ), and Warnings and Precautions ( 5.2 )]. Examples: isocarboxazid, moclobemide, phenelzine, selegiline, tranylcypromine Other Serotonergic Drugs Clinical Impact: The concomitant use of serotonergic drugs including trazodone hydrochloride and other serotonergic drugs increases the risk of serotonin syndrome. Intervention: Monitor patients for signs and symptoms of serotonin syndrome, particularly during trazodone hydrochloride initiation. If serotonin syndrome occurs, consider discontinuation of trazodone hydrochloride and/or concomitant serotonergic drugs [see Warnings and Precautions ( 5.2 )]. Examples: triptans, antidepressants (tricyclic and serotonin uptake inhibitors), fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort Antiplatelet Agents and Anticoagulants Clinical Impact: Serotonin release by platelets plays an important role in hemostasis. The concurrent use of an antiplatelet agent or anticoagulant with trazodone hydrochloride may potentiate the risk of bleeding. Intervention: Inform patients of the increased risk of bleeding with the concomitant use of trazodone hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio (INR) when initiating or discontinuing trazodone hydrochloride [see Warnings and Precautions ( 5.5 )]. Examples: warfarin, rivaroxaban, dabigatran, clopidogrel Strong CYP3A4 Inhibitors Clinical Impact: The concomitant use of trazodone hydrochloride and strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone hydrochloride alone. Intervention: If trazodone hydrochloride is used with a potent CYP3A4 inhibitor, the risk of adverse reactions, including cardiac arrhythmias, may be increased and a lower dose of trazodone hydrochloride should be considered [see Dosage and Administration ( 2.5 ), Warnings and Precautions ( 5.3 )]. Examples: itraconazole, ketoconazole, clarithromycin, indinavir Strong CYP3A4 Inducers Clinical Impact: The concomitant use of trazodone hydrochloride and strong CYP3A4 inducers decreased the exposure of trazodone compared to the use of trazodone hydrochloride alone. Intervention: Patients should be closely monitored to see if there is a need for an increased dose of trazodone hydrochloride when taking CYP3A4 inducers [see Dosage and Administration ( 2.5 )]. Examples: rifampin, carbamazepine, phenytoin, St. John’s wort Digoxin and Phenytoin Clinical Impact: Digoxin and phenytoin are narrow therapeutic index drugs. Concomitant use of trazodone hydrochloride can increase digoxin or phenytoin concentrations. Intervention: Measure serum digoxin or phenytoin concentrations before initiating concomitant use of trazodone hydrochloride. Continue monitoring and reduce digoxin or phenytoin dose as necessary. Examples: digoxin, phenytoin Central Nervous System (CNS)

Depressants Clinical

Impact: Trazodone hydrochloride may enhance the response CNS depressants. Intervention: Patients should be counseled that trazodone hydrochloride may enhance the response to alcohol, barbiturates, and other CNS depressants. Examples: alcohol, barbiturates QT Interval Prolongation Clinical Impact: Concomitant use of drugs that prolong the QT interval may add to the QT effects of trazodone hydrochloride and increase the risk of cardiac arrhythmia. Intervention: Avoid the use of trazodone hydrochloride tablets in combination with other drugs known to prolong QTc [see Warnings and Precautions ( 5.3 )]. Examples: Class 1A antiarrhythmics: quinidine, procainamide, disopyramide; Class 3 antiarrhythmics: amiodarone, sotalol; Antipsychotics: ziprasidone, chlorpromazine, thioridazine; Antibiotics: gatifloxacin

Trazodone hydrochloride tablets are contraindicated in: Patients taking, or within 14 days of stopping, monoamine oxidase inhibitors (MAOIs), including MAOIs such as linezolid or intravenous methylene blue, because of an increased risk of serotonin syndrome [see Warnings and Precautions (5.2) , Drug Interactions (7.1) ]. Concomitant use of monoamine oxidase inhibitors (MAOIs), or use within 14 days of stopping MAOIs ( 4 ). Concomitant use of monoamine oxidase inhibitors (MAOIs), or use within 14 days of stopping MAOIs ( 4 ).

AND PRECAUTIONS Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents (e.g., SSRI, SNRI, triptans), but also when taken alone. If it occurs, discontinue trazodone hydrochloride tablets and initiate supportive treatment ( 5.2 ).

Cardiac

Arrhythmias: Increases the QT interval. Avoid use with drugs that also increase the QT interval and in patients with risk factors for prolonged QT interval ( 5.3 )

Orthostatic

Hypotension and Syncope: Warn patients of risk and symptoms of hypotension ( 5.4 ).

Increased

Risk of Bleeding: Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), other antiplatelet drugs, warfarin, and other anticoagulants may increase this risk ( 5.5 ). Priapism: Cases of painful and prolonged penile erections and priapism have been reported. Immediate medical attention should be sought if signs and symptoms of prolonged penile erections or priapism are observed ( 5.6 ). Activation of Mania or Hypomania: Screen for bipolar disorder and monitor for mania or hypomania ( 5.7 ). Potential for Cognitive and Motor Impairment: Has potential to impair judgment, thinking, and motor skills. Advise patients to use caution when operating machinery ( 5.9 ). Angle-Closure Glaucoma: Avoid use of antidepressants, including trazodone hydrochloride tablets, in patients with untreated anatomically narrow angles. ( 5.10 ).

5.1 Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and over 4,400 pediatric patients, the incidence of suicidal thoughts and behaviors in pediatric and young adult patients was greater in antidepressant-treated patients than in placebo-treated patients. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 1 . No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about antidepressant drug effect on suicide.

Table

1: Risk Differences of the Number of Cases of Suicidal Thoughts or Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range (years) Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1000 Patients Treated Increases Compared to Placebo <18 14 additional patients 18-24 5 additional patients Decreases Compared to Placebo 25-64 1 fewer patient ≥65 6 fewer patients It is unknown whether the risk of suicidal thoughts and behaviors in pediatric and young adult patients extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression. Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing trazodone hydrochloride tablets, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

5.2 Serotonin Syndrome Serotonin-norepinephrine reuptake inhibitors (SNRIs) and SSRIs, including trazodone hydrochloride tablets, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs <span class="opacity-50 text-xs">[see Contraindications(4) , Drug Interactions (7.1) ]</span>. Serotonin syndrome can also occur when these drugs are used alone. Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of trazodone hydrochloride tablets with MAOIs is contraindicated. In addition, do not initiate trazodone hydrochloride tablets in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking trazodone hydrochloride tablets discontinue trazodone hydrochloride tablets before initiating treatment with the MAOI <span class="opacity-50 text-xs">[see Contraindications (4) , Drug Interactions (7.1) ]</span>. Monitor all patients taking trazodone hydrochloride tablets for the emergence of serotonin syndrome. Discontinue treatment with trazodone hydrochloride tablets and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of trazodone hydrochloride tablets with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

5.3 Cardiac Arrhythmias Clinical studies indicate that trazodone hydrochloride may be arrhythmogenic in patients with preexisting cardiac disease. Arrhythmias identified include isolated PVCs, ventricular couplets, tachycardia with syncope, and torsade de pointes. Postmarketing events, including torsade de pointes have been reported at doses of 100 mg or less with the immediate-release form of trazodone hydrochloride tablets. Trazodone hydrochloride tablets should also be avoided in patients with a history of cardiac arrhythmias, as well as other circumstances that may increase the risk of the occurrence of torsade de pointes and/or sudden death, including symptomatic bradycardia, hypokalemia or hypomagnesemia, and the presence of congenital prolongation of the QT interval. Trazodone hydrochloride tablets are not recommended for use during the initial recovery phase of myocardial infarction. Caution should be used when administering trazodone hydrochloride tablets to patients with cardiac disease and such patients should be closely monitored, since antidepressant drugs (including trazodone hydrochloride tablets) may cause cardiac arrhythmias <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> . Trazodone hydrochloride tablets prolongs the QT/QTc interval. The use of trazodone hydrochloride tablets should be avoided in patients with known QT prolongation or in combination with other drugs that are inhibitors of CYP3A4 (e.g., itraconazole, clarithromycin, voriconazole), or known to prolong QT interval including Class 1A antiarrhythmics (e.g., quinidine, procainamide) or Class 3 antiarrhythmics (e.g., amiodarone, sotalol), certain antipsychotic medications (e.g., ziprasidone, chlorpromazine, thioridazine), and certain antibiotics (e.g., gatifloxacin). Concomitant administration of drugs may increase the risk of cardiac arrhythmia <span class="opacity-50 text-xs">[see Drug Interactions (7.1) ]</span>.

5.4 Orthostatic Hypotension and Syncope Hypotension, including orthostatic hypotension and syncope has been reported in patients receiving trazodone hydrochloride. Concomitant use with an antihypertensive may require a reduction in the dose of the antihypertensive drug.

5.5 Increased Risk of Bleeding Drugs that interfere with serotonin reuptake inhibition, including trazodone hydrochloride tablets, increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDS), other antiplatelet drugs, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to drugs that interfere with serotonin reuptake have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages. Inform patients about the risk of bleeding associated with the concomitant use of trazodone hydrochloride tablets and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing trazodone hydrochloride tablets.

5.6 Priapism Cases of priapism (painful erections greater than 6 hours in duration) have been reported in men receiving trazodone hydrochloride tablets. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Men who have an erection lasting greater than 4 hours, whether painful or not, should immediately discontinue the drug and seek emergency medical attention <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) , Overdosage (10) ]</span>. Trazodone hydrochloride tablets should be used with caution in men who have conditions that might predispose them to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia), or in men with anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, or Peyronie’s disease).

5.7 Activation of Mania or Hypomania In patients with bipolar disorder, treating a depressive episode with trazodone hydrochloride tablets or another antidepressant may precipitate a mixed/manic episode. Activation of mania/hypomania has been reported in a small proportion of patients with major affective disorder who were treated with antidepressants. Prior to initiating treatment with trazodone hydrochloride tablets, screen patients for any personal or family history of bipolar disorder, mania, or hypomania <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

5.8 Discontinuation Syndrome Adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt discontinuation, include: nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible [See Dosage and Administration (2.6) ].

5.9 Potential for Cognitive and Motor Impairment Trazodone hydrochloride tablets may cause somnolence or sedation and may impair the mental and/or physical ability required for the performance of potentially hazardous tasks. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely.

5.10 Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including trazodone hydrochloride tablets, may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Avoid use of antidepressants, including trazodone hydrochloride tablets, in patients with untreated anatomically narrow angles.

5.11 Hyponatremia Hyponatremia may occur as a result of treatment with SNRIs and SSRIs, including trazodone hydrochloride tablets. Cases with serum sodium lower than 110 mmol/L have been reported. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In patients with symptomatic hyponatremia, discontinue trazodone hydrochloride tablets and institute appropriate medical intervention. Elderly patients, patients taking diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia with SSRIs and SNRIs <span class="opacity-50 text-xs">[see Use in Specific Populations (8.5) ]</span> .