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Hepatotoxicity (See BOXED WARNING.)
Cases of life-threatening hepatic failure have been reported in patients treated with SERZONE (nefazodone) .
The reported rate in the United States is about 1 case of liver failure resulting in death or transplant per 250,000 -300,000 patient-years of SERZONE (nefazodone) treatment. This represents a rate of about 3-4 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 SERZONE (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 SERZONE (nefazodone) therapy. Although some reports described dark urine and nonspecific prodromal symptoms (eg, 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, gastroin-testinal 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.
SERZONE (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as increased serum AST or serum ALT levels ≥3 times the upper limit of NORMAL, while on SERZONE (nefazodone) should be withdrawn from the drug. These patients should be presumed to be at increased risk for liver injury if SERZONE (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.
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. There has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients. Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in shortterm studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders.
Pooled analyses of short-term, placebo-controlled trials of nine antidepressant drugs (SSRIs and others) in children and adolescents with MDD, OCD, or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal behavior or thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. There was considerable variation in risk among drugs, but a tendency toward an increase for almost all drugs studied. The risk of suicidality was most consistently observed in the MDD trials, but there were signals of risk arising from some trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in any of these trials. It is unknown whether the suicidality risk in pediatric patients extends to longer-term use, ie, beyond several months. It is also unknown whether the suicidality risk extends to adults.
All pediatric patients being treated with antidepressants for any indication should be 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. Such observation would generally include at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits.
Adults with MDD or co-morbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed similarly for clinical worsening and suicidality, 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 pediatric 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 SERZONE (nefazodone) should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Families and caregivers of adults being treated for depression should be similarly advised.
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 SERZONE (nefazodone) is not approved for use in treating bipolar depression.
Interaction with Triazolobenzodiazepines
Interaction studies of nefazodone with two triazolobenzodiazepines, ie, 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.
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 SERZONE (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 SERZONE (nefazodone) should be avoided for most patients, including the elderly. In the exceptional case where coadministration of triazolam with SERZONE (nefazodone) may be considered appropriate, only the lowest possible dose of triazolam should be used (see CONTRAINDICATIONS and PRECAUTIONS).
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 SERZONE (nefazodone) , a 50% reduction in the initial alprazolam dosage is recommended. No dosage adjustment is required for SERZONE (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 torsades 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 SERZONE (nefazodone) . Consequently, it is recommended that SERZONE (nefazodone) not be used in combination with carbamazepine (see CONTRAINDICATIONS and PRECAUTIONS).
Hepatotoxicity (See BOXED WARNING.)
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. SERZONE (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, SERZONE (nefazodone hydrochloride) should be used cautiously in patients with a history of mania.
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).
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
SERZONE (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 products 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, the AUC values of nefazodone and HO-NEF were increased by approximately 25%.
INFORMATION FOR PATIENTS
(See Patient Information.)
Patients should be informed that SERZONE (nefazodone) therapy has been associated with liver abnormalities ranging from asymptomatic reversible serum transaminase increases to cases of liver failure resulting in transplant and/or death. At present, there is no way to predict who is likely to develop liver failure. Ordinarily, patients with active liver disease should not be treated with SERZONE (nefazodone) . Patients should be advised to be alert for signs of liver dysfunction (jaundice, anorexia, gastrointestinal complaints, malaise, etc) and to report them to their doctor immediately if they occur.
Patients and their families should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, mania, worsening of depression, and suicidal ideation, especially early during antidepressant treatment. Such symptoms should be reported to the patients physician, especially if they are severe, abrupt in onset, or were not part of the patients presenting symptoms.
Time to Response/Continuation
As with all antidepressants, several weeks on treatment may be required to obtain the full antidepressant effect. Once improvement is noted, it is important for patients to continue drug treatment as directed by their physician.
Interference With Cognitive and Motor Performance
Since any psychoactive drug may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that SERZONE (nefazodone) therapy does not adversely affect their ability to engage in such activities.
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.
Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions. Significant caution is indicated if SERZONE (nefazodone) is to be used in combination with XANAX®, concomitant use with HALCION® should be avoided for most patients including the elderly, and concomitant use with SELDANE®, HISMANAL®, PROPULSID®, ORAP®, or TEGRETOL® is contraindicated (see CONTRAINDICATIONS and WARNINGS).
Patients should be advised to avoid alcohol while taking SERZONE (nefazodone hydrochloride).
There have been reports of visual disturbances associated with the use of nefazodone, including blurred vision, scotoma, and visual trails. Patients should be advised to notify their physician if they develop visual disturbances.(See ADVERSE REACTIONS.)
There are no specific laboratory tests recommended.
Carcinogenesis, Mutagenesis, Impairment of Fertility
There is no evidence of carcinogenicity with nefazodone. The dietary administration of nefazodone to rats and mice for 2 years at daily doses of up to 200 mg/kg and 800 mg/kg,respectively, which are approximately 3 and 6 times, respectively, the maximum human daily dose on a mg/m2 basis, produced no increase in tumors.
Nefazodone has been shown to have no genotoxic effects based on the following assays: bacterial mutation assays, a DNA repair assay in cultured rat hepatocytes, a mammalian mutation assay in Chinese hamster ovary cells, anin vivo cytoge-netics assay in rat bone marrow cells, and a rat dominant lethal study.
Impairment of Fertility
A fertility study in rats showed a slight decrease in fertility at 200 mg/kg/day (approximately three times the maximum human daily dose on a mg/m2 basis) but not at 100 mg/kg/day (approximately 1.5 times the maximum human daily dose on a mg/m2 basis).
Teratogenic Effects - Pregnancy Category C
Reproduction studies have been performed in pregnant rabbits and rats at daily doses up to 200 and 300 mg/kg, respectively (approximately 6 and 5 times, respectively, the maximum human daily dose on a mg/m2 basis). No malformations were observed in the offspring as a result of nefazodone treatment. However, increased early pup mortality was seen in rats at a dose approximately five times the maximum human dose, and decreased pup weights were seen at this and lower doses, when dosing began during pregnancy and continued until weaning. The cause of these deaths is not known. The no-effect dose for rat pup mortality was 1.3 times the human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women. Nefazodone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery
The effect of SERZONE (nefazodone hydrochloride) on labor and delivery in humans is unknown.
It is not known whether SERZONE (nefazodone) or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when SERZONE (nefazodone) is administered to a nursing woman.
Safety and effectiveness in the pediatric population have not been established (see BOXED WARNING and WARNINGS: Clinical Worsening and Suicide Risk). Two placebo-controlled trials in 286 pediatric patients with MDD have been conducted with SERZONE (nefazodone) , and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of SERZONE (nefazodone) in a child or adolescent must balance the potential risks with the clinical need.
Of the approximately 7000 patients in clinical studies who received SERZONE (nefazodone) for the treatment of depression, 18% were 65 years and older, while 5% were 75 years and older. Based on monitoring of adverse events, vital signs, electrocardiograms, and results of laboratory tests, no overall differences in safety between elderly and younger patients were observed in clinical studies. Efficacy in the elderly has not been demonstrated in placebo-controlled trials. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Due to the increased systemic exposure to nefazodone seen in single-dose studies in elderly patients (see CLINICAL PHARMACOLOGY: Pharmacokinetics), treatment should be initiated at half the usual dose, but titration upward should take place over the same range as in younger patients (see DOSAGE AND ADMINISTRATION). The usual precautions should be observed in elderly patients who have concomitant medical illnesses or who are receiving concomitant drugs.
Last reviewed on RxList: 5/13/2008
This monograph has been modified to include the generic and brand name in many instances.
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