DESYREL® (trazodone hydrochloride) tablets

DESYREL® (trazodone hydrochloride) tablets

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DESYREL® (trazodone hydrochloride) tablets

DESYREL (trazodone hydrochloride) tablets for oral administration contain trazodone hydrochloride, a selective serotonin reuptake inhibitor and 5HT2 receptor antagonist. DESYREL 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 odorless crystalline powder which is freely soluble in water.

Molecular Formula: C19H22CIN5O • HCl

Molecular Weight: 408.33

Each tablet, 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:

50 mg and 100 mg: Corn starch, dibasic calcium phosphate, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, sodium starch glycolate, and triacetin

150 mg: magnesium stearate, microcrystalline cellulose, pregelatinized starch, and stearic acid

300 mg: magnesium stearate, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, and stearic acid

Indications and usage

DESYREL is a selective serotonin reuptake inhibitor indicated for the treatment of major depressive disorder (MDD)

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.

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
  • Prior to initiating treatment with DESYREL or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania
  • DESYREL should be taken shortly after a meal or light snack.
  • Tablets should be swallowed whole or broken in half along the score line.
  • When discontinued, gradual dose reduction is recommended

Contraindications

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

Warnings and precautions

Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients: 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 DESYREL, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

Serotonin Syndrome: Serotonin-norepinephrine reuptake inhibitors (SNRIs) and SSRIs, including DESYREL, 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. 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).

Cardiac Arrhythmias: DESYREL prolongs the QT/QTc interval. The use of DESYREL 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

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.

Increased Risk of Bleeding: Drugs that interfere with serotonin reuptake inhibition, including DESYREL, 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. Bleeding events related to drugs that interfere with serotonin reuptake have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.

Priapism: DESYREL 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).

Activation of Mania or Hypomania: In patients with bipolar disorder, treating a depressive episode with DESYREL 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 DESYREL, screen patients for any personal or family history of bipolar disorder, mania, or hypomania

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

Potential for Cognitive and Motor Impairment: DESYREL® 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.

Angle-Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs including DESYREL 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 DESYREL, in patients with untreated anatomically narrow angles.

Hyponatremia: Hyponatremia may occur as a result of treatment with SNRIs and SSRIs, including DESYREL. 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).

Adverse reactions

  • Blood and lymphatic system disorders: hemolytic anemia, leukocytosis
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  • 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.
  • 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
  • Respiratory, thoracic and mediastinal disorders: apnea
  • Skin and subcutaneous tissue disorders: alopecia, hirsutism, leukonychia, pruritus, psoriasis, rash, urticaria Vascular disorders: vasodilation

Drug interactions

Monoamine Oxidase Inhibitors (MAOIs): The concomitant use of MAOIs and serotonergic drugs including DESYREL increases the risk of serotonin syndrome. DESYREL is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue

Examples: isocarboxazid, moclobemide, phenelzine, selegiline, tranylcypromine

Other Serotonergic Drugs: The concomitant use of serotonergic drugs including DESYREL and other serotonergic drugs increases the risk of serotonin syndrome. Monitor patients for signs and symptoms of serotonin syndrome, particularly during DESYREL initiation. If serotonin syndrome occurs, consider discontinuation of DESYREL and/or concomitant serotonergic drugs. Examples: triptans, antidepressants (tricyclic and serotonin uptake inhibitors), fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort

Antiplatelet Agents and Anticoagulants: Serotonin release by platelets plays an important role in hemostasis. The concurrent use of an antiplatelet agent or anticoagulant with DESYREL may potentiate the risk of bleeding. Inform patients of the increased risk of bleeding with the concomitant use of DESYREL and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio (INR) when initiating or discontinuing DESYREL. Examples: warfarin, rivaroxaban, dabigatran, clopidogrel

Strong CYP3A4 Inhibitors: The concomitant use of DESYREL and strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of DESYREL alone. If DESYREL is used with a potent CYP3A4 inhibitor, the risk of adverse reactions, including cardiac arrhythmias, may be increased and a lower dose of DESYREL should be considered. Examples: itraconazole, ketoconazole, clarithromycin, indinavir

Strong CYP3A4 Inducers: The concomitant use of DESYREL and strong CYP3A4 inducers decreased the exposure of trazodone compared to the use of DESYREL alone. Patients should be closely monitored to see if there is a need for an increased dose of DESYREL when taking CYP3A4 inducers. Examples: rifampin, carbamazepine, phenytoin, St. John’s wort

Digoxin and Phenytoin: Digoxin and phenytoin are narrow therapeutic index drugs. Concomitant use of DESYREL can increase digoxin or phenytoin concentrations. Measure serum digoxin or phenytoin concentrations before initiating concomitant use of DESYREL. Continue monitoring and reduce digoxin or phenytoin dose as necessary. Examples: digoxin, phenytoin

Central Nervous System (CNS) Depressants: Desyrel may enhance the response CNS depressants. Patients should be counseled that DESYREL may enhance the response to alcohol, barbiturates, and other CNS depressants. Examples: alcohol, barbiturates

QT Interval Prolongation: Concomitant use of drugs that prolong the QT interval may add to the QT effects of DESYREL and increase the risk of cardiac arrhythmia. Avoid the use of DESYREL in combination with other drugs known to prolong QTc.

Examples: Class 1A antiarrhythmics: quinidine, procainamide, disopyramide; Class 3 antiarrhythmics: amiodarone, sotalol; Antipsychotics: ziprasidone, chlorpromazine, thioridazine; Antibiotics: gatifloxacin

Use in specific populations

Pregnancy: Pregnancy Category C

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 6 to 9 times the maximum recommended human dose (MRHD) of 400 mg/day on mg/m2 in adolescents. There was 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.

Nursing Mothers: Trazodone 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.

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

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

Renal Impairment: Trazodone has not been studied in patients with renal impairment. Trazodone should be used with caution in this population.

Hepatic Impairment: Trazodone has not been studied in patients with hepatic impairment. Trazodone should be used with caution in this population.

Drug abuse and dependence

Controlled Substance: DESYREL® is not a controlled substance.

Abuse: Although 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 DESYREL 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 DESYREL 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.

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