Nefazodone hydrochloride is administered orally, usually in 2 equally divided doses daily.1 Concomitant administration of nefazodone and food delays absorption and decreases bioavailability of the drug by about 20%.1 However, the manufacturer states that this effect is unlikely to be clinically important and that nefazodone generally can be given orally without regard to meals.2,12
Although the effects of concomitant use of nefazodone and monoamine oxidase (MAO) inhibitors have not been evaluated in humans or animals, serious (sometimes fatal) reactions related to serotonin syndrome have occurred in patients receiving MAO inhibitors concomitantly with other antidepressants that have pharmacologic properties similar to nefazodone (e.g., selective serotonin-reuptake inhibitors).1 Therefore, nefazodone should not be used concomitantly with MAO inhibitors and it is recommended that at least 2 weeks elapse between discontinuance of an MAO inhibitor and initiation of nefazodone and that an interval of at least 1 week elapse between discontinuance of nefazodone and initiation of an MAO inhibitor.1 For information on the serotonin syndrome, see Drug Interactions: Drugs Associated with Serotonin Syndrome, in the Monoamine Oxidase Inhibitors General Statement 28:16.04.12 and see Serotonin Syndrome under Drug Interactions: Drugs Associated with Serotonin Syndrome, in Fluoxetine Hydrochloride 28:16.04.20.
The manufacturer states that concomitant use of nefazodone is contraindicated in patients receiving terfenadine (no longer commercially available in the US), astemizole (no longer commercially available in the US), cisapride, or pimozide since nefazodone may inhibit metabolism of these drugs and increase the potential for serious adverse cardiac effects.1 Concomitant use of carbamazepine and nefazodone is contraindicated since this may reduce plasma concentrations of nefazodone and hydroxynefazodone by 95% resulting in levels insufficient to achieve an antidepressant effect.1 Concomitant use of nefazodone and alprazolam or triazolam results in clinically important increases in plasma concentrations of these benzodiazepines but does not affect the pharmacokinetics of nefazodone.1 Concomitant use of triazolam and nefazodone should be avoided for most patients, including the elderly; however, in exceptional cases when concomitant use of the drugs may be considered appropriate, triazolam dosage should be reduced 75% and the lowest possible dosage should be used.1 If alprazolam is used concomitantly with nefazodone, a 50% reduction in initial dosage of the benzodiazepine is recommended.1
Dispensing and Administration Precautions
Because of similarity in spelling between Serzone® (the former trade name for nefazodone hydrochloride; no longer commercially available in the US under this trade name) and Seroquel® (the trade name for quetiapine fumarate, an antipsychotic agent), dispensing errors have been reported to the US Food and Drug Administration (FDA) and the manufacturer of Seroquel® (AstraZeneca).14,15,16 According to the medication error reports, the overlapping strengths (100 and 200 mg), dosage forms (tablets), and dosing intervals (twice daily) and the fact that these 2 drugs were stored closely together in pharmacies also were critical in causing these errors.14,15,16 These medication errors may be associated with adverse CNS (e.g., mental status deterioration, hallucination, paranoia, muscle weakness, lethargy, dizziness) and GI effects (e.g., nausea, vomiting, diarrhea).14,15 As of November 2001, 4 patients required emergency room visits and 3 patients were reportedly hospitalized because of dispensing errors involving these 2 agents.14,15 One female patient 25 years of age experienced fever and respiratory arrest after mistakenly taking Seroquel® for 3 days instead of taking Serzone®, and eventually died, although a causal relationship has not been established.14,15 FDA also is concerned that several patients unintentionally ingested Serzone® or Seroquel® for a prolonged period of time before the error was discovered.15 Therefore, extra care should be exercised in ensuring the accuracy of both oral and written prescriptions for Seroquel® and Serzone®.14,15 Although the Serzone brand was discontinued in June 2004, clinicians may continue to refer to nefazodone by the former brand name in prescribing.26 Some experts recommend that pharmacists assess the measures of avoiding dispensing errors and implement them as appropriate (e.g., by verifying all orders for these agents by spelling both the trade and generic names to prescribers, using computerized name alerts, attaching reminders to drug containers and pharmacy shelves, separating the drugs on pharmacy shelves, counseling patients).15
Patients should be advised to question the dispensing pharmacist regarding any changes in the appearance of their prescription in terms of shape, color, or size of the tablets.16 Dispensing errors involving Serzone® (nefazodone) and Seroquel® (quetiapine) should be reported to the manufacturers or directly to the FDA MedWatch program by phone (800-FDA-1088), fax (800-FDA-0178), by the Internet ([Web]), or by mail (FDA Safety Information and Adverse Event Reporting Program, FDA, 5600 Fishers Lane, Rockville, MD 20852-9787).16
Severe, life-threatening, and in some cases fatal hepatic failure has been reported in patients receiving nefazodone.1 The onset of hepatic injury generally occurred after approximately 2 weeks to 6 months of nefazodone therapy in patients who subsequently developed hepatic failure that resulted in liver transplantation or death.1 Although some reports described prodromal symptoms (e.g., anorexia, malaise, other GI symptoms) or dark urine occurring before onset of jaundice, such prodromal symptoms were not reported in other cases.1 The incidence of hepatic failure resulting in death or liver transplantation in the US associated with nefazodone use has been estimated to be approximately 1 case per 250,000-300,000 patient-years of use (3-4 times the estimated rate of hepatic failure in the general population).1 However, this is considered an underestimate because of underreporting, and the true risk of nefazodone-related hepatic failure may be substantially greater.1
Although there is no evidence to suggest that the presence of preexisting liver disease increases the likelihood of developing hepatic failure, nefazodone therapy generally should not be initiated in patients with active liver disease or elevated serum transaminase concentrations since baseline abnormalities can complicate monitoring of such patients.1 Early detection of drug-induced hepatic injury along with immediate withdrawal of the suspected drug is believed to enhance the likelihood of recovery.1 Therefore, patients receiving nefazodone should be advised to be alert for manifestations of hepatic dysfunction (e.g., jaundice, anorexia, GI complaints, malaise) and to contact their clinician immediately if they occur.1 Nefazodone should be discontinued if clinical signs or symptoms suggest hepatic failure.1 The drug also should be discontinued and should not be reinitiated in patients who develop evidence of hepatocellular injury (e.g., serum aminotransferase [AST or ALT] concentrations of 3 times the upper limit of normal or higher).1 Development of hepatocellular injury during nefazodone therapy is a contraindication to future use of the drug.1
Worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior may occur in both adult and pediatric (see Pediatric Precautions under Dosage and Administration: Administration) patients with major depressive disorder or other psychiatric disorders, whether or not they are taking antidepressants.19,20,21,22 This risk may persist until clinically important remission occurs.19 Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.19,20,21 However, 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 during the early phases of treatment.19 Pooled analyses of short-term, placebo-controlled studies of antidepressants (i.e., selective serotonin-reuptake inhibitors and other antidepressants) have shown an increased risk of suicidality in children, adolescents, and young adults (18-24 years of age) with major depressive disorder and other psychiatric disorders.19,20 An increased suicidality risk was not demonstrated with antidepressants compared with placebo in adults older than 24 years of age, and a reduced risk was observed in adults 65 years of age or older.19,20 It currently is unknown whether the suicidality risk extends to longer-term use (i.e., beyond several months); however, there is substantial evidence from placebo-controlled maintenance trials in adults with major depressive disorder that antidepressants can delay the recurrence of depression.19,20
The US Food and Drug Administration (FDA) recommends that all patients being treated with antidepressants for any indication be appropriately monitored and closely observed for clinical worsening, suicidality, and unusual changes in behavior, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.19,20,21 Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be advised to monitor patients on a daily basis for the emergence of agitation, irritability, or unusual changes in behavior as well as the emergence of suicidality, and to report such symptoms immediately to a health-care provider.19,21
Although a causal relationship between the emergence of symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania 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.19,21 Consequently, consideration should be given to changing the therapeutic regimen or discontinuing therapy in patients whose depression is persistently worse or in patients experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if such manifestations are severe, abrupt in onset, or were not part of the patient's presenting symptoms.19 FDA also recommends that the drugs be prescribed in the smallest quantity consistent with good patient management, in order to reduce the risk of overdosage.1,19
It is generally believed (though not established in controlled trials) that treating a major depressive episode with an antidepressant alone may increase the likelihood of precipitating a mixed or manic episode in patients at risk for bipolar disorder.19 Therefore, patients should be adequately screened for bipolar disorder prior to initiating treatment with an antidepressant; such screening should include a detailed psychiatric history (e.g., family history of suicide, bipolar disorder, and depression).19
Safety and efficacy of nefazodone in children have not been established.1
FDA has determined that antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder and other psychiatric disorders.19 However, FDA also states that depression and certain other psychiatric disorders are themselves associated with an increased risk of suicide.19 (See Cautions: Pediatric Precautions, in Fluoxetine Hydrochloride 28:16.04.20.) Anyone considering the use of nefazodone in a child or adolescent for any clinical use must therefore balance the potential risks with the clinical need.19,21,22 (See Suicidality Precautions under Dosage and Administration: Administration.)
Patients should be monitored for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustment.19,20,21 (See Suicidality Precautions under Dosage and Administration: Administration.)
For the treatment of major depressive disorder in adults, the recommended initial dosage of nefazodone hydrochloride is 100 mg twice daily.1,10 Based on the tolerance and clinical response of the patient, dosage may be increased by increments of 100-200 mg daily at intervals of not less than 1 week up to a maximum of 600 mg daily.1,2,10 While a relationship between dosage and antidepressant effect has not been established, the effective dosage of nefazodone hydrochloride in controlled clinical studies generally ranged from 300-600 mg daily.1,12
Because geriatric or debilitated patients may have reduced nefazodone clearance and/or increased sensitivity to the adverse effects of CNS-active drugs, therapy with nefazodone hydrochloride should be initiated at a dosage of 50 mg twice daily in such patients and subsequent dosage adjustments generally made in smaller increments and at longer intervals than in younger patients.1 A nefazodone hydrochloride dosage of 200-400 mg daily generally provided optimum therapeutic effect in patients 65 years of age or older in controlled studies.1,11,12
Although the optimum duration of nefazodone therapy has not been established, acute depressive episodes may require 6 months or longer of sustained antidepressant medication.1 Whether the dosage of nefazodone required to induce remission of depression would be comparable to that required to maintain euthymia currently is not known.1
Dosage in Renal and Hepatic Impairment 
While the manufacturer makes no specific recommendations for modification of dosage in patients with hepatic impairment, AUC values for nefazodone and its active metabolite hydroxynefazodone are increased by approximately 25% in patients with cirrhosis; therefore, nefazodone should be used with caution in patients with clinically important hepatic dysfunction.1,12 The manufacturer makes no specific recommendations for modification of dosage in patients with renal impairment.1 Limited data indicate that steady-state plasma concentrations of nefazodone in patients with renal impairment (creatinine clearance: 7-60 mL/minute per 1.73 m2 body surface area) do not differ from those in healthy individuals.1,12