Trazodone Hydrochloride

Pronunciation: (TRAZ-oh-done HYE-droe-KLOR-ide)
Class: Antidepressant

Trade Names

Oleptro
- Tablets, ER 150 mg
- Tablets, ER 300 mg

Trazodone Hydrochloride
- Tablets 50 mg
- Tablets 100 mg
- Tablets 150 mg
- Tablets 300 mg

Apo-Trazodone (Canada)
Apo-Trazodone D (Canada)
Gen-Trazodone (Canada)
PMS-Trazodone (Canada)
ratio-Trazodone (Canada)

Pharmacology

Undetermined; thought to be related to potentiation of serotonergic activity in the CNS.

Pharmacokinetics

Absorption

Well absorbed after administration. T _max for the immediate-release tablet is 1 h on an empty stomach and 2 h with food. C _max and T _max for ER tablets are 1,188 ng/mL and 9 h, respectively, under fasting conditions; C _max increases approximately 86% when taken with a high-fat meal.

Distribution

89% to 95% protein bound.

Metabolism

Metabolized to an active metabolite, m-chlorophenylpiperazine, by CYP3A4.

Elimination

70% to 75% is recovered in the urine (less than 1% as unchanged drug). Terminal half-life is 10 h (ER).

Special Populations

Renal Function Impairment

No data available.

Hepatic Function Impairment

No data available.

Indications and Usage

Treatment of depression (immediate-release); treatment of major depressive disorder (ER).

Unlabeled Uses

Treatment of aggressive behavior, alcohol withdrawal, cocaine withdrawal, insomnia, and panic disorder (with or without agoraphobia); prevention of migraine.

Contraindications

None well documented.

Dosage and Administration

Adults Immediate-release

PO 150 mg/day in divided doses initially; increase in 50 mg increments every 3 to 4 days up to max of 400 mg/day (outpatients) or 600 mg/day (inpatients).

ER

PO 150 mg once daily initially, increase in 75 mg increments every 3 days up to a max of 375 mg once daily.

General Advice

Immediate-release tablets should be taken shortly after a meal or light snack.
ER tablets should be taken at the same time every day, preferably at bedtime, on an empty stomach.
ER tablets can be swallowed whole or administered as a half tablet by breaking along the score line; they should not be crushed or chewed.

Storage/Stability

Store at 56° to 86°F.

Drug Interactions

Alcohol, barbiturates, CNS depressants

CNS depressant effects may be additive. Avoid coadministration.

Antihypertensive agents (eg, propranolol)

May cause additive hypotensive effects. Monitor BP and be prepared to adjust the antihypertensive agent dose as needed.

Carbamazepine

Plasma concentrations of trazodone and its active metabolite may be decreased, and carbamazepine levels may be increased. Monitor patient when starting or stopping either agent and adjust the trazodone or carbamazepine dose as needed.

CYP3A4 inhibitors (eg, azole antifungals [itraconazole, ketoconazole], clarithromycin, nefazodone, protease inhibitors [eg, indinavir, ritonavir])

May increase trazodone levels, increasing adverse reactions (eg, sedation). Monitor patient response and adjust dose of trazodone as needed. Caution the patient about the increased risk of sedation when one of these agents is started in patients receiving trazodone.

Delavirdine, Ginkgo biloba , phenothiazines (eg, chlorpromazine)

Elevated trazodone serum concentrations may occur, increasing the pharmacologic and toxic effects. Monitor patient and adjust dose of trazodone as needed. Caution the patient about the increased risk of sedation when one of these agents is coadministered with trazodone.

Digoxin, hydantoins

Serum levels may be elevated by trazodone, increasing the pharmacologic and adverse reactions. Monitor serum concentrations of these agents when starting or stopping trazodone. Adjust the dose as needed.

Dopamine antagonists (eg, metoclopramide), elective 5-HT ₁ receptor agonists (eg, sumatriptan), SSRIs (eg, fluoxetine), SNRIs (eg, venlafaxine), tryptophan

Serotonin syndrome, including altered consciousness, increased muscle tone, irritability, myoclonus, and shivering, may occur. If coadministration cannot be avoided, start with a low dose of trazodone and closely monitor the patient. Serotonin syndrome requires immediate medical attention, including supportive care and withdrawal of the serotonergic agent. Concurrent use with tryptophan is not recommended.

MAOIs (eg, phenelzine)

In patients receiving serotonergic drugs in combination with MAOIs, serious, sometimes fatal reactions have been reported. It is recommended that trazodone not be coadministered with an MAOI or within 14 days of discontinuing an MAOI. Similarly, do not give an MAOI within 14 days of stopping trazodone.

NSAIDs (eg, ibuprofen), salicylates (eg, aspirin)

The risk of bleeding may be increased. Use with caution. Monitor for bleeding and caution patients about the potential risk of bleeding.

Sodium oxybate (GHB)

Concurrent use of sodium oxybate (GHB) and trazodone may result in an increase in sleep duration and CNS depression. Sodium oxybate (GHB) is contraindicated in patients receiving other sedative hypnotics.

Warfarin

Reports of increased and decreased PT. Monitor anticoagulant parameters frequently when starting or stopping trazodone. Adjust the warfarin dose as needed.

Adverse Reactions

Cardiovascular

Hypotension, tachycardia/palpitations (7%); syncope (5%); hypertension (2%); arrhythmia, atrial fibrillation, bradycardia, cardiac arrest, cardiospasm, cerebrovascular accident, CHF, conduction block, MI, orthostatic hypotension, sinus bradycardia, torsades de pointes, vasodilation, ventricular ectopic activity including ventricular arrhythmia and QT prolongation (postmarketing).

CNS

Somnolence/sedation (46%); drowsiness (41%); headache (33%); dizziness/light-headedness (28%); fatigue, nervousness (15%); insomnia (10%); confusion (6%); excitement, incoordination, nightmares/vivid dreams, tremors (5%); anger/hostility (4%); decreased concentration, head full/heavy, malaise, tremor (3%); disorientation (2%); agitation, coordination abnormal, dysgeusia, migraine (at least 1%); memory impairment, paresthesia (1%); anxiety, aphasia, ataxia, extrapyramidal symptoms, generalized tonic-clonic seizures, hallucination, paranoid reaction, psychosis, stupor, tardive dyskinesia, vertigo, weakness (postmarketing).

Dermatologic

Skin condition/edema (7%); night sweats (at least 1%); sweating/clamminess (1%); alopecia, hirsutism, leukonychia, pruritus, psoriasis, rash, urticaria (postmarketing).

EENT

Blurred vision (15%); nasal/sinus congestion (6%); eyes itching/red/tired (3%); visual disturbance (at least 1%); tinnitus (1%); diplopia (postmarketing).

GI

Dry mouth (34%); nausea (21%); nausea/vomiting (13%); diarrhea (9%); constipation (8%); abdominal/gastric disorder (6%); decreased appetite (4%); abdominal pain (at least 1%); bad taste in mouth (1%); increased salivation (postmarketing).

Genitourinary

Decreased libido, erectile dysfunction (2%); micturition urgency (at least 1%); breast enlargement or engorgement, clitorism, lactation, priapism, urinary incontinence, urinary retention (postmarketing).

Hematologic-Lymphatic

Hemolytic anemia, leukocytosis, methemoglobinemia (postmarketing).

Lab Tests

Hyperbilirubinemia, increased amylase, liver enzyme alterations (postmarketing).

Metabolic-Nutritional

Weight loss (6%); weight gain (5%); edema (at least 1%); SIADH (postmarketing).

Musculoskeletal

Musculoskeletal aches/pains (6%); back pain (5%); myalgia (at least 1%).

Respiratory

Dyspnea (at least 1%); apnea (postmarketing).

Miscellaneous

Chills, cholestasis (postmarketing).

Precautions

Warnings

Antidepressants increase the risk of suicidal thinking and behavior in short-term studies in children, adolescents, and young adults with major depressive disorder and other psychiatric disorders. Closely observe patients who are started on therapy for clinical worsening, suicidal, or unusual changes in behavior. Trazodone is not approved for use in children.

Monitor

Appropriately monitor all patients being treated with antidepressants for any indication and closely observe for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy or at times of dosage changes, either increases or decreases. WBC and differential counts are recommended in patients developing fever, sore throat, or other signs of infection during therapy. Closely monitor patients with preexisting cardiac disease

Pregnancy

Category C .

Lactation

Excreted.

Children

Safety and efficacy not established.

Elderly

Use with caution. Antidepressants have been associated with cases of clinically significant hyponatremia in elderly patients who may be at greater risk for this adverse reaction.

Renal Function

Use with caution.

Hepatic Function

Use with caution.

Hazardous Tasks

May cause somnolence or sedation and impair the mental and/or physical ability required to perform potentially hazardous tasks.

Abnormal bleeding

Bleeding events, ranging from ecchymosis, hematoma, epistaxis, petechiae, and life-threatening hemorrhage, have been reported with other medications that interfere with serotonin reuptake. Aspirin, NSAIDs, and warfarin may add to this risk.

Bipolar disorder

Screen patients with depression for risk of bipolar disorder prior to initiating therapy.

Cardiac disease

Not recommended for patients in acute recovery from MI. Use with caution in patients with cardiac disease; arrythmias may occur.

Elective surgery

Prior to elective surgery, discontinue trazodone for as long a possible because of possible interaction with general anesthetics.

Electroconvulsive therapy

Avoid coadministration.

Hyponatremia

May occur. Use with caution in elderly patients, volume-depleted patients, and patients taking diuretics.

Hypotension

Hypotension, including orthostatic hypotension and syncope, has been reported.

Priapism

Priapism (prolonged, painful inappropriate penile erection) has been reported. Condition may require surgical intervention. Use with caution in men who have conditions that might predispose them to priapism (eg, sickle cell anemia, multiple myeloma, leukemia) or in men with anatomical deformation of the penis.

QT prolongation

Trazodone is known to prolong the QT/QTc interval and there have been postmarketing reports of torsades de pointes with trazodone immediate release.

Serotonin syndrome/NMS-like reaction

Life-threatening serotonin syndrome or NMS-like reactions may occur, particularly with coadministration of serotonergic drugs.

Suicide

Closely monitor patients at risk. Prescribe the smallest quantity consistent with good patient management to reduce the risk of overdose.

Withdrawal

Withdrawal symptoms have been reported. Reduce dose gradually before complete discontinuation of treatment.

Overdosage

Symptoms

Death, drowsiness, ECG changes, priapism, respiratory arrest, seizures, vomiting.

Patient Information

Advise patient to read the Medication Guide before starting therapy and with each refill.
Advise patient, family, and caregiver to be alert to changes in behavior, worsening of depression, and suicidal thinking, especially during initiation of therapy and when the dose is increased or decreased. Advise them to report such symptoms to their health care provider.
Inform patients that serotonin syndrome could occur with trazodone use and symptoms include changes in mental status, autonomic instability, neuromuscular aberrations, and/or GI symptoms.
Warn patients of the potential for hypotension with trazodone use, including orthostatic hypotension and syncope.
Advise patients with prolonged or inappropriate penile erection to immediately discontinue the drug and consult with their health care provider.
Inform patients of the potential risk of bleeding and bleeding-related events, including life-threatening hemorrhages, with the concomitant use of trazodone and NSAIDs, aspirin, or other drugs that affect coagulation or bleeding.
Inform patients not to discontinue therapy with trazodone abruptly without discussing it with their health care provider. Withdrawal symptoms, including anxiety, agitation, and sleep disturbances, may occur.
Advise patient that trazodone may cause somnolence or sedation and to use caution while driving or performing other tasks requiring mental alertness until effect is determined.
Instruct patients to take trazodone ER tablets at the same time every day, preferably at bedtime and on an empty stomach. ER tablets may be broken in half and swallowed whole but should not be chewed or crushed.
Instruct patients to take trazodone immediate release shortly after a meal or a light snack.