Trazodone Hydrochloride

AvKARE, Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATIONHIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use TRAZODONE hydrochloride tablets USP safely and effectively. See full prescribing information for TRAZODONE hydrochloride tablets USP. TRAZODONE HYDROCHLORIDE TABLETS USP, for oral useInitial U.S. Approval: 1981BOXED WARNING 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). INDICATIONS AND USAGETrazodone hydrochloride tablets USP are indicated for the treatment of major depressive disorder (1).• Efficacy was established in trials of trazodone immediate release formulation in patients with major depressive disorder (14).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).DOSAGE FORMS AND STRENGTHSBisectable tablets of 50 mg, 100 mg, 150 mg, and 300 mg (3).CONTRAINDICATIONSNone (4).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).• Discontinuation Symptoms: May occur with abrupt discontinuation and include anxiety and sleep disturbance. Upon discontinuation, taper trazodone hydrochloride tablets and monitor for symptoms (5.12).Side Effects 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 AvKARE Customer Response Line at 1-855-361-3993 or drugsafety@avkare.com ; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch DRUG INTERACTIONS• CNS Depressants: Trazodone may enhance effects of alcohol, barbiturates, or other CNS depressants (7).• CYP3A4 Inhibitors: May necessitate lower dose of trazodone hydrochloride tablets (7).• CYP3A4 Inducers (e.g., Carbamazepine): May necessitate higher dose of trazodone hydrochloride tablets (7).• Digoxin or Phenytoin: Monitor for increased serum levels (7).• Warfarin: Monitor for increased or decreased prothrombin time (7).USE IN SPECIFIC POPULATIONS• Pregnancy: Based on animal data, may cause fetal harm (8.1).• Nursing Mothers: Use with caution (8.3).• Pediatric Patients: trazodone hydrochloride tablets are not approved in pediatric patients (8.4).• Renal or Hepatic Impairment: Use with caution (8.6, 8.7).

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 TRAZODONE HYDROCHLORIDE INDICATIONS AND USAGE
• 2 TRAZODONE HYDROCHLORIDE DOSAGE AND ADMINISTRATION
• 3 DOSAGE FORMS AND STRENGTHS
• 4 TRAZODONE HYDROCHLORIDE CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Clinical Worsening and Suicide Risk
  • 5.2 Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-Like Reactions
  • 5.3 Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania
  • 5.4 QT Prolongation and Risk of Sudden Death
  • 5.5 Use in Patients With Heart Disease
  • 5.6 Orthostatic Hypotension and Syncope
  • 5.7 Abnormal Bleeding
  • 5.8 Interaction With MAOIs
  • 5.9 Priapism
  • 5.10 Hyponatremia
  • 5.11 Potential for Cognitive and Motor Impairment
  • 5.12 Discontinuation Symptoms
• 6 TRAZODONE HYDROCHLORIDE ADVERSE REACTIONS
  • 6.1 Clinical Studies Experience
  • 6.2 Postmarketing Experience
• 7 DRUG INTERACTIONS
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Renal Impairment
  • 8.7 Hepatic Impairment
• 9 DRUG ABUSE AND DEPENDENCE
  • 9.1 Controlled Substance
  • 9.2 Abuse
• 10 OVERDOSAGE
  • 10.1 Human Experience
  • 10.2 Management of Overdose
• 11 TRAZODONE HYDROCHLORIDE DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 14 CLINICAL STUDIES
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION
  • 17.1 Information for Patients
• Medication guide
• PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Trazodone hydrochloride tablets USP are indicated for the treatment of major depressive disorder (MDD) in adults. The efficacy of trazodone hydrochloride tablets USP has been established in trials with the immediate release formulation of trazodone [see Clinical Studies (14)].

2 DOSAGE AND ADMINISTRATION

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. Trazodone hydrochloride tablets should be taken shortly after a meal or light snack.

Dose Selection

An initial dose of 150 mg/day in divided doses is suggested. 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.
• Patients should be monitored for withdrawal symptoms when discontinuing treatment with trazodone hydrochloride tablets. The dose should be gradually reduced whenever possible [see Warnings and Precautions (5.12)].

Maintenance Treatment

The efficacy of trazodone hydrochloride tablets for the maintenance treatment of MDD has not been evaluated. While there is no body of evidence available to answer the question of how long a patient treated with trazodone hydrochloride tablets should continue the drug, it is generally recommended that treatment be continued for several months after an initial response. Patients should be maintained on the lowest effective dose and be periodically reassessed to determine the continued need for maintenance treatment.

Important Administration Instructions

Trazodone hydrochloride tablets are scored to provide flexibility in dosing.

Trazodone hydrochloride tablets can be swallowed whole or administered as a half tablet by breaking the tablet along the score line.

3 DOSAGE FORMS AND STRENGTHS

Trazodone hydrochloride tablets are available in the following strengths:

50 mg- White, round, compressed tablet, debossed “PLIVA 433” on one side and scored on the other side.

100 mg- White, round, compressed tablets, debossed “PLIVA 434” on one side and scored on the other side.

150 mg- White, trapezoid, flat-face, beveled edge tablet, scored and debossed as “PLIVA” and “441” on one side and tri-scored and debossed as “50” in each section on the other side.

300 mg- White, oval, flat-faced, beveled-edge tablet with one side scored with a full bisect and having two partial trisects. Debossed with stylized barr/733 on one side and 100 100 100 on the other side with the middle 100 perpendicular to the others.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

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.

 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 andPrecautions (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/QT_c interval. Some drugs that prolong the QT/QT_c 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/QT_c prolongations may also increase risk, especially in susceptible individuals, such as those with hypokalemia, hypomagnesemia, or a genetic predisposition to prolonged QT/QT_c.

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 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.

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 (5.12)]

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.

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	Incidence less than 1%	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	Incidence less than 1%	0
Dizziness/Light-Headedness	19.7	5.3	28	15.2
Drowsiness	23.9	6.3	40.8	19.6
Excitement	1.1	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	Incidence less than 1%	Incidence less than 1%
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	Incidence less than 1%
Temors	2.8	1.1	5.1	3.8
Sexual Function
Decreased Libido	Incidence less than 1%	1.1	1.3	Incidence less than 1%
Other
Decreased Appetite	3.5	5.3	0	Incidence less than 1%
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	Incidence less than 1%	1.1	5.1	5.7
Sweating/Clamminess	1.4	1.1	Incidence less than 1%	Incidence less than 1%
Tinnitus	1.4	0	0	Incidence less than 1%
Weight Gain	1.4	0	4.5	1.9
Weight Loss	Incidence less than 1%	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, torsade 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)].

7 DRUG INTERACTIONS

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 [see Warnings and Precautions (5.7)].

Warfarin

There have been reports of altered (either increased or decreased) prothrombin times in taking both warfarin and trazodone.

8 USE IN SPECIFIC POPULATIONS

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 two studies using the rat when given at dose levels approximately 30 to 50 times the proposed maximum human dose. There was also an increase in congenital anomalies in one of three rabbit studies at approximately 15 to 50 times the maximum human dose. 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.

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 [see Boxed Warning and Warnings and Precautions (5.1)]. Trazodone hydrochloride should not be used in children or adolescents.

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.

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.

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. However, it is difficult to predict the extent to which a CNS-active drug will be misused, diverted, and abused. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of trazodone hydrochloride (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).

10 OVERDOSAGE

10.1 Human Experience

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.

10.2 Management of Overdose

There is no specific antidote for trazodone hydrochloride overdose.

Treatment should consist of those general measures employed in the management of overdosage with any drug effective in the treatment of major depressive disorder.

Ensure an adequate airway, oxygenation and ventilation. Monitor cardiac rhythm and vital signs.

General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients. Activated charcoal should be administered. Forced diuresis may be useful in facilitating elimination of the drug.

In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose.

11 DESCRIPTION

Trazodone hydrochloride is a triazolopyridine. It is a white, odorless crystalline powder which is freely soluble in water.

Chemical Name: 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-1,2,4-triazolo[4,3-a]pyridin-3(2H)-one hydrochloride.

Structural Formula:

Each tablet, for oral administration, contains 50 mg, 100 mg and 150 mg of trazodone hydrochloride, USP. In addition, each tablet contains colloidal silicon dioxide, lactose anhydrous, magnesium stearate, microcrystalline cellulose and sodium starch glycolate.

Each tablet, for oral administration, contains 300 mg of trazodone hydrochloride, USP. In addition, each tablet contains colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, pregelatinized starch, sodium lauryl sulfate and sodium starch glycolate.

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 potentiation of serotonergic activity in the CNS.

12.2 Pharmacodynamics

Preclinical studies have shown that trazodone selectively inhibits neuronal reuptake of serotonin and acts as an antagonist at 5-HT-2A/2C serotonin receptors.

Trazodone is not a monoamine oxidase inhibitor and, unlike amphetamine-type drugs, does not stimulate the central nervous system.

Trazodone antagonizes alpha 1-adrenergic receptors, a property which may be associated with postural hypotension.

12.3 Pharmacokinetics

Absorption

In humans, trazodone hydrochloride is well 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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No drug- or dose-related occurrence of carcinogenesis was evident in rats receiving trazodone in daily oral doses up to 300 mg/kg for 18 months.

14 CLINICAL STUDIES

The efficacy and safety of trazodone hydrochloride was established from both inpatient and outpatient trials of the trazodone immediate release formulation in the treatment of major depressive disorder.

16 HOW SUPPLIED/STORAGE AND HANDLING

Trazodone hydrochloride tablets USP are available as follows:

50 mg: White, round, compressed tablet, debossed “PLIVA 433” on one side and scored on the other side. Available in bottles of 1000. NDC   42291-833-10

100 mg: White, round, compressed tablets, debossed “PLIVA 434” on one side and scored on the other side. Available in bottles of 1000. NDC   42291-834-10

150 mg: White, trapezoid, flat-face, beveled edge tablet, scored and debossed as “PLIVA” and “441” on one side and tri-scored and debossed as “50” in each section on the other side. Available in bottles of 500. NDC   42291-835-50

Directions for using the correct score when breaking the tablet please refer to the following:

- For 50 mg, break the score on either the left or right side of the tablet (one-third of a tablet).

- For 75 mg, break the score down the middle of the tablet (one-half of a tablet).

- For 100 mg, break the score on either the left or right side of the tablet (two-thirds of a tablet).

- For 150 mg, use the entire tablet.

300 mg: White, oval, flat-faced, beveled-edge tablet with one side scored with a full bisect and having
two partial trisects. Debossed with stylized barr/733 on one side and 100 100 100 on the other side with
the middle 100 perpendicular to the others. Available in bottles of 1000  NDC 42291-836-01

-For 100 mg, break the score on either the left or right side of the tablet (one-third of a tablet).