Trazodone Hydrochloride

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 142 95 157 158 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 disorders: alopecia, hirsutism, leukonychia, pruritus, psoriasis, rash, urticaria Vascular disorders: vasodilation

4 CONTRAINDICATIONS None ( 4 ). 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)].

11 DESCRIPTION Trazodone hydrochloride is a selective serotonin reuptake inhibitor and 5HT2 receptor antagonist. Trazodone hydrochloride, USP is a triazolopyridine derivative designated as 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]- 1,2,4-triazolo[4, 3-a]pyridin-3(2H)-one hydrochloride. It is a white to off-white, crystalline powder which is sparingly soluble in chloroform and in water. The structural formula is represented as follows: Molecular Formula: C 19 H 22 C l N 5O •HCl Molecular Weight: 408.33 Each trazodone hydrochloride tablet, USP for oral administration contains 50 mg, 100 mg, 150 mg or 300 mg of trazodone hydrochloride, USP. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, pregelatinized starch, sodium lauryl sulfate, and sodium starch glycolate. The USP Dissolution Test is pending. Trazodone Hydrochloride Tablets USP

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 (2.1). Trazodone hydrochloride tablets should be taken shortly after a meal or light snack (2.2). Tablets should be swallowed whole or broken in half along the score line (2.2). When discontinued, gradual dose reduction is recommended (2.6). 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.

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.

9.2 Abuse Although trazodone hydrochloride has not been systematically studied in preclinical or clinical studies for its potential for abuse, no indication of drug-seeking behavior was seen in the clinical studies with trazodone hydrochloride.

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Trazodone hydrochloride tablets are not a controlled substance. 9.2 Abuse Although trazodone hydrochloride has not been systematically studied in preclinical or clinical studies for its potential for abuse, no indication of drug-seeking behavior was seen in the clinical studies with trazodone hydrochloride.

10 OVERDOSAGE Death from overdose has occurred in patients ingesting trazodone and other CNS depressant drugs concurrently (alcohol; alcohol and chloral hydrate and diazepam; amobarbital; chlordiazepoxide; or meprobamate). The most severe reactions reported to have occurred with overdose of trazodone alone have been priapism, respiratory arrest, seizures, and ECG changes, including QT prolongation. The reactions reported most frequently have been drowsiness and vomiting. Overdosage may cause an increase in incidence or severity of any of the reported adverse reactions. There is no specific antidote for trazodone hydrochloride overdose. In managing overdosage, consider the possibility of multiple drug involvement. For current information on the management of poisoning or overdose, contact a poison control center (1-800-222-1222 or www.poison.org).

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, 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

12 CLINICAL PHARMACOLOGY 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. 12.2 Pharmacodynamics Preclinical studies have shown that trazodone selectively inhibits neuronal reuptake of serotonin (Ki = 367 nM) and acts as an antagonist at 5-HT-2A (Ki = 35.6 nM) serotonin receptors. Trazodone is also an antagonist at several other monoaminergic receptors including 5-HT2B (Ki = 78.4 nM), 5-HT2C (Ki = 224 nM), α1A (Ki = 153 nM), α2C (Ki = 155 nM) receptors and it is a partial agonist at 5HT1A (Ki = 118 nM) receptor. Trazodone antagonizes alpha 1-adrenergic receptors, a property which may be associated with postural hypotension. 12.3 Pharmacokinetics Absorption In humans, trazodone hydrochloride is absorbed after oral administration without selective localization in any tissue. When trazodone hydrochloride is taken shortly after ingestion of food, there may be an increase in the amount of drug absorbed, a decrease in maximum concentration and a lengthening in the time to maximum concentration. Peak plasma levels occur approximately one hour after dosing when trazodone hydrochloride is taken on an empty stomach or 2 hours after dosing when taken with food. Metabolism In vitro studies in human liver microsomes show that trazodone is metabolized, via oxidative cleavage, to an active metabolite, m-chlorophenylpiperazine (mCPP) by CYP3A4. Other metabolic pathways that may be involved in the metabolism of trazodone have not been well characterized. Trazodone is extensively metabolized; less than 1% of an oral dose is excreted unchanged in the urine. Elimination In some patients trazodone may accumulate in the plasma. Protein Binding Trazodone is 89 to 95% protein bound in vitro at concentrations attained with therapeutic doses in humans.

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.

12.2 Pharmacodynamics Preclinical studies have shown that trazodone selectively inhibits neuronal reuptake of serotonin (Ki = 367 nM) and acts as an antagonist at 5-HT-2A (Ki = 35.6 nM) serotonin receptors. Trazodone is also an antagonist at several other monoaminergic receptors including 5-HT2B (Ki = 78.4 nM), 5-HT2C (Ki = 224 nM), α1A (Ki = 153 nM), α2C (Ki = 155 nM) receptors and it is a partial agonist at 5HT1A (Ki = 118 nM) receptor. Trazodone antagonizes alpha 1-adrenergic receptors, a property which may be associated with postural hypotension.

12.3 Pharmacokinetics Absorption In humans, trazodone hydrochloride is absorbed after oral administration without selective localization in any tissue. When trazodone hydrochloride is taken shortly after ingestion of food, there may be an increase in the amount of drug absorbed, a decrease in maximum concentration and a lengthening in the time to maximum concentration. Peak plasma levels occur approximately one hour after dosing when trazodone hydrochloride is taken on an empty stomach or 2 hours after dosing when taken with food. Metabolism In vitro studies in human liver microsomes show that trazodone is metabolized, via oxidative cleavage, to an active metabolite, m-chlorophenylpiperazine (mCPP) by CYP3A4. Other metabolic pathways that may be involved in the metabolism of trazodone have not been well characterized. Trazodone is extensively metabolized; less than 1% of an oral dose is excreted unchanged in the urine. Elimination In some patients trazodone may accumulate in the plasma. Protein Binding Trazodone is 89 to 95% protein bound in vitro at concentrations attained with therapeutic doses in humans.

20230810

8

3 DOSAGE FORMS AND STRENGTHS Scored tablets of 50mg, 100mg, 150 mg and 300 mg ( 3 ). Trazodone hydrochloride tablets, USP are available in the following strengths: Trazodone hydrochloride tablets USP, 50 mg are white to off-white, round-shape, biconvex beveled tablets, bisect on one side and plain on other side. The bisected side oftablet is debossed with '8' on upper side of bisect and '05' on lower side of bisect. Trazodone hydrochloride tablets USP, 100 mg are white to off-white, round-shape, biconvex beveled tablets, bisect on one side and plain on other side. The bisected side of tablet is debossed with '8' on upper side of bisect and '06' on lower side of bisect. Trazodone hydrochloride tablets USP, 150 mg are white to off-white, oval-shape, flat faced beveled tablets having one full bisect and two trisect notches on one side and two trisects on other side. The full bisected side of tablet is debossed with '8' on one side of bisect and '07' on other bisect segments. Trazodone hydrochloride tablets USP, 300 mg are white to off-white, oval-shape, flat faced beveled tablets having one full bisect and two trisect notches on one side and two trisects on other side. The full bisected side of tablet is debossed with '8' on one side of bisect and '08' on other bisect segment.

Trazodone Hydrochloride Trazodone Hydrochloride SILICON DIOXIDE MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE STARCH, PREGELATINIZED CORN SODIUM LAURYL SULFATE SODIUM STARCH GLYCOLATE TYPE A POTATO TRAZODONE HYDROCHLORIDE TRAZODONE WHITE TO OFF-WHITE ROUND 8;05

13 NONCLINICAL TOXICOLOGY Carcinogenesis No drug- or dose-related occurrence of carcinogenesis was evident in rats receiving trazodone in daily oral doses up to7.3 times the maximum recommended human dose (MRSD) of 400 mg/day on mg/m 2 basis. Mutagenesis No genotoxicity studies were conducted with trazodone. Impairment of Fertility Trazodone has no effect on fertility in rats at doses up to 6 times the MRHD on mg/m 2 basis in adolescents.

ANDA205253

Trazodone Hydrochloride

Trazodone Hydrochloride

68071-4410

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL pdp

Manufactured by: Cadila Healthcare Limited Ahmedabad, India. Distributed by: Zydus Pharmaceuticals (USA) Inc. Pennington, NJ 08534 Rev.: 07/17

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Suicidal Thoughts and Behaviors Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dosage is adjusted up or down and instruct them to report such symptoms to the healthcare provider [ see Box Warning and Warnings and Precautions (5.1) ]. Dosage and Administration Advise patients that trazodone hydrochloride tablets should be taken shortly after a meal or light snack. Advise patients regarding the importance of following dosage titration instructions [see Dosage and Administration (2)] . Serotonin Syndrome Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of trazodone hydrochloride tablets with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, St. John's Wort, and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid). Patients should contact their health care provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome [see Warnings and Precautions (5.2) and Drug Interactions (7)] . Activation of Mania/Hypomania Advise patients and their caregivers to observe for signs of activation of mania/hypomania and instruct them to report such symptoms to the healthcare provider [see Warnings and Precautions (5.7)] . Increased Risk of Bleeding Inform patients about the concomitant use of trazodone hydrochloride tablets with aspirin, NSAIDs, other antiplatelet drugs, warfarin, or other anticoagulants because the combined use of drugs that interfere with serotonin reuptake and these medications has been associated with an increased risk of bleeding. Advise them to inform their health care providers if they are taking or planning to take any prescription or over-the-counter medications that increase the risk of bleeding [see Warnings and Precautions (5.5)] . Discontinuation Syndrome Advise patients not to abruptly discontinue trazodone hydrochloride tablets and to discuss any tapering regimen with their healthcare provider. Adverse reactions can occur when trazodone hydrochloride tablets are discontinued [see Warnings and Precautions (5.8)]. Concomitant Medications Advise patients to inform their health care providers if they are taking, or plan to take any prescription or over-the-counter medications since there is a potential for interactions [see Drug Interactions (7.1)].

14 CLINICAL STUDIES The efficacy and safety of trazodone hydrochloride were established from inpatient and outpatient trials of the trazodone immediate release formulation in the treatment of major depressive disorder.

8.5 Geriatric Use Reported clinical literature and experience with trazodone has not identified differences in responses between elderly and younger patients. However, as experience in the elderly with trazodone hydrochloride is limited, it should be used with caution in geriatric patients. Serotonergic antidepressants have been associated with cases of clinically significant hyponatremia in elderly patients who may be at greater risk for this adverse reaction [ see Warnings and Precautions (5.11) ].

8.3 Nursing Mothers Trazodone and/or its metabolites have been found in the milk of lactating rats, suggesting that the drug may be secreted in human milk. Caution should be exercised when trazodone is administered to a nursing woman.

8.4 Pediatric Use Safety and effectiveness in the pediatric population have not been established. Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients [ see Boxed Warning, Warnings and Precautions ( 5.1 ) ].

8.1 Pregnancy Teratogenic Effects Pregnancy Category C Trazodone hydrochloride has been shown to cause increased fetal resorption and other adverse effects on the fetus in the rat when given at dose levels approximately 6 to 9 times the maximum recommended human dose (MRHD) of 400 mg/day on mg/m 2 in adolescents. There is also an increase in congenital anomalies in the rabbit at approximately 6 to 17 times the MRHD on mg/m 2 basis in adolescents. There are no adequate and well-controlled studies in pregnant women. Trazodone hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data No teratogenic effects were observed when trazodone was given to pregnant rats and rabbits during the period of organogenesis at oral doses up to 450 mg/kg/day. This dose is 9 and 17 times, in rats and rabbits, respectively, the maximum recommended human dose (MRHD) of 400 mg/day on mg/m 2 basis in adolescents. Increased fetal resorption and other adverse effects on the fetus in rats at 6 to 9 times the MRHD and increase in congenital anomalies in rabbits at 6 to 17 times the MRHD on mg/m 2 basis in adolescents were observed.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm ( 8.1 ). Nursing Mothers: Use with caution ( 8.3 ). 8.1 Pregnancy Teratogenic Effects Pregnancy Category C Trazodone hydrochloride has been shown to cause increased fetal resorption and other adverse effects on the fetus in the rat when given at dose levels approximately 6 to 9 times the maximum recommended human dose (MRHD) of 400 mg/day on mg/m 2 in adolescents. There is also an increase in congenital anomalies in the rabbit at approximately 6 to 17 times the MRHD on mg/m 2 basis in adolescents. There are no adequate and well-controlled studies in pregnant women. Trazodone hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data No teratogenic effects were observed when trazodone was given to pregnant rats and rabbits during the period of organogenesis at oral doses up to 450 mg/kg/day. This dose is 9 and 17 times, in rats and rabbits, respectively, the maximum recommended human dose (MRHD) of 400 mg/day on mg/m 2 basis in adolescents. Increased fetal resorption and other adverse effects on the fetus in rats at 6 to 9 times the MRHD and increase in congenital anomalies in rabbits at 6 to 17 times the MRHD on mg/m 2 basis in adolescents were observed. 8.3 Nursing Mothers Trazodone and/or its metabolites have been found in the milk of lactating rats, suggesting that the drug may be secreted in human milk. Caution should be exercised when trazodone is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness in the pediatric population have not been established. Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients [ see Boxed Warning, Warnings and Precautions ( 5.1 ) ]. 8.5 Geriatric Use Reported clinical literature and experience with trazodone has not identified differences in responses between elderly and younger patients. However, as experience in the elderly with trazodone hydrochloride is limited, it should be used with caution in geriatric patients. Serotonergic antidepressants have been associated with cases of clinically significant hyponatremia in elderly patients who may be at greater risk for this adverse reaction [ see Warnings and Precautions (5.11) ]. 8.6 Renal Impairment Trazodone has not been studied in patients with renal impairment. Trazodone should be used with caution in this population. 8.7 Hepatic Impairment Trazodone has not been studied in patients with hepatic impairment. Trazodone should be used with caution in this population.

16 HOW SUPPLIED/STORAGE AND HANDLING Trazodone Hydrochloride Tablets USP, 50 mg are white to off-white, round-shape, biconvex beveled tablets, bisect on one side and plain on other side. The bisected side of tablet is debossed with 8 on upper side of bisect and 05 on lower side of bisect and are supplied as follows: NDC 68071-4410-2 BOTTLES OF 20 NDC 68071-4410-8 BOTTLES OF 28 NDC 68071-4410-3 BOTTLES OF 30 NDC 68071-4410-4 BOTTLES OF 45 NDC 68071-4410-5 BOTTLES OF 56 NDC 68071-4410-6 BOTTLES OF 60 NDC 68071-4410-9 BOTTLES OF 90 -For 50 mg, break the score on either the left or right side of the tablet (one-third of a tablet). Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense with a child-resistant closure in a tight, light-resistant container. Trazodone Hydrochloride Tablets USP

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS WARNING: SUICIDAL THOUGHTS AND BEHAVIORS Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors [see Warnings and Precautions (5.1)] . Trazodone is not approved for use in pediatric patients [see Use in Specific Populations (8.4)] . WARNING: SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. Antidepresants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients (5.1) Closely monitor for clinical worsening and emergence ofsuicidal thoughts and behaviors (5.1) Trazodone is not approved for use in pediatric patients (8.4)