Trazodone

Special Alerts

Antidepressant Use in Pediatric Patients - October 15, 2004

In March 2004, the Food and Drug Administration (FDA) issued a Public Health Advisory concerning the use of antidepressant medications in which they called attention to reports of both suicidal ideation and suicide attempts in children taking antidepressant drugs for the treatment of major depressive disorder (MDD). In September 2004, a review of the existing data was completed by two FDA Advisory Committees. The FDA has now instructed the manufacturers of ALL antidepressants to revise the labeling for their products to include a boxed warning and expanded warning statements that alert healthcare providers to an increased risk of suicidality (suicidal thinking and behavior) in children and adolescents being treated with these agents, and to include additional information about the results of pediatric studies. The FDA also informed manufacturers that a Patient Medication Guide (MedGuide), which will be given to patients receiving the drugs advising them of the risk and precautions, is appropriate for these drug products.

The risk of suicidality for these drugs was identified in a combined analysis of short-term (up to 4 months) placebo-controlled trials of nine antidepressant drugs, including the selective serotonin reuptake inhibitors (SSRIs) and others, in children and adolescents with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. A total of 24 trials involving over 4400 patients were included. The analysis showed a greater risk of suicidality during the first few months of treatment in those receiving antidepressants. The average risk of such events on drug was 4%, compared to a rate of 2% in groups receiving placebo. No suicides occurred in these trials. Based on this data, the FDA has determined that the following points are appropriate for inclusion in the boxed warning:

Antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with MDD and other psychiatric disorders.

Anyone considering the use of an antidepressant in a child or adolescent for any clinical use must balance the risk of increased suicidality with the clinical need.

Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior.

Families and caregivers should be advised to closely observe the patient and to communicate with the prescriber.

A statement regarding whether the particular drug is approved for any pediatric indication(s) and, if so, which one(s).

Among the antidepressants, only fluoxetine is approved for use in treating MDD in pediatric patients. Clomipramine, fluoxetine, fluvoxamine, and sertraline are approved for OCD in pediatric patients. None of the drugs is FDA approved for other psychiatric indications in children.

Pediatric patients being treated with antidepressants for any indication should be closely observed for clinical worsening, as well as agitation, irritability, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes (either increases or decreases). This monitoring should include daily observation by families and caregivers and frequent contact with the physician. It is also recommended that prescriptions for antidepressants be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

In addition to the boxed warning and other information in professional labeling on antidepressants, MedGuides are being prepared for all of the antidepressants to provide information about the risk of suicidality in children and adolescents for patients and their families and caregivers. MedGuides are intended to be distributed by the pharmacist with each prescription or refill of a medication.

The FDA plans to work closely with the manufacturers of all approved antidepressant products to optimize the safe use of these drugs and implement the proposed labeling changes and other safety communications in a timely manner.

Additional information can be found on the FDA website at: http://www.fda.gov/medwatch/SAFETY/2004/safety04.htm#ssri, last accessed October 21, 2004.

Trazodone: New Drug Interaction Warnings - May 12, 2004

Bristol-Myers-Squibb is notifying healthcare providers of important drug interaction warnings recently added to the Desyrel® (trazodone hydrochloride) product labeling. Specific information/clinical studies related to individual drug-drug interactions is limited, but the characteristics of trazodone's metabolism allow for the prediction of a number of potential interactions. Trazodone is metabolized by CYP3A4, and serum levels may be affected by other drugs which act as strong inhibitors (ketoconazole) or inducers (carbamazepine) of this isoenzyme. Dosage adjustment and/or careful monitoring may be required in patients receiving concurrent therapy.

The letter is available at http://www.fda.gov/medwatch/SAFETY/2004/Desyrel_DHCP.pdf, last accessed May 14, 2004.

Pronunciation

(TRAZ oh done)

U.S. Brand Names

Desyrel®

Synonyms

Trazodone Hydrochloride

Generic Available

Yes

Canadian Brand Names

Alti-Trazodone; Apo-Trazodone®; Apo-Trazodone D®; Desyrel®; Gen-Trazodone; Novo-Trazodone; Nu-Trazodone; PMS-Trazodone

Use

Treatment of depression

Use - Unlabeled/Investigational

Potential augmenting agent for antidepressants, hypnotic

Pregnancy Risk Factor

Lactation

Enters breast milk/use caution (AAP rates "of concern")

Contraindications

Hypersensitivity to trazodone or any component of the formulation

Warnings/Precautions

Priapism, including cases resulting in permanent dysfunction, has occurred with the use of trazodone. Not recommended for use in a patient during the acute recovery phase of MI. Trazodone should be initiated with caution in patients who are receiving concurrent or recent therapy with a MAO inhibitor. May cause sedation, resulting in impaired performance of tasks requiring alertness (eg, operating machinery or driving). Sedative effects may be additive with other CNS depressants and ethanol. The degree of sedation is very high relative to other antidepressants. May worsen psychosis in some patients or precipitate a shift to mania or hypomania in patients with bipolar disease. May increase the risks associated with electroconvulsive therapy. This agent should be discontinued, when possible, prior to elective surgery. Therapy should not be abruptly discontinued in patients receiving high doses for prolonged periods.

Use with caution in patients at risk of hypotension or in patients where transient hypotensive episodes would be poorly tolerated (cardiovascular disease or cerebrovascular disease). The risk of postural hypotension is high relative to other antidepressants. The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Use caution in high-risk patients during initiation of therapy. Prescriptions should be written for the smallest quantity consistent with good patient care.

Antidepressants increase the risk of suicidal thinking and behavior in children and adolescents with MDD and other depressive disorders; consider risk prior to prescribing. Closely monitor for clinical worsening, suicidality, or unusual changes in behavior; the child's family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. A medication guide should be dispensed with each prescription. Trazodone is not FDA approved for use in children.

Use caution in patients with a previous seizure disorder or condition predisposing to seizures such as brain damage, alcoholism, or concurrent therapy with other drugs which lower the seizure threshold. Use with caution in patients with hepatic or renal dysfunction and in elderly patients. Use with caution in patients with a history of cardiovascular disease (including previous MI, stroke, tachycardia, or conduction abnormalities). However, the risk of conduction abnormalities with this agent is low relative to other antidepressants.

Adverse Reactions

>10%:

Central nervous system: Dizziness, headache, sedation

Gastrointestinal: Nausea, xerostomia

Ocular: Blurred vision

1% to 10%:

Cardiovascular: Syncope, hyper-/hypotension, edema

Central nervous system: Confusion, decreased concentration, fatigue, incoordination

Gastrointestinal: Diarrhea, constipation, weight gain/loss

Neuromuscular & skeletal: Tremor, myalgia

Respiratory: Nasal congestion

<1% (Limited to important and life-threatening): Agitation, allergic reactions, alopecia, anxiety, bradycardia, extrapyramidal symptoms, hepatitis, priapism, rash, seizure, speech impairment, tachycardia, urinary retention

Overdosage/Toxicology

Symptoms of overdose include drowsiness, vomiting, hypotension, tachycardia, incontinence, coma, and priapism. Treatment is symptom-directed and supportive.

Drug Interactions

Substrate of CYP2D6 (minor), 3A4 (major); Inhibits CYP2D6 (moderate), 3A4 (weak)

Antipsychotics: Trazodone, in combination with other psychotropics (low potency antipsychotics), may result in additional hypotension (isolated case reports); monitor.

Azole antifungals: Serum concentrations of trazodone may be increased by azole antifungals, via inhibition of CYP3A4. Ketoconazole has been specifically studied. Consider a lower dose of trazodone.

Buspirone: Serotonergic effects may be additive (limited documentation); monitor.

Carbamazepine: Serum concentrations of trazodone may be decreased by carbamazepine, due to induction of CYP3A4. Other CYP inducers are likely to share this effect.

CNS depressants: Sedative effects may be additive with CNS depressants. Includes ethanol, barbiturates, benzodiazepines, narcotic analgesics, and other sedative agents; monitor for increased effect

CYP2D6 substrates: Trazodone may increase the levels/effects of CYP2D6 substrates. Example substrates include amphetamines, selected beta-blockers, dextromethorphan, fluoxetine, lidocaine, mirtazapine, nefazodone, paroxetine, risperidone, ritonavir, thioridazine, tricyclic antidepressants, and venlafaxine.

CYP2D6 prodrug substrates: Trazodone may decrease the levels/effects of CYP2D6 prodrug substrates. Example prodrug substrates include codeine, hydrocodone, oxycodone, and tramadol.

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of trazodone. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

CYP3A4 inhibitors: May increase the levels/effects of trazodone. Example inhibitors include azole antifungals, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, and verapamil.

Linezolid: Due to MAO inhibition (see note on MAO inhibitors), this combination should be avoided

MAO inhibitors: Concurrent use may lead to serotonin syndrome; avoid concurrent use or use within 14 days

Meperidine: Combined use, theoretically, may increase the risk of serotonin syndrome

Protease inhibitors: Serum concentrations of trazodone may be increased by protease inhibitors, via inhibition of CYP3A4. Consider a lower dose of trazodone.

Serotonin agonists: Theoretically, may increase the risk of serotonin syndrome; includes sumatriptan, naratriptan, rizatriptan, and zolmitriptan

SSRIs: Combined use of trazodone with an SSRI may, theoretically, increase the risk of serotonin syndrome; in addition, some SSRIs may inhibit the metabolism of trazodone resulting in elevated plasma levels and increased sedation; includes fluoxetine and fluvoxamine (see CYP inhibition); low doses of trazodone appear to represent little risk

Venlafaxine: Combined use with trazodone may increase the risk of serotonin syndrome

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may increase CNS depression).

Food: Time to peak serum levels may be increased if trazodone is taken with food.

Herb/Nutraceutical: Avoid valerian, St John's wort, SAMe, kava kava (may increase risk of serotonin syndrome and/or excessive sedation).

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): 1-3 weeks; sleep aid: 1-3 hours

Protein binding: 85% to 95%

Metabolism: Hepatic via CYP3A4 to an active metabolite (mCPP)

Half-life elimination: 7-8 hours, two compartment kinetics

Time to peak, serum: 30-100 minutes; delayed with food (up to 2.5 hours)

Excretion: Primarily urine; secondarily feces

Dosage

Oral: Therapeutic effects may take up to 6 weeks to occur; therapy is normally maintained for 6-12 months after optimum response is reached to prevent recurrence of depression

Children 6-12 years: Depression (unlabeled use): 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: Depression (unlabeled use): Initial: 25-50 mg/day; increase to 100-150 mg/day in divided doses

Adults:

Depression: Initial: 150 mg/day in 3 divided doses (may increase by 50 mg/day every 3-7 days); maximum: 600 mg/day

Sedation/hypnotic (unlabeled use): 25-50 mg at bedtime (often in combination with daytime SSRIs); may increase up to 200 mg at bedtime

Elderly: 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

Administration

Dosing after meals may decrease lightheadedness and postural hypotension

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

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. Take exactly as directed; do not increase dose or frequency. It may take 2-4 weeks to achieve desired results. Take after meals. Avoid excessive alcohol and caffeine. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. You may experience drowsiness, lightheadedness, dizziness (use caution when driving or engaging in tasks requiring alertness until response to drug is known); postural hypotension (use caution when climbing stairs or changing position from lying or sitting to standing); nausea, dry mouth (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); constipation (increased exercise, fluids, fruit, or fiber may help); or diarrhea (buttermilk, yogurt, or boiled milk may help). Report persistent dizziness or headache; muscle cramping, tremors, or altered gait; blurred vision or eye pain; chest pain or irregular heartbeat; suicidal ideation; or worsening of condition. Report prolonged or inappropriate erections. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Do not breast-feed.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Xerostomia (especially in the elderly; may contribute to periodontal diseases and oral discomfort; normal salivary flow resumes upon discontinuation). Trazodone elicits anticholinergic effects; much less frequent than with tricyclic antidepressants.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Dosage Forms

Tablet, as hydrochloride: 50 mg, 100 mg, 150 mg, 300 mg

References

"American Academy of Pediatrics Committee on Drugs. The Transfer of Drugs and Other Chemicals Into Human Milk," Pediatrics , 2001, 108(3):776-89.

Battistella PA, Ruffilli R, Cernetti R, et al, "A Placebo-Controlled Crossover Trial Using Trazodone in Pediatric Migraine," Headache , 1993, 33(1):36-9.

Bayer AJ, Pathy MSJ, and Ankier SI, "Pharmacokinetic and Pharmacodynamic Characteristics of Trazodone in the Elderly," Br J Clin Pharmacol , 1983, 16:371-6.

Fishbain DA, "Priapism Associated With Trazodone Therapy," J Urol , 1989, 142(3):831.

Gerson SC, Plotkin DA, and Jarvik LF, "Antidepressant Drug Studies, 1964-1986: Empirical Evidence for Aging Patients," J Clin Psychopharmacol , 1988, 8(5):311-21.

Lejoyeux M, et al, "Serotonin Syndrome: Incidence, Symptoms, and Treatment," CNS Drugs , 1994, 2:132-43.

Lesar T, Kingston R, Dahms R, et al, "Trazodone Overdose," Ann Emerg Med , 1982, 12(4):221-3.

Mokhlesi B, Leikin JB, Murray P, et al, "Adult Toxicology in Critical Care: Part II: Specific Poisonings," Chest , 2003, 123(3):897-922.

Reeves RR and Bullen JA, "Serotonin Syndrome Produced by Paroxetine and Low-Dose Trazodone," Psychosomatics , 1995, 36(2):159-60.

Zmitek A, "Trazodone-Induced Mania," Br J Psychiatry , 1987, 151:274-5.

Zubieta JK and Alessi NE, "Acute and Chronic Administration of Trazodone in the Treatment of Disruptive Behavior Disorders in Children," J Clin Psychopharmacol , 1992, 12(5):346-51.

International Brand Names

Alti-Trazodone (CA); Apo-Trazodone® (CA); Apo-Trazodone D® (CA); Azona® (FI); Bimaran® (AR); Deprax® (ES); Depsan® (HU); Depyrel® (IL); Desirel® (TH); Desyrel® (CA, JP, TR); Devidon® (SI); Donaren® (BR); Gen-Trazodone (CA); Molipaxin® (GB, IE, ZA); Novo-Trazodone (CA); Nu-Trazodone (CA); PMS-Trazodone (CA); Reslin® (JP); Taxagon AD® (AR); Thombran® (DE); Trazodil® (IL); Trazodona® (CO); Trazodone-Continental® (LU); Trazodone® (GB); Trazodone MK® (CO); Trazodon Hexal® (DE); Trazodon Neuraxpharm® (DE); Trazolan® (BE, CY, LU, NL); Trazone® (ID, PT); Triticum® (PT); Trittico AC® (CO); Trittico® (AT, CL, CO, CZ, EG, HK, IT, JO, KW, LB, PL, RO, RU)

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