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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(nef AY zoe done)
Generic Available (U.S.)
Yes
Index Terms
Medication Guide
An FDA-approved patient medication guide, which is available with the product information and at http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=4522, must be dispensed with this medication.
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of depression
Use: Unlabeled
Post-traumatic stress disorder (PTSD)
Pregnancy Risk Factor
C
Pregnancy Considerations
Nefazodone is classified as pregnancy category C due to adverse effects observed in animal studies. When nefazodone is taken during pregnancy, an increased risk of major malformations has not been observed in the small number of pregnancies studied. The long-term effects on neurobehavior have not been evaluated.Women treated for major depression and who are euthymic prior to pregnancy are more likely to experience a relapse when medication is discontinued as compared to pregnant women who continue taking antidepressant medications. Therapy during pregnancy should be individualized; treatment of depression during pregnancy should incorporate the clinical expertise of the mental health clinician, obstetrician, primary healthcare provider, and pediatrician. If treatment during pregnancy is required, consider tapering therapy during the third trimester to prevent potential withdrawal symptoms in the infant. If this is done and the woman is considered to be at risk of relapse from her major depressive disorder, the medication can be restarted following delivery. Treatment algorithms have been developed by the ACOG and the APA for the management of depression in women prior to conception and during pregnancy (Yonkers, 2009).
Lactation
Enters breast milk/use caution
Breast-Feeding Considerations
Nefazodone and its metabolites are excreted in breast milk. Drowsiness, lethargy, poor feeding, and failure to maintain body temperature have been reported in a premature nursing infant. Adverse events were not observed in two case reports of older infants. The long-term effects on neurobehavior have not been studied. The manufacturer recommends that caution be exercised when administering nefazodone to nursing women.
Contraindications
Hypersensitivity to nefazodone, related compounds (phenylpiperazines), or any component of the formulation; liver injury due to previous nefazodone treatment, active liver disease, or elevated serum transaminases; concurrent use or use of MAO inhibitors within previous 14 days; use in a patient during the acute recovery phase of MI; concurrent use with carbamazepine, cisapride, or pimozide; concurrent therapy with triazolam or alprazolam is generally contraindicated (dosage must be reduced by 75% for triazolam and 50% for alprazolam; such reductions may not be possible with available dosage forms).
Warnings/Precautions
Boxed warnings:
• Suicidal thinking/behavior: See “Major psychiatric warnings” below.
Major psychiatric warnings:
• Suicidal thinking/behavior: [U.S. Boxed Warning]: Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18-24 years of age) with major depressive disorder (MDD) and other psychiatric disorders; consider risk prior to prescribing. Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥65 years. Closely monitor patients for clinical worsening, suicidality, or unusual changes in behavior, particularly during the initial 1-2 months of therapy or during periods of dosage adjustments (increases or decreases); the patient's family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. A medication guide concerning the use of antidepressants should be dispensed with each prescription. Nefazodone is not FDA approved for use in children.
• The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Patients treated with antidepressants should be observed 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. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy.
• Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their healthcare provider if any of these symptoms or worsening depression or psychosis occur.
Concerns related to adverse effects:
• Anticholinergic effects: May cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention); use with caution in patients with decreased gastrointestinal motility, paralytic ileus, urinary retention, BPH, xerostomia, or visual problems. The degree of anticholinergic blockade produced by this agent is very low relative to other antidepressants.
• Hepatic failure: Cases of life-threatening hepatic failure have been reported (risk should be considered when choosing an agent for the treatment of depression); discontinue if clinical signs or symptoms suggest liver failure.
• Orthostatic hypotension: May cause orthostatic hypotension (risk is low relative to other antidepressants); use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, hypovolemia, or concurrent medication use which may predispose to hypotension/bradycardia).
• Sedation: May cause sedation, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). The degree of sedation is low relative to other antidepressants.
• Sexual dysfunction: Rare reports of priapism have occurred. The incidence of sexual dysfunction with nefazodone is generally lower than with SSRIs.
Disease-related concerns:
• Cardiovascular disease: Use with caution in patients with a history of cardiovascular disease (including previous MI, stroke, tachycardia, or conduction abnormalities); the risk conduction abnormalities with this agent is very low relative to other antidepressants.
• Mania/hypomania: May worsen psychosis in some patients or precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Patients presenting with depressive symptoms should be screened for bipolar disorder. Nefazodone is not FDA approved for the treatment of bipolar depression.
• Renal impairment: Use with caution in patients with renal impairment.
• Seizure disorder: Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications which may lower seizure threshold.
Concurrent drug therapy issues:
• Sedatives: Effects may be potentiated when used with other sedative drugs; does not potentiate ethanol but use is not advised.
Special populations:
• Elderly: Use with caution in the elderly.
Other warnings/precautions:
• Discontinuation of therapy: Therapy should not be abruptly discontinued in patients receiving high doses for prolonged periods.
• Electroconvulsive therapy: May increase the risks associated with electroconvulsive therapy; consider discontinuing, when possible, prior to ECT treatment.
Adverse Reactions
>10%:
Central nervous system: Headache, drowsiness, insomnia, agitation, dizziness
Gastrointestinal: Xerostomia, nausea, constipation
Neuromuscular & skeletal: Weakness
1% to 10%:
Cardiovascular: Bradycardia, hypotension, peripheral edema, postural hypotension, vasodilation
Central nervous system: Chills, fever, incoordination, lightheadedness, confusion, memory impairment, abnormal dreams, decreased concentration, ataxia, psychomotor retardation, tremor
Dermatologic: Pruritus, rash
Endocrine & metabolic: Breast pain, impotence, libido decreased
Gastrointestinal: Gastroenteritis, vomiting, dyspepsia, diarrhea, increased appetite, thirst, taste perversion
Genitourinary: Urinary frequency, urinary retention
Hematologic: Hematocrit decreased
Neuromuscular & skeletal: Arthralgia, hypertonia, paresthesia, neck rigidity, tremor
Ocular: Blurred vision (9%), abnormal vision (7%), eye pain, visual field defect
Otic: Tinnitus
Respiratory: Bronchitis, cough, dyspnea, pharyngitis
Miscellaneous: Flu syndrome, infection
<1%: Abdomen enlarged, abnormal gait, accommodation abnormality, acne, allergic reaction, alopecia, ALT increased, amenorrhea, anemia, angina pectoris, anorgasmia, apathy, arthritis, AST increased, asthma, attention decreased, AV block, breast enlargement, bruising, bursitis, cellulitis, cerebrovascular accident, colitis, CHF, conjunctivitis, cystitis, deafness, depersonalization, derealization, diplopia, dry eyes, dry skin, dehydration, dysarthria, ear pain, eczema, ejaculation abnormal, epistaxis, eructation, esophagitis, euphoria, face edema, gastritis, gingivitis, glaucoma, gout, halitosis, hallucinations, hangover effect, hematuria, hemorrhage, hernia, hiccup, hostility, hyperacusis, hypercholesteremia, hyperesthesia, hyperkinesia, hypertension, hyperventilation, hypoglycemia, hypotonia, keratoconjunctivitis, kidney calculus, lactic dehydrogenase increased, laryngitis, leukopenia, libido increased, liver function tests abnormal, lymphadenopathy, maculopapular rash, malaise, menorrhagia, metrorrhagia, mouth ulceration, muscle stiffness, myoclonus, mydriasis, neuralgia, neuroleptic malignant syndrome, night blindness, nocturia, oliguria, oral moniliasis, pallor, paranoid reaction, pelvic pain, periodontal abscess, peptic ulcer, photophobia, photosensitivity, pneumonia, polyuria, ptosis, rectal hemorrhage, salivation increased, stomatitis, suicide attempt, suicidal thoughts, suicide, syncope, tachycardia, taste loss, tendonitis, contracture, tenosynovitis, thinking abnormal, twitching, ulcerative colitis, urticaria, uterine fibroids enlarged, uterine hemorrhage, urinary incontinence, urinary urgency, ventricular extrasystoles, vaginal hemorrhage, varicose vein, vertigo, vesiculobullous rash, voice alteration, weight loss, yawn
Postmarketing and/or case reports: Angioedema, convulsions, galactorrhea, grand mal seizure, gynecomastia, hepatic failure, hepatic necrosis, hepatitis, hyponatremia, priapism, prolactin increased, rhabdomyolysis (with lovastatin/simvastatin), serotonin syndrome, Stevens-Johnson syndrome, thrombocytopenia
Metabolism/Transport Effects
Substrate of CYP2D6 (major), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP1A2 (weak), CYP2B6 (weak), CYP2C8 (weak), CYP2D6 (weak), CYP3A4 (strong); Induces P-glycoprotein
Drug Interactions
Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Risk D: Consider therapy modification
Alfuzosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alfuzosin. Risk X: Avoid combination
Almotriptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Almotriptan. Management: Limit initial almotriptan adult dose to 6.25 mg and maximum adult dose to 12.5 mg/24-hrs when used with a strong CYP3A4 inhibitor. Avoid concurrent use in patients with impaired hepatic or renal function. Risk D: Consider therapy modification
Alosetron: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alosetron. Risk C: Monitor therapy
ARIPiprazole: CYP3A4 Inhibitors (Strong) may increase the serum concentration of ARIPiprazole. Management: Decrease aripiprazole dose to 50% of the usual dose with concomitant use of strong CYP3A4 inhibitors or to 25% of usual dose with concomitant use of strong CYP3A4 and 2D6 inhibitors or with use of a strong 3A4 inhibitor in a poor 2D6 metabolizer Risk D: Consider therapy modification
Benzodiazepines (metabolized by oxidation): Nefazodone may decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk D: Consider therapy modification
Bortezomib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bortezomib. Risk C: Monitor therapy
Brentuximab Vedotin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Risk C: Monitor therapy
Brinzolamide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brinzolamide. Risk C: Monitor therapy
Budesonide (Nasal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Nasal). Risk C: Monitor therapy
Budesonide (Systemic, Oral Inhalation): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Systemic, Oral Inhalation). Management: Consider reducing the oral budesonide dose when used together with a CYP3A4 inhibitor. This interaction is likely less severe with orally inhaled budesonide. Monitor patients closely for signs/symptoms of corticosteroid excess. Risk D: Consider therapy modification
BusPIRone: May enhance the serotonergic effect of Antidepressants (Serotonin Reuptake Inhibitor/Antagonist). Risk C: Monitor therapy
CarBAMazepine: May decrease the serum concentration of Nefazodone. Concentrations of active Nefazodone metabolites may also be reduced. Nefazodone may increase the serum concentration of CarBAMazepine. Also, concentrations of the active CarBAMazepine epoxide metabolite may be reduced. Risk X: Avoid combination
Cardiac Glycosides: Nefazodone may increase the serum concentration of Cardiac Glycosides. Risk C: Monitor therapy
Ciclesonide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ciclesonide. Specifically, concentrations of the active des-ciclesonide metabolite may be increased. Risk C: Monitor therapy
Cisapride: Nefazodone may increase the serum concentration of Cisapride. Risk X: Avoid combination
CloZAPine: Nefazodone may decrease the metabolism of CloZAPine. Risk C: Monitor therapy
Colchicine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Colchicine. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a strong CYP3A4 inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. Risk D: Consider therapy modification
Conivaptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Conivaptan. Risk X: Avoid combination
Corticosteroids (Orally Inhaled): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Corticosteroids (Orally Inhaled). Management: Monitor for signs and symptoms of adrenal suppression if inhaled budesonide or mometasone are coadministered with a strong CYP3A4 inhibitor. Avoid combining inhaled fluticasone with any strong CYP3A4 inhibitor. Exceptions: Beclomethasone; Beclomethasone (Oral Inhalation); Triamcinolone; Triamcinolone (Systemic). Risk C: Monitor therapy
Crizotinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Crizotinib. Risk X: Avoid combination
CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Risk C: Monitor therapy
CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Risk D: Consider therapy modification
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
CYP3A4 Substrates: CYP3A4 Inhibitors (Strong) may decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
Dabigatran Etexilate: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Dabigatran Etexilate. Management: Avoid concurrent use of dabigatran with a p-glycoprotein inducer when possible. Closely monitor for decreased levels/effects of dabigatran if concomitantly administering a p-glycoprotein inducer, particularly strong inducers. Risk X: Avoid combination
Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Dienogest: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dienogest. Risk C: Monitor therapy
Dronedarone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dronedarone. Risk X: Avoid combination
Dutasteride: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dutasteride. Risk C: Monitor therapy
Eplerenone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eplerenone. Risk X: Avoid combination
Everolimus: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Everolimus. Risk X: Avoid combination
FentaNYL: CYP3A4 Inhibitors (Strong) may increase the serum concentration of FentaNYL. Management: Monitor patients extra closely for several days following initiation of the combination, and fentanyl dosage reductions should be made as appropriate. Risk D: Consider therapy modification
Fesoterodine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Fesoterodine. Management: Avoid fesoterodine doses greater than 4 mg daily in adult patients who are also receiving strong CYP3A4 inhibitors. Risk D: Consider therapy modification
Fluticasone (Nasal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fluticasone (Nasal). Risk C: Monitor therapy
Fluticasone (Oral Inhalation): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fluticasone (Oral Inhalation). Risk X: Avoid combination
GuanFACINE: CYP3A4 Inhibitors (Strong) may increase the serum concentration of GuanFACINE. Risk C: Monitor therapy
Halofantrine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Halofantrine. Risk X: Avoid combination
Iloperidone: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Iloperidone. Specifically, concentrations of the metabolites P88 and P95 may be increased. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Iloperidone. Management: Reduce iloperidone dose by half when administered with a strong CYP3A4 inhibitor. Risk D: Consider therapy modification
Ixabepilone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ixabepilone. Risk D: Consider therapy modification
Lapatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lapatinib. Management: If an overlap in therapy cannot be avoided, consider reducing lapatinib dose to 500 mg/day during, and within 1 week of completing, treatment with the strong CYP3A4 inhibitor. Risk X: Avoid combination
Linagliptin: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of Linagliptin. Management: Strongly consider using an alternative to any strong P-glycoprotein inducer in patients who are being treated with linagliptin. If this combination is used, monitor patients closely for evidence of reduced linagliptin effectiveness. Risk D: Consider therapy modification
Linezolid: May enhance the serotonergic effect of Nefazodone. This could result in serotonin syndrome. Management: Consider alternatives. When this combination is indicated, closely monitor for signs/symptoms of serotonin toxicity/serotonin syndrome. If such symptoms occur, consider discontinuation of one or both agents. Risk D: Consider therapy modification
Lovastatin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lovastatin. Risk X: Avoid combination
Lumefantrine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lumefantrine. Risk C: Monitor therapy
Lurasidone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lurasidone. Risk X: Avoid combination
MAO Inhibitors: May enhance the orthostatic hypotensive effect of Orthostatic Hypotension Producing Agents. Risk C: Monitor therapy
Maraviroc: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Maraviroc. Management: Reduce the adult dose of maraviroc to 150 mg twice daily when used with a strong CYP3A4 inhibitor. Do not use maraviroc with strong CYP3A4 inhibitors in patients with Clcr less than 30 mL/min. Risk D: Consider therapy modification
Methylene Blue: Nefazodone may enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid combination
MethylPREDNISolone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of MethylPREDNISolone. Management: Consider methylprednisolone dose titration and/or adjustments in patients receiving strong CYP3A4 inhibitors (eg, azole antifungals, protease inhibitors) and monitor for increased steroid related adverse effects. Risk D: Consider therapy modification
Nilotinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nilotinib. Risk X: Avoid combination
Nisoldipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nisoldipine. Risk X: Avoid combination
Paricalcitol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Paricalcitol. Risk C: Monitor therapy
Pazopanib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pazopanib. Management: Avoid concurrent use of pazopanib with strong inhibitors of CYP3A4 whenever possible. If it is not possible to avoid such a combination, reduce pazopanib adult dose to 400 mg. Further dose reductions may also be required. Risk D: Consider therapy modification
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy
P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
Pimecrolimus: CYP3A4 Inhibitors (Strong) may decrease the metabolism of Pimecrolimus. Risk C: Monitor therapy
Pimozide: Nefazodone may increase the serum concentration of Pimozide. Risk X: Avoid combination
Pimozide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pimozide. Risk X: Avoid combination
Prasugrel: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Prasugrel. Risk C: Monitor therapy
Propafenone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Propafenone. Risk C: Monitor therapy
Protease Inhibitors: May increase the serum concentration of Nefazodone. Risk C: Monitor therapy
Ranolazine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ranolazine. Risk X: Avoid combination
Rivaroxaban: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Rivaroxaban. Risk X: Avoid combination
RomiDEPsin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of RomiDEPsin. Risk X: Avoid combination
Ruxolitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ruxolitinib. Management: Reduce ruxolitinib initial adult dose to 10 mg twice daily in patients receiving strong CYP3A4 inhibitors whose platelet count is 100*10^9/L or greater. Avoid in patients with lower platelet count. Risk D: Consider therapy modification
Salmeterol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Salmeterol. Risk X: Avoid combination
Saxagliptin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Saxagliptin. Management: Limit saxagliptin adult dose to 2.5 mg/day and monitor for increased saxagliptin levels/effects (e.g., hypoglycemia) when used with a strong CYP3A4 inhibitor. Monitor for decreased saxagliptin levels/effects if discontinuing CYP3A4 inhibitor. Risk D: Consider therapy modification
Selective Serotonin Reuptake Inhibitors: May enhance the serotonergic effect of Antidepressants (Serotonin Reuptake Inhibitor/Antagonist). This may cause serotonin syndrome. Risk C: Monitor therapy
Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Risk D: Consider therapy modification
Sildenafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sildenafil. Management: When used for treatment of pulmonary arterial hypertension, use of sildenafil with strong CYP3A4 inhibitors should be avoided. When used for erectile dysfunction, starting dose should be reduced to 25 mg. Max dose with ritonavir is 25 mg per 48 hours. Risk D: Consider therapy modification
Silodosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Silodosin. Risk X: Avoid combination
Simvastatin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Simvastatin. Risk X: Avoid combination
SORAfenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of SORAfenib. Risk C: Monitor therapy
Tacrolimus: Antidepressants (Serotonin Reuptake Inhibitor/Antagonist) may decrease the metabolism of Tacrolimus. Risk D: Consider therapy modification
Tacrolimus (Systemic): Antidepressants (Serotonin Reuptake Inhibitor/Antagonist) may decrease the metabolism of Tacrolimus (Systemic). Risk D: Consider therapy modification
Tacrolimus (Topical): Antidepressants (Serotonin Reuptake Inhibitor/Antagonist) may decrease the metabolism of Tacrolimus (Topical). Risk C: Monitor therapy
Tadalafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tadalafil. Management: Recommendations regarding use of tadalafil in patients also receiving strong CYP3A4 inhibitors may vary based on indication and/or international labeling. Consult appropriate product labeling. Risk D: Consider therapy modification
Tamsulosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tamsulosin. Risk X: Avoid combination
Ticagrelor: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Ticagrelor. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ticagrelor. Risk X: Avoid combination
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Tolterodine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tolterodine. Management: The maximum recommended dose of long-acting tolterodine is 2 mg/day when used together with a strong CYP3A4 inhibitor. Risk D: Consider therapy modification
Tolvaptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tolvaptan. Risk X: Avoid combination
Toremifene: CYP3A4 Inhibitors (Strong) may enhance the adverse/toxic effect of Toremifene. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Toremifene. Risk X: Avoid combination
Vardenafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vardenafil. Management: Recommendations regarding concomitant use of vardenafil with strong CYP3A4 inhibitors may vary depending on brand name (e.g., Levitra, Staxyn) or by international labeling. Consult appropriate product labeling for specific recommendations. Risk D: Consider therapy modification
Vemurafenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vemurafenib. Risk C: Monitor therapy
Vilazodone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vilazodone. Management: Limit maximum adult vilazodone dose to 20 mg/day in patients receiving strong CYP3A4 inhibitors. Risk D: Consider therapy modification
Zuclopenthixol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Zuclopenthixol. Management: Consider zuclopenthixol dosage reduction with concomitant use of a strong CYP3A4 inhibitor (eg, ketoconazole) in poor CYP2D6 metabolizers or with strong CYP2D6 inhibitors (eg, paroxetine). Monitor for increased zuclopenthixol levels/toxicity. Risk D: Consider therapy modification
Ethanol/Nutrition/Herb Interactions
Ethanol: May increase CNS depression; monitor for increased effects with coadministration. Caution patients about effects.
Food: Nefazodone absorption may be delayed and bioavailability may be decreased if taken with food.
Herb/Nutraceutical: Avoid valerian, St John's wort, SAMe, kava kava (may increase risk of serotonin syndrome and/or excessive sedation).
Storage
Store at room temperature, below 40°C (104°F) in a tight container.
Mechanism of Action
Inhibits neuronal reuptake of serotonin and norepinephrine; also blocks 5-HT2 and alpha1 receptors; has no significant affinity for alpha2, beta-adrenergic, 5-HT1A, cholinergic, dopaminergic, or benzodiazepine receptors
Pharmacodynamics/Kinetics
Onset of action: Therapeutic: Up to 6 weeks
Distribution: Vd: 0.22-0.87 L/kg
Protein binding: >99%
Metabolism: Hepatic to three active metabolites: Triazoledione, hydroxynefazodone, and m-chlorophenylpiperazine (mCPP)
Bioavailability: 20% (variable)
Half-life elimination: Parent drug: 2-4 hours; active metabolites persist longer
Time to peak, serum: 1 hour, prolonged in presence of food
Excretion: Primarily urine (as metabolites); feces
Dosage
Oral:
Adults:
Depression: 200 mg/day, administered in 2 divided doses initially, with a range of 300-600 mg/day in 2 divided doses thereafter
Post-traumatic stress disorder (PTSD) (unlabeled use): Initial: 100 mg twice daily; target dose: 600 mg/day (average daily dose: 463 mg)
Elderly: Initial: 50 mg twice daily; increase dose to 100 mg twice daily in 2 weeks; usual maintenance dose: 200-400 mg/day
Administration: Oral
Dosing after meals may decrease lightheadedness and postural hypotension, but may also decrease absorption and therefore effectiveness.
Monitoring Parameters
If AST/ALT increase >3 times ULN, the drug should be discontinued and not reintroduced; mental status for depression, suicide ideation (especially at the beginning of therapy or when doses are increased or decreased), anxiety, social functioning, mania, panic attacks
Reference Range
Therapeutic plasma levels have not yet been defined
Patient Education
It may take 2-3 weeks to achieve desired results. Avoid alcohol. Maintain adequate hydration unless instructed to restrict fluid intake. You may experience drowsiness, dizziness, lightheadedness, nausea, vomiting, or orthostatic hypotension. Report persistent insomnia or excessive daytime sedation; suicide ideation; muscle cramping, tremors, weakness, tiredness, or change in gait; chest pain, palpitations, or rapid heartbeat; vision changes or eye pain; respiratory difficulty or breathlessness; malaise, loss of appetite, GI complaints, abdominal pain, or blood in stool; yellowing of skin or eyes (jaundice); or worsening of condition.
Geriatric Considerations
Data on nefazodone in the elderly are limited, specifically regarding efficacy; clinical trials in adult patients have found it superior to placebo and similar to imipramine. Nefazodone's Cmax and AUC have been reported to be increased twofold in the elderly and women after a single dose compared to younger patients; however, these differences were markedly reduced with multiple dosing with women having AUC values of nefazodone and its hydroxy metabolite remaining approximately 50% higher
A systematic review and meta-analysis of antidepressant placebo-controlled trials in persons with depression and dementia found evidence "suggestive" of efficacy but not of sufficient strength to "confirm" efficacy. Antidepressant trials in this patient population are small and underpowered. Older patients with depression being treated with an antidepressant should be closely monitored for response and adverse effects. Treatment should be switched or augmented when response is inadequate with a therapeutic dose. Antidepressants that are not tolerated should be discontinued and an alternative agent should be started.
Additional Information
May cause less sexual dysfunction than other antidepressants. Women and elderly receiving single doses attain significant higher peak concentrations than male volunteers.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Significant xerostomia (normal salivary flow resumes upon discontinuation) and taste perversion.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
Nefazodone inhibits reuptake of both serotonin and norepinephrine and also blocks some serotonin receptors. No precautions with vasoconstrictors appear to be necessary.
Mental Health: Child/Adolescent Considerations
No new information on nefazodone in children and adolescents. It is never used in children and adolescents due to U.S boxed warning for hepatotoxicity.
Mental Health: Comment
Due to its 5-HT2 antagonistic activity, nefazodone is associated with a low incidence of sexual dysfunction. Nefazodone may be useful for individuals with post-traumatic stress disorder. Nefazodone has a lower incidence of sedation and orthostasis than trazodone, primarily related to its noradrenergic activity.
Nursing: Physical Assessment/Monitoring
Monitor for clinical worsening and suicide ideation. Taper dosage slowly when discontinuing.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral, as hydrochloride: 50 mg, 100 mg, 150 mg, 200 mg, 250 mg
Pricing: U.S. (www.drugstore.com)
Tablets (Nefazodone HCl)
50 mg (60): $45.99
100 mg (60): $54.99
150 mg (30): $26.99
200 mg (60): $56.99
250 mg (60): $59.99
References
Bandelow B, Zohar J, Hollander E, et al, “World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disorders -- First Revision,” World J Biol Psychiatry, 2008, 9(4): 248-312. Available at http://www.wfsbp.org/fileadmin/pdf/guides/Guidelines_Anxiety_revision.pdf
Benedek DM, Friedman MJ, Zatzick D, et al, “Guideline Watch (March 2009): Practice Guideline for the Treatment of Patients With Acute Stress Disorder and Posttraumatic Stress Disorder.” Available at http://www.psychiatryonline.com/pracGuide/loadGuidelinePdf.aspx?file=AcuteStressDisorder-PTSD_GuidelineWatch
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(6):234-41.
Mokhlesi B, Leikin JB, Murray P, et al, “Adult Toxicology in Critical Care: Part II: Specific Poisonings,” Chest, 2003, 123(3):897-922.
Nelson JC and Devanand DP, "A Systematic Review and Meta-Analysis of Placebo-Controlled Antidepressant Studies in People With Depression and Dementia," J Am Geriatr Soc, 2011, 59(4):577-85.
Pass SE and Simpson RW, “Discontinuation and Reinstitution of Medications During the Perioperative Period,” Am J Health Syst Pharm, 2004, 61(9):899-912.
Rickels K, Schweizer E, Clary C, et al, “Nefazodone and Imipramine in Major Depression: A Placebo-Controlled Trial,” Br J Psychiatry, 1994, 164(6):802-5.
Shea JP, Shulka UA, Rittman KA, “Single Dose Pharmacokinetics of Nefazodone in Elderly Subjects, Renally Impaired Patients, and Patients With Hepatic Cirrhosis in Comparison to Healthy Volunteers,” Clin Pharmacol Ther, 1988, 43:146.
Wilens TE, Spencer TJ, Biederman J, et al, “Case Study: Nefazodone for Juvenile Mood Disorders,” J Am Acad Child Adolesc Psychiatry, 1997, 36(4):481-5.
Yonkers KA, Wisner KL, Stewart DE, et al, “The Management of Depression During Pregnancy: A Report From the American Psychiatric Association and the American College of Obstetricians and Gynecologists,” Obstet Gynecol, 2009, 114(3):703-13.
International Brand Names
Lexi-Comp.com
Last full review/revision January 2012
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