Nefazodone Hydrochloride

Pronunciation

Class: Serotonin Modulators
VA Class: CN609
CAS Number: 82752-99-6

Warning(s)

  • Hepatic Effects
  • Severe, life-threatening, sometimes fatal hepatic failure reported.13 (See Hepatic Effects under Cautions.)

  • Avoid use in patients with active liver disease or elevated serum transaminase concentrations.13

  • Discontinue and do not reinitiate therapy in patients who develop evidence of hepatocellular injury (e.g., AST or ALT concentrations ≥3 times the ULN).13

  • Suicidality
  • Antidepressants may increase risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (18–24 years of age) with major depressive disorder and other psychiatric disorders; balance this risk with clinical need.d e Nefazodone is not approved for use in pediatric patients.a (See Pediatric Use under Cautions.)

  • In pooled data analyses, risk of suicidality was not increased in adults >24 years of age and apparently was reduced in adults ≥65 years of age with antidepressant therapy compared with placebo.d e

  • Depression and certain other psychiatric disorders are themselves associated with an increased risk of suicide.d e f

  • Appropriately monitor and closely observe all patients who are started on nefazodone therapy for clinical worsening, suicidality, or unusual changes in behavior; involve family members and/or caregivers in this process.d e f (See Worsening of Depression and Suicidality Risk under Cautions.)

Introduction

Antidepressant; serotonin modulator.1 2 3 5 7 8

Uses for Nefazodone Hydrochloride

Major Depressive Disorder

Management of major depressive disorder.1 2 3 4 7 8 10 11

Slideshow: Depression, the Risk of Suicide, and Treatment Options

Effective in both inpatient or outpatient setting.1 2 3 4 8

Nefazodone Hydrochloride Dosage and Administration

General

  • Allow at least 2 weeks to elapse between discontinuance of an MAO inhibitor and initiation of nefazodone and an interval of at least 1 week to elapse between discontinuance of nefazodone and initiation of an MAO inhibitor.1 Also allow at least 1 week to elapse between discontinuance of fluoxetine and initiation of nefazodone.1 (See Specific Drugs under Interactions.)

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

  • Sustained therapy may be required; monitor periodically for need for continued therapy.1

Administration

Oral Administration

Administer twice daily without regard to meals.1 2 12

Dosage

Available as nefazodone hydrochloride; dosage expressed in terms of the salt.1

Adults

Major Depressive Disorder
Oral

Initially, 100 mg twice daily.1 10 Dosages may be increased by increments of 100–200 mg daily at intervals of not less than 1 week.1 2 10

Usual dosage: 300–600 mg daily.1 12

Prescribing Limits

Adults

Major Depressive Disorder
Oral

Maximum dosage: 600 mg daily.1 2 10

Special Populations

Geriatric or Debilitated Patients

Initially, 50 mg twice daily.1 Subsequent dosage adjustments should be made in smaller increments and at longer intervals than in younger patients.1

Usual dosage in geriatric individuals: 200–400 mg daily.1 11 12

Cautions for 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 Effects

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

Worsening of Depression and Suicidality Risk

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

Bipolar Disorder

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

Drug Interactions

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

Cardiovascular Effects

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

Activation of Mania or Hypomania

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.)

Seizures

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

Priapism

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

Possible Prescribing and Dispensing Errors

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

CNS Effects

Drowsiness and dizziness reported.1

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

Electroconvulsive Therapy (ECT)

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

Specific Populations

Pregnancy

Category C.1

Lactation

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

Pediatric Use

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.)

Geriatric Use

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.)

Hepatic Impairment

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

Interactions for Nefazodone Hydrochloride

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

Drug

Interaction

Comments

Alcohol

No clinically important psychomotor interactions reported in limited study1

Concomitant use not recommended 1

Anesthetics, general

Limited information1

Discontinue nefazodone for as long as clinically feasible prior to elective surgery1

Antihistamines (astemizole, terfenadine)

Possible pharmacokinetic interaction and potential for serious or life-threatening reactions (e.g., cardiac arrhythmias) with astemizole or terfenadine (drugs no longer commercially available in the US)1

Concomitant use contraindicated1

Benzodiazepines

Alprazolam: Increased AUC and half-life of alprazolam; no changes in nefazodone plasma concentrations1

Lorazepam: Pharmacokinetic interaction unlikely1

Triazolam: Increased AUC and half-life of triazolam; no changes in nefazodone plasma concentrations1

Alprazolam: Reduce initial alprazolam dosage by 50%1

Lorazepam: Dosage adjustment not needed1

Triazolam: Concomitant use not recommended; if unavoidable, reduce initial triazolam dosage by 75%1

Buspirone

Marked increase in plasma buspirone concentrationsa

Reduce initial dose of buspirone (2.5 mg daily); base subsequent adjustments on clinical assessmenta

Carbamazepine

Marked decrease in plasma nefazodone concentrations; increased plasma carbamazepine concentrations1

Concomitant use contraindicated1

Cimetidine

Pharmacokinetic interaction unlikely1

Cisapride

Possible pharmacokinetic interaction and potential for serious or life-threatening reactions (e.g., cardiac arrhythmias)1

Concomitant use contraindicated1

CNS agents, other

Limited information1

Use with caution1

Desipramine

No changes in the pharmacokinetics of desipramine and its metabolites or in the pharmacokinetics of nefazodone; increased plasma concentrations of some nefazodone metabolites1

Adjust dosages based on clinical response1

Digoxin

Increased digoxin AUC; no changes in the pharmacokinetics of nefazodone or its metabolites 1

Monitor plasma digoxin concentrations1

Fluoxetine

No changes in the pharmacokinetics of fluoxetine and its metabolites or in the pharmacokinetics of nefazodone; increased plasma concentrations of some nefazodone metabolites1

Increased incidence of headache, lightheadedness, nausea, paresthesia reported 1

Allow at least 1 week to elapse between discontinuance of fluoxetine and initiation of nefazodone; reduce initial dose of nefazodone 1

Haloperidol

Decreased haloperidol clearance; no changes in pharmacokinetics of nefazodone.1 Pharmacodynamic effects of haloperidol not altered.1

Adjust haloperidol dosages as needed1

HMG-CoA reductase inhibitors (statins)

Increased concentrations of some HMG-CoA reductase inhibitors; increased risk of myopathy (including rhabdomyolysis) 1

Caution if used with HMG-CoA reductase inhibitors metabolized by CYP3A4 pathway (e.g., atorvastatin, lovastatin, simvastatin); dosage adjustment of the HMG-CoA reductase inhibitor recommended1

Consider using HMG-CoA reductase inhibitors with a low potential for interaction (e.g., pravastatin, fluvastatin)1

Hypotensive agents

Potential additive hypotensive effects1

Use with caution1

Immunosuppressants (cyclosporine, tacrolimus)

Marked increase in immunosuppressant plasma concentrations1

Monitor immunosuppressant concentrations and adjust dosage accordingly1

Lithium

No changes in the pharmacokinetics of lithium or nefazodone; decreased plasma concentrations of some nefazodone metabolites1

Not considered clinically important1

MAO inhibitors

Potentially serious or fatal serotonin syndrome or NMS1

Concomitant use not recommended1

Allow at least 2 weeks to elapse between discontinuance of an MAO inhibitor and initiation of nefazodone; allow at least 1 week to elapse between discontinuance of nefazodone and initiation of an MAO inhibitor1

Phenytoin

Single dose of phenytoin: No changes in pharmacokinetics of phenytoin1

Adjust phenytoin dosages as needed1

Pimozide

Possible pharmacokinetic interaction and potential for serious or life-threatening reactions (e.g., cardiac arrhythmias)1

Concomitant use contraindicated1

Propranolol

Decreased propranolol concentrations; no changes in the pharmacokinetics of nefazodone 1

Adjust propranolol dosages as needed1

Theophylline

Pharmacokinetic or pharmacologic interactions unlikely1

Warfarin

No clinically important pharmacokinetic or pharmacologic interaction in limited study 1

Monitor PT1

Nefazodone Hydrochloride Pharmacokinetics

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

Stability

Storage

Oral

Tablets

<40°C.1

Actions

  • Mechanism of action as an antidepressant may involve inhibition of reuptake of serotonin (5-hydroxtryptamine [5-HT]) and norepinephrine at the presynaptic membrane, antagonism at serotonin type 2 (5-HT2) receptors, and down-regulation of 5-HT2 receptor binding sites.1 2 3 4 7 8 10 11 c

  • Has little or no affinity for α2-adrenergic, β-adrenergic, muscarinic, dopaminergic, histamine H1, 5-HT1A, or GABA-benzodiazepine receptors.1 2 6 7 8 11 12

Advice to Patients

  • 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.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Nefazodone Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

50 mg*

Nefazodone Hydrochloride Tablets

Dr. Reddy's, Eon, Par, Ranbaxy, Teva

100 mg*

150 mg*

200 mg*

250 mg*

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Nefazodone HCl 100MG Tablets (TEVA PHARMACEUTICALS USA): 60/$54.99 or 180/$151.96

Nefazodone HCl 150MG Tablets (TEVA PHARMACEUTICALS USA): 30/$26.99 or 60/$48.97

Nefazodone HCl 200MG Tablets (TEVA PHARMACEUTICALS USA): 60/$56.99 or 180/$160.98

Nefazodone HCl 250MG Tablets (TEVA PHARMACEUTICALS USA): 60/$59.99 or 180/$167.97

Nefazodone HCl 50MG Tablets (TEVA PHARMACEUTICALS USA): 60/$45.99 or 180/$130.97

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions August 1, 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Bristol-Myers Squibb Company. Serzone (nefazodone hydrochloride) tablets prescribing information. Princeton, NJ; 2000 Jun.

2. Bristol-Myers Squibb Company. Serzone (nefazodone hydrochloride) product information (executive summary). Princeton, NJ; 1998 May.

3. Rickels K, Schweizer E, Clary C et al. Nefazodone and imipramine in major depression: a placebo-controlled trial. Br J Psychiatry. 1994; 164:802-5. [IDIS 331957] [PubMed 7952987]

4. Fontaine R, Ontiveros A, Elie R et al. A double-blind comparison of nefazodone, imipramine, and placebo in major depression. J Clin Psychiatry. 1994; 55:234-41. [IDIS 333409] [PubMed 8071277]

5. Mayol RF, Cole CA, Luke GM et al. Characterization of the metabolites of the antidepressant drug nefazodone in human urine and plasma. Drug Metab Disp Biol Fate Chem. 1994; 22:304-11.

6. Richelson E. Pharmacology of antidepressants—characteristics of the ideal drug. Mayo Clin Proc. 1994; 69:1069-81. [IDIS 338485] [PubMed 7967761]

7. Fontaine R. Novel serotonergic mechanisms and clinical experience with nefazodone. Clin Neuropharmacol. 1993; 16:S45-50. [PubMed 8131154]

8. Ansseau M, Darimont P, Lecoq A et al. Controlled comparison of nefazodone and amitriptyline in major depressive inpatients. Psychopharmacogology. 1994; 115:254-60.

9. Anton SF, Robinson DS, Roberts DL et al. Long-term treatment of depression with nefazodone. Psychopharmacology. 1994; 30:165-9.

10. Anon. Nefazodone for depression. Med Lett Drugs Ther. 1995; 37:33-5. [PubMed 7707998]

11. Ayd FJ Jr. Nefazodone: The latest FDA approved antidepressant. Int Drug Ther Newsl. 1995; 30:17-20.

12. Bristol-Myers Squibb Company, Princeton, NJ: Personal communication.

13. Bristol-Myers Squibb Company. Serzone (nefazodone hydrochloride) tablets prescribing information. Princeton, NJ; 2001 Nov.

14. Block G. Dear healthcare professional letter: Dispensing errors alert. Wilmington, DE: AstraZeneca LP; 2002 May 20.

15. Kim H, Phillips J. Medication errors associated with Serzone and Seroquel. Drug Topics. 2002;1:38. From the Drug Topics website ().

16. Jody D. Dear healthcare provider letter: dispensing error alert involving Serzone (nefazodone) and Seroquel (quetiapine) tablets. Princeton, NJ: Bristol Myer Squibb; 2002 Dec 9. From the FDA website ()

17. Anon. FDA issues public health advisory entitled: Reports of suicidality in pediatric patients being treated with antidepressant medications for major depressive disorder (MDD). FDA Talk Paper. Rockville, MD: Food and Drug Administration; 2003 Oct 27. From the FDA website: http: / / www.fda.gov / Drugs / DrugSafety / PostmarketDrugSafetyInformationforPatientsandProviders / DrugSafetyInformationforHeathcareProfessionals / PublicHealthAdvisories / ucm168828.htm

18. Anon. Reports of suicidality in pediatric patients being treated with antidepressant medications for major depressive disorder (MDD). FDA Public Health Advisory. Rockville, MD: Food and Drug Administration; 2003 Oct 27. From the FDA website: ().

19. Food and Drug Administration. Class suicidality labeling language for antidepressants. From the FDA website: ().

20. Food and Drug Administration. Public health advisory: suicidality in children and adolescents being treated with antidepressant medications. Rockville, MD; 2004 Oct 15. From the FDA website: ().

25. Food and Drug Administration. Medication guide: about using antidepressants in children or teenagers. Rockville, MD; 2005 Jan 16. From the FDA website: ().

26. AstraZeneca Pharmaceuticals, Wilmington, DE: Personal communications.

a. Bristol-Myers Squibb Company. Serzone (nefazodone hydrochloride) tablets prescribing information. Princeton, NJ; 2002 Oct.

b. Food and Drug Administration (FDA). FDA Public Health Advisory regarding worsening depression and suicidality in patients being treated with antidepressant medications. From FDA website (). 2003 Mar 22.

c. DeVane CL, Grothe DR, Smith SL. Pharmacology of antidepressants: focus on nefazodone. J Clin Psychiatry. 2002: 63 (suppl 1):10-17.

d. Food and Drug Administration. FDA news: FDA proposes new warnings about suicidal thinking, behavior in young adults who take antidepressant medications. Rockville, MD; 2007 May 2. From the FDA web site:

e. Food and Drug Administration. Antidepressant use in children, adolescents, and adults: class revisions to product labeling. Rockville, MD; 2007 May 2. From the FDA web site:

f. Food and Drug Administration. Revisions to medication guide: antidepressant medicines, depression and other serious mental illnesses and suicidal thoughts or actions. Rockville, MD; 2007 May 2. From the FDA web site:

g. Bridge JA, Iyengar S, Salary CB. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. JAMA. 2007; 297:1683-96. [PubMed 17440145]

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