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 is 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

or 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 ). 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 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 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, 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. trazodone hydrochloride 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 is not recommended for use during the initial recovery phase of myocardial infarction. caution should be used when administering trazodone hydrochloride to patients with cardiac disease and such patients should be closely monitored, since antidepressant drugs (including trazodone hydrochloride ) may cause cardiac arrhythmias [see adverse reactions ( 6.2 )]. trazodone hydrochloride prolongs the qt/qtc interval. the use of trazodone hydrochloride 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, 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 and antiplatelet agents or anticoagulants. for patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing trazodone hydrochloride. 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 )].

ay 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.

fatigue, diarrhea, nasal congestion, weight loss ( 6 ). to report suspected adverse reactions, contact teva pharmaceuticals usa, inc. at 1-888-838-2872 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 placebo trazodone hydrochloride tablets placebo n =142 n=95 n =157 n=158 allergic 3% 1% 7% 1% skin condition/edema 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 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

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 is 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

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 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 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.

ase 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.

ension. 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.

. protein binding trazodone is 89 to 95% protein bound in vitro at concentrations attained with therapeutic doses in humans.

eft or right side of the tablet (one-third of a tablet). - for 75 mg, break the score down the middle of the tablet (one-half of a tablet). - for 100 mg, break the score on either the left or right side of the tablet (two-thirds of a tablet). - for 150 mg, use the entire tablet. store at 20°c to 25°c (68°f to 77°f) [see usp controlled room temperature]. dispense in a tight, light-resistant container as defined in the usp. keep this and all medications out of the reach of children. 50 mg 75 mg 100 mg 150 mg

r 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 is 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 )]. pregnancy advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy with trazodone hydrochloride tablets. advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to trazodone hydrochloride tablets during pregnancy [see use in special populations ( 8.1 )]. manufactured in croatia by: pliva hrvatska d.o.o. zagreb, croatia manufactured for: teva pharmaceuticals usa, inc. parsippany, nj 07054 rev. i 7/2020