nefazodone hydrochloride 150 MG Oral Tablet

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.

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 changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for nefazodone hydrochloride tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that nefazodone hydrochloride tablets are not approved for use in treating bipolar depression. Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including nefazodone hydrochloride tablets may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Hepatotoxicity (See BOXED 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 treatment. This represents a rate of about 3 to 4 times the estimated background rate of liver failure. This rate is an underestimate because of under reporting, and the true risk could be considerably greater than this. A large cohort study of antidepressant users found no cases of liver failure leading to death or transplant among nefazodone users in about 30,000 patient-years of exposure. The spontaneous report data and the cohort study results provide estimates of the upper and lower limits of the risk of liver failure in nefazodone-treated patients, but are not capable of providing a precise risk estimate. The time to liver injury for the reported liver failure cases resulting in death or transplant generally ranged from 2 weeks to 6 months on nefazodone therapy. Although some reports described dark urine and nonspecific prodromal symptoms (e.g., anorexia, malaise, and gastrointestinal symptoms), other reports did not describe the onset of clear prodromal symptoms prior to the onset of jaundice. The physician may consider the value of liver function testing. Periodic serum transaminase testing has not been proven to prevent serious injury but it is generally believed that early detection of drug-induced hepatic injury along with immediate withdrawal of the suspect drug enhances the likelihood for recovery. Patients should be advised to be alert for signs and symptoms of liver dysfunction (jaundice, anorexia, gastrointestinal complaints, malaise, etc.)

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.

CLINICAL PHARMACOLOGY Pharmacodynamics The mechanism of action of nefazodone, as with other antidepressants, is unknown. Preclinical studies have shown that nefazodone inhibits neuronal uptake of serotonin and norepinephrine. Nefazodone occupies central 5-HT 2 receptors at nanomolar concentrations, and acts as an antagonist at this receptor. Nefazodone was shown to antagonize alpha 1 -adrenergic receptors, a property which may be associated with postural hypotension. In vitro binding studies showed that nefazodone had no significant affinity for the following receptors: alpha 2 and beta adrenergic, 5-HT 1A , cholinergic, dopaminergic, or benzodiazepine. 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. Clinical Efficacy Trial Results Studies in Outpatients with Depression During its premarketing development, the efficacy of nefazodone was evaluated at doses within the therapeutic range in five well-controlled, short-term (6 to 8 weeks) clinical investigations. These trials enrolled outpatients meeting DSM-III or DSM-IIIR criteria for major depression. Among these trials, two demonstrated the effectiveness of nefazodone, and two provided additional support for that conclusion. One trial was a 6 week dose-titration study comparing nefazodone in two dose ranges (up to 300 mg/day and up to 600 mg/day [mean modal dose for this group was about 400 mg/day], on a BID schedule) and placebo. The second trial was an 8 week dose-titration study comparing nefazodone (up to 600 mg/day; mean modal dose was 375 mg/day), imipramine (up to 300 mg/day), and placebo, all on a BID schedule. Both studies demonstrated nefazodone, at doses titrated between 300 mg to 600 mg/day (therapeutic dose range), to be superior to placebo on at least three of the following four measures: 17 Item Hamilton Depression Rating Scale or HDRS (total score), Hamilton Depressed Mood item, Clinical Global Impressions (CGI) Severity score, and CGI Improvement score. Significant differences were also found for certain factors of the HDRS (e.g., anxiety factor, sleep disturbance factor, and retardation factor). In the two supportive studies, nefazodone was titrated up to 500 or 600 mg/day (mean modal doses of 462 mg/day and 363 mg/day). In the fifth study, the differentiation in response rates between nefazodone and placebo was not statistically significant. Three additional trials were conducted using subtherapeutic doses of nefazodone. Overall, approximately two thirds of patients in these trials were women, and an analysis of the effects of gender on outcome did not suggest any differential responsiveness on the basis of sex. There were too few elderly patients in these trials to reveal possible age-related differences in response. Since its initial marketing as an antidepressant drug product, additional clinical investigations of nefazodone have been conducted. These studies explored nefazodone’s use under conditions not evaluated fully at the time initial marketing approval was granted