Nefazodone

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 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.

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 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 pain, palpitation, migraine, sweating, flatulence, vomiting, anorexia, tooth disorder, weight gain, edema, myalgia, cramp, agitation, anxiety, depression, hypesthesia, CNS stimulation, dysphoria, emotional lability, sinusitis, rhinitis, dysmenorrhea d , dysuria. Vasodilatation – flushing, feeling warm. Abnormal vision – scotoma, visual trails. Incidence adjusted for gender. Dose Dependency of Adverse Events The table that follows enumerates adverse events that were more frequent in the nefazodone dose range of 300 to 600 mg/day than in the nefazodone dose range of up to 300 mg/day. This table shows only those adverse events for which there was a statistically significant difference (p ≤ 0.05) in incidence between the nefazodone dose ranges as well as a difference between the high dose range and placebo. Dose Dependency of Adverse Events in Placebo-Controlled Trials a Percent of Patients Body System Preferred Term Nefazodone 300 to 600 mg/day (n = 209) Nefazodone ≤ 300 mg/day (n = 211) Pla

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 1 week, there was an increased incidence of transient adverse events such as headache, lightheadedness, nausea, or paresthesia, possibly due to the elevated mCPP levels. Patients who are switched from fluoxetine to nefazodone without an adequate washout period may experience similar transient adverse events. The possibility of this happening can be minimized by allowing a washout period before initiating nefazodone therapy and by reducing the initial dose of nefazodone. Because of the long half-life of fluoxetine and its metabolites, this washout period may range from one to several weeks depending on the dose of fluoxetine and other individual patient variables. Phenytoin – Pretreatment for 7 days with 200 mg BID of nefazodone had no effect on the pharmacokinetics of a single 300 mg oral dose of phenytoin. However, due to the nonlinear pharmacokinetics of phenytoin, the failure to observe a significant effect on the single-dose pharmacokinetics of phenytoin does not preclude the poss