FDA label 467cacc2-6470-342c-e054-00144ff8d46c

WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders . Anyone considering the use of trazodone hydrochloride tablets or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need . Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older . Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide . Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior . Families and caregivers should be advised of the need for close observation and communication with the prescriber . Trazodone hydrochloride tablets are not approved for use in pediatric patients [see Warnings and Precautions (5.1) and Patient Counseling Information (17.1) ] . WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS See full prescribing information for complete boxed warning. Increased risk of suicidal thinking and behavior in children, adolescents and young adults taking antidepressants for major depressive disorder (MDD) and other psychiatric disorders. Trazodone is not approved for use in pediatric patients ( 5.1 ).

5.4 QT Prolongation and Risk of Sudden Death Trazodone is known to prolong the QT/QTc interval. Some drugs that prolong the QT/QTc interval can cause Torsades de Pointes with sudden, unexplained death. The relationship of QT prolongation is clearest for larger increases (20 msec and greater), but it is possible that smaller QT/QTc prolongations may also increase risk, especially in susceptible individuals, such as those with hypokalemia, hypomagnesemia, or a genetic predisposition to prolonged QT/QTc. Although Torsades de Pointes has not been observed with the use of trazodone hydrochloride tablets at recommended doses in premarketing trials, experience is too limited to rule out an increased risk. However, there have been postmarketing reports of Torsades de Pointes with the immediate-release form of trazodone (in the presence of multiple confounding factors), even at doses of 100 mg per day or less.

5.5 Use in Patients with Heart Disease Trazodone hydrochloride is not recommended for use during the initial recovery phase of myocardial infarction. Caution should be used when administering trazodone hydrochloride tablets to patients with cardiac disease and such patients should be closely monitored, since antidepressant drugs (including trazodone hydrochloride) may cause cardiac arrhythmias. QT prolongation has been reported with trazodone therapy [see Warnings and Precautions (5.4) ]. Clinical studies in patients with pre-existing cardiac disease indicate that trazodone hydrochloride may be arrhythmogenic in some patients in that population. Arrhythmias identified include isolated PVCs, ventricular couplets, tachycardia with syncope, and Torsades de Pointes. Postmarketing events have been reported at doses of 100 mg or less with the immediate-release form of trazodone. Concomitant administration of drugs that prolong the QT interval or that are inhibitors of CYP3A4 may increase the risk of cardiac arrhythmia.

5.6 Orthostatic Hypotension and Syncope 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.

5.7 Abnormal Bleeding Postmarketing data have shown an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal (GI) bleeding. While no association between trazodone and bleeding events, in particular GI bleeding, was shown, patients should be cautioned about potential risk of bleeding associated with the concomitant use of trazodone and NSAIDs, aspirin, or other drugs that affect coagulation or bleeding. Other bleeding events related to SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Clinical Worsening and Suicide Risk [see Boxed Warning and Warnings and Precautions (5.1) ] Serotonin Syndrome or NMS-like Reactions [see Warnings and Precautions (5.2) ] QT Prolongation and Risk of Sudden Death [see Warnings and Precautions (5.4) ] Orthostatic Hypotension [see Warnings and Precautions (5.6) ] Abnormal bleeding events [see Warnings and Precautions (5.7) ] Priapism [see Warnings and Precautions (5.9) ] Hyponatremia [see Warnings and Precautions (5.10) ] Cognitive and Motor Impairment [see Warnings and Precautions (5.11) ] Discontinuation symptoms [see Warnings and Precautions (5.13) ] The most common adverse reactions (reported in ≥ 5% and at twice the rate of placebo) are: Somnolence/sedation, dizziness, constipation, vision blurred. Table 2 presents the summary of adverse events (AEs) leading to discontinuation of trazodone hydrochloride tablets treatment with an incidence of at least 1% and at least twice that for placebo. Table 2: Adverse Reactions with Discontinuation as Action Taken (≥ 1%) Incidence and Incidence 2x Placebo Trazodone N = 202 Somnolence/Sedation 8 (4.0%) Dizziness 7 (3.5%) Confusional state 2 (1.0%) Coordination abnormal 2 (1.0%) Headache 2 (1.0%) Nausea 2 (1.0%) Balance disorder/Gait disturbance 2 (1.0%) Most common adverse reactions (incidence ≥ 5% and twice that of placebo) are: somnolence/sedation, dizziness, constipation, vision blurred ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Qualitest Pharmaceuticals at 1-800-444-4011 or FDA at 1-800-FDA-1088 or www . fda . gov/medwatch . 6.1 Clinical Studies Experience The table below is presented solely to indicate the relative frequency of adverse events reported in representative controlled clinical studies conducted to evaluate the safety and efficacy of trazodone hydrochloride. The figures cited cannot be used to predict concisely the incidence of untoward events in the course of usual medical practice where patient characteristics and other factors often differ from those which prevailed in the clinical trials. These incidence figures, also, cannot be compared with those obtained from other clinical studies involving related drug products and placebo as each group of drug trials is conducted under a different set of conditions. Table 3: Adverse Reactions: Percentage of Patients (> 2%) as Observed in Controlled Clinical Studies Inpatients Outpatients Trazodone Placebo Trazodone Placebo Number of Patients 142 95 157 158 % of Patients Reporting Allergic Skin Condition/Edema 2.8 1.1 7 1.3 Autonomic Blurred Vision 6.3 4.2 14.7 3.8 Constipation 7 4.2 7.6 5.7 Dry Mouth 14.8 8.4 33.8 20.3 Cardiovascular Hypertension 2.1 1.1 1.3 Incidence less than 1% Hypotension 7 1.1 3.8 0 Shortness of Breath 1.1 1.3 0 Syncope 2.8 2.1 4.5 1.3 Tachycardia/Palpitations 0 0 7 7 CNS Anger/Hostility 3.5 6.3 1.3 2.5 Confusion 4.9 0 5.7 7.6 Decreased Concentration 2.8 2.1 1.3 0 Disorientation 2.1 0 0 Dizziness/Light-headedness 19.7 5.3 28 15.2 Drowsiness 23.9 6.3 40.8 19.6 Excitement 1.4 1.1 5.1 5.7 Fatigue 11.3 4.2 5.7 2.5 Headache 9.9 5.3 19.8 15.8 Insomnia 9.9 10.5 6.4 12 Impaired Memory 1.4 0 Nervousness 14.8 10.5 6.4 8.2 Gastrointestinal Abdominal/Gastric Disorder 3.5 4.2 5.7 4.4 Bad Taste in Mouth 1.4 0 0 0 Diarrhea 0 1.1 4.5 1.9 Nausea/Vomiting 9.9 1.1 12.7 9.5 Musculoskeletal Musculoskeletal Aches/Pains 5.6 3.2 5.1 2.5 Neurological Incoordination 4.9 0 1.9 0 Paresthesia 1.4 0 0 Tremors 2.8 1.1 5.1 3.8 Sexual Function Decreased Libido 1.1 1.3 Other Decreased Appetite 3.5 5.3 0 Eyes Red/Tired/Itching 2.8 0 0 0 Head Full-Heavy 2.8 0 0 0 Malaise 2.8 0 0 0 Nasal/Sinus Congestion 2.8 0 5.7 3.2 Nightmares/Vivid Dreams 1.1 5.1 5.7 Sweating/Clamminess 1.4 1.1 Tinnitus 1.4 0 0 Weight Gain 1.4 0 4.5 1.9 Weight Loss 3.2 5.7 2.5 Occasional sinus bradycardia has occurred in long-term studies. In addition to the relatively common (i.e., greater than 1%) untoward events enumerated above, the following adverse events have been reported to occur in association 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, hyper-salivation, hypomania, impaired speech, impotence, increased appetite, increased libido, increased urinary frequency, missed periods, muscle twitches, numbness, and retrograde ejaculation. 6.2 Postmarketing Experience Spontaneous reports regarding trazodone hydrochloride received from postmarketing experience include the following: abnormal dreams, agitation, alopecia, anxiety, aphasia, apnea, ataxia, breast enlargement or engorgement, cardiospasm, cerebrovascular accident, chills, cholestasis, clitorism, congestive heart failure, diplopia, edema, extrapyramidal symptoms, grand mal seizures, hallucinations, hemolytic anemia, hirsutism, hyperbilirubinemia, increased amylase, increased salivation, insomnia, leukocytosis, leukonychia, jaundice, lactation, liver enzyme alterations, methemoglobinemia, nausea/vomiting (most frequently), paresthesia, paranoid reaction, priapism [see Warnings and Precautions (5.9) and Patient Counseling Information (17.1) ], pruritus, psoriasis, psychosis, rash, stupor, inappropriate ADH syndrome, tardive dyskinesia, unexplained death, urinary incontinence, urinary retention, urticaria, vasodilation, vertigo, and weakness. Cardiovascular system effects which have been reported include the following: conduction block, orthostatic hypotension and syncope, palpitations, bradycardia, atrial fibrillation, myocardial infarction, cardiac arrest, arrhythmia, ventricular ectopic activity, including ventricular tachycardia and QT prolongation. In postmarketing surveillance, prolonged QT interval, Torsades de Pointes, and ventricular tachycardia have been reported with the immediate-release form of trazodone at doses of 100 mg per day or less [see Warnings and Precautions (5.4) ].

6.1 Clinical Studies Experience The table below is presented solely to indicate the relative frequency of adverse events reported in representative controlled clinical studies conducted to evaluate the safety and efficacy of trazodone hydrochloride. The figures cited cannot be used to predict concisely the incidence of untoward events in the course of usual medical practice where patient characteristics and other factors often differ from those which prevailed in the clinical trials. These incidence figures, also, cannot be compared with those obtained from other clinical studies involving related drug products and placebo as each group of drug trials is conducted under a different set of conditions. Table 3: Adverse Reactions: Percentage of Patients (> 2%) as Observed in Controlled Clinical Studies Inpatients Outpatients Trazodone Placebo Trazodone Placebo Number of Patients 142 95 157 158 % of Patients Reporting Allergic Skin Condition/Edema 2.8 1.1 7 1.3 Autonomic Blurred Vision 6.3 4.2 14.7 3.8 Constipation 7 4.2 7.6 5.7 Dry Mouth 14.8 8.4 33.8 20.3 Cardiovascular Hypertension 2.1 1.1 1.3 Incidence less than 1% Hypotension 7 1.1 3.8 0 Shortness of Breath 1.1 1.3 0 Syncope 2.8 2.1 4.5 1.3 Tachycardia/Palpitations 0 0 7 7 CNS Anger/Hostility 3.5 6.3 1.3 2.5 Confusion 4.9 0 5.7 7.6 Decreased Concentration 2.8 2.1 1.3 0 Disorientation 2.1 0 0 Dizziness/Light-headedness 19.7 5.3 28 15.2 Drowsiness 23.9 6.3 40.8 19.6 Excitement 1.4 1.1 5.1 5.7 Fatigue 11.3 4.2 5.7 2.5 Headache 9.9 5.3 19.8 15.8 Insomnia 9.9 10.5 6.4 12 Impaired Memory 1.4 0 Nervousness 14.8 10.5 6.4 8.2 Gastrointestinal Abdominal/Gastric Disorder 3.5 4.2 5.7 4.4 Bad Taste in Mouth 1.4 0 0 0 Diarrhea 0 1.1 4.5 1.9 Nausea/Vomiting 9.9 1.1 12.7 9.5 Musculoskeletal Musculoskeletal Aches/Pains 5.6 3.2 5.1 2.5 Neurological Incoordination 4.9 0 1.9 0 Paresthesia 1.4 0 0 Tremors 2.8 1.1 5.1 3.8 Sexual Function Decreased Libido 1.1 1.3 Other Decreased Appetite 3.5 5.3 0 Eyes Red/Tired/Itching 2.8 0 0 0 Head Full-Heavy 2.8 0 0 0 Malaise 2.8 0 0 0 Nasal/Sinus Congestion 2.8 0 5.7 3.2 Nightmares/Vivid Dreams 1.1 5.1 5.7 Sweating/Clamminess 1.4 1.1 Tinnitus 1.4 0 0 Weight Gain 1.4 0 4.5 1.9 Weight Loss 3.2 5.7 2.5 Occasional sinus bradycardia has occurred in long-term studies. In addition to the relatively common (i.e., greater than 1%) untoward events enumerated above, the following adverse events have been reported to occur in association 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, hyper-salivation, hypomania, impaired speech, impotence, increased appetite, increased libido, increased urinary frequency, missed periods, muscle twitches, numbness, and retrograde ejaculation.

6.2 Postmarketing Experience Spontaneous reports regarding trazodone hydrochloride received from postmarketing experience include the following: abnormal dreams, agitation, alopecia, anxiety, aphasia, apnea, ataxia, breast enlargement or engorgement, cardiospasm, cerebrovascular accident, chills, cholestasis, clitorism, congestive heart failure, diplopia, edema, extrapyramidal symptoms, grand mal seizures, hallucinations, hemolytic anemia, hirsutism, hyperbilirubinemia, increased amylase, increased salivation, insomnia, leukocytosis, leukonychia, jaundice, lactation, liver enzyme alterations, methemoglobinemia, nausea/vomiting (most frequently), paresthesia, paranoid reaction, priapism [see Warnings and Precautions (5.9) and Patient Counseling Information (17.1) ], pruritus, psoriasis, psychosis, rash, stupor, inappropriate ADH syndrome, tardive dyskinesia, unexplained death, urinary incontinence, urinary retention, urticaria, vasodilation, vertigo, and weakness. Cardiovascular system effects which have been reported include the following: conduction block, orthostatic hypotension and syncope, palpitations, bradycardia, atrial fibrillation, myocardial infarction, cardiac arrest, arrhythmia, ventricular ectopic activity, including ventricular tachycardia and QT prolongation. In postmarketing surveillance, prolonged QT interval, Torsades de Pointes, and ventricular tachycardia have been reported with the immediate-release form of trazodone at doses of 100 mg per day or less [see Warnings and Precautions (5.4) ].

<table width="580px"> <caption>Table 2: Adverse Reactions with Discontinuation as Action Taken (&#x2265; 1%) Incidence and Incidence 2x Placebo</caption> <col width="1px"/> <col width="1px"/> <tbody> <tr> <td styleCode=" Toprule "> </td> <td align="center" styleCode=" Toprule ">Trazodone </td> </tr> <tr> <td styleCode=" Botrule "> </td> <td align="center" styleCode=" Botrule "> <content styleCode="bold">N = 202</content> </td> </tr> <tr> <td>Somnolence/Sedation </td> <td align="center">8 (4.0%)</td> </tr> <tr> <td>Dizziness </td> <td align="center">7 (3.5%)</td> </tr> <tr> <td>Confusional state </td> <td align="center">2 (1.0%) </td> </tr> <tr> <td>Coordination abnormal </td> <td align="center">2 (1.0%) </td> </tr> <tr> <td>Headache </td> <td align="center">2 (1.0%) </td> </tr> <tr> <td>Nausea </td> <td align="center">2 (1.0%) </td> </tr> <tr> <td styleCode=" Botrule ">Balance disorder/Gait disturbance </td> <td align="center" styleCode=" Botrule ">2 (1.0%) </td> </tr> </tbody> </table>