1 INDICATIONS AND USAGE

Trazodone hydrochloride tablets, USP are indicated for the treatment of major depressive disorder (MDD) in adults.

4 CONTRAINDICATIONS

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)] .

5 WARNINGS AND PRECAUTIONS

5.1 Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients

In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and over 4,400 pediatric patients, the incidence of suicidal thoughts and behaviors in pediatric and young adult patients was greater in antidepressant-treated patients than in placebo-treated patients. The drug- placebo differences in the number of cases of suicidal thoughts and behaviors per 1,000 patients treated are provided in Table 1.

No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about antidepressant drug effect on suicide.

Table 1: Risk Differences of the Number of Cases of Suicidal Thoughts or Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients

** Age Range** ** (years)**	** Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1,000 Patients Treated**
	Increases Compared to Placebo
< 18	14 additional patients
18 - 24	5 additional patients
	Decreases Compared to Placebo
25 - 64	1 fewer patient
≥ 65	6 fewer patients

It is unknown whether the risk of suicidal thoughts and behaviors in pediatric and young adult patients extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression.

Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing trazodone hydrochloride tablets, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

5.2 Serotonin Syndrome

Serotonin-norepinephrine reuptake inhibitors (SNRIs) and SSRIs, including trazodone, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk isincreased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs****[see Contraindications ( 4), Drug Interactions (7.1)]****. Serotonin syndrome can also occur when these drugs are used alone.

Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

The concomitant use of trazodone with MAOIs is contraindicated. In addition, do not initiate trazodone in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking trazodone hydrochloride tablets, discontinue trazodone before initiating treatment with the MAOI [see Contraindications ( 4), Drug Interactions ( 7.1)] .

Monitor all patients taking trazodone for the emergence of serotonin syndrome. Discontinue treatment with trazodone and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of trazodone with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

5.3 Cardiac Arrhythmias

Clinical studies indicate that trazodone hydrochloride may be arrhythmogenic in patients with preexisting cardiac disease. Arrhythmias identified include isolated PVCs, ventricular couplets, tachycardia with syncope, and torsade de pointes. Postmarketing events, including torsade de pointes have been reported at doses of 100 mg or less with the immediate-release form of trazodone. Trazodone should also be avoided in patients with a history of cardiac arrhythmias, as well as other circumstances that may increase the risk of the occurrence of torsade de pointes and/or sudden death, including symptomatic bradycardia, hypokalemia or hypomagnesemia, and the presence of congenital prolongation of the QT interval. Trazodone is not recommended for use during the initial recovery phase of myocardial infarction. Caution should be used when administering trazodone to patients with cardiac disease and such patients should be closely monitored, since antidepressant drugs (including trazodone) may cause cardiac arrhythmias [see Adverse Reactions ( 6.2)] .

Trazodone prolongs the QT/QTc interval. The use of trazodone should be avoided in patients with known QT prolongation or in combination with other drugs that are inhibitors of CYP3A4 (e.g., itraconazole, clarithromycin, voriconazole), or known to prolong QT interval including Class 1A antiarrhythmics (e.g., quinidine, procainamide) or Class 3 antiarrhythmics (e.g., amiodarone, sotalol), certain antipsychotic medications (e.g., ziprasidone, chlorpromazine, thioridazine), and certain antibiotics (e.g., gatifloxacin). Concomitant administration of drugs may increase the risk of cardiac arrhythmia [see Drug Interactions ( 7.1)].

5.4 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.

5.5 Increased Risk of Bleeding

Drugs that interfere with serotonin reuptake inhibition, including trazodone, increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDS), other antiplatelet drugs, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to drugs that interfere with serotonin reuptake have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.

Inform patients about the risk of bleeding associated with the concomitant use of trazodone and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing trazodone.

5.6 Priapism

Cases of priapism (painful erections greater than 6 hours in duration) have been 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 4 hours, whether painful or not, should immediately discontinue the drug and seek emergency medical attention [see Adverse Reactions ( 6.2), 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).

5.7 Activation of Mania or Hypomania

In patients with bipolar disorder, treating a depressive episode with trazodone or another antidepressant may precipitate a mixed/manic episode. Activation of mania/hypomania has been reported in a small proportion of patients with major affective disorder who were treated with antidepressants. Prior to initiating treatment with trazodone, screen patients for any personal or family history of bipolar disorder, mania, or hypomania [see Dosage and Administration ( 2.3)] .

5.8 Discontinuation Syndrome

Adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt discontinuation, include: nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible [See Dosage and Administration ( 2.6)].

5.9 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.

5.10 Angle-Closure Glaucoma

The pupillary dilation that occurs following use of many antidepressant drugs including trazodone hydrochloride may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Avoid use of antidepressants, including trazodone, in patients with untreated anatomically narrow angles.

5.11 Hyponatremia

Hyponatremia may occur as a result of treatment with SNRIs and SSRIs, including trazodone. Cases with serum sodium lower than 110 mmol/L have been reported. 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. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).

In patients with symptomatic hyponatremia, discontinue trazodone and institute appropriate medical intervention. Elderly patients, patients taking diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia with SSRIs and SNRIs [see Use in Specific Populations ( 8.5)] .

6 ADVERSE REACTIONS

The following serious adverse reactions are described elsewhere in the labeling:

• Suicidal Thoughts and Behavior in Children, Adolescents and Young Adults [see Boxed Warning and Warnings and Precautions ( 5.1)]
• Serotonin Syndrome [see Warnings and Precautions ( 5.2)]
• Cardiac Arrythmias [see Warnings and Precautions ( 5.3)]
• Orthostatic Hypotension and Syncope [see Warnings and Precautions ( 5.4)]
• Increased risk of Bleeding [see Warnings and Precautions ( 5.5)]
• Priapism [see Warnings and Precautions ( 5.6)]
• Activation of Mania or Hypomania [see Warnings and Precautions ( 5.7)]
• Discontinuation Syndrome [see Warnings and Precautions ( 5.8)]
• Potential for Cognitive and Motor Impairment [see Warnings and Precautions ( 5.9)]
• Angle-Closure Glaucoma [see Warnings and Precautions ( 5.10)]
• Hyponatremia [see Warnings and Precautions ( 5.11)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Table 2: Common Adverse Reactions Occurring in ≥ 2% of Trazodone Hydrochloride Tablets-treated Patients and Greater than the Rate of Placebo- Treated Patients as Observed in Controled Clinical Studies

	Inpatients	Outpatients
	Trazodone Hydrochloride Tablets N=142	Placebo N=95	Trazodone Hydrochloride Tablets N=157	Placebo N=158
Allergic
Skin Condition/Edema	3%	1%	7%	1%
Autonomic
Blurred Vision	6%	4%	15%	4%
Constipation	7%	4%	8%	6%
Dry Mouth	15%	8%	34%	20%
Cardiovascular
Hypertension	20%	1%	1%
Hypotension	7%	1%	4%	0
Syncope	3%	2%	5%	1%
CNS
Confusion	5%	0	6%	8%
Decreased Concentration	3%	2%	1%	0
Disorientation	2%	0		0
Dizziness/Light-Headedness	20%	5%	28%	15%
Drowsiness	24%	6%	41%	20%
Fatigue	11%	4%	6%	3%
Headache	10%	5%	20%	16%
Nervousness	15%	11%	6%	8%
** Gastrointestinal**
Abdominal/Gastric Disorder	4%	4%	6%	4%
Diarrhea	0	1%	5%	1%
Nausea/Vomiting	10%	1%	13%	10%
** Musculoskeletal**
Aches/Pains	6%	3%	5%	3%
** Neurological**
Incoordination	5%	0	2%
Tremors	3%	1%	5%	4%
** Other**
Eyes Red/Tired/Itching	3%	0	0	0
Head Full-Heavy	3%	0	0	0
Malaise	3%	0	0	0
Nasal/Sinus Congestion	3%	0	6%	3%
Weight Gain	1%	0	5%	2%
Weight Loss		3%	6%	3%

Other adverse reactions occurring at an incidence of <2% with the use of trazodone hydrochloride in the controlled clinical studies: akathisia, allergic reaction, anemia, chest pain, delayed urine flow, early menses, flatulence, hallucinations/delusions, hematuria, hypersalivation, hypomania, impaired memory, impaired speech, impotence, increased appetite, increased libido, increased urinary frequency, missed periods, muscle twitches, numbness, paresthesia, retrograde ejaculation shortness of breath, and tachycardia/palpitations. Occasional sinus bradycardia has occurred in long- term studies.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of trazodone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure:

**Blood and lymphatic system disorders:**hemolytic anemia, leukocytosis

**Cardiac disorders:**cardiospasm, congestive heart failure, conduction block, orthostatic hypotension and syncope, palpitations, bradycardia, atrial fibrillation, myocardial infarction, cardiac arrest, arrhythmia, ventricular ectopic activity, including ventricular tachycardia and QT prolongation. Prolonged QT interval, torsade de pointes, and ventricular tachycardia have been reported at doses of 100 mg per day or less [see Warnings and Precautions ( 5.3)].

**Endocrine disorders:**inappropriate ADH syndrome

**Eye disorders:**diplopia

**Gastrointestinal disorders:**increased salivation, nausea/vomiting

**General disorders and administration site conditions:**chills, edema, unexplained death, weakness

**Hepatobiliary disorders:**cholestasis, jaundice, hyperbilirubinemia, liver enzyme alterations

**Investigations:**increased amylase

**Metabolism and nutrition disorders:**methemoglobinemia

**Nervous system disorders:**aphasia, ataxia, cerebrovascular accident, extrapyramidal symptoms, grand mal seizures, paresthesia, tardive dyskinesia, vertigo

**Psychiatric disorders:**abnormal dreams, agitation, anxiety, hallucinations, insomnia, paranoid reaction, psychosis, stupor

**Renal and urinary disorders:**urinary incontinence, urinary retention

**Reproductive system and breast disorders:**breast enlargement or engorgement, clitorism, lactation, priapism [see Warnings and Precautions ( 5.6)]

**Respiratory, thoracic and mediastinal disorders:**apnea

**Skin and subcutaneous tissue disorders:**alopecia, hirsutism, leukonychia, pruritus, psoriasis, rash, urticaria

**Vascular disorders:**vasodilation

7 DRUG INTERACTIONS

7.1 Drugs Having Clinically Important Interactions with Trazodone

Hydrochloride Tablets

Table 3: Clinically Important Drug Interactions with Trazodone Hydrochloride Tablets

** 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

2 DOSAGE AND ADMINISTRATION

2.1 Dose Selection

An initial dose of 150 mg/day in divided doses is suggested. The dosage should be initiated at a low-dose and increased gradually, noting the clinical response and any evidence of intolerance. Occurrence of drowsiness may require the administration of a major portion of the daily dose at bedtime or a reduction of dosage.

The dose may be increased by 50 mg/day every 3 to 4 days. The maximum dose for outpatients usually should not exceed 400 mg/day in divided doses. Inpatients (i.e., more severely depressed patients) may be given up to but not in excess of 600 mg/day in divided doses.

Once an adequate response has been achieved, dosage may be gradually reduced, with subsequent adjustment depending on therapeutic response.

2.2 Important Administration Instructions

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

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

2.3 Screen for Bipolar Disorder Prior to Starting Trazodone Hydrochloride

Tablets

Prior to initiating treatment with trazodone hydrochloride tablets or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions ( 5.7)] .

2.4 Switching to or from Monoamine Oxidase Inhibitor Antidepressant

At least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (MAOI) antidepressant and initiation of trazodone hydrochloride tablets. In addition, at least 14 days must elapse after stopping trazodone hydrochloride tablets before starting an MAOI antidepressant [see Contraindications ( 4), Warnings and Precautions ( 5.2)] .

2.5 Dosage Recommendations for Concomitant Use with Strong CYP3A4

Inhibitors or Inducers

Coadministration with Strong CYP3A4 Inhibitors

Consider reducing trazodone 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 Hydrochloride Tablets

Adverse reactions may occur upon discontinuation of trazodone hydrochloride tablets [See Warnings and Precautions ( 5.8)] . Gradually reduce the dosage rather than stopping trazodone hydrochloride tablets abruptly whenever possible.

3 DOSAGE FORMS AND STRENGTHS

50 mg Tablets, white to off white, round, biconvex, uncoated tablets debossed with "13" bisect "30" on one side and plain on other side.

100 mg Tablets, white to off white, round, biconvex, uncoated tablets debossed with "13" bisect "31" on one side and plain on other side.

150 mg Tablets, white to off white, oval, flat faced beveled edge uncoated tablets with a full bisect and two partial trisects. Debossed "13" bisect "32" on one side and "50 50 50" on other side.

300 mg white to off white, oval, flat faced beveled edge uncoated tablets with a full bisect and two partial trisects. Debossed "13" bisect "33" on one side and "100 100 100" on other side with middle "100" perpendicular to others.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research- programs/pregnancyregistry/antidepressants/

Risk Summary

Published prospective cohort studies, case series, and case reports over several decades with trazodone use in pregnant women have not identified any drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). 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 7.3 to 11 times the maximum recommended human dose (MRHD) of 400 mg/day in adults on a mg/m 2 basis. There was also an increase in congenital anomalies in the rabbit at approximately 7.3 to 22 times the MRHD on a mg/m 2 basis (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryofetal risk

A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. The women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression that women who continued antidepressants. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum.

Data

Human Data

While available studies cannot definitively establish the absence of risk, published data from prospective cohort studies, case series, and case reports over several decades have not identified an association with trazodone use during pregnancy and major birth defects, miscarriage, or other adverse maternal or fetal outcomes. All available studies have methodological limitations, including small sample size and inconsistent comparator groups.

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 11 and 22 times, in rats and rabbits, respectively, the maximum recommended human dose (MRHD) of 400 mg/day in adults on a mg/m 2 basis. Increased fetal resorption and other adverse effects on the fetus in rats at 7.3 to 11 times the MRHD and increase in congenital anomalies in rabbits at 7.3 to 22 times the MRHD on a mg/m 2 basis were observed. No further details on these studies are available.

8.2 Lactation

Risk Summary

Data from published literature report the transfer of trazodone into human milk. There are no data on the effect of trazodone on milk production. Limited data from postmarketing reports have not identified and association of adverse effects on the breastfed child.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for trazodone and any potential adverse effects on the breastfed child from trazodone or from the underlying maternal condition.

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 withtrazodone 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.

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.