NDC 61919-473 Trazodone Hydrochloride

Trazodone Hydrochloride

NDC Product Code 61919-473

NDC Code: 61919-473

Proprietary Name: Trazodone Hydrochloride What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Trazodone Hydrochloride What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Product Characteristics

Color(s):
WHITE (C48325 - WHITE TO OFF WHITE)
Shape: OVAL (C48345)
Size(s):
17 MM
Imprint(s):
8;07
Score: 3

NDC Code Structure

NDC 61919-473-30

Package Description: 30 TABLET in 1 BOTTLE

NDC 61919-473-60

Package Description: 60 TABLET in 1 BOTTLE

NDC 61919-473-90

Package Description: 90 TABLET in 1 BOTTLE

NDC Product Information

Trazodone Hydrochloride with NDC 61919-473 is a a human prescription drug product labeled by Direct Rx. The generic name of Trazodone Hydrochloride is trazodone hydrochloride. The product's dosage form is tablet and is administered via oral form.

Labeler Name: Direct Rx

Dosage Form: Tablet - A solid dosage form containing medicinal substances with or without suitable diluents.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Trazodone Hydrochloride Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • TRAZODONE HYDROCHLORIDE 150 mg/1
  • TRAZODONE HYDROCHLORIDE 150 mg/1
  • TRAZODONE HYDROCHLORIDE 150 mg/1

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2)
  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)
  • STARCH, PREGELATINIZED CORN (UNII: O8232NY3SJ)
  • SODIUM LAURYL SULFATE (UNII: 368GB5141J)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.
  • Oral - Administration to or by way of the mouth.
  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Serotonin Reuptake Inhibitor - [EPC] (Established Pharmacologic Class)
  • Serotonin Reuptake Inhibitor - [EPC] (Established Pharmacologic Class)
  • Serotonin Reuptake Inhibitor - [EPC] (Established Pharmacologic Class)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Direct Rx
Labeler Code: 61919
FDA Application Number: ANDA205253 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 03-07-2018 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2020 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Information for Patients

Trazodone

Trazodone is pronounced as (traz' oh done)

Why is trazodone medication prescribed?
Trazodone is used to treat depression. Trazodone is in a class of medications called serotonin modulators. It works by increasing the amount of serotonin, a natural subst...
[Read More]

* Please review the disclaimer below.

Trazodone Hydrochloride Product Label Images

Trazodone Hydrochloride Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

Boxed Warning

WARNING: SUICIDAL THOUGHTS AND BEHAVIORSWARNING: SUICIDAL THOUGHTS AND BEHAVIORSAntidepressants 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 is not approved for use in pediatric patients [see Use in Specific Populations (8.4)].

Indications & Usage

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

Dosage & Administration

2.1 Dose SelectionAn 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 Improtant Administration InstructionsTrazodone 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 TrazodonePrior 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 Switchning to or from Monoamine Oxidase Inhibitor AntidepressantAt least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (MAOI) antidepressant and initiation of trazodone hydrochloride tablets. In addition, atleast 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 InducersCoadministration with Strong CYP3A4 InhibitorsConsider reducing trazodone dose based on tolerability when trazodone is coadministered with a strong CYP3A4 inhibitor [see Drug Interactions (7.1)].Coadministration with Strong CYP3A4 InducersConsider 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 TrazodoneAdverse reactions may occur upon discontinuation of trazodone [See Warnings and Precautions (5.8)]. Gradually reduce the dosage rather than stopping trazodone abruptly whenever possible.

Dosage Forms & Strengths

Trazodone hydrochloride tablets, USP are available in the following strengths:Trazodone hydrochloride tablets USP, 50 mg are white to off-white, round-shape, biconvex beveled tablets, bisect on one side and plain on other side. The bisected side oftablet is debossed with '8' on upper side of bisect and '05' on lower side of bisect.Trazodone hydrochloride tablets USP, 100 mg are white to off-white, round-shape, biconvex beveled tablets, bisect on one side and plain on other side. The bisected side of tablet is debossed with '8' on upper side of bisect and '06' on lower side of bisect.Trazodone hydrochloride tablets USP, 150 mg are white to off-white, oval-shape, flat faced beveled tablets having one full bisect and two trisect notches on one side and two trisects on other side. The full bisected side of tablet is debossed with '8' on one side of bisect and '07' on other bisect segments.Trazodone hydrochloride tablets USP, 300 mg are white to off-white, oval-shape, flat faced beveled tablets having one full bisect and two trisect notches on one side and two trisects on other side. The full bisected side of tablet is debossed with '8' on one side of bisect and '08' on other bisect segment.

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)].

Warnings And Precautions

5.1 Suicidal Thoughts and Behaviors in Pediatric and Young Adult PatientsIn 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 SyndromeSerotonin-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, 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 with MAOIs is contraindicated. In addition, do not initiate trazodone 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, discontinue trazodone before initiating treatment with the MAOI [see Contraindications (4), Drug Interactions (7.1)].Monitor all patients taking trazodone for the emergence of serotonin syndrome. Discontinue treatment with trazodone and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of trazodone with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.5.3 Cardiac ArrhythmiasClinical 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. Trazodone 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 is not recommended for use during the initial recovery phase of myocardial infarction. Caution should be used when administering trazodone to patients with cardiac disease and such patients should be closely monitored, since antidepressant drugs (including trazodone) may cause cardiac arrhythmias [see Adverse Reactions (6.2)].Trazodone prolongs the QT/QTc interval. The use of trazodone 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 SyncopeHypotension, 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 BleedingDrugs that interfere with serotonin reuptake inhibition, including trazodone, 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 and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing trazodone.5.6 PriapismCases of priapism (painful erections greater than 6 hours in duration) have been reported in men receiving trazodone. 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 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 HypomaniaIn patients with bipolar disorder, treating a depressive episode with trazodone 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, screen patients for any personal or family history of bipolar disorder, mania, or hypomania [see Dosage and Administration (2.3)].5.8 Discontinuation SyndromeAdverse 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 ImpairmentTrazodone 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 GlaucomaThe pupillary dilation that occurs following use of many antidepressant drugs including trazodone 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, in patients with untreated anatomically narrow angles.5.11 HyponatremiaHyponatremia may occur as a result of treatment with SNRIs and SSRIs, including trazodone. 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 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)].

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 ExperienceBecause 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

142

95

157

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 ExperienceThe 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, leukocytosisCardiac 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 syndromeEye disorders: diplopiaGastrointestinal disorders: increased salivation, nausea/vomitingGeneral disorders and administration site conditions: chills, edema, unexplained death, weaknessHepatobiliary disorders: cholestasis, jaundice, hyperbilirubinemia, liver enzyme alterationsInvestigations: increased amylaseMetabolism and nutrition disorders: methemoglobinemiaNervous system disorders: aphasia, ataxia, cerebrovascular accident, extrapyramidal symptoms, grand mal seizures, paresthesia, tardive dyskinesia, vertigoPsychiatric disorders: abnormal dreams, agitation, anxiety, hallucinations, insomnia, paranoid reaction, psychosis, stuporRenal and urinary disorders: urinary incontinence, urinary retentionReproductive system and breast disorders: breast enlargement or engorgement, clitorism, lactation, priapism [see Warnings and Precautions (5.6)]Respiratory, thoracic and mediastinal disorders: apneaSkin and subcutaneous tissue disorders: alopecia, hirsutism, leukonychia, pruritus, psoriasis, rash, urticariaVascular disorders: vasodilation

Drug Interactions

MAOIsMAOIs should not be used within 14 days of trazodone [see Warnings and Precautions (5.8)].Central Nervous System (CNS) DepressantsTrazodone may enhance the response to alcohol, barbiturates, and other CNS depressants.Cytochrome P450 3A4 InhibitorsIn vitro drug metabolism studies suggest that there is a potential for drug interactions when trazodone is given with cytochrome P450 3A4 (CYP3A4) inhibitors. The effect of short-term administration of ritonavir (200 mg twice daily, 4 doses) on the pharmacokinetics of a single dose of trazodone (50 mg) has been studied in 10 healthy subjects. The Cmax of trazodone increased by 34%, the AUC increased 2.4 fold, the half-life increased by 2.2 fold, and the clearance decreased by 52%. Adverse effects including nausea, hypotension, and syncope were observed when ritonavir and trazodone were coadministered. It is likely that ketoconazole, indinavir, and other CYP3A4 inhibitors such as itraconazole may lead to substantial increases in trazodone plasma concentrations with the potential for adverse effects. If trazodone is used with a potent CYP3A4 inhibitor, the risk of cardiac arrhythmia may be increased [see Warnings and Precautions (5.4)] and a lower dose of trazodone should be considered.Cytochrome P450 Inducers (e.g., Carbamazepine)Carbamazepine induces CYP3A4. Following coadministration of carbamazepine 400 mg per day with trazodone 100 mg to 300 mg daily, carbamazepine reduced plasma concentrations of trazodone and m-chlorophenlypiperazine (an active metabolite) by 76% and 60% respectively, compared to pre-carbamazepine values. Patients should be closely monitored to see if there is a need for an increased dose of trazodone when taking both drugs.Digoxin and PhenytoinIncreased serum digoxin or phenytoin levels have been reported in patients receiving trazodone concurrently with either of these drugs. Monitor serum levels and adjust dosages as needed.Serotonergic DrugsBased on the mechanism of action of trazodone and the potential for serotonin syndrome, caution is advised when trazodone is coadministered with other drugs that may affect the neurotransmitter systems [see Warnings and Precautions (5.2)].NSAIDs, Aspirin, or Other Drugs Affecting Coagulation or BleedingDue to a possible association between serotonin modulating drugs and gastrointestinal bleeding, patients should be monitored for and cautioned about the potential risk of bleeding associated with the concomitant use of trazodone and NSAIDs, aspirin, or other drugs that affect coagulation or bleeding [see Warnings and Precautions (5.7)].WarfarinThere have been reports of altered (either increased or decreased) prothrombin times in taking both warfarin and trazodone.7.1 Drugs Having Clinically Important Interactions with TrazodoneTable 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 arrhythmia.

Intervention:

Avoid the use of trazodone 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

Use In Specific Populations

8.1 PregnancyTeratogenic EffectsPregnancy Category CTrazodone 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/m2in adolescents. There is 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 DataNo 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 MothersTrazodone 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 UseSafety 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 UseReported 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 ImpairmentTrazodone has not been studied in patients with renal impairment. Trazodone should be used with caution in this population.8.7 Hepatic ImpairmentTrazodone has not been studied in patients with hepatic impairment. Trazodone should be used with caution in this population.

Drug Abuse And Dependence

9.1 Controlled SubstanceTrazodone hydrochloride tablets are not a controlled substance.9.2 AbuseAlthough 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.

Overdosage

Death from overdose has occurred in patients ingesting trazodone 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 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).

Description

Trazodone hydrochloride is a selective serotonin reuptake inhibitor and 5HT2 receptor antagonist. Trazodone hydrochloride, USP is 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 to off-white, crystalline powder which is sparingly soluble in chloroform and in water. The structural formula is represented as follows:[Trazodone Hydrochloride Tablets USP]Molecular Formula: C19H22ClN5O•HClMolecular Weight: 408.33Each trazodone hydrochloride tablet, USP for oral administration contains 50 mg, 100 mg, 150 mg or 300 mg of trazodone hydrochloride, USP. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, pregelatinized starch, sodium lauryl sulfate, and sodium starch glycolate.The USP Dissolution Test is pending.

Clinical Pharmacology

12.1 Mechanism of ActionThe 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 PharmacodynamicsPreclinical 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 5HT1A (Ki = 118 nM) receptor.Trazodone antagonizes alpha 1-adrenergic receptors, a property which may be associated with postural hypotension.12.3 PharmacokineticsAbsorptionIn 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.MetabolismIn 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.EliminationIn some patients trazodone may accumulate in the plasma.Protein BindingTrazodone is 89 to 95% protein bound in vitro at concentrations attained with therapeutic doses in humans.

Nonclinical Toxicology

CarcinogenesisNo drug- or dose-related occurrence of carcinogenesis was evident in rats receiving trazodone in daily oral doses up to7.3 times the maximum recommended human dose (MRSD) of 400 mg/day on mg/m2basis.MutagenesisNo genotoxicity studies were conducted with trazodone.Impairment of FertilityTrazodone has no effect on fertility in rats at doses up to 6 times the MRHD on mg/m2 basis in adolescents.

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.

How Supplied

Trazodone Hydrochloride Tablets USP, 150 mg are white to off-white, oval-shape, flat faced beveled tablets having one full bisect and two trisect notches on one side and two trisects on other side. The full bisected side of tablet is debossed with '8' on one side of bisect and '07' on other bisect segments Directions for using the correct score when breaking the tablet, please refer to thefollowing:-For 100 mg, break the score on either the left or right side of the tablet (one-third of atablet).[Trazodone Hydrochloride Tablets USP]-For 150 mg, break the score down the middle of the tablet (one-half of a tablet).[Trazodone Hydrochloride Tablets USP]-For 200 mg, break the score on either the left or right side of the tablet (two-thirds of atablet).[Trazodone Hydrochloride Tablets USP]-For 300 mg, use the entire tablet.[Trazodone Hydrochloride Tablets USP]Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Dispense with a child-resistant closure in a tight, light-resistant container.

* Please review the disclaimer below.