WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Clinical Worsening/Suicide Risk: Monitor for clinical worsening and suicidal thinking and behavior (5.1). • Serotonin Syndrome or Neuroleptic Malignant Syndrome-Like Reactions: Have been reported with antidepressants. Discontinue trazodone hydrochloride tablets and initiate supportive treatment (5.2, 7). • Activation of Mania/Hypomania: Screen for bipolar disorder and monitor for mania/hypomania (5.3). • QT Prolongation: Increases the QT interval. Avoid use with drugs that also increase the QT interval and in patients with risk factors for prolonged QT interval (5.4). • Use in Patients With Heart Disease: Use with caution in patients with cardiac disease (5.5). • Orthostatic Hypotension and Syncope: Have occurred. Warn patients of risk and symptoms of hypotension (5.6). • Abnormal Bleeding: May increase the risk of bleeding. Use with NSAIDs, aspirin, or other drugs that affect coagulation may compound this risk (5.7, 7). • Interaction With MAOIs: Do not use concomitantly or within 14 days of monoamine oxidase inhibitors (5.8, 7). • Priapism: Has occurred. Warn male patients of this risk and how/when to seek medical attention (5.9). • Hyponatremia: Can occur in association with SIADH (5.10). • Potential for Cognitive and Motor Impairment: Has potential to impair judgment, thinking, and motor skills. Advise patients to use caution when operating machinery (5.11). •Angle-Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. (5.12) • Discontinuation Symptoms: May occur with abrupt discontinuation and include anxiety and sleep disturbance. Upon discontinuation, taper trazodone hydrochloride tablets and monitor for symptoms (5.13). 5.1 Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders and these disorders themselves are the strongest predictors of suicide. There has been a long standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with MDD and other psychiatric disorders. 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 with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients Treated Increases Compared to Placebo < 18 14 additional cases 18 to 24 5 additional cases Decreases Compared to Placebo 25 to 64 1 fewer case ≥ 65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for trazodone should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. 5.2 Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-Like Reactions The development of a potentially life-threatening serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions have been reported with antidepressants alone and may occur with trazodone treatment, but particularly with concomitant use of other serotoninergic drugs (including SSRIs, SNRIs and triptans) and with drugs that impair metabolism of serotonin (including monoamine oxidase inhibitors [MAOIs]), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Treatment with trazodone hydrochloride tablets and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above reactions occur and supportive symptomatic treatment should be initiated. Trazodone hydrochloride tablets should not be used within 14 days of an MAOI [see Warnings and Precautions (5.8) and Drug Interactions (7)]. If concomitant treatment with trazodone hydrochloride tablets and an SSRI, SNRI or a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of trazodone hydrochloride tablets with serotonin precursors (such as tryptophan) is not recommended. 5.3 Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described for clinical worsening and suicide risk represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that trazodone hydrochloride tablets are not approved for use in treating bipolar depression. 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 torsade 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 torsade 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 torsade 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 preexisting 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 torsade 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. 5.8 Interaction With MAOIs In patients receiving serotonergic drugs in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal reactions including hyperthermia, rigidity, myoclonus, autonomic instability with rapid fluctuation in vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued antidepressant treatment and have been started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Furthermore, limited animal data on the effects of combined use of serotonergic antidepressants and MAOIs suggest that these drugs may act synergistically to elevate blood pressure and evoke behavioral excitation. Therefore, it is recommended that trazodone hydrochloride tablets should not be used in combination with an MAOI or within 14 days of discontinuing treatment with an MAOI. Similarly, at least 14 days should be allowed after stopping trazodone hydrochloride tablets before starting an MAOI. 5.9 Priapism Rare cases of priapism (painful erections greater than 6 hours in duration) were 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 6 hours, whether painful or not, should immediately discontinue the drug and seek emergency medical attention [see Adverse Reactions (6.2) and 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). 5.10 Hyponatremia Hyponatremia may occur as a result of treatment with antidepressants. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with antidepressants. Also, patients taking diuretics or who are otherwise volume-depleted can be at greater risk. Discontinuation of trazodone hydrochloride tablets should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. 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. 5.11 Potential for Cognitive and Motor Impairment Trazodone hydrochloride tablets 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 5.12 Angle-Closure Glaucoma Angle-Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs including trazodone hydrochloride tablets may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy 5.13 Discontinuation Symptoms Withdrawal symptoms including anxiety, agitation and sleep disturbances, have been reported with trazodone. Clinical experience suggests that the dose should be gradually reduced before complete discontinuation of the treatment.