Trazodone Hydrochloride

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

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 ( 2.1 ). 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, and should not be chewed or crushed ( 2.2 ). When discontinued, gradual dose reduction is recommended ( 2.6 ). 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, USP are available in the following strengths: Trazodone hydrochloride tablets, USP 50 mg are white, round, convex, bisected, film-coated tablets, debossed ‘S/14’ on one side and having ‘break-line’ on other side Trazodone hydrochloride tablets, USP 100 mg are white, round, convex, bisected, film-coated tablets, debossed ‘S/26’ on one side and ‘break line’ on other side Trazodone hydrochloride tablets, USP 150 mg are white, round, flat-faced beveled, quadrisected tablets, debossed: Upper side = Break line (quadrisect) Lower side = S 53 Bisectable tablets of 50 mg, 100 mg and 150 mg ( 3 ).

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

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 Arrhythmias [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) ] 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 Sun Pharmaceutical Industries, Inc. at 1-800-406-7984 or drugsafety@sunpharma.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 Controlled 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 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 ventri …

7 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 ). 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 reduc …

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 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 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 than 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 an 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 and any potential adverse effects on the breastfed child from trazodone hydrochloride 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 a …

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.

11 DESCRIPTION Trazodone hydrochloride tablets, USP for oral administration contain trazodone hydrochloride, a selective serotonin reuptake inhibitor and 5HT2 receptor antagonist. Trazodone hydrochloride is a triazolopyridine derivative designated as 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-1,2,4-triazolo[4,3-a]pyridin-3(2 H )-one hydrochloride. It is a white, odorless crystalline powder which is freely soluble in water. The structural formula is represented as follows: Molecular Formula: C 19 H 22 ClN 5 O ∙ HCl Molecular Weight: 408.33 Each tablet, for oral administration, contains 50 mg, 100 mg or 150 mg of trazodone hydrochloride, USP. Trazodone hydrochloride tablets, USP, 50 mg and 100 mg, contain the following inactive ingredients: anhydrous lactose, carnauba wax, colloidal silicon dioxide, crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, and titanium dioxide. Trazodone hydrochloride tablets, USP, 150 mg, contain the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, crospovidone, magnesium stearate, and microcrystalline cellulose. structure

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, and syndrome of inappropriate antidiuretic hormone secretion (SIADH). 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).

16 HOW SUPPLIED/STORAGE AND HANDLING Trazodone hydrochloride tablets, USP are available as follows: Trazodone hydrochloride tablets, USP 50 mg are white, round, convex, bisected, film-coated tablets, debossed 'S/14' on one side and having break-line on other side. Bottles of 100 CRC NDC 57664-014-72 Bottles of 500 NCRC NDC 57664-014-74 Bottles of 1000 NCRC NDC 57664-014-75 Trazodone hydrochloride tablets, USP 100 mg are white, round, convex, bisected, film-coated tablets, debossed 'S/26' on one side and break line on other side Bottles of 100 CRC NDC 57664-026-72 Bottles of 500 NCRC NDC 57664-026-74 Bottles of 1000NCRC NDC-57664-026-75 Trazodone hydrochloride tablets, USP 150 mg are white, round, flat-faced bevelled, quadrisected tablets, debossed "S53" on one side and having 'break-line' on other side (quadrisect). Bottles of 100 CRC NDC 57664-053-72 Bottles of 500 NCRC NDC-57664-053-74 Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature] DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.