FDA label 3c536fc0-9e01-3c62-e054-00144ff8d46c

BOXED WARNING Suicidality and Antidepressant Drugs Before prescribing nefazodone hydrochloride tablets, the physician should be thoroughly familiar with the details of this prescribing information. 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serum AST or serum ALT levels3 times the upper limit of NORMAL, while on nefazodone hydrochloride tablets should be withdrawn from the drug.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.

WARNINGS Clinical Worsening and Suicide Risk 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 Table1. Table 1 Age RangeDrug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients TreatedIncreases Compared to Placebo< 1814 additional cases18 to 245 additional casesDecreases Compared to Placebo25 to 641 fewer case656 fewer casesNo 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 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.) and to report them to their doctor immediately if they occur. Ongoing clinical assessment of patients should govern physician interventions, including diagnostic evaluations and treatment. Nefazodone 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 levels3 times the upper limit of NORMAL, while on nefazodone should be withdrawn from the drug. These patients should be presumed to be at increased risk for liver injury if nefazodone is reintroduced. Accordingly, such patients should not be considered for re-treatment. Potential for Interaction With Monoamine Oxidase Inhibitors In patients receiving antidepressants with pharmacological properties similar to nefazodone in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions. For a selective serotonin reuptake inhibitor (SSRI), these reactions have included hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued that drug and have been started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Severe hyperthermia and seizures, sometimes fatal, have been reported in association with the combined use of tricyclic antidepressants and MAOIs. These reactions have also been reported in patients who have recently discontinued these drugs and have been started on an MAOI. Although the effects of combined use of nefazodone and MAOI have not been evaluated in humans or animals, because nefazodone is an inhibitor of both serotonin and norepinephrine reuptake, it is recommended that nefazodone not be used in combination with an MAOI, or within 14 days of discontinuing treatment with an MAOI. At least 1 week should be allowed after stopping nefazodone before starting an MAOI. Interaction With Triazolobenzodiazepines Interaction studies of nefazodone with two triazolobenzodiazepines, i.e., triazolam and alprazolam, metabolized by cytochrome P450 3A4, have revealed substantial and clinically important increases in plasma concentrations of these compounds when administered concomitantly with nefazodone. Triazolam When a single oral 0.25 mg dose of triazolam was coadministered with nefazodone (200 mg BID) at steady state, triazolam half-life and AUC increased 4 fold and peak concentrations increased 1.7 fold. Nefazodone plasma concentrations were unaffected by triazolam. Coadministration of nefazodone potentiated the effects of triazolam on psychomotor performance tests. If triazolam is coadministered with nefazodone, a 75% reduction in the initial triazolam dosage is recommended. Because not all commercially available dosage forms of triazolam permit sufficient dosage reduction, coadministration of triazolam with nefazodone should be avoided for most patients, including the elderly. In the exceptional case where coadministration of triazolam with nefazodone may be considered appropriate, only the lowest possible dose of triazolam should be used (see CONTRAINDICATIONS and PRECAUTIONS). Alprazolam When alprazolam (1 mg BID) and nefazodone (200 mg BID) were coadministered, steady-state peak concentrations, AUC and half-life values for alprazolam increased by approximately 2 fold. Nefazodone plasma concentrations were unaffected by alprazolam. If alprazolam is coadministered with nefazodone, a 50% reduction in the initial alprazolam dosage is recommended. No dosage adjustment is required for nefazodone. Potential Terfenadine, Astemizole, Cisapride, and Pimozide Interactions Terfenadine, astemizole, cisapride, and pimozide are all metabolized by the cytochrome P450 3A4 (CYP3A4) isozyme, and it has been demonstrated that ketoconazole, erythromycin, and other inhibitors of CYP3A4 can block the metabolism of these drugs, which can result in increased plasma concentrations of parent drug. Increased plasma concentrations of terfenadine, astemizole, cisapride, and pimozide are associated with QT prolongation and with rare cases of serious cardiovascular adverse events, including death, due principally to ventricular tachycardia of the torsade de pointes type. Nefazodone has been shown in vitro to be an inhibitor of CYP3A4. Consequently, it is recommended that nefazodone not be used in combination with either terfenadine, astemizole, cisapride, or pimozide (see CONTRAINDICATIONS and PRECAUTIONS). Interaction With Carbamazepine The coadministration of carbamazepine 200 mg BID with nefazodone 200 mg BID, at steady state for both drugs, resulted in almost 95% reductions in AUCs for nefazodone and hydroxynefazodone, likely resulting in insufficient plasma nefazodone and hydroxynefazodone concentrations for achieving an antidepressant effect for nefazodone. Consequently, it is recommended that nefazodone not be used in combination with carbamazepine (see CONTRAINDICATIONS and PRECAUTIONS).

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, p0.05), 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 Trials1, Nefazodone 300 to 600 mg/day Dose Range Percent of PatientsBody SystemPreferred TermNefazodone (n = 393)Placebo (n = 394)Body as a WholeHeadache3633Asthenia115Infection86Flu syndrome32Chills21Fever21Neck rigidity10CardiovascularPostural hypotension41Hypotension21DermatologicalPruritus21Rash21GastrointestinalDry mouth2513Nausea2212Constipation148Dyspepsia97Diarrhea87Increased appetite53Nausea & vomiting21MetabolicPeripheral edema32Thirst1< 1MusculoskeletalArthralgia1< 1NervousSomnolence2514Dizziness175Insomnia119Lightheadedness103Confusion72Memory impairment42Paresthesia42Vasodilatation242Abnormal dreams32Concentration decreased31Ataxia20Incoordination21Psychomotor retardation21Tremor21Hypertonia10Libido decreased1< 1RespiratoryPharyngitis65Cough increased31Special SensesBlurred vision93Abnormal vision371Tinnitus21Taste perversion21Visual field defect20UrogenitalUrinary frequency21Urinary tract infection21Urinary retention21Vaginitis421Breast pain41< 1 2 Vasodilatationflushing, feeling warm. 3 Abnormal visionscotoma, visual trails. 4 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 (p0.05) 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 * * Events for which there was a statistically significant difference (p0.05) between the nefazodone dose groups.Percent of PatientsBody SystemPreferred TermNefazodone 300 to 600 mg/day (n = 209)Nefazodone300 mg/day (n = 211)Placebo (n = 212)GastrointestinalNausea231412Constipation17109NervousSomnolence281613Dizziness22114Confusion821Special SensesAbnormal Vision1002Blurred Vision932Tinnitus301 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 of7%). 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 or32% female) compared to 1.5% of placebo patients (0.05 < p0.10). Decreases in hematocrit, presumably dilutional, have been reported with many other drugs that block alpha1-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 of15 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. Body as a wholeInfrequent: allergic reaction, malaise, photosensitivity reaction, face edema, hangover effect, abdomen enlarged, hernia, pelvic pain, and halitosis. Rare: cellulitis. Cardiovascular systemInfrequent: tachycardia, hypertension, syncope, ventricular extrasystoles, and angina pectoris. Rare: AV block, congestive heart failure, hemorrhage, pallor, and varicose vein. Dermatological systemInfrequent: dry skin, acne, alopecia, urticaria, maculopapular rash, vesiculobullous rash, and eczema. Gastrointestinal systemFrequent: 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 systemInfrequent: ecchymosis, anemia, leukopenia, and lymphadenopathy . Metabolic and nutritional systemInfrequent: weight loss, gout, dehydration, lactic dehydrogenase increased, SGOT increased, and SGPT increased. Rare: hypercholesteremia and hypoglycemia. Musculoskeletal systemInfrequent: arthritis, tenosynovitis, muscle stiffness, and bursitis. Rare: tendinous contracture. Nervous systemInfrequent: 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 systemFrequent: dyspnea and bronchitis. Infrequent: asthma, pneumonia, laryngitis, voice alteration, epistaxis, hiccup. Rare: hyperventilation and yawn. Special sensesFrequent: eye pain. Infrequent: dry eye, ear pain, abnormality of accommodation, diplopia, conjunctivitis, mydriasis, keratoconjunctivitis, hyperacusis, and photophobia. Rare: deafness, glaucoma, night blindness, and taste loss. Urogenital systemFrequent: impotencea. Infrequent: cystitis, urinary urgency, metrorrhagiaa, amenorrheaa, polyuria, vaginal hemorrhagea, breast enlargementa, menorrhagiaa, urinary incontinence, abnormal ejaculationa, hematuria, nocturia, and kidney calculus. Rare: uterine fibroids enlargeda, uterine hemorrhagea, 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: