Nefazodone Hydrochloride

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) Placebo (n = 212) Gastrointestinal Nausea 23 14 12 Constipation 17 10 9 Nervous Somnolence 28 16 13 Dizziness 22 11 4 Confusion 8 2 1 Special Senses Abnormal Vision 10 0 2 Blurred Vision 9 3 2 Tinnitus 3 0 1 a. Events for which there was a statistically significant difference (p ≤ 0.05) between the nefazodone dose groups. Visual Disturbances In controlled clinical trials, blurred vision occurred in 9% of nefazodone-treated patients compared to 3% of placebo-treated patients. In these same trials abnormal vision, including scotomata and visual trails, occurred in 7% of nefazodone-treated patients compared to 1% of placebo-treated (see Treatment-Emergent Adverse Experience table, above). Dose-dependency was observed for these events in these trials, with none of the scotomata and visual trails at doses below 300 mg/day. However, scotomata and visual trails observed at doses below 300 mg/day have been reported in postmarketing experience with nefazodone (see PRECAUTIONS , Information for Patients ). Vital Sign Changes (See PRECAUTIONS , Postural Hypotension .) Weight Changes In a pooled analysis of placebo-controlled premarketing studies, there were no differences between nefazodone and placebo groups in the proportions of patients meeting criteria for potentially important increases or decreases in body weight (a change of ≥ 7%). Laboratory Changes Of the serum chemistry, serum hematology, and urinalysis parameters monitored during placebo-controlled premarketing studies with nefazodone, a pooled analysis revealed a statistical trend between nefazodone and placebo for hematocrit, i.e., 2.8% of nefazodone patients met criteria for a potentially important decrease in hematocrit (≤ 37% male or ≤ 32% female) compared to 1.5% of placebo patients (0.05 < p ≤ 0.10). Decreases in hematocrit, presumably dilutional, have been reported with many other drugs that block alpha 1 -adrenergic receptors. There was no apparent clinical significance of the observed changes in the few patients meeting these criteria. ECG Changes Of the ECG parameters monitored during placebo-controlled premarketing studies with nefazodone, a pooled analysis revealed a statistically significant difference between nefazodone and placebo for sinus bradycardia, i.e., 1.5% of nefazodone patients met criteria for a potentially important decrease in heart rate (≤ 50 bpm and a decrease of ≥ 15 bpm) compared to 0.4% of placebo patients (p < 0.05). There was no obvious clinical significance of the observed changes in the few patients meeting these criteria. Other Events Observed During the Premarketing Evaluation of Nefazodone During its premarketing assessment, multiple doses of nefazodone were administered to 3496 patients in clinical studies, including more than 250 patients treated for at least one year. The conditions and duration of exposure to nefazodone varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, fixed-dose and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. In the tabulations that follow, reported adverse events were classified using standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 3496 patients exposed to multiple doses of nefazodone who experienced an event of the type cited on at least one occasion while receiving nefazodone. All reported events are included except those already listed in the Treatment-Emergent Adverse Experience Incidence table, those events listed in other safety-related sections of this insert, those adverse experiences subsumed under COSTART terms that are either overly general or excessively specific so as to be uninformative, those events for which a drug cause was very remote, and those events which were not serious and occurred in fewer than two patients. It is important to emphasize that, although the events reported occurred during treatment with nefazodone, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Body as a whole – Infrequent: allergic reaction, malaise, photosensitivity reaction, face edema, hangover effect, abdomen enlarged, hernia, pelvic pain, and halitosis. Rare: cellulitis. Cardiovascular system – Infrequent: tachycardia, hypertension, syncope, ventricular extrasystoles, and angina pectoris. Rare: AV block, congestive heart failure, hemorrhage, pallor, and varicose vein. Dermatological system – Infrequent: dry skin, acne, alopecia, urticaria, maculopapular rash, vesiculobullous rash, and eczema. Gastrointestinal system – Frequent: gastroenteritis. Infrequent: eructation, periodontal abscess, abnormal liver function tests, gingivitis, colitis, gastritis, mouth ulceration, stomatitis, esophagitis, peptic ulcer, and rectal hemorrhage. Rare: glossitis, hepatitis, dysphagia, gastrointestinal hemorrhage, oral moniliasis, and ulcerative colitis. Hemic and lymphatic system – Infrequent: ecchymosis, anemia, leukopenia, and lymphadenopathy . Metabolic and nutritional system – Infrequent: weight loss, gout, dehydration, lactic dehydrogenase increased, SGOT increased, and SGPT increased. Rare: hypercholesteremia and hypoglycemia. Musculoskeletal system – Infrequent: arthritis, tenosynovitis, muscle stiffness, and bursitis. Rare: tendinous contracture. Nervous system – Infrequent: vertigo, twitching, depersonalization, hallucinations, suicide attempt, apathy, euphoria, hostility, suicidal thoughts, abnormal gait, thinking abnormal, attention decreased, derealization, neuralgia, paranoid reaction, dysarthria, increased libido, suicide, and myoclonus. Rare: hyperkinesia, increased salivation, cerebrovascular accident, hyperesthesia, hypotonia, ptosis, and neuroleptic malignant syndrome. Respiratory system – Frequent: dyspnea and bronchitis. Infrequent: asthma, pneumonia, laryngitis, voice alteration, epistaxis, hiccup. Rare: hyperventilation and yawn. Special senses – Frequent: eye pain. Infrequent: dry eye, ear pain, abnormality of accommodation, diplopia, conjunctivitis, mydriasis, keratoconjunctivitis, hyperacusis, and photophobia. Rare: deafness, angle-closure glaucoma, night blindness, and taste loss. Urogenital system – Frequent: impotence a . Infrequent: cystitis, urinary urgency, metrorrhagia a , amenorrhea a , polyuria, vaginal hemorrhage a , breast enlargement a , menorrhagia a , urinary incontinence, abnormal ejaculation a , hematuria, nocturia, and kidney calculus. Rare: uterine fibroids enlarged a , uterine hemorrhage a , anorgasmia, and oliguria. a Adjusted for gender. Postintroduction Clinical Experience Postmarketing experience with nefazodone has shown an adverse experience profile similar to that seen during the premarketing evaluation of nefazodone. Voluntary reports of adverse events temporally associated with nefazodone have been received since market introduction that are not listed above and for which a causal relationship has not been established. These include: Anaphylactic reactions; angioedema; convulsions (including grand mal seizures); galactorrhea; gynecomastia (male); hyponatremia; liver necrosis and liver failure, in some cases leading to liver transplantation and/or death (see WARNINGS ); priapism (see PRECAUTIONS ); prolactin increased; rhabdomyolysis involving patients receiving the combination of nefazodone and lovastatin or simvastatin (see PRECAUTIONS ); serotonin syndrome; and Stevens-Johnson syndrome; and thrombocytopenia. To report SUSPECTED ADVERSE EVENTS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch for voluntary reporting of adverse reactions.

Pharmacokinetics Nefazodone is rapidly and completely absorbed but is subject to extensive metabolism, so that its absolute bioavailability is low, about 20%, and variable. Peak plasma concentrations occur at about one hour and the half-life of nefazodone is 2 to 4 hours. Both nefazodone and its pharmacologically similar metabolite, hydroxynefazodone, exhibit nonlinear kinetics for both dose and time, with AUC and C max increasing more than proportionally with dose increases and more than expected upon multiple dosing over time, compared to single dosing. For example, in a multiple-dose study involving BID dosing with 50, 100, and 200 mg, the AUC for nefazodone and hydroxynefazodone increased by about 4 fold with an increase in dose from 200 to 400 mg per day; C max increased by about 3 fold with the same dose increase. In a multiple-dose study involving BID dosing with 25, 50, 100, and 150 mg, the accumulation ratios for nefazodone and hydroxynefazodone AUC, after 5 days of BID dosing relative to the first dose, ranged from approximately 3 to 4 at the lower doses (50 to 100 mg/day) and from 5 to 7 at the higher doses (200 to 300 mg/day); there were also approximately 2 to 4 fold increases in C max after 5 days of BID dosing relative to the first dose, suggesting extensive and greater than predicted accumulation of nefazodone and its hydroxy metabolite with multiple dosing. Steady-state plasma nefazodone and metabolite concentrations are attained within 4 to 5 days of initiation of BID dosing or upon dose increase or decrease. Nefazodone is extensively metabolized after oral administration by n-dealkylation and aliphatic and aromatic hydroxylation, and less than 1% of administered nefazodone is excreted unchanged in urine. Attempts to characterize three metabolites identified in plasma, hydroxynefazodone (HO-NEF), meta-chlorophenylpiperazine (mCPP), and a triazole-dione metabolite, have been carried out. The AUC (expressed as a multiple of the AUC for nefazodone dosed at 100 mg BID) and elimination half-lives for these three metabolites were as follows: AUC Multiples and T 1/2 for Three Metabolites of Nefazodone (100 mg BID) Metabolite AUC Multiple T 1/2 HO-NEF 0.4 1.5 to 4 h mCPP 0.07 4 to 8 h Triazole-dione 4.0 18 h HO-NEF possesses a pharmacological profile qualitatively and quantitatively similar to that of nefazodone. mCPP has some similarities to nefazodone, but also has agonist activity at some serotonergic receptor subtypes. The pharmacological profile of the triazole-dione metabolite has not yet been well characterized. In addition to the above compounds, several other metabolites were present in plasma but have not been tested for pharmacological activity. After oral administration of radiolabeled nefazodone, the mean half-life of total label ranged between 11 and 24 hours. Approximately 55% of the administered radioactivity was detected in urine and about 20 to 30% in feces. Distribution Nefazodone is widely distributed in body tissues, including the central nervous system (CNS). In humans the volume of distribution of nefazodone ranges from 0.22 to 0.87 L/kg. Protein Binding At concentrations of 25 to 2500 ng/mL nefazodone is extensively (> 99%) bound to human plasma proteins in vitro . The administration of 200 mg BID of nefazodone for 1 week did not increase the fraction of unbound warfarin in subjects whose prothrombin times had been prolonged by warfarin therapy to 120 to 150% of the laboratory control (see PRECAUTIONS , Drug Interactions ). While nefazodone did not alter the in vitro protein binding of chlorpromazine, desipramine, diazepam, diphenylhydantoin, lidocaine, prazosin, propranolol, or verapamil, it is unknown whether displacement of either nefazodone or these drugs occurs in vivo . There was a 5% decrease in the protein binding of haloperidol; this is probably of no clinical significance. Effect of Food Food delays the absorption of nefazodone and decreases the bioavailability of nefazodone by approximately 20%. Renal Disease In studies involving 29 renally impaired patients, renal impairment (creatinine clearances ranging from 7 to 60 mL/min/1.73 m 2 ) had no effect on steady-state nefazodone plasma concentrations. Liver Disease In a multiple-dose study of patients with liver cirrhosis, the AUC values for nefazodone and HO-NEF at steady state were approximately 25% greater than those observed in normal volunteers. Age/Gender Effects After single doses of 300 mg to younger (18 to 45 years) and older patients (> 65 years), C max and AUC for nefazodone and hydroxynefazodone were up to twice as high in the older patients. With multiple doses, however, differences were much smaller, 10 to 20%. A similar result was seen for gender, with a higher C max and AUC in women after single doses but no difference after multiple doses. Treatment with nefazodone should be initiated at half the usual dose in elderly patients, especially women (see DOSAGE AND ADMINISTRATION ), but the therapeutic dose range is similar in younger and older patients.