Medication

1 INDICATIONS AND USAGE Trazodone hydrochloride tablets are indicated for the treatment of major depressive disorder (MDD) in adults. Trazodone hydrochloride is a selective serotonin reuptake inhibitor indicated for the treatment of major depressive disorder (MDD) ( 1 ).

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 Important 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 Hydrochloride Tablets 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 Switching 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 hydrochloride tablets dose based on tolerability when trazodone hydrochloride tablets are coadministered with a strong CYP3A4 inhibitor [see Drug Interactions ( 7.1 )]. Coadministration with Strong CYP3A4 Inducers Consider increasing trazodone hydrochloride tablets dose based on therapeutic response when trazodone hydrochloride tablets are coadministered with a strong CYP3A4 inducer [see Drug Interactions ( 7.1 )]. 2.6 Discontinuation of Treatment with Trazodone Hydrochloride Tablets Adverse reactions may occur upon discontinuation of trazodone hydrochloride tablets [See Warnings and Precautions ( 5.8 )]. Gradually reduce the dosage rather than stopping trazodone hydrochloride tablets abruptly whenever possible.

6 ADVERSE REACTIONS 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 )] 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 Accord Healthcare Inc. at 1-866-941-7875 or www.accordhealthcare.us or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 Hydrochloride -treated Patients and Greater than the Rate of Placebo-Treated Patients as Observed in Controled Clinical Studies Inpatients Outpatients Trazodone Hydrochloride N=142 Placebo N=95 Trazodone Hydrochloride N=157 Placebo 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 hydrochloride tablets. 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 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