Trazodone Hydrochloride

1 INDICATIONS AND USAGE Trazodone is a selective serotonin reuptake inhibitor indicated for the treatment of major depressive disorder (MDD) ( 1 ). Trazodone hydrochloride tablets are indicated for the treatment of major depressive disorder (MDD) in adults.

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

5 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 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, in patients with untreated anatomically narrow angles. ( 5.10 ). 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 to 24 5 additional patients Decreases Compared to Placebo 25 to 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, 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 is increased 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…

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

7 DRUG INTERACTIONS CNS Depressants: Trazodone may enhance effects of alcohol, barbiturates, or other CNS depressants ( 7 ). CYP3A4 Inhibitors: Consider trazodone dose reduction based on tolerability ( 2.5 , 7 ). CYP3A4 Inducers: Increase in trazodone 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 ). 7.1 Drugs Having Clinically Important Interactions with Trazodone Table 3 Clinically Important Drug Interactions with Trazodone 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 a…

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 hydrochloride tablets 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 times 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 times 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 times 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 times to 11 times the MRHD and increase in congenital anomalies in rabbits at 7.3 times 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 hydrochloride tablets and any potential adverse effects on the breastfed child from trazodone hydrochloride tablets or from the underlying maternal condition.

6 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 Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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-treated Patients and Greater than the Rate of Placebo-Treated Patients as Observed in Controlled Clinical Studies Inpatients Outpatients Trazodone Placebo Trazodone Placebo N=142 N=95 N=157 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 )]. …