Nefazodone Hydrochloride 50 mg Tablet, 100-count — NDC 0093-7178-01 (Billing 00093-7178-01)

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 recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to chan… [Excerpted — this section continues on DailyMed.]

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 p… [Excerpted — this section continues on DailyMed.]

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 somnolence, adverse events also observed with either drug alone. If the two drugs are to be used in combination, a low dose of buspirone (e.g., 2.5 mg QD) is recommended. Subsequent dose adjustment of either drug should be based on clinical assessment.

Pimozide – See CONTRAINDICATIONS , WARNINGS , and PRECAUTIONS , Pharmacokinetics of Nefazodone in ‘Poor Metabolizers’ and Potential Interaction With Drugs That Inhibit and/or Are Metabolized by Cytochrome P450 Isozymes. Fluoxetine – When fluoxetine (20 mg QD) and nefazodone (200 mg BID) were administered at steady state there were no changes in the pharmacokinetic parameters for fluoxetine or its metabolite, norfluoxetine. Similarly, there were no changes in the pharmacokinetic parameters of nefazodone or HO-NEF; however, the mean AUC levels of the nefazodone metabolites mCPP and triazole-dione increased by 3 to 6 fold and 1.3 fold, respectively.

When a 200 mg dose of nefazodone was administered to subjects who had been receiving fluoxetine for… [Excerpted — this section continues on DailyMed.]

PRECAUTIONS General Hepatotoxicity (See BOXED WARNING .) Postural Hypotension A pooled analysis of the vital signs monitored during placebo-controlled premarketing studies revealed that 5.1% of nefazodone patients compared to 2.5% of placebo patients (p ≤ 0.01) met criteria for a potentially important decrease in blood pressure at some time during treatment (systolic blood pressure ≤ 90 mmHg and a change from baseline of ≥ 20 mmHg). While there was no difference in the proportion of nefazodone and placebo patients having adverse events characterized as ‘syncope’ (nefazodone, 0.2%; placebo, 0.3%), the rates for adverse events characterized as ‘postural hypotension’ were as follows: nefazodone (2.8%), tricyclic antidepressants (10.9%), SSRI (1.1%), and placebo (0.8%).

Thus, the prescriber should be aware that there is some risk of postural hypotension in association with nefazodone use. Nefazodone should be used with caution in patients with known cardiovascular or cerebrovascular disease that could be exacerbated by hypotension (history of myocardial infarction, angina, or ischemic stroke) and conditions that would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medication). Activation of Mania/Hypomania During premarketing testing, hypomania or mania occurred in 0.3% of nefazodone-treated unipolar patients, compared to 0.3% of tricyclic- and 0.4% of placebo-treated patients.

In patients classified as bipolar the rate of manic episodes was 1.6% for nefazodone, 5.1% for the combined tricyclic-treated groups, and 0% for placebo-treated patients. Activation of mania/hypomania is a known risk in a small proportion of patients with major affective disorder treated with other marketed antidepressants. As with all antidepressants, nefazodone should be used cautiously in patients with a history of mania.

Seizures During premarketing testing, a recurrence of a petit mal seizure was observed in a patient receiving nefazodone who had a history of such seizures. In addition, one nonstudy participant reportedly experienced a convulsion (type not documented) following a multiple-drug overdose (see OVERDOSAGE ). Rare occurrences of convulsions (including grand mal seizures) following nefazodone administration have been reported since market introduction.

A causal relationship to nefazodone has not been established (see ADVERSE REACTIONS ). Priapism While priapism did not occur during premarketing experience with nefazodone, rare reports of priapism have been received since market introduction. A causal relationship to nefazodone has not been established (see ADVERSE REACTIONS ).

If patients present with prolonged or inappropriate erections, they should discontinue therapy immediately and consult their physicians. If the condition persists for more than 24 hours, a urologist should be consulted to determine appropriate management. Use in Patients with Concomitant Illness Nefazodone has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease.

Patients with these diagnoses were systematically excluded from clinical studies during the product’s premarketing testing. Evaluation of electrocardiograms of 1153 patients who received nefazodone in 6 to 8 week, double-blind, placebo-controlled trials did not indicate that nefazodone is associated with the development of clinically important ECG abnormalities. However, sinus bradycardia, defined as heart rate ≤ 50 bpm and a decrease of at least 15 bpm from baseline, was observed in 1.5% of nefazodone-treated patients compared to 0.4% of placebo-treated patients (p ≤ 0.05).

Because patients with a recent history of myocardial infarction or unstable heart disease were excluded from clinical trials, such patients should be treated with caution. In patients with cirrhosis of the liver, AUC values of nefazodone and HO-NEF were increased by approximately 25%. Information for Patie… [Excerpted — this section continues on DailyMed.]

DRUG ABUSE AND DEPENDENCE Controlled Substance Class Nefazodone is not a controlled substance. Physical and Psychological Dependence In animal studies, nefazodone did not act as a reinforcer for intravenous self-administration in monkeys trained to self-administer cocaine, suggesting no abuse liability. In a controlled study of abuse liability in human subjects, nefazodone showed no potential for abuse.

Nefazodone has not been systematically studied in humans for its potential for tolerance, physical dependence, or withdrawal. While the premarketing clinical experience with nefazodone did not reveal any tendency for a withdrawal syndrome or any drug-seeking behavior, it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of nefazodone (e.g., development of tolerance, dose escalation, drug-seeking behavior).

Controlled Substance Class Nefazodone is not a controlled substance.