Trazodone Hydrochloride

Clinical Worsening and Suicide Risk

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. There has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients. Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders.

Pooled analyses of short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with MDD, OCD, or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal behavior or thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. There was considerable variation in risk among drugs, but a tendency toward an increase for almost all drugs studied. The risk of suicidality was most consistently observed in the MDD trials, but there were signals of risk arising from some trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in any of these trials. It is unknown whether the suicidality risk in pediatric patients extends to longer-term use, ie, beyond several months. It is also unknown whether the suicidality risk extends to adults.

All pediatric patients being treated with antidepressants for any indication should be observed closely 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 dose changes, either increases or decreases. Such observation would generally include at least weekly face-toface contact with patients or their family members or caregivers during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits.

Adults with MDD or co-morbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed similarly 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. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

Families and caregivers of pediatric patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for DESYREL (trazodone hydrochloride) should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Families and caregivers of adults being treated for depression should be similarly advised.

Screening Patients for Bipolar Disorder

A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that DESYREL (trazodone hydrochloride) is not approved for use in treating bipolar depression.

TRAZODONE HAS BEEN ASSOCIATED WITH THE OCCURRENCE OF PRIAPISM. IN MANY OF THE CASES REPORTED, SURGICAL INTERVENTION WAS REQUIRED AND, IN A SOME OF THESE CASES, PERMANENT IMPAIRMENT OF ERECTILE FUNCTION OR IMPOTENCE RESULTED. MALE PATIENTS WITH PROLONGED OR INAPPROPRIATE ERECTIONS SHOULD IMMEDIATELY DISCONTINUE THE DRUG AND CONSULT THEIR PHYSICIAN.

The detumescence of priapism and drug-induced penile erections has been accomplished by both pharmacologic, eg, the intracavernosal injection of alpha-adrenergic stimulants such as epinephrine and norepinephrine, as well as surgical procedures.2-7 Any pharmacologic or surgical procedure utilized in the treatment of priapism should be performed under the supervision of a urologist or a physician familiar with the procedure and should not be initiated without urologic consultation if the priapism has persisted for more than 24 hours.

DESYREL (trazodone hydrochloride) is not recommended for use during the initial recovery phase of myocardial infarction.

Caution should be used when administering DESYREL (trazodone hydrochloride) to patients with cardiac disease, and such patients should be closely monitored, since antidepressant drugs (including DESYREL (trazodone hydrochloride) ) have been associated with the occurrence of cardiac arrhythmias. Recent clinical studies in patients with pre-existing cardiac disease indicate that DESYREL (trazodone hydrochloride) may be arrhythmogenic in some patients in that population. Arrhythmias identified include isolated PVCs, ventricular couplets, and in two patients, short episodes (3–4 beats) of ventricular tachycardia.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Major Depressive Disorder

Management of major depressive disorder with or without anxiety.201

Effective in both inpatient and outpatient settings.201

Schizophrenic Disorder

Has been used for the short-term management of depressive episodes in patients with schizophrenia†.b d

Alcohol Dependence

Has been used as adjunctive therapy for the management of alcohol dependence†.b

Anxiety States

Has been used for the management of anxiety states†.b

General

• Individualize dosages according to individual requirements and response.b

• Monitor for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustments.212 213 218 (See Worsening of Depression and Suicidality Risk under Cautions.)

• Sustained therapy may be required;201 use lowest effective dose and monitor periodically for need for continued therapy.201

Administration

Oral Administration

Administer orally after a meal or a light snack.201

If drowsiness occurs, administer a major portion of the daily dosage at bedtime or reduce dosage.201

Dosage

Available as trazodone hydrochloride; dosage is expressed in terms of the salt.201

Adults

Initially, 150 mg daily, given in divided doses.201 Daily dosage may be increased in 50-mg increments every 3 or 4 days based on patient’s response and tolerance.201

Prescribing Limits

Adults

Maximum 400 mg daily.201

Maximum 600 mg daily.201

Absorption

Bioavailability

Rapidly and almost completely absorbed from the GI tract; b peak plasma concentration usually attained within 1–2 hours.201

Onset

Antidepressant effects evident within 1 week; optimal antidepressant effects usually attained after 2–4 weeks.201

Food

Food reduces peak plasma concentrations, delays time to peak plasma concentration, and increases extent of absorption.b

Distribution

Extent

Distribution into human body tissues and fluids not determined.b

Widely distributed; crosses the blood-brain barrier and the placenta in animals.b

Distributed into milk in rats; not known whether trazodone is distributed into milk in humans.201

Plasma Protein Binding

89–95%.b

Elimination

Metabolism

Extensively metabolized in the liver via hydroxylation, oxidation, N-oxidation, and splitting of the pyridine ring.b In vitro studies indicate metabolism by CYP3A4 to an active metabolite, m-chlorophenylpiperazine; other metabolic pathways not well characterized.210 211

Elimination Route

Excreted principally in urine (70–75%) as metabolites and in feces via biliary elimination.b

Half-life

5–9 hours.201

Storage

Oral

Room temperature.201 Protect from temperatures >40°C.201

• Mechanism of action as an antidepressant is presumed to be linked to potentiation of serotonergic activity in the CNS resulting from inhibition of reuptake of serotonin (5-HT) at the presynaptic neuronal membrane.b

• Does not influence reuptake of dopamine or norepinephrine; does not inhibit MAO; does not stimulate the CNS; exhibits little anticholinergic activity.b

• Produces varying degrees of sedation resulting from its central α1-adrenergic and/or histamine blocking activity.b

• Importance of providing copy of written patient information (medication guide) each time trazodone is dispensed.212 213 218 a Importance of advising patients to read the patient information before taking trazodone.a

• Risk of suicidality; importance of patients, caregivers, and families being alert to and immediately reporting emergence of suicidality, worsening depression, or unusual changes in behavior, especially during the first few months of therapy or during periods of dosage adjustment.212 213 218 (See Worsening of Depression and Suicidality Risk under Cautions.)

• Importance of men discontinuing the drug and notifying clinician if prolonged or inappropriate penile erection occurs.201

• Risks associated with concomitant use with alcohol, barbiturates, and other CNS depressants.201

• Potential for drug to impair mental alertness or physical coordination; avoid driving or operating machinery until effects on individual are known.201

• Importance of taking trazodone shortly after a meal or light snack to enhance absorption and to minimize risk of dizziness/lightheadedness.201

• Importance of continuing trazodone therapy even if improvement is evident within 2 weeks, unless directed otherwise by their clinician.201

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.201

• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs.201

• Importance of informing patients of other important precautionary information.201 (See Cautions.)