TRAZODONE HYDROCHLORIDE- trazodone hydrochloride tablet, film coated 
Par Pharmaceutical

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use TRAZODONE HYDROCHLORIDE TABLETS safely and effectively. See full prescribing information for TRAZODONE HYDROCHLORIDE TABLETS.

TRAZODONE HYDROCHLORIDE tablets, for oral use
Initial U.S. Approval: 1981

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS
See full prescribing information for complete boxed warning.

•  Antidepresants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients (5.1)
•  Closely monitor for clinical worsening and emergence of suicidal thoughts and behaviors (5.1)
•  Trazodone hydrochloride tablets are not approved for use in pediatric patients (8.4)

INDICATIONS AND USAGE

Trazodone hydrochloride tablets are a selective serotonin reuptake inhibitor indicated for the treatment of major depressive disorder (MDD) (1).

DOSAGE AND ADMINISTRATION

  • Starting dose: 150 mg in divided doses daily. May be increased by 50 mg per day every three to four days. Maximum dose: 400 mg per day in divided doses (2.1).
  • Trazodone hydrochloride tablets should be taken shortly after a meal or light snack (2.2).
  • Tablets should be swallowed whole or broken in half along the score line (2.2).
  • When discontinued, gradual dose reduction is recommended (2.6).

DOSAGE FORMS AND STRENGTHS

  • Scored tablets: 50 mg, 100 mg (3).

CONTRAINDICATIONS

  • Concomitant use of monoamine oxidase inhibitors (MAOIs), or use within 14 days of stopping MAOIs (4).

WARNINGS AND PRECAUTIONS

• Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents (e.g., SSRI, SNRI, triptans), but also when taken alone. If it occurs, discontinue trazodone hydrochloride tablets and initiate supportive treatment (5.2).
• Cardiac Arrhythmias: Increases the QT interval. Avoid use with drugs that also increase the QT interval and in patients with risk factors for prolonged QT interval (5.3)
• Orthostatic Hypotension and Syncope: Warn patients of risk and symptoms of hypotension (5.4).
• Increased Risk of Bleeding: Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), other antiplatelet drugs, warfarin, and other anticoagulants may increase this risk (5.5).
• Priapism: Cases of painful and prolonged penile erections and priapism have been reported. Immediate medical attention should be sought if signs and symptoms of prolonged penile erections or priapism are observed (5.6).
• Activation of Mania or Hypomania: Screen for bipolar disorder and monitor for mania or hypomania (5.7).
• Potential for Cognitive and Motor Impairment: Has potential to impair judgment, thinking, and motor skills. Advise patients to use caution when operating machinery (5.9).
• Angle-Closure Glaucoma: Avoid use of antidepressants, including trazodone hydrochloride tablets, in patients with untreated anatomically narrow angles. (5.10).

ADVERSE REACTIONS

Most common adverse reactions (incidence ≥ 5% and twice that of placebo) are: edema, blurred vision, syncope, drowsiness, fatigue, diarrhea, nasal congestion, weight loss (6).

To report SUSPECTED ADVERSE REACTIONS, contact Par Pharmaceutical at 1-800-828-9393 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

• CNS Depressants: trazodone hydrochloride tablets may enhance effects of alcohol, barbiturates, or other CNS depressants (7).
• CYP3A4 Inhibitors: Consider trazodone hydrochloride tablets dose reduction based on tolerability (2.5, 7).
• CYP3A4 Inducers: Increase in trazodone hydrochloride tablets dosage may be necessary (2.5, 7).
• Digoxin or Phenytoin: Monitor for increased digoxin or phenytoin serum levels (7).
• Warfarin: Monitor for increased or decreased prothrombin time (7).

USE IN SPECIFIC POPULATIONS

  • Pregnancy: Based on animal data, may cause fetal harm (8.1).
  • Nursing Mothers: Use with caution (8.3).


See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 6/2017

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Dose Selection

2.2 Important Administration Instructions

2.3 Screen for Bipolar Disorder Prior to Starting Trazodone Hydrochloride Tablets

2.4 Switching to or from Monoamine Oxidase Inhibitor Antidepressant

2.5 Dosage Recommendations for Concomitant Use with Strong CYP3A4 Inhibitors or Inducers

2.6 Discontinuation of Treatment with Trazodone Hydrochloride Tablets

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients

5.2 Serotonin Syndrome

5.3 Cardiac Arrhythmias

5.4 Orthostatic Hypotension and Syncope

5.5 Increased Risk of Bleeding

5.6 Priapism

5.7 Activation of Mania or Hypomania

5.8 Discontinuation Syndrome

5.9 Potential for Cognitive and Motor Impairment

5.10 Angle-Closure Glaucoma

5.11 Hyponatremia

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Drugs Having Clinically Important Interactions With Trazodone Hydrochloride Tablets

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

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

*
Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors [see Warnings and Precautions (5.1)]. Trazodone hydrochloride tablets are not approved for use in pediatric patients [see Use in Specific Populations (8.4)].

1 INDICATIONS AND USAGE

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

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 hydrochloride tablets dose based on tolerability when trazodone hydrochloride tablets are coadministered with a strong CYP3A4 inhibitor [see Drug Interactions (7.1)].

Coadministration with Strong CYP3A4 Inducers

Consider increasing trazodone hydrochloride tablets dose based on therapeutic response when trazodone hydrochloride tablets are 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

Trazodone hydrochloride tablets are available in the following strengths:

50 mg - white, film-coated, round, convex, scored tablets, debossed “61” bisect “60” on one side and debossed “V” on the reverse side.

100 mg - white, film-coated, round, convex, scored tablets, debossed “61” bisect “61” on one side and debossed “V” on the reverse side.

4 CONTRAINDICATIONS

Trazodone hydrochloride tablets are contraindicated in:

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 1000 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 1000 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 hydrochloride tablets, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, 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 hydrochloride tablets with MAOIs is contraindicated. In addition, do not initiate trazodone hydrochloride tablets 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 hydrochloride tablets before initiating treatment with the MAOI [see Contraindications (4), Drug Interactions (7.1)].

Monitor all patients taking trazodone hydrochloride tablets for the emergence of serotonin syndrome. Discontinue treatment with trazodone hydrochloride tablets and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of trazodone hydrochloride tablets 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 hydrochloride tablets.  Trazodone hydrochloride tablets 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 hydrochloride tablets are 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 tablets) may cause cardiac arrhythmias [see Adverse Reactions (6.2)].

Trazodone hydrochloride tablets prolongs the QT/QTc interval. The use of trazodone hydrochloride tablets 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 hydrochloride tablets, 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 hydrochloride tablets and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing trazodone hydrochloride tablets.

5.6 Priapism

Cases of priapism (painful erections greater than 6 hours in duration) have been reported in men receiving trazodone hydrochloride tablets. 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 hydrochloride tablets 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 hydrochloride tablets 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 hydrochloride tablets, 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 tablets 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 hydrochloride tablets, in patients with untreated anatomically narrow angles.

5.11 Hyponatremia

Hyponatremia may occur as a result of treatment with SNRIs and SSRIs, including trazodone hydrochloride tablets.  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 hydrochloride tablets 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%

*Incidence less than 1%

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 hydrochloride tablets. 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 hydrochloride tablets increases the risk of serotonin syndrome.

Intervention:

Trazodone hydrochloride tablets are 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 hydrochloride tablets and other serotonergic drugs increases the risk of serotonin syndrome.

Intervention:

Monitor patients for signs and symptoms of serotonin syndrome, particularly during trazodone hydrochloride tablets initiation. If serotonin syndrome occurs, consider discontinuation of trazodone hydrochloride tablets 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 hydrochloride tablets may potentiate the risk of bleeding.

Intervention:

Inform patients of the increased risk of bleeding with the concomitant use of trazodone hydrochloride tablets and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio (INR) when initiating or discontinuing trazodone hydrochloride tablets [see Warnings and Precautions (5.5)].

Examples:

warfarin, rivaroxaban, dabigatran, clopidogrel

Strong CYP3A4 Inhibitors

Clinical Impact:

The concomitant use of trazodone hydrochloride tablets and strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone hydrochloride tablets alone.

Intervention:

If trazodone hydrochloride tablets are used with a potent CYP3A4 inhibitor, the risk of adverse reactions, including cardiac arrhythmias, may be increased and a lower dose of trazodone hydrochloride tablets 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 hydrochloride tablets and strong CYP3A4 inducers decreased the exposure of trazodone compared to the use of trazodone hydrochloride tablets alone.

Intervention:

Patients should be closely monitored to see if there is a need for an increased dose of trazodone hydrochloride tablets 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 hydrochloride tablets can increase digoxin or phenytoin concentrations.

Intervention:

Measure serum digoxin or phenytoin concentrations before initiating concomitant use of trazodone hydrochloride tablets. Continue monitoring and reduce digoxin or phenytoin dose as necessary.

Examples:

digoxin, phenytoin

Central Nervous System (CNS) Depressants

Clinical Impact:

Trazodone hydrochloride tablets may enhance the response CNS depressants.

Intervention:

Patients should be counseled that trazodone hydrochloride tablets 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 hydrochloride tablets and increase the risk of cardiac arrhythmia.

Intervention:

Avoid the use of trazodone hydrochloride tablets 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


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 the rat when given at dose levels approximately 6 to 9 times the maximum recommended human dose (MRHD) of 400 mg/day on mg/m2 in adolescents.  There was also an increase in congenital anomalies in the rabbit at approximately 6 to 17 times the MRHD on mg/m2 basis in adolescents.  There are no adequate and well-controlled studies in pregnant women.  Trazodone hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Animal Data

No teratogenic effects were observed when trazodone was given to pregnant rats and rabbits during the period of organogenesis at oral doses up to 450 mg/kg/day. This dose is 9 and 17 times, in rats and rabbits, respectively, the maximum recommended human dose (MRHD) of 400 mg/day on mg/m2 basis in adolescents. Increased fetal resorption and other adverse effects on the fetus in rats at 6 to 9 times the MRHD and increase in congenital anomalies in rabbits at 6 to 17 times the MRHD on mg/m2 basis in adolescents were observed.

8.3 Nursing Mothers

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

8.4 Pediatric Use

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

8.5 Geriatric Use

Reported clinical literature and experience with trazodone has not identified differences in responses between elderly and younger patients. However, as experience in the elderly with trazodone hydrochloride is limited, it should be used with caution in geriatric patients.

Serotonergic antidepressants have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see Warnings and Precautions (5.11)].

 

8.6 Renal Impairment

Trazodone has not been studied in patients with renal impairment. Trazodone should be used with caution in this population.

8.7 Hepatic Impairment

Trazodone has not been studied in patients with hepatic impairment. Trazodone should be used with caution in this population.

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Trazodone hydrochloride tablets are not a controlled substance.

9.2 Abuse

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

10 OVERDOSAGE

Death from overdose has occurred in patients ingesting trazodone hydrochloride tablets 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 hydrochloride tablets alone have been priapism, respiratory arrest, seizures, and ECG changes, including QT prolongation.  The reactions reported most frequently have been drowsiness and vomiting. Overdosage may cause an increase in incidence or severity of any of the reported adverse reactions.

There is no specific antidote for trazodone hydrochloride overdose. In managing overdosage, consider the possibility of multiple drug involvement. For current information on the management of poisoning or overdose, contact a poison control center (1-800-222-1222 or www.poison.org).

11 DESCRIPTION

Trazodone hydrochloride tablets for oral administration contain trazodone hydrochloride, a selective serotonin reuptake inhibitor and 5HT2 receptor antagonist. Trazodone hydrochloride tablets are a triazolopyridine derivative designated as 2-[3-[4-(3-chlorophenyl)-1-­piperazinyl]propyl]-1,2,4-triazolo [4,3-a]pyridin-3(2H)-one hydrochloride. It is a white odorless crystalline powder which is freely soluble in water. The structural formula is represented as follows:

This is the structural formula for Trazodone Hydrochloride.

Molecular Formula:     C19H22ClN5O•HCl

Molecular Weight:       408.33

Each tablet, for oral administration, contains 50 mg or 100 mg of trazodone hydrochloride, USP. In addition, each tablet contains hypromellose, lactose monohydrate, magnesium stearate, polydextrose, polyethylene glycol, povidone, pregelatinized corn starch, silicon dioxide, and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of trazodone’s antidepressant action is not fully understood, but is thought to be related to its enhancement of serotonergic activity in the CNS. Trazodone is both a selective serotonin reuptake inhibitor (SSRI) and a 5HT2 receptor antagonist and the net result of this action on serotonergic transmission and its role in trazodone’s antidepressant effect is unknown.

12.2 Pharmacodynamics

Preclinical studies have shown that trazodone selectively inhibits neuronal reuptake of serotonin (Ki = 367 nM) and acts as an antagonist at 5-HT-2A (Ki = 35.6 nM) serotonin receptors.  Trazodone is also an antagonist at several other monoaminergic receptors including 5-HT2B (Ki = 78.4 nM), 5-HT2C (Ki = 224 nM), α1A (Ki = 153 nM), α2C (Ki = 155 nM) receptors and it is a partial agonist at 5-­HT1A (Ki = 118 nM) receptor.

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

12.3 Pharmacokinetics

Absorption
In humans, trazodone hydrochloride is absorbed after oral administration without selective localization in any tissue. When trazodone hydrochloride is taken shortly after ingestion of food, there may be an increase in the amount of drug absorbed, a decrease in maximum concentration and a lengthening in the time to maximum concentration. Peak plasma levels occur approximately one hour after dosing when trazodone hydrochloride is taken on an empty stomach or 2 hours after dosing when taken with food.

Metabolism
In vitro studies in human liver microsomes show that trazodone is metabolized, via oxidative cleavage, to an active metabolite, m- chlorophenylpiperazine (mCPP) by CYP3A4. Other metabolic pathways that may be involved in the metabolism of trazodone have not been well characterized. Trazodone is extensively metabolized; less than 1% of an oral dose is excreted unchanged in the urine.

Elimination
In some patients trazodone may accumulate in the plasma.

Protein Binding
Trazodone is 89 to 95% protein bound in vitro at concentrations attained with therapeutic doses in humans.

13 NONCLINICAL TOXICOLOGY

Carcinogenesis

No drug- or dose-related occurrence of carcinogenesis was evident in rats receiving trazodone in daily oral doses up to 7.3 times the maximum recommended human dose (MRSD) of 400 mg/day on mg/m2 basis.

Mutagenesis

No genotoxicity studies were conducted with trazodone.

Impairment of Fertility

Trazodone has no effect on fertility in rats at doses up to 6 times the MRHD on mg/m2 basis in adolescents.

14 CLINICAL STUDIES

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

16 HOW SUPPLIED/STORAGE AND HANDLING

Trazodone hydrochloride tablets USP, 50 mg are white, film-coated, round, convex, scored tablets, debossed “61” bisect “60” on one side and debossed “V” on the reverse side. They are available as follows:

Bottles of 100: NDC 0603-6160-21
Bottles of 500: NDC 0603-6160-28
Bottles of 1000: NDC 0603-6160-32

Trazodone hydrochloride tablets USP, 100 mg are white, film-coated, round, convex, scored tablets, debossed “61” bisect “61” on one side and debossed “V” on the reverse side. They are available as follows:

Bottles of 100: NDC 0603-6161-21
Bottles of 500: NDC 0603-6161-28
Bottles of 1000: NDC 0603-6161-32

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Dispense contents with a child-resistant closure (as required) and in a tight, light-resistant container as defined in the USP/NF.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Suicidal Thoughts and Behaviors

Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dosage is adjusted up or down and instruct them to report such symptoms to the healthcare provider [see Box Warning and Warnings and Precautions (5.1)].

Dosage and Administration

Advise patients that trazodone hydrochloride tablets should be taken shortly after a meal or light snack. Advise patients regarding the importance of following dosage titration instructions [see Dosage and Administration (2)].

Serotonin Syndrome

Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of trazodone hydrochloride tablets with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, St. John’s Wort, and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid). Patients should contact their health care provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome [see Warnings and Precautions (5.2) and Drug Interactions (7)].

Activation of Mania/Hypomania

Advise patients and their caregivers to observe for signs of activation of mania/hypomania and instruct them to report such symptoms to the healthcare provider [see Warnings and Precautions (5.7)].

Increased Risk of Bleeding

Inform patients about the concomitant use of trazodone hydrochloride tablets with aspirin, NSAIDs, other antiplatelet drugs, warfarin, or other anticoagulants because the combined use of drugs that interfere with serotonin reuptake and these medications has been associated with an increased risk of bleeding. Advise them to inform their health care providers if they are taking or planning to take any prescription or over-the-counter medications that increase the risk of bleeding [see Warnings and Precautions (5.5)].

Discontinuation Syndrome

Advise patients not to abruptly discontinue trazodone hydrochloride tablets and to discuss any tapering regimen with their healthcare provider. Adverse reactions can occur when trazodone hydrochloride tablets are discontinued [see Warnings and Precautions (5.8)].

 Concomitant Medications

Advise patients to inform their health care providers if they are taking, or plan to take any prescription or over-the-counter medications since there is a potential for interactions [see Drug Interactions (7.1)].

MEDICATION GUIDE

What is the most important information I should know about trazodone hydrochloride tablets?

Antidepressant medicines, depression or other serious mental illnesses, and suicidal thoughts or actions: Talk to your healthcare provider about:

1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment.

2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a higher risk of having suicidal thoughts or actions. These include people who have or have a family history of bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions.

3. How can I watch for and try to prevent suicidal thoughts and actions?

Call a healthcare provider right away if you have any of the following symptoms, especially if they are new, worse, or worry you:

What else do I need to know about antidepressant medicines?

It is not known if trazodone hydrochloride tablets are safe and effective in children.

What are trazodone hydrochloride tablets?

Trazodone hydrochloride tablets are a prescription medicine used in adults to treat major depressive disorder (MDD). Trazodone hydrochloride tablets belong to a class of medicines known as SSRIs (or selective serotonin reuptake inhibitors).

Do not take trazodone hydrochloride tablets:

Before you take trazodone hydrochloride tablets tell your healthcare provider about all of your medical conditions, including if you:

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Using trazodone hydrochloride tablets with certain other medicines can affect each other causing serious side effects.

Especially tell your healthcare provider if you take:

Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I take trazodone hydrochloride tablets?

What should I avoid while taking trazodone hydrochloride tablets?

What are the possible side effects of trazodone hydrochloride tablets?

Trazodone hydrochloride tablets can cause serious side effects or death, including:

Get medical help right away, if you have any of the symptoms listed above.

The most common side effects of trazodone hydrochloride tablets include:

These are not all the possible side effects of trazodone hydrochloride tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store trazodone hydrochloride tablets?

Keep trazodone hydrochloride tablets and all medicines out of the reach of children.

 General information about the safe and effective use of trazodone hydrochloride tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use trazodone hydrochloride tablets for a condition for which it was not prescribed. Do not give trazodone hydrochloride tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about trazodone hydrochloride tablets that is written for health professionals.

What are the ingredients in trazodone hydrochloride tablets?

Active ingredient: trazodone hydrochloride, USP

Inactive ingredients: 50 mg and 100 mg: hypromellose, lactose monohydrate, magnesium stearate, polydextrose, polyethylene glycol, povidone, pregelatinized corn starch, silicon dioxide, and titanium dioxide.

Distributed by:
Par Pharmaceutical
Chestnut Ridge, NY 10977

8183136
Revised: 06/17
R7

PRINCIPAL DISPLAY PANEL - 50 mg

This is an image of the label for traZODONE Hydrochloride Tablets USP 50 mg 100 count.

PRINCIPAL DISPLAY PANEL - 100 mg

This is an image of the label for traZODONE Hydrochloride Tablets USP 100 mg 100 count.
TRAZODONE HYDROCHLORIDE 
trazodone hydrochloride tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0603-6160
Route of Administration ORAL
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
TRAZODONE HYDROCHLORIDE (UNII: 6E8ZO8LRNM) (TRAZODONE - UNII:YBK48BXK30) TRAZODONE HYDROCHLORIDE 50 mg
Inactive Ingredients
Ingredient Name Strength
HYPROMELLOSES (UNII: 3NXW29V3WO)  
LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
MAGNESIUM STEARATE (UNII: 70097M6I30)  
POLYDEXTROSE (UNII: VH2XOU12IE)  
POLYETHYLENE GLYCOLS (UNII: 3WJQ0SDW1A)  
POVIDONE (UNII: FZ989GH94E)  
STARCH, CORN (UNII: O8232NY3SJ)  
SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
Product Characteristics
Color WHITE Score 2 pieces
Shape ROUND Size 9mm
Flavor Imprint Code 61;60;V
Contains     
Packaging
# Item Code Package Description Marketing Start Date Marketing End Date
1 NDC:0603-6160-13 15 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 05/30/2010 07/31/2015
2 NDC:0603-6160-16 30 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 05/30/2010 10/31/2015
3 NDC:0603-6160-20 60 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 05/30/2010 07/31/2015
4 NDC:0603-6160-02 90 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 05/30/2010 02/28/2017
5 NDC:0603-6160-21 100 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 05/30/2010
6 NDC:0603-6160-28 500 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 05/30/2010
7 NDC:0603-6160-32 1000 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 05/30/2010
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA072192 05/30/2010
TRAZODONE HYDROCHLORIDE 
trazodone hydrochloride tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0603-6161
Route of Administration ORAL
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
TRAZODONE HYDROCHLORIDE (UNII: 6E8ZO8LRNM) (TRAZODONE - UNII:YBK48BXK30) TRAZODONE HYDROCHLORIDE 100 mg
Inactive Ingredients
Ingredient Name Strength
HYPROMELLOSES (UNII: 3NXW29V3WO)  
LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
MAGNESIUM STEARATE (UNII: 70097M6I30)  
POLYDEXTROSE (UNII: VH2XOU12IE)  
POLYETHYLENE GLYCOLS (UNII: 3WJQ0SDW1A)  
POVIDONE (UNII: FZ989GH94E)  
STARCH, CORN (UNII: O8232NY3SJ)  
SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
Product Characteristics
Color WHITE Score 2 pieces
Shape ROUND Size 11mm
Flavor Imprint Code 61;61;V
Contains     
Packaging
# Item Code Package Description Marketing Start Date Marketing End Date
1 NDC:0603-6161-16 30 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 05/30/2010 07/31/2015
2 NDC:0603-6161-20 60 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 05/30/2010 07/31/2015
3 NDC:0603-6161-02 90 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 05/30/2010 05/31/2016
4 NDC:0603-6161-21 100 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 05/30/2010
5 NDC:0603-6161-04 180 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 05/30/2010 10/31/2017
6 NDC:0603-6161-28 500 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 05/30/2010
7 NDC:0603-6161-32 1000 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 05/30/2010
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA072193 05/30/2010
Labeler - Par Pharmaceutical (011103059)
Establishment
Name Address ID/FEI Business Operations
Vintage Pharmaceuticals, LLC 825839835 ANALYSIS(0603-6160, 0603-6161) , LABEL(0603-6160, 0603-6161) , MANUFACTURE(0603-6160, 0603-6161) , PACK(0603-6160, 0603-6161)

Revised: 6/2017
Document Id: caff4726-69fe-437a-b3d9-8dbcd98f49aa
Set id: 324d2543-477d-4c0b-bfa0-d76cb4e5cd48
Version: 16
Effective Time: 20170630
 
Par Pharmaceutical