Nefazodone Hydrochloride

Contraindications

• Hepatocellular injury during nefazodone therapy.13

• Concomitant use with terfenadine or astemizole (drugs no longer commercially available in the US), cisapride, pimozide, or carbamazepine.1 Avoid concomitant use with triazolam.1 (See Drug Interactions under Cautions.)

• Known hypersensitivity to nefazodone, other phenylpiperazine antidepressants, or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Hepatic failure resulting in death or liver transplantation reported; incidence estimated to be approximately 3–4 times that in the general population.13

Time to hepatic injury in patients who develop hepatic failure resulting in transplantation or death is 2 weeks to 6 months.13

Prodromal symptoms (e.g., anorexia, malaise, other GI symptoms) or dark urine may or may not occur before onset of jaundice.13

Early detection of hepatic injury and immediate withdrawal of nefazodone is believed to enhance likelihood of recovery.13

Consider monitoring liver function.13

Discontinue in patients with signs and symptoms suggestive of liver failure.13

Discontinue and do not reinitiate in patients with signs of hepatocellular injury (i.e., ALT or AST concentrations ≥3 times the ULN).13

Possible worsening of depression and/or emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior in both adult and pediatric patients with major depressive disorder, whether or not they are taking antidepressants; may persist until clinically important remission occurs.d e f g However, suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.d e f

Appropriately monitor and closely observe patients receiving nefazodone for any reason, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.1 d e f (See Boxed Warning and also see Pediatric Use under Cautions.)

Anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania may be precursors to emerging suicidality.e f Consider changing or discontinuing therapy in patients whose depression is persistently worse or in those with emerging suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if severe, abrupt in onset, or not part of patient’s presenting symptoms.d e f (See General under Dosage and Administration.)

Prescribe in smallest quantity consistent with good patient management to reduce risk of overdosage.1 e

Observe these precautions for patients with psychiatric (e.g., major depressive disorder, OCD) or nonpsychiatric disorders.e

May unmask bipolar disorder. e (See Activation of Mania or Hypomania under Cautions.)

Screen for risk of bipolar disorder by obtaining detailed psychiatric history (e.g., family history of suicide, bipolar disorder, depression) prior to initiating therapy.e

Concomitant use with MAO inhibitor associated with serious, sometimes fatal reactions, including manifestations resembling serotonin syndrome (e.g., hyperthermia, rigidity, myoclonus, autonomic instability, mental status changes) or neuroleptic malignant syndrome (NMS).1 (See Specific Drugs under Interactions.)

May enhance effects of some benzodiazepines.1 Use with caution; dosage modifications recommended.1 (See Specific Drugs under Interactions.)

Concomitant use with certain nonsedating antihistamines (astemizole, terfenadine [no longer commercially available in the US]), cisapride, or pimozide may result in serious and/or life-threatening cardiac events due to possible effects of nefazodone on hepatic metabolism of the drugs.1 (See Contraindications under Cautions.)

Pharmacokinetic interaction with carbamazepine.1 Concomitant use contraindicated.1 (See Specific Drugs under Interactions.)

General Precautions

Postural hypotension reported.1

Not systematically evaluated in patients with a recent history of MI or unstable heart disease.1

Caution in patients with known cardiovascular or cerebrovascular disease that could be exacerbated by hypotension (e.g., history of angina, MI, or ischemic stroke) and conditions that would predispose patients to hypotension (e.g., concomitant use of antihypertensive drugs, dehydration, hypovolemia).1

Possible activation of mania and hypomania, particularly in patients with bipolar disorder; caution in patients with history of mania.1 (See Bipolar Disorder under Cautions.)

Risk of seizures; use with caution in patients with a history of seizures.1

Risk of developing priapism.1

Discontinue immediately and consult a clinician if prolonged or inappropriate erections occur.1 Consult a urologist for appropriate management if priapism persists for >24 hours.1

Ensure accuracy of prescription; similarity in spelling of Serzone (the former trade name for nefazodone) and Seroquel (the trade name for quetiapine, an antipsychotic agent) may result in errors.14 15

Drowsiness and dizziness reported.1

Performance of activities requiring mental alertness and physical coordination may be impaired.1

Effects of concomitant use with ECT have not been systematically evaluated.1

Specific Populations

Category C.1

Not known whether nefazodone is distributed into milk; caution advised.1

Safety and efficacy not established in children <18 years of age.1

FDA warns that a greater risk of suicidal thinking or behavior (suicidality) occurred during first few months of antidepressant treatment (4%) compared with placebo (2%) in children and adolescents with major depressive disorder, OCD, or other psychiatric disorders based on pooled analyses of 24 short-term, placebo-controlled trials of 9 antidepressant drugs (SSRIs and others).e However, a more recent meta-analysis of 27 placebo-controlled trials of 9 antidepressants (SSRIs and others) in patients <19 years of age with major depressive disorder, OCD, or non-OCD anxiety disorders suggests that the benefits of antidepressant therapy in treating these conditions may outweigh the risks of suicidal behavior or suicidal ideation.g No suicides occurred in these pediatric trials.e g

Carefully consider these findings when assessing potential benefits and risks of nefazodone in a child or adolescent for any clinical use.d e f g (See Worsening of Depression and Suicidality Risk under Cautions.)

No substantial differences in safety relative to younger adults, but increased sensitivity cannot be ruled out.1 Dosage adjustment advised.1 (See Special Populations under Dosage and Administration.)

In pooled data analyses, a reduced risk of suicidality was observed in adults ≥65 years of age with antidepressant therapy compared with placebo.d e (See Boxed Warning and also see Worsening of Depression and Suicidality Risk under Cautions.)

Not recommended in patients with active liver disease or elevated serum transaminase concentrations; baseline abnormalities can complicate patient monitoring.13 (See Hepatic Effects under Boxed Warning and Hepatic Effects under Cautions.)

Common Adverse Effects

Somnolence, dry mouth, nausea, dizziness, constipation, asthenia, lightheadedness, blurred vision, confusion, abnormal vision.1

Metabolized by CYP3A4.c

Inhibits CYP3A4 and, to a lesser extent, CYP2D6.a Does not inhibit CYP1A2.a

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interaction likely with drugs that are inhibitors, inducers, or substrates of CYP3A4 with possible alteration in the metabolism of nefazodone and/or other drug.1

Protein-Bound Drugs

Potential pharmacokinetic interaction (nefazodone displacement by, or nefazodone displacement of, other protein-bound drugs from binding site).1

Specific Drugs

Absorption

Bioavailability

Completely and rapidly absorbed from the GI tract; undergoes extensive first-pass metabolism, which results in an oral bioavailability of approximately 20%.1 Peak plasma concentrations achieved within 1 hour.1

Food

Food delays the absorption and decreases the bioavailability by approximately 20%.1

Special Populations

Geriatric individuals: Peak plasma concentration and AUC increased compared with younger adults.1

Hepatic impairment: Nefazodone AUC increased in patients with cirrhosis.1

Renal impairment (Clcr 7–60 mL/minute): No effect on steady-state concentrations.1

Distribution

Extent

Widely distributed in body tissues, including the CNS.1

Plasma Protein Binding

>99%.1

Elimination

Metabolism

Metabolized by oxidative pathways (CYP3A4) and aromatic hydroxylation to several active metabolites.1 c

Elimination Route

Excreted in urine (55%) as metabolites and feces (20–30%).1

Half-life

Nefazodone: 2–4 hours.1

Metabolites: 1.5–18 hours.1

Storage

Oral

<40°C.1

• Risk of suicidality; importance of patients, family, and caregivers 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.d e f FDA recommends providing written patient information (medication guide) explaining risks of suicidality each time the drug is dispensed.d e f

• Risk of serious, life-threatening hepatic failure; importance of advising patients to be alert for manifestations of hepatic dysfunction (e.g., jaundice, anorexia, GI complaints, malaise) and to contact their clinician immediately if they occur.13

• Importance of notifying a clinician if sensitivity reactions (e.g., rash, hives) or visual disturbances (e.g., blurred vision, scotoma, visual trails) occur.1 a

• Potential for drug to impair mental alertness or physical coordination; avoid driving or operating machinery until effects on individual are known.1

• Importance of avoiding alcohol during nefazodone therapy.1

• Importance of continuing therapy even if improvement is not evident for several weeks, unless directed otherwise by their clinician.1

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)