PRINCIPAL DISPLAY PANEL

NDC 69584-884-90

traZODONE
Hydrochloride
Tablets, USP

50 mg

PHARMACIST: PLEASE DISPENSE
MEDICATION GUIDE TO EACH PATIENT

Rx ONLY 1000 TABLETS

Print Medication Guide at:
https://www.oxford-rx.com/med-guides

EACH TABLET CONTAINS:
****Trazodone Hydrochloride, USP...........50 mg

**USUAL DOSAGE:**See package insert for full
prescribing information.

KEEP THIS AND ALL MEDICATIONS
OUT OF REACH OF CHILDREN

---

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

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

KEEP TIGHTLY CLOSED

---

MANUFACTURED BY:
OXFORD PHARMACEUTICALS, LLC
BIRMINGHAM, ALABAMA 35211
8000119 Rev. 05/2022 R00

---

OXFORD
PHARMACEUTICALS, LLC

---

NDC 69584-885-90

traZODONE
Hydrochloride
Tablets, USP

100 mg

PHARMACIST: PLEASE DISPENSE
MEDICATION GUIDE TO EACH PATIENT

Rx ONLY 1000 TABLETS

Print Medication Guide at:
https://www.oxford-rx.com/med-guides

EACH TABLET CONTAINS:
****Trazodone Hydrochloride, USP...........100 mg

**USUAL DOSAGE:**See package insert for full
prescribing information.

KEEP THIS AND ALL MEDICATIONS
OUT OF REACH OF CHILDREN

---

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

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

KEEP TIGHTLY CLOSED

---

MANUFACTURED BY:
OXFORD PHARMACEUTICALS, LLC
BIRMINGHAM, ALABAMA 35211
8000122 Rev. 05/2022 R00

---

OXFORD
PHARMACEUTICALS, LLC

---

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, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [seeContraindications(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)].

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.