Nefazodone Hydrochloride

FDA Drug Information • Also known as: Nefazodone Hydrochloride

Brand Names: Nefazodone Hydrochloride
Route: ORAL
Dosage Form: TABLET
Product Type: HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of nefazodone hydrochloride tablets or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Nefazodone hydrochloride tablets are not approved for use in pediatric patients (see WARNINGS, Clinical Worsening and Suicide Risk ; PRECAUTIONS, Information for Patients ; and PRECAUTIONS, Pediatric Use ). Warning Cases of life-threatening hepatic failure have been reported in patients treated with nefazodone hydrochloride tablets. The reported rate in the United States is about 1 case of liver failure resulting in death or transplant per 250,000 to 300,000 patient-years of nefazodone hydrochloride treatment. The total patient-years is a summation of each patient’s duration of exposure expressed in years. For example, 1 patient-year is equal to 2 patients each treated for 6 months, 3 patients each treated for 4 months, etc. (see WARNINGS ). Ordinarily, treatment with nefazodone hydrochloride tablets should not be initiated in individuals with active liver disease or with elevated baseline serum transaminases. There is no evidence that pre-existing liver disease increases the likelihood of developing liver failure, however, baseline abnormalities can complicate patient monitoring. Patients should be advised to be alert for signs and symptoms of liver dysfunction (jaundice, anorexia, gastrointestinal complaints, malaise, etc.) and to report them to their doctor immediately if they occur. Nefazodone hydrochloride tablets should be discontinued if clinical signs or symptoms suggest liver failure (see PRECAUTIONS, Information for Patients ). Patients who develop evidence of hepatocellular injury such as increased serum AST or serum ALT levels ≥ 3 times the upper limit of NORMAL, while on nefazodone hydrochloride tablets should be withdrawn from the drug. These patients should be presumed to be at increased risk for liver injury if nefazodone hydrochloride is reintroduced. Accordingly, such patients should not be considered for re-treatment.

Description

DESCRIPTION Nefazodone hydrochloride tablets, USP are an antidepressant for oral administration with a chemical structure unrelated to selective serotonin reuptake inhibitors, tricyclics, tetracyclics, or monoamine oxidase inhibitors (MAOI). Nefazodone hydrochloride is a synthetically derived phenylpiperazine antidepressant. The chemical name for nefazodone hydrochloride is 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one monohydrochloride. The structural formula is: Nefazodone hydrochloride is a nonhygroscopic, white crystalline solid. It is freely soluble in chloroform, soluble in propylene glycol, and slightly soluble in polyethylene glycol and water. Nefazodone hydrochloride tablets, USP are supplied as capsule-shaped tablets containing 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg of nefazodone hydrochloride, USP and the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, sodium starch glycolate and povidone. Additionally, the 50 mg tablets include ferric oxide red as a colorant, the 150 mg tablets include ferric oxide red and yellow as colorants, and the 200 mg tablets include ferric oxide yellow as a colorant. 1

What Is Nefazodone Hydrochloride Used For?

INDICATIONS AND USAGE Nefazodone hydrochloride tablets are indicated for the treatment of depression. When deciding among the alternative treatments available for this condition, the prescriber should consider the risk of hepatic failure associated with nefazodone hydrochloride treatment (see WARNINGS ). In many cases, this would lead to the conclusion that other drugs should be tried first. The efficacy of nefazodone in the treatment of depression was established in 6 to 8 week controlled trials of outpatients and in a 6 week controlled trial of depressed inpatients whose diagnoses corresponded most closely to the DSM-III or DSM-IIIR category of major depressive disorder (see CLINICAL PHARMACOLOGY ). A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks). It must include either depressed mood or loss of interest or pleasure and at least five of the following nine symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation. The efficacy of nefazodone in reducing relapse in patients with major depression who were judged to have had a satisfactory clinical response to 16 weeks of open-label nefazodone treatment for an acute depressive episode has been demonstrated in a randomized placebo-controlled trial (see CLINICAL PHARMACOLOGY ). Although remitted patients were followed for as long as 36 weeks in the study cited (i.e., 52 weeks total), the physician who elects to use nefazodone for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

Dosage and Administration

DOSAGE AND ADMINISTRATION When deciding among the alternative treatments available for depression, the prescriber should consider the risk of hepatic failure associated with nefazodone hydrochloride treatment (see WARNINGS ). Initial Treatment The recommended starting dose for nefazodone hydrochloride tablets USP is 200 mg/day, administered in two divided doses (BID). In the controlled clinical trials establishing the antidepressant efficacy of nefazodone, the effective dose range was generally 300 to 600 mg/day. Consequently, most patients, depending on tolerability and the need for further clinical effect, should have their dose increased. Dose increases should occur in increments of 100 mg/day to 200 mg/day, again on a BID schedule, at intervals of no less than 1 week. As with all antidepressants, several weeks on treatment may be required to obtain a full antidepressant response. Dosage for Elderly or Debilitated Patients The recommended initial dose for elderly or debilitated patients is 100 mg/day, administered in two divided doses (BID). These patients often have reduced nefazodone clearance and/or increased sensitivity to the side effects of CNS-active drugs. It may also be appropriate to modify the rate of subsequent dose titration. As steady-state plasma levels do not change with age, the final target dose based on a careful assessment of the patient’s clinical response may be similar in healthy younger and older patients. Maintenance/Continuation/Extended Treatment There is no body of evidence available from controlled trials to indicate how long the depressed patient should be treated with nefazodone. It is generally agreed, however, that pharmacological treatment for acute episodes of depression should continue for up to 6 months or longer. Whether the dose of antidepressant needed to induce remission is identical to the dose needed to maintain euthymia is unknown. Systematic evaluation of the efficacy of nefazodone has shown that efficacy is maintained for periods of up to 36 weeks following 16 weeks of open-label acute treatment (treated for 52 weeks total) at dosages that averaged 438 mg/day. For most patients, their maintenance dose was that associated with response during acute treatment (see CLINICAL PHARMACOLOGY ). The safety of nefazodone in long-term use is supported by data from both double-blind and open-label trials involving more than 250 patients treated for at least one year. Switching Patients to or From a Monoamine Oxidase Inhibitor At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with nefazodone. In addition, at least 7 days should be allowed after stopping nefazodone before starting an MAOI.

Side Effects (Adverse Reactions)

ADVERSE REACTIONS Associated with Discontinuation of Treatment Approximately 16% of the 3496 patients who received nefazodone in worldwide premarketing clinical trials discontinued treatment due to an adverse experience. The more common (≥ 1%) events in clinical trials associated with discontinuation and considered to be drug related (i.e., those events associated with dropout at a rate approximately twice or greater for nefazodone compared to placebo) included: nausea (3.5%), dizziness (1.9%), insomnia (1.5%), asthenia (1.3%), and agitation (1.2%). Incidence in Controlled Trials Commonly Observed Adverse Events in Controlled Clinical Trials The most commonly observed adverse events associated with the use of nefazodone (incidence of 5% or greater) and not seen at an equivalent incidence among placebo-treated patients (i.e., significantly higher incidence for nefazodone compared to placebo, p ≤ 0.05), derived from the table below, were: somnolence, dry mouth, nausea, dizziness, constipation, asthenia, lightheadedness, blurred vision, confusion, and abnormal vision. Adverse Events Occurring at an Incidence of 1% or More Among Nefazodone-Treated Patients The table that follows enumerates adverse events that occurred at an incidence of 1% or more, and were more frequent than in the placebo group, among nefazodone-treated patients who participated in short-term (6 to 8 week) placebo-controlled trials in which patients were dosed with nefazodone to ranges of 300 to 600 mg/day. This table shows the percentage of patients in each group who had at least one episode of an event at some time during their treatment. Reported adverse events were classified using standard COSTART-based Dictionary terminology. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side-effect incidence rate in the population studied. Treatment-Emergent Adverse Experience Incidence in 6 to 8 Week Placebo-Controlled Clinical Trials a , Nefazodone 300 to 600 mg/day Dose Range Percent of Patients Body System Preferred Term Nefazodone (n = 393) Placebo (n = 394) Body as a Whole Headache 36 33 Asthenia 11 5 Infection 8 6 Flu syndrome 3 2 Chills 2 1 Fever 2 1 Neck rigidity 1 0 Cardiovascular Postural hypotension 4 1 Hypotension 2 1 Dermatological Pruritus 2 1 Rash 2 1 Gastrointestinal Dry mouth 25 13 Nausea 22 12 Constipation 14 8 Dyspepsia 9 7 Diarrhea 8 7 Increased appetite 5 3 Nausea & vomiting 2 1 Metabolic Peripheral edema 3 2 Thirst 1 < 1 Musculoskeletal Arthralgia 1 < 1 Nervous Somnolence 25 14 Dizziness 17 5 Insomnia 11 9 Lightheadedness 10 3 Confusion 7 2 Memory impairment 4 2 Paresthesia 4 2 Vasodilatation b 4 2 Abnormal dreams 3 2 Concentration decreased 3 1 Ataxia 2 0 Incoordination 2 1 Psychomotor retardation 2 1 Tremor 2 1 Hypertonia 1 0 Libido decreased 1 < 1 Respiratory Pharyngitis 6 5 Cough increased 3 1 Special Senses Blurred vision 9 3 Abnormal vision c 7 1 Tinnitus 2 1 Taste perversion 2 1 Visual field defect 2 0 Urogenital Urinary frequency 2 1 Urinary tract infection 2 1 Urinary retention 2 1 Vaginitis d 2 1 Breast pain d 1 < 1 a Events reported by at least 1% of patients treated with nefazodone and more frequent than the placebo group are included; incidence is rounded to the nearest 1% (< 1% indicates an incidence less than 0.5%). Events for which the nefazodone incidence was equal to or less than placebo are not listed in the table, but included the following: abdominal pain, pain, back pain, accidental injury, chest pain, neck...

Warnings and Precautions

WARNINGS 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. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, 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. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1 . Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo < 18 14 additional cases 18 to 24 5 additional cases Decreases Compared to Placebo 25 to 64 1 fewer case ≥ 65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It 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 depression that the use of antidepressants can delay the...

Drug Interactions

Drug Interactions Drugs Highly Bound to Plasma Protein Because nefazodone is highly bound to plasma protein (see CLINICAL PHARMACOLOGY , Pharmacokinetics ), administration of nefazodone to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse events. Conversely, adverse effects could result from displacement of nefazodone by other highly bound drugs. Warfarin – There were no effects on the prothrombin or bleeding times or upon the pharmacokinetics of R-warfarin when nefazodone (200 mg BID) was administered for 1 week to subjects who had been pretreated for 2 weeks with warfarin. Although the coadministration of nefazodone did decrease the subjects’ exposure to S-warfarin by 12%, the lack of effects on the prothrombin and bleeding times indicates this modest change is not clinically significant. Although these results suggest no adjustments in warfarin dosage are required when nefazodone is administered to patients stabilized on warfarin, such patients should be monitored as required by standard medical practices. CNS-Active Drugs Monoamine Oxidase Inhibitors – See WARNINGS . Haloperidol – When a single oral 5 mg dose of haloperidol was coadministered with nefazodone (200 mg BID) at steady state, haloperidol apparent clearance decreased by 35% with no significant increase in peak haloperidol plasma concentrations or time of peak. This change is of unknown clinical significance. Pharmacodynamic effects of haloperidol were generally not altered significantly. There were no changes in the pharmacokinetic parameters for nefazodone. Dosage adjustment of haloperidol may be necessary when coadministered with nefazodone. Lorazepam – When lorazepam (2 mg BID) and nefazodone (200 mg BID) were coadministered to steady state, there was no change in any pharmacokinetic parameter for either drug compared to each drug administered alone. Therefore, dosage adjustment is not necessary for either drug when coadministered. Triazolam/Alprazolam – See CONTRAINDICATIONS and WARNINGS . Alcohol – Although nefazodone did not potentiate the cognitive and psychomotor effects of alcohol in experiments with normal subjects, the concomitant use of nefazodone and alcohol in depressed patients is not advised. Buspirone – In a study of steady-state pharmacokinetics in healthy volunteers, coadministration of buspirone (2.5 or 5 mg BID) with nefazodone (250 mg BID) resulted in marked increases in plasma buspirone concentrations (increases up to 20 fold in C max and up to 50 fold in AUC) and statistically significant decreases (about 50%) in plasma concentrations of the buspirone metabolite 1-pyrimidinylpiperazine. With 5 mg BID doses of buspirone, slight increases in AUC were observed for nefazodone (23%) and its metabolites hydroxynefazodone (17%) and mCPP (9%). Subjects receiving nefazodone 250 mg BID and buspirone 5 mg BID experienced lightheadedness, asthenia, dizziness, and...

Contraindications

CONTRAINDICATIONS Coadministration of terfenadine, astemizole, cisapride, pimozide, or carbamazepine with nefazodone hydrochloride is contraindicated (see WARNINGS and PRECAUTIONS ). Nefazodone hydrochloride tablets are contraindicated in patients who were withdrawn from nefazodone because of evidence of liver injury (see BOXED WARNING ). Nefazodone hydrochloride tablets are also contraindicated in patients who have demonstrated hypersensitivity to nefazodone hydrochloride, its inactive ingredients, or other phenylpiperazine antidepressants. The coadministration of triazolam and nefazodone causes a significant increase in the plasma level of triazolam (see WARNINGS and PRECAUTIONS ), and a 75% reduction in the initial triazolam dosage is recommended if the two drugs are to be given together. Because not all commercially available dosage forms of triazolam permit a sufficient dosage reduction, the coadministration of triazolam and nefazodone should be avoided for most patients, including the elderly.

Pregnancy and Breastfeeding

Pregnancy Teratogenic Effects Pregnancy category C Reproduction studies have been performed in pregnant rabbits and rats at daily doses up to 200 and 300 mg/kg, respectively (approximately 6 and 5 times, respectively, the maximum human daily dose on a mg/m 2 basis). No malformations were observed in the offspring as a result of nefazodone treatment. However, increased early pup mortality was seen in rats at a dose approximately five times the maximum human dose, and decreased pup weights were seen at this and lower doses, when dosing began during pregnancy and continued until weaning. The cause of these deaths is not known. The no-effect dose for rat pup mortality was 1.3 times the human dose on a mg/m 2 basis. There are no adequate and well-controlled studies in pregnant women. Nefazodone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers It is not known whether nefazodone or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when nefazodone is administered to a nursing woman.

Overdosage

OVERDOSAGE Human Experience In premarketing clinical studies, there were seven reports of nefazodone overdose alone or in combination with other pharmacological agents. The amount of nefazodone ingested ranged from 1000 mg to 11,200 mg. Commonly reported symptoms from overdose of nefazodone included nausea, vomiting, and somnolence. One nonstudy participant took 2000 to 3000 mg of nefazodone with methocarbamol and alcohol; this person reportedly experienced a convulsion (type not documented). None of these patients died. In postmarketing experience, overdose with nefazodone alone and in combination with alcohol and/or other substances has been reported. Commonly reported symptoms were similar to those reported from overdose in premarketing experience. While there have been rare reports of fatalities in patients taking overdoses of nefazodone, predominantly in combination with alcohol and/or other substances, no causal relationship to nefazodone has been established. Overdosage Management Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients. Activated charcoal should be administered. Due to the wide distribution of nefazodone in body tissues, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for nefazodone are known. In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control...

How Supplied

HOW SUPPLIED Nefazodone hydrochloride tablets USP, 50 mg, are light-pink to pink (mottled), capsule-shaped, beveled-edged tablets, debossed “7178” on one side and debossed “93” on the other side. They are available in bottles of 100 (NDC 0093-7178-01). Nefazodone hydrochloride tablets USP, 100 mg, are white to off-white, capsule-shaped tablets, debossed “1024” on one side and scored on the other side with a debossed “93” on one side of the score. They are available in bottles of 60 (NDC 0093-1024-06). Nefazodone hydrochloride tablets USP, 150 mg, are peach (mottled), capsule-shaped tablets, debossed “7113” on one side and scored on the other side with a debossed “93” on one side of the score. They are available in bottles of 60 (NDC 0093-7113-06). Nefazodone hydrochloride tablets USP, 200 mg, are light-yellow to yellow (mottled), capsule-shaped tablets, debossed “1025” on one side and debossed “93” on the other side. They are available in bottles of 60 (NDC 0093-1025-06). Nefazodone hydrochloride tablets USP, 250 mg, are white to off-white, capsule-shaped tablets, debossed “1026” on one side and debossed “93” on the other side. They are available in bottles of 60 (NDC 0093-1026-06). Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). Brands listed are the trademarks of their registered owners. Manufactured In Israel By: Teva Pharmaceutical Ind. Ltd. Kfar Saba, 4410202, Israel Manufactured For: Teva Pharmaceuticals Parsippany, NJ 07054 Rev. Q 7/2025

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.