Trazodone Hydrochloride (Page 3 of 6)

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of trazodone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure:

Blood and lymphatic system disorders: hemolytic anemia, leukocytosis

Cardiac disorders: cardiospasm, congestive heart failure, conduction block, orthostatic hypotension and syncope, palpitations, bradycardia, atrial fibrillation, myocardial infarction, cardiac arrest, arrhythmia, ventricular ectopic activity, including ventricular tachycardia and QT prolongation. Prolonged QT interval, torsade de pointes, and ventricular tachycardia have been reported at doses of 100 mg per day or less [see Warnings and Precautions (5.3)].

Endocrine disorders: inappropriate ADH syndrome

Eye disorders: diplopia

Gastrointestinal disorders: increased salivation, nausea/vomiting

General disorders and administration site conditions: chills, edema, unexplained death, weakness

Hepatobiliary disorders: cholestasis, jaundice, hyperbilirubinemia, liver enzyme alterations

Investigations: increased amylase

Metabolism and nutrition disorders: methemoglobinemia

Nervous system disorders: aphasia, ataxia, cerebrovascular accident, extrapyramidal symptoms, grand mal seizures, paresthesia, tardive dyskinesia, vertigo

Psychiatric disorders: abnormal dreams, agitation, anxiety, hallucinations, insomnia, paranoid reaction, psychosis, stupor

Renal and urinary disorders: urinary incontinence, urinary retention

Reproductive system and breast disorders: breast enlargement or engorgement, clitorism, lactation, priapism [see Warnings and Precautions (5.6)]

Respiratory, thoracic and mediastinal disorders: apnea

Skin and subcutaneous tissue disorders: alopecia, hirsutism, leukonychia, pruritus, psoriasis, rash, urticaria

Vascular disorders: vasodilation

7 DRUG INTERACTIONS

MAOIs

MAOIs should not be used within 14 days of trazodone [see Warnings and Precautions (5.8)].

Central Nervous System (CNS) Depressants

Trazodone may enhance the response to alcohol, barbiturates, and other CNS depressants.

Cytochrome P450 3A4 Inhibitors

In vitro drug metabolism studies suggest that there is a potential for drug interactions when trazodone is given with cytochrome P450 3A4 (CYP3A4) inhibitors. The effect of short-term administration of ritonavir (200 mg twice daily, 4 doses) on the pharmacokinetics of a single dose of trazodone (50 mg) has been studied in 10 healthy subjects. The Cmax of trazodone increased by 34%, the AUC increased 2.4 fold, the half-life increased by 2.2 fold, and the clearance decreased by 52%. Adverse effects including nausea, hypotension, and syncope were observed when ritonavir and trazodone were coadministered. It is likely that ketoconazole, indinavir, and other CYP3A4 inhibitors such as itraconazole may lead to substantial increases in trazodone plasma concentrations with the potential for adverse effects. If trazodone is used with a potent CYP3A4 inhibitor, the risk of cardiac arrhythmia may be increased [see Warnings and Precautions (5.4)] and a lower dose of trazodone should be considered.

Cytochrome P450 Inducers (e.g., Carbamazepine)

Carbamazepine induces CYP3A4. Following coadministration of carbamazepine 400 mg per day with trazodone 100 mg to 300 mg daily, carbamazepine reduced plasma concentrations of trazodone and m-chlorophenlypiperazine (an active metabolite) by 76% and 60% respectively, compared to pre-carbamazepine values. Patients should be closely monitored to see if there is a need for an increased dose of trazodone when taking both drugs.

Digoxin and Phenytoin

Increased serum digoxin or phenytoin levels have been reported in patients receiving trazodone concurrently with either of these drugs. Monitor serum levels and adjust dosages as needed.

Serotonergic Drugs

Based on the mechanism of action of trazodone and the potential for serotonin syndrome, caution is advised when trazodone is coadministered with other drugs that may affect the neurotransmitter systems [see Warnings and Precautions (5.2) ].

NSAIDs, Aspirin, or Other Drugs Affecting Coagulation or Bleeding

Due to a possible association between serotonin modulating drugs and gastrointestinal bleeding, patients should be monitored for and cautioned about the potential risk of bleeding associated with the concomitant use of trazodone and NSAIDs, aspirin, or other drugs that affect coagulation or bleeding [see Warnings and Precautions (5.7) ].

Warfarin

There have been reports of altered (either increased or decreased) prothrombin times in taking both warfarin and trazodone.

7.1 Drugs Having Clinically Important Interactions with Trazodone

Table 3 Clinically Important Drug Interactions with Trazodone
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact: The concomitant use of MAOIs and serotonergic drugs including trazodone increases the risk of serotonin syndrome.
Intervention: Trazodone 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 and other serotonergic drugs increases the risk of serotonin syndrome.
Intervention: Monitor patients for signs and symptoms of serotonin syndrome, particularly during trazodone initiation. If serotonin syndrome occurs, consider discontinuation of trazodone 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 may potentiate the risk of bleeding.
Intervention: Inform patients of the increased risk of bleeding with the concomitant use of trazodone and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio (INR) when initiating or discontinuing trazodone [see Warnings and Precautions (5.5)].
Examples: warfarin, rivaroxaban, dabigatran, clopidogrel
Strong CYP3A4 Inhibitors
Clinical Impact: The concomitant use of trazodone and strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone.
Intervention: If trazodone is used with a potent CYP3A4 inhibitor, the risk of adverse reactions, including cardiac arrhythmias, may be increased and a lower dose of trazodone 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 and strong CYP3A4 inducers decreased the exposure of trazodone compared to the use of trazodone alone.
Intervention: Patients should be closely monitored to see if there is a need for an increased dose of trazodone 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 can increase digoxin or phenytoin concentrations.
Intervention: Measure serum digoxin or phenytoin concentrations before initiating concomitant use of trazodone. Continue monitoring and reduce digoxin or phenytoin dose as necessary.
Examples: digoxin, phenytoin
Central Nervous System (CNS) Depressants
Clinical Impact: Trazodone may enhance the response CNS depressants.
Intervention: Patients should be counseled that trazodone 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 and increase the risk of cardiac arrhythmia.
Intervention: Avoid the use of trazodone 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

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