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Product Name
:
DEPRICO
Chemical Name
:
Trazodone HCl
Therapeutic Category
:
Central nervous system drugs
Pharmacologic Category
:
Antidepressant, Serotonin Reuptake Inhibitor/Antagonist
Pharmaceutical Form
:
Tablets
Composition
:
Trazodone HCl 50mg / 150mg
Dosing
 
Dosing: Adult
Depression: Oral: Initial: 150 mg/day in 3 divided doses (may increase by 50 mg/day every 3-7 days); maximum dose: 600 mg/day
Note: Therapeutic effects may take up to 6 weeks. Therapy is normally maintained for 6-12 months after optimum response is reached to prevent recurrence of depression.
Sedation/hypnotic (unlabeled use): Oral: 25-50 mg at bedtime (often in combination with daytime SSRIs). May increase up to 200 mg at bedtime.

Dosing: Pediatric

Depression (unlabeled use):
Children 6-12 years: Initial: 1.5-2 mg/kg/day in divided doses; increase gradually every 3-4 days as needed; maximum: 6 mg/kg/day in 3 divided doses
Adolescents: Initial: 25-50 mg/day; increase to 100-150 mg/day in divided doses

Dosing: Geriatric

Immediate release: Oral: 25-50 mg at bedtime with 25-50 mg/day dose increase every 3 days for inpatients and weekly for outpatients, if tolerated; usual dose: 75-150 mg/day
Use
 
Treatment of major depressive disorder
Use - Unlabeled/Investigational
Potential Clavoxilg agent for antidepressants, hypnotic
Adverse Reactions
 
>10%:
Central nervous system: Sedation (≤46%), headache (10% to 33%), dizziness (20% to 28%), fatigue (6% to 15%)
Gastrointestinal: Xerostomia (15% to 34%), nausea (10% to 21%)
Ocular: Blurred vision (5% to 15%)
1% to 10%:
Cardiovascular: Edema (3% to 7%), hypotension (≤7%), syncope (≤5%), hypertension (1% to 2%)
Central nervous system: Confusion (5% to 6%), incoordination (2% to 5%), concentration decreased (1% to 3%), disorientation (≤2%), memory impairment (≤1%), agitation, migraine
Endocrine & metabolic: Libido decreased (1% to 2%)
Gastrointestinal: Diarrhea (5% to 9%), constipation (7% to 8%), abdominal pain, abnormal taste, flatulence, vomiting, weight gain/loss
Genitourinary: Ejaculation disorder (2%), urinary urgency
Neuromuscular & skeletal: Back pain (≤5%), tremor (1% to 5%), paresthesia (≤1%), myalgia
Ocular: Visual disturbance
Respiratory: Nasal congestion (3% to 6%), dyspnea
Miscellaneous: Night sweats
<1% (Limited to important or life-threatening): Abnormal dreams, abnormal orgasm, acne, akathisia, allergic reactions, alopecia, amylase increased, anemia, anxiety, aphasia, apnea, appetite increased, arrhythmia, ataxia, atrial fibrillation, bladder pain, bradycardia, breast enlargement/engorgement, cardiac arrest, cardiospasm, cerebrovascular accident, chest pain, CHF, chills, cholestasis, clitorism, conduction block, diplopia, early menses, erectile dysfunction, extrapyramidal symptoms, eye pain, flushing, gait disturbance, hallucination, hearing loss (partial), hematuria, hemolytic anemia, hepatitis, hirsutism, hyperbilirubinemia, hyperhidrosis, hypersalivation, hypersensitivity, hypoesthesia, hypomania, impaired speech, impotence, insomnia, jaundice, lactation, leukocytosis, leukonychia, libido increased, liver enzyme alteration, methemoglobinemia, MI, muscle twitching, orthostatic hypotension, palpitation, paranoia, photophobia, photosensitivity reaction, priapism, pruritus, psoriasis, psychosis, QT prolongation, rash, reflux esophagitis, retrograde ejaculation, salivation increased, seizure, SIADH, speech impairment, stupor, tachycardia, tardive dyskinesia, tinnitus, torsade de pointes, urinary frequency increased, urinary retention, urinary incontinence, urticaria, vasodilation, ventricular ectopy, ventricular tachycardia, vertigo, dry eyes, weakness
Contraindications
 
Hypersensitivity to trazodone or any component of the formulation
Warnings / Precautions Drug
 
Boxed warnings:
• Suicidal thinking/behavior: See “Major psychiatric warnings” below.
Major psychiatric warnings:
• Suicidal thinking/behavior: [U.S. Boxed Warning]: Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18-24 years of age) with major depressive disorder (MDD) and other psychiatric disorders; consider risk prior to prescribing. Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥65 years of age. Closely monitor patients for clinical worsening, suicidality, or unusual changes in behavior, particularly during the initial 1-2 months of therapy or during periods of dosage adjustments (increases or decreases); the patient’s family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. A medication guide concerning the use of antidepressants should be dispensed with each prescription.Trazodone is not FDA approved for use in children.
• The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Patients treated with antidepressants should be observed for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy.
• Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their healthcare provider if any of these symptoms or worsening depression or psychosis occur.
Concerns related to adverse effects:
• Bleeding risk: Drugs that interfere with serotonin reuptake (eg, SSRIs) have been associated with bleeding ranging from relatively minor bruising and epistaxis to life-threatening hemorrhage; similar to these agents, trazodone may also impair platelet aggregation resulting in increased risk of bleeding events, particularly if used concomitantly with aspirin, NSAIDs, warfarin or other anticoagulants.
• Orthostatic hypotension/syncope: May cause orthostatic hypotension and syncope (risk is high relative to other antidepressants); use with caution in patients at risk of these effects or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, hypovolemia, or concurrent medication use which may predispose to hypotension/bradycardia).
• Priapism: Painful erection >6 hours in duration; rare. Instruct patient to seek medical assistance for erection lasting >4 hours. Use with caution in patients who have conditions which may predispose them to priapism (eg, sickle cell anemia, multiple myeloma, leukemia).
• QT prolongation/proarrhythmia: Although the risk of conduction abnormalities is low relative to other antidepressants, QT prolongation (with or without torsade de pointes) and ventricular tachycardia has been observed with the use of trazodone (reports limited to immediate-release formulation); use with caution in patients with pre-existing cardiac disease. Other arrhythmias reported include isolated PVCs, ventricular couplets, and tachycardia with syncope. Concurrent use of CYP3A4 inhibitors may increase the risk of QT prolongation and/or proarrhythmia.
• Sedation: May cause sedation, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). The degree of sedation is very high relative to other antidepressants.
• Serotonin syndrome (SS)/neuroleptic malignant syndrome (NMS)-like reactions: SS and NMS-like reactions may occur with trazodone when used alone, particularly if used with other serotonergic agents (eg, serotonin/norepinephrine reuptake inhibitors [SNRIs], selective serotonin reuptake inhibitors [SSRIs], or triptans), drugs that impair serotonin metabolism (eg, MAO inhibitors), or antidopaminergic agents (eg, antipsychotics). Identification and differentiation of SS (eg, tremor, myoclonus, agitation) and more severe NMS-like reactions (eg, hyperthermia, muscle rigidity, autonomic instability, mental status changes) can be complex; monitor patients closely for either syndrome. Discontinue treatment (and any concomitant serotonergic and/or antidopaminergic agents) immediately if signs/symptoms arise.
SIADH and hyponatremia: Some antidepressant agents (eg, SSRIs) have been associated with the development of SIADH; hyponatremia has been reported (including severe cases with serum sodium <110 mmol/L), predominately in the elderly. Volume depletion and/or concurrent use of diuretics likely increases risk.
Disease-related concerns:
• Cardiovascular disease: Use with caution in patients with a history of cardiovascular disease (including previous MI, stroke, tachycardia, or conduction abnormalities); the risk conduction abnormalities with this agent is low relative to other antidepressants. Not recommended for use in a patient during the acute recovery phase of MI.
• Hepatic impairment: Use with caution in patients with hepatic impairment.
• Mania/hypomania: May worsen psychosis in some patients or precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Patients presenting with depressive symptoms should be screened for bipolar disorder. Trazodone is not FDA approved for the treatment of bipolar depression.
• Renal impairment: Use with caution in patients with renal impairment.
• Seizure disorder: Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications which may lower seizure threshold.
Concurrent drug therapy issues:
• Antihypertensives: Use with caution in patients taking antihypertensives; may increase the risk of hypotension or syncope.
• Cytochrome P450-mediated interactions: Use with caution in patients taking strong CYP3A4 inhibitors and moderate or strong CYP3A4 inducers (see Drug Interactions); monitor or consider alternative agents that avoid or lessen the potential for CYP-mediated interactions.
• Drugs with QT prolongation potential: Concurrent use with other drugs known to prolong QTc interval is not recommended.
• MAO inhibitors: Trazodone should be initiated with caution in patients who are receiving concurrent or recent therapy with a MAO inhibitor. Oleptro™: Avoid use in combination with or within 14 days of an MAO inhibitor.
• Sedatives: Effects may be potentiated when used with other sedative drugs or ethanol.
• Serotonergic agents (eg, SSRIs, SNRIs, triptans): If concurrent use is clinically warranted, carefully observe patient during treatment initiation and dose increases. Do not use concurrently with serotonin precursors (eg, tryptophan).
Special populations:
• Elderly: Use with caution in the elderly.
Other warnings/precautions:
• Discontinuation of therapy: Therapy should not be abruptly discontinued in patients receiving high doses for prolonged periods; gradually reduce dosage prior to complete discontinuation to avoid withdrawal symptoms (eg, anxiety, agitation, sleep disturbance).
• Electroconvulsive therapy: May increase the risks associated with electroconvulsive therapy; consider discontinuing, when possible, prior to ECT treatment.
Metabolism/Transport Effects
Substrate of CYP2D6 (minor), 3A4 (major); Inhibits CYP3A4 (weak); Induces P-glycoprotein
Interactions
 
BusPIRone: May enhance the serotonergic effect of Antidepressants (Serotonin Reuptake Inhibitor/Antagonist). Risk C: Monitor therapy
Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Risk X: Avoid combination
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
Dabigatran Etexilate: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Dabigatran Etexilate. Management: Avoid concurrent use of dabigatran with a p-glycoprotein inducer when possible. Closely monitor for decreased levels/effects of dabigatran if concomitantly administering a p-glycoprotein inducer, particularly strong inducers. Risk X: Avoid combination
Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Linagliptin: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Linagliptin. Management: Strongly consider using an alternative to any strong P-glycoprotein inducer in patients who are being treated with linagliptin. If this combination is used, monitor patients closely for evidence of reduced linagliptin effectiveness. Risk D: Consider therapy modification
MAO Inhibitors: May enhance the orthostatic hypotensive effect of Orthostatic Hypotension Producing Agents. Risk C: Monitor therapy
Methylene Blue: TraZODone may enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid combination
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy
P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
Protease Inhibitors: May increase the serum concentration of TraZODone. Risk D: Consider therapy modification
Saquinavir: May enhance the adverse/toxic effect of TraZODone. Saquinavir may increase the serum concentration of TraZODone. Risk X: Avoid combination
Selective Serotonin Reuptake Inhibitors: May enhance the serotonergic effect of Antidepressants (Serotonin Reuptake Inhibitor/Antagonist). This may cause serotonin syndrome. Risk C: Monitor therapy
Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Risk D: Consider therapy modification
Sibutramine: May enhance the serotonergic effect of Serotonin Modulators. This may cause serotonin syndrome. Risk X: Avoid combination
Telaprevir: May increase the serum concentration of TraZODone. Risk C: Monitor therapy
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Venlafaxine: May enhance the serotonergic effect of TraZODone. This could result in serotonin syndrome. Risk D: Consider therapy modification
Pregnancy
 
C
Pregnancy Implications
Trazodone is classified as pregnancy category C due to adverse effects observed in animal studies. When trazodone is taken during pregnancy, an increased risk of major malformations has not been observed in the small number of pregnancies studied. The long-term effects on neurobehavior have not been evaluated.
Women treated for major depression and who are euthymic prior to pregnancy are more likely to experience a relapse when medication is discontinued as compared to pregnant women who continue taking antidepressant medications. Therapy during pregnancy should be individualized; treatment of depression during pregnancy should incorporate the clinical expertise of the mental health clinician, obstetrician, primary healthcare provider, and pediatrician. If treatment during pregnancy is required, consider tapering therapy during the third trimester to prevent potential withdrawal symptoms in the infant. If this is done and the woman is considered to be at risk of relapse from her major depressive disorder, the medication can be restarted following delivery. Treatment algorithms have been developed by the ACOG and the APA for the management of depression in women prior to conception and during pregnancy (Yonkers, 2009).
Lactation
 
Enters breast milk/use caution (AAP rates “of concern”; AAP 2001 update pending)
Breast-Feeding Considerations
Trazodone is excreted into breast milk; breast milk concentrations peak ~2 hours following administration. It is not known if the trazodone metabolite is found in breast milk. The long-term effects on neurobehavior have not been studied. The manufacturer recommends that caution be exercised when administering trazodone to nursing women.
Monitoring Parameters
 
Suicide ideation (especially at the beginning of therapy or when doses are increased or decreased)
Reference Range
Plasma levels do not always correlate with clinical effectiveness
Therapeutic: 0.5-2.5 mcg/mL
Potentially toxic: >2.5 mcg/mL
Toxic: >4 mcg/mL
Mechanism of Action
 
Inhibits reuptake of serotonin, causes adrenoreceptor subsensitivity, and induces significant changes in 5-HT presynaptic receptor adrenoreceptors. Trazodone also significantly blocks histamine (H1) and alpha1-adrenergic receptors.
Pharmacodynamics / Kinetics
 
Onset of action: Therapeutic (antidepressant): Up to 6 weeks; sleep aid: 1-3 hours
Absorption: Well absorbed; Extended release: Cmax increases ~86% when taken shortly after ingestion of a high-fat meal compared to fasting conditions
Protein binding: 85% to 95%
Metabolism: Hepatic via CYP3A4 (extensive) to an active metabolite (mCPP)
Half-life elimination: 7-10 hours
Time to peak, serum:
Immediate release: 30-100 minutes; delayed with food (up to 2.5 hours)
Excretion: Primarily urine (<1% excreted unchanged); secondarily feces
 
   
 
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