Serzone® (nefazodone hydrochloride) is an antidepressant for oral administration with a chemical structure unrelated to selective serotonin reuptake inhibitors, tricyclics, tetracyclics, or monoamine oxidase inhibitors (MAOI).
Nefazodone hydrochloride is a synthetically derived phenylpiperazine antidepressant. The chemical name for nefazodone hydrochloride is 2 - [3 - [4 - (3 - chlorophenyl) - 1 - piperazinyl]propyl] - 5 - ethyl - 2,4 - dihydro - 4 - (2 - phenoxyethyl) - 3H - 1,2,4 - triazol - 3 - one monohydrochloride. The molecular formula is C25H32ClN5O2• HCl, which corresponds to a molecular weight of 506.5. The structural formula is:
Nefazodone hydrochloride is a nonhygroscopic, white crystalline solid. It is freely soluble in chloroform, soluble in propylene glycol, and slightly soluble in polyethylene glycol and water.
Serzone is supplied as hexagonal tablets containing 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg of nefazodone hydrochloride and the following inactive ingredients: microcrystalline cellulose, povidone, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate, and iron oxides (red and/or yellow) as colorants.
Serzone - 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-HT2 receptors at nanomolar concentrations, and acts as an antagonist at this receptor. Nefazodone was shown to antagonize alpha1-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: alpha2 and beta adrenergic, 5-HT1A, cholinergic, dopaminergic, or benzodiazepine.
Pharmacokinetics
Nefazodone hydrochloride 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 2–4 hours.
Both nefazodone and its pharmacologically similar metabolite, hydroxynefazodone, exhibit nonlinear kinetics for both dose and time, with AUC and Cmax 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; Cmax 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 (50–100 mg/day) and from 5 to 7 at the higher doses (200–300 mg/day); there were also approximately 2- to 4-fold increases in Cmax 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 T1/2 for Three Metabolites of Nefazodone (100 mg BID)
| Metabolite |
AUC Multiple |
T1/2 |
|---|
| HO-NEF |
0.4 |
1.5-4 h |
| mCPP |
0.07 |
4-8 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 radiolabelled 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 20–30% 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 25–2500 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 120-150% 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/1.73m2) 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 (18-45 years) and older patients (>65years), Cmax and AUC for nefazodone and hydroxynefazodone were up to twice as high in the older patients. With multiple doses, however, differences were much smaller, 10–20%. A similar result was seen for gender, with a higher Cmax and AUC in women after single doses but no difference after multiple doses.
Treatment with Serzone 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 Major Depressive DisorderDuring its premarketing development, the efficacy of Serzone was evaluated at doses within the therapeutic range in five well-controlled, short-term (6–8 weeks) clinical investigations. These trials enrolled outpatients meeting DSM-III or DSM-IIIR criteria for major depressive disorder. Among these trials, two demonstrated the effectiveness of Serzone, and two provided additional support for that conclusion.
One trial was a 6-week dose-titration study comparing Serzone 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 Serzone (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 Serzone, 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 (eg, anxiety factor, sleep disturbance factor, and retardation factor). In the two supportive studies, Serzone 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 Serzone and placebo was not statistically significant. Three additional trials were conducted using subtherapeutic doses of Serzone.
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 Serzone have been conducted. These studies explored Serzone’s use under conditions not evaluated fully at the time initial marketing approval was granted.
Studies in “Inpatients”Two studies were conducted to evaluate Serzone’s effectiveness in hospitalized patients with major depressive disorder. These were 6-week, dose-titration trials comparing Serzone (up to 600 mg/day) and placebo, on a BID schedule. In one study, Serzone was superior to placebo. In this study, the mean modal dose of Serzone was 503 mg/day, and 85% of these inpatients were melancholic; at baseline, patients were distributed at the higher end of the 7-point CGI Severity scale, as follows: 4=moderately ill (17%); 5=markedly ill (48%); 6=severely ill (32%). In the other study, the differentiation in response rates between Serzone and placebo was not statistically significant. This result may be explained by the “high” rate of spontaneous improvement among the patients randomized to placebo.
Studies of “Relapse Prevention in Patients Recently Recovered (Clinically) from Major Depressive Disorder”Two studies were conducted to assess Serzone’s capacity to maintain a clinical remission in acutely depressed patients who were judged to have responded adequately (HDRS total score ≤10) after a 16-week period of open treatment with Serzone (titration up to 600 mg/day). In one study, Serzone was superior to placebo. In this study, patients (n=131) were randomized to continuation on Serzone or placebo for an additional 36 weeks (1 year total). This study demonstrated a significantly lower relapse rate (HDRS total score ≥18) for patients taking Serzone compared to those on placebo. The second study was of appropriate design and power, but the sample of patients admitted for evaluation did not suffer relapses at a high enough incidence to provide a meaningful test of Serzone’s efficacy for this use.
Comparisons of Clinical Trial ResultsHighly variable results have been seen in the clinical development of all antidepressant drugs. Furthermore, in those circumstances when the drugs have not been studied in the same controlled clinical trial(s), comparisons among the findings of studies evaluating the effectiveness of different antidepressant drug products are inherently unreliable. Because conditions of testing (eg, patient samples, investigators, doses of the treatments administered and compared, outcome measures, etc) vary among trials, it is virtually impossible to distinguish a difference in drug effect from a difference due to one or more of the confounding factors just enumerated.
Indications and Usage for Serzone
Serzone (nefazodone hydrochloride) is indicated for the treatment of major depressive disorder. When deciding among the alternative treatments available for this condition, the prescriber should consider the risk of hepatic failure associated with Serzone treatment (see WARNINGS). In many cases, this would lead to the conclusion that other drugs should be tried first.
The efficacy of Serzone in the treatment of major depressive disorder was established in 6–8 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 Serzone in reducing relapse in patients with major depressive disorder who were judged to have had a satisfactory clinical response to 16 weeks of open-label Serzone 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 (ie, 52 weeks total), the physician who elects to use Serzone for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.
Contraindications
Coadministration of terfenadine, astemizole, cisapride, pimozide, or carbamazepine with Serzone (nefazodone hydrochloride) is contraindicated (see WARNINGS and PRECAUTIONS).
Serzone tablets are contraindicated in patients who were withdrawn from Serzone because of evidence of liver injury (see BOXED WARNING). Serzone 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 Serzone should be avoided for most patients, including the elderly.
Warnings
Hepatotoxicity (See BOXED WARNING.)
Cases of life-threatening hepatic failure have been reported in patients treated with Serzone.
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 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 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 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, 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.
Serzone 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 should be withdrawn from the drug. These patients should be presumed to be at increased risk for liver injury if Serzone 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 short-term 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 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 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.
TriazolamWhen 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, 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 should be avoided for most patients, including the elderly. In the exceptional case where coadministration of triazolam with Serzone may be considered appropriate, only the lowest possible dose of triazolam should be used (see CONTRAINDICATIONS and PRECAUTIONS).
AlprazolamWhen 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, a 50% reduction in the initial alprazolam dosage is recommended. No dosage adjustment is required for Serzone.
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 CarbamazepineThe 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. Consequently, it is recommended that Serzone not be used in combination with carbamazepine (see CONTRAINDICATIONS and PRECAUTIONS).
Precautions
General
Hepatotoxicity (See BOXED WARNING.) Postural Hypotension
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 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.
Seizures
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).
Priapism
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 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 product’s 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
Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Serzone and should counsel them in its appropriate use. A patient Medication Guide About Using Antidepressants in Children and Teenagers is available for Serzone. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Serzone.
Clinical Worsening and Suicide RiskPatients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, agressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
HepatotoxicityPatients should be informed that Serzone 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. 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.
SuicidePatients 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 patient’s physician, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
Time to Response/ContinuationAs 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 PerformanceSince 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 therapy does not adversely affect their ability to engage in such activities.
PregnancyPatients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.
NursingPatients should be advised to notify their physician if they are breast-feeding an infant (see PRECAUTIONS: Nursing Mothers).
Concomitant MedicationPatients 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 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).
AlcoholPatients should be advised to avoid alcohol while taking Serzone.
Allergic ReactionsPatients should be advised to notify their physician if they develop a rash, hives, or a related allergic phenomenon.
Visual DisturbancesThere 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.)
Laboratory Tests
There are no specific laboratory tests recommended.
Drug Interactions
Drugs Highly Bound to Plasma ProteinBecause nefazodone is highly bound to plasma protein (see CLINICAL PHARMACOLOGY: Pharmacokinetics), administration of Serzone to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse events. Conversely, adverse effects could result from displacement of nefazodone by other highly bound drugs.
Warfarin—There were no effects on the prothrombin or bleeding times or upon the pharmacokinetics of R-warfarin when nefazodone (200 mg BID) was administered for 1 week to subjects who had been pretreated for 2 weeks with warfarin. Although the coadministration of nefazodone did decrease the subjects’ exposure to S-warfarin by 12%, the lack of effects on the prothrombin and bleeding times indicates this modest change is not clinically significant. Although these results suggest no adjustments in warfarin dosage are required when nefazodone is administered to patients stabilized on warfarin, such patients should be monitored as required by standard medical practices.
CNS-Active DrugsMonoamine Oxidase Inhibitors—See WARNINGS.
Haloperidol—When a single oral 5-mg dose of haloperidol was coadministered with nefazodone (200 mg BID) at steady state, haloperidol apparent clearance decreased by 35% with no significant increase in peak haloperidol plasma concentrations or time of peak. This change is of unknown clinical significance. Pharmacodynamic effects of haloperidol were generally not altered significantly. There were no changes in the pharmacokinetic parameters for nefazodone. Dosage adjustment of haloperidol may be necessary when coadministered with nefazodone.
Lorazepam—When lorazepam (2 mg BID) and nefazodone (200 mg BID) were coadministered to steady state, there was no change in any pharmacokinetic parameter for either drug compared to each drug administered alone. Therefore, dosage adjustment is not necessary for either drug when coadministered.
Triazolam/Alprazolam—See CONTRAINDICATIONS and WARNINGS.
Alcohol—Although nefazodone did not potentiate the cognitive and psychomotor effects of alcohol in experiments with normal subjects, the concomitant use of Serzone and alcohol in depressed patients is not advised.
Buspirone—In a study of steady-state pharmacokinetics in healthy volunteers, coadministration of buspirone (2.5 or 5 mg BID) with nefazodone (250 mg BID) resulted in marked increases in plasma buspirone concentrations (increases up to 20-fold in Cmax and up to 50-fold in AUC) and statistically significant decreases (about 50%) in plasma concentrations of the buspirone metabolite 1-pyrimidinylpiperazine. With 5-mg BID doses of buspirone, slight increases in AUC were observed for nefazodone (23%) and its metabolites hydroxynefazodone (17%) and mCPP (9%). Subjects receiving nefazodone 250 mg BID and buspirone 5 mg BID experienced lightheadedness, asthenia, dizziness, and somnolence, adverse events also observed with either drug alone. If the two drugs are to be used in combination, a low dose of buspirone (eg, 2.5 mg QD) is recommended. Subsequent dose adjustment of either drug should be based on clinical assessment.
Pimozide—See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Pharmacokinetics of Nefazodone in ‘Poor Metabolizers’ and Potential Interaction with Drugs that Inhibit and/or Are Metabolized by Cytochrome P450 Isozymes.
Fluoxetine—When fluoxetine (20 mg QD) and nefazodone (200 mg BID) were administered at steady state there were no changes in the pharmacokinetic parameters for fluoxetine or its metabolite, norfluoxetine. Similarly, there were no changes in the pharmacokinetic parameters of nefazodone or HO-NEF; however, the mean AUC levels of the nefazodone metabolites mCPP and triazole-dione increased by 3- to 6-fold and 1.3-fold, respectively. When a 200-mg dose of nefazodone was administered to subjects who had been receiving fluoxetine for 1 week, there was an increased incidence of transient adverse events such as headache, lightheadedness, nausea, or paresthesia, possibly due to the elevated mCPP levels. Patients who are switched from fluoxetine to nefazodone without an adequate washout period may experience similar transient adverse events. The possibility of this happening can be minimized by allowing a washout period before initiating nefazodone therapy and by reducing the initial dose of nefazodone. Because of the long half-life of fluoxetine and its metabolites, this washout period may range from one to several weeks depending on the dose of fluoxetine and other individual patient variables.
Phenytoin—Pretreatment for 7 days with 200 mg BID of nefazodone had no effect on the pharmacokinetics of a single 300-mg oral dose of phenytoin. However, due to the nonlinear pharmacokinetics of phenytoin, the failure to observe a significant effect on the single-dose pharmacokinetics of phenytoin does not preclude the possibility of a clinically significant interaction with nefazodone when phenytoin is dosed chronically. However, no change in the initial dosage of phenytoin is considered necessary and any subsequent adjustment of phenytoin dosage should be guided by usual clinical practices.
Desipramine—When nefazodone (150 mg BID) and desipramine (75 mg QD) were administered together there were no changes in the pharmacokinetics of desipramine or its metabolite, 2-hydroxy desipramine. There were also no changes in the pharmacokinetics of nefazodone or its triazole-dione metabolite, but the AUC and Cmax of mCPP increased by 44% and 48%, respectively, while the AUC of HO-NEF decreased by 19%. No changes in doses of either nefazodone or desipramine are necessary when the two drugs are given concomitantly. Subsequent dose adjustments should be made on the basis of clinical response.
Lithium—In 13 healthy subjects the coadministration of nefazodone (200 mg BID) with lithium (500 mg BID) for 5 days (steady-state conditions) was found to be well tolerated. When the two drugs were coadministered, there were no changes in the steady-state pharmacokinetics of either lithium, nefazodone, or its metabolite HO-NEF; however, there were small decreases in the steady-state plasma concentrations of two nefazodone metabolites, mCPP and triazole-dione, which are considered not to be of clinical significance. Therefore, no dosage adjustment of either lithium or nefazodone is required when they are coadministered.
Carbamazepine—The coadministration of nefazodone (200 mg BID) for 5 days to 12 healthy subjects on carbamazepine who had achieved steady state (200 mg BID) was found to be well tolerated. Steady-state conditions for carbamazepine, nefazodone, and several of their metabolites were achieved by day 5 of coadministration. With coadministration of the two drugs there were significant increases in the steady-state Cmax and AUC of carbamazepine (23% and 23%, respectively), while the steady-state Cmax and the AUC of the carbamazepine metabolite, 10,11 epoxycarbamazepine, decreased by 21% and 20%, respectively. The coadministration of the two drugs significantly reduced the steady-state Cmax and AUC of nefazodone by 86% and 93%, respectively. Similar reductions in the Cmax and AUC of HO-NEF were also observed (85% and 94%), while the reductions in Cmax and AUC of mCPP and triazole-
