Trazodone

12.1 Mechanism of Action The mechanism of trazodone's antidepressant action is not fully understood, but is thought to be related to its enhancement of serotonergic activity in the CNS. Trazodone is both a selective serotonin reuptake inhibitor (SSRI) and a 5HT2 receptor antagonist and the net result of this action on serotonergic transmission and its role in trazodone's antidepressant effect is unknown.

1 INDICATIONS AND USAGE 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.

2 DOSAGE AND ADMINISTRATION 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 ). 2.1 Dose Selection 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. 2.2 Improtant Administration Instructions 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. 2.3 Screen for Bipolar Disorder Prior to Starting Trazodone 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 )]. 2.4 Switchning to or from Monoamine Oxidase Inhibitor Antidepressant 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 )]. 2.5 Dosage Recommendations for Concomitant Use with Strong CYP3A4 Inhibitors or Inducers 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 )]. 2.6 Discontinuation of Treatment with Trazodone 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.

6 ADVERSE REACTIONS 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 )] 6.1 Clinical Trials Experience 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. Table 2 Common Adverse Reactions Occurring in ≥ 2% of Trazodone-treated Patients and Greater than the Rate of Placebo-Treated Patients as Observed in Controlled Clinical Studies Inpatients Outpatients Trazodone Placebo Trazodone Placebo N=142 N=95 N=157 N=158 Allergic Skin Condition/Edema 3% 1% 7% 1% Autonomic Blurred Vision 6% 4% 15% 4% Constipation 7% 4% 8% 6% Dry Mouth 15% 8% 34% 20% Cardiovascular Hypertension 20% 1% 1% * Hypotension 7% 1% 4% 0 Syncope 3% 2% 5% 1% CNS Confusion 5% 0 6% 8% Decreased Concentration 3% 2% 1% 0 Disorientation 2% 0 * 0 Dizziness/Light-Headedness 20% 5% 28% 15% Drowsiness 24% 6% 41% 20% Fatigue 11% 4% 6% 3% Headache 10% 5% 20% 16% Nervousness 15% 11% 6% 8% Gastrointestinal Abdominal/Gastric Disorder 4% 4% 6% 4% Diarrhea 0 1% 5% 1% Nausea/Vomiting 10% 1% 13% 10% Musculoskeletal Aches/Pains 6% 3% 5% 3% Neurological Incoordination 5% 0 2% * Tremors 3% 1% 5% 4% Other Eyes Red/Tired/Itching 3% 0 0 0 Head Full-Heavy 3% 0 0 0 Malaise 3% 0 0 0 Nasal/Sinus Congestion 3% 0 6% 3% Weight Gain 1% 0 5% 2% Weight Loss * 3% 6% 3% 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. 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 disor

7 DRUG INTERACTIONS CNS Depressants: Trazodone may enhance effects of alcohol, barbiturates, or other CNS depressants ( 7 ). CYP3A4 Inhibitors: Consider trazodone dose reduction based on tolerability ( 2.5 , 7 ). CYP3A4 Inducers: Increase in trazodone 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 ). 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 C max 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 [s ee 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, clopido