Trazodone is a selective serotonin reuptake inhibitor indicated for the treatment of major depressive disorder (MDD) ( 1).

Trazodone hydrochloride tablets are indicated for the treatment of major depressive disorder (MDD) in adults.

• Starting dose: 150 mg in divided doses daily. May be increased by 50 mg per day every three to four days. Maximum dose: 400 mg per day in divided doses ( 2).
• Trazodone hydrochloride tablets should be taken shortly after a meal or light snack ( 2).
• Tablets should be swallowed whole or broken in half along the score line, and should not be chewed or crushed ( 2).
• When discontinued, gradual dose reduction is recommended ( 2).

An initial dose of 150 mg/day in divided doses is suggested. The dosage should be initiated at a low-dose and increased gradually, noting the clinical response and any evidence of intolerance. Occurrence of drowsiness may require the administration of a major portion of the daily dose at bedtime or a reduction of dosage.

The dose may be increased by 50 mg/day every 3 to 4 days. The maximum dose for outpatients usually should not exceed 400 mg/day in divided doses. Inpatients (i.e., more severely depressed patients) may be given up to but not in excess of 600 mg/day in divided doses.

Once an adequate response has been achieved, dosage may be gradually reduced, with subsequent adjustment depending on therapeutic response.

Trazodone hydrochloride tablets can be swallowed whole or administered as a half tablet by breaking the tablet along the score line.

Trazodone hydrochloride tablets should be taken shortly after a meal or light snack.

Prior to initiating treatment with trazodone hydrochloride tablets or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions ( 5.7)].

At least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (MAOI) antidepressant and initiation of trazodone hydrochloride tablets. In addition, at least 14 days must elapse after stopping trazodone hydrochloride tablets before starting an MAOI antidepressant [see Contraindications ( 4), Warnings and Precautions ( 5.2)].

Coadministration with Strong CYP3A4 Inhibitors

Consider reducing trazodone dose based on tolerability when trazodone is coadministered with a strong CYP3A4 inhibitor [see Drug Interactions ( 7.1)].

Coadministration with Strong CYP3A4 Inducers

Consider increasing trazodone dose based on therapeutic response when trazodone is coadministered with a strong CYP3A4 inducer [see Drug Interactions ( 7.1)].

Adverse reactions may occur upon discontinuation of trazodone [See Warnings and Precautions ( 5.8)]. Gradually reduce the dosage rather than stopping trazodone abruptly whenever possible.

•   Concomitant use of monoamine oxidase inhibitors (MAOIs), or use within 14 days of stopping MAOIs ( 4).

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)].

•   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 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, in patients with untreated anatomically narrow angles. ( 5.10).

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 1,000 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.

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, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

Serotonin-norepinephrine reuptake inhibitors (SNRIs) and SSRIs, including trazodone, 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 [see Contraindications ( 4), Drug Interactions ( 7.1)] . 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 with MAOIs is contraindicated. In addition, do not initiate trazodone 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, discontinue trazodone before initiating treatment with the MAOI [see Contraindications ( 4), Drug Interactions ( 7.1)].

Monitor all patients taking trazodone for the emergence of serotonin syndrome. Discontinue treatment with trazodone and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of trazodone with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

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. Trazodone 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 is not recommended for use during the initial recovery phase of myocardial infarction. Caution should be used when administering trazodone to patients with cardiac disease and such patients should be closely monitored, since antidepressant drugs (including trazodone) may cause cardiac arrhythmias [see Adverse Reactions ( 6.2)] .

Trazodone prolongs the QT/QTc interval. The use of trazodone 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 [see Drug Interactions ( 7.1)].

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.

Drugs that interfere with serotonin reuptake inhibition, including trazodone, 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 and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing trazodone.

Cases of priapism (painful erections greater than 6 hours in duration) have been reported in men receiving trazodone. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Men who have an erection lasting greater than 4 hours, whether painful or not, should immediately discontinue the drug and seek emergency medical attention [see Adverse Reactions ( 6.2), Overdosage ( 10)].

Trazodone 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).

In patients with bipolar disorder, treating a depressive episode with trazodone 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, screen patients for any personal or family history of bipolar disorder, mania, or hypomania [see Dosage and Administration ( 2.3)] .

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)].

Trazodone 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.

The pupillary dilation that occurs following use of many antidepressant drugs including trazodone 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, in patients with untreated anatomically narrow angles.

Hyponatremia may occur as a result of treatment with SNRIs and SSRIs, including trazodone. 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 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 [see Use in Specific Populations ( 8.5)] .

Most common adverse reactions (incidence ≥ 5% and twice that of placebo) are: edema, blurred vision, syncope, drowsiness, fatigue, diarrhea, nasal congestion, weight loss ( 6).

To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

The following serious adverse reactions are described elsewhere in the labeling:

• Suicidal Thoughts and Behavior in Children, Adolescents and Young Adults [see Boxed Warning and Warnings and Precautions ( 5.1)]
• Serotonin Syndrome [see Warnings and Precautions ( 5.2)]
• Cardiac Arrythmias [see Warnings and Precautions ( 5.3)]
• Orthostatic Hypotension and Syncope [see Warnings and Precautions ( 5.4)]
• Increased Risk of Bleeding [see Warnings and Precautions ( 5.5)]
• Priapism [see Warnings and Precautions ( 5.6)]
• Activation of Mania or Hypomania [see Warnings and Precautions ( 5.7)]
• Discontinuation Syndrome [see Warnings and Precautions ( 5.8)]
• Potential for Cognitive and Motor Impairment [see Warnings and Precautions ( 5.9)]
• Angle-Closure Glaucoma [see Warnings and Precautions ( 5.10)]
• Hyponatremia [see Warnings and Precautions ( 5.11)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Other adverse reactions occurring at an incidence of <2% with the use of trazodone hydrochloride in the controlled clinical studies: akathisia, allergic reaction, anemia, chest pain, delayed urine flow, early menses, flatulence, hallucinations/delusions, hematuria, hypersalivation, hypomania, impaired memory, impaired speech, impotence, increased appetite, increased libido, increased urinary frequency, missed periods, muscle twitches, numbness, paresthesia, retrograde ejaculation, shortness of breath, and tachycardia/palpitations. Occasional sinus bradycardia has occurred in long-term studies.

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