Regulatory project manager

AttachmentRx only
(nefazodone hydrochloride)

Before prescribing SERZONE, the physician should be thoroughly familiar with thedetails of this prescribing information.
Cases of life-threatening hepatic failure have been reported in patients treated with

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.
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. (
Ordinarily, treatment with SERZONE 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.

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3 times the upper limit of NORMAL, while on SERZONE should be withdrawn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.

DESCRIPTIONSERZONE® (nefazodone hydrochloride) is an antidepressant for oral administration witha 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, whichcorresponds to a molecular weight of 506.5. The structural formula is: Nefazodone hydrochloride is a nonhygroscopic, white crystalline solid. It isfreely soluble in chloroform, soluble in propylene glycol, and slightly soluble inpolyethylene 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.
CLINICAL PHARMACOLOGYPharmacodynamicsThe mechanism of action of nefazodone, as with other antidepressants, is unknown.
Preclinical studies have shown that nefazodone inhibits neuronal uptake ofserotonin and norepinephrine.
Nefazodone occupies central 5-HT2 receptors at nanomolar concentrations, andacts as an antagonist at this receptor. Nefazodone was shown to antagonizealpha1-adrenergic receptors, a property which may be associated with posturalhypotension. In vitro binding studies showed that nefazodone had no significantaffinity for the following receptors: alpha2 and beta adrenergic, 5-HT1A,cholinergic, dopaminergic, or benzodiazepine.
PharmacokineticsNefazodone hydrochloride is rapidly and completely absorbed but is subject to extensivemetabolism, so that its absolute bioavailability is low, about 20%, and variable. Peakplasma concentrations occur at about one hour and the half-life of nefazodone is 2–4hours.
Both nefazodone and its pharmacologically similar metabolite, hydroxynefazodone, exhibit nonlinear kinetics for both dose and time, with AUC and Cmax increasing morethan proportionally with dose increases and more than expected upon multiple dosingover time, compared to single dosing. For example, in a multiple-dose study involvingBID dosing with 50, 100, and 200 mg, the AUC for nefazodone and hydroxynefazodoneincreased by about 4-fold with an increase in dose from 200 to 400 mg per day; Cmaxincreased by about 3-fold with the same dose increase. In a multiple-dose study involvingBID dosing with 25, 50, 100, and 150 mg, the accumulation ratios for nefazodone andhydroxynefazodone AUC, after 5 days of BID dosing relative to the first dose, rangedfrom approximately 3 to 4 at the lower doses (50–100 mg/day) and from 5 to 7 at thehigher doses (200–300 mg/day); there were also approximately 2- to 4-fold increases inCmax after 5 days of BID dosing relative to the first dose, suggesting extensive and greaterthan predicted accumulation of nefazodone and its hydroxy metabolite with multipledosing. Steady-state plasma nefazodone and metabolite concentrations are attained within4 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 inplasma, hydroxynefazodone (HO-NEF), meta-chlorophenylpiperazine (mCPP), and atriazole-dione metabolite, have been carried out. The AUC (expressed as a multiple of theAUC for nefazodone dosed at 100 mg BID) and elimination half-lives for these threemetabolites were as follows: Three Metabolites of Nefazodone (100 mg BID) Metabolite
AUC Multiple
HO-NEF possesses a pharmacological profile qualitatively and quantitativelysimilar to that of nefazodone. mCPP has some similarities to nefazodone, butalso has agonist activity at some serotonergic receptor subtypes. Thepharmacological profile of the triazole-dione metabolite has not yet been wellcharacterized. In addition to the above compounds, several other metaboliteswere 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 administeredradioactivity 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 from0.22 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-statenefazodone 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 thanthose 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 upto twice as high in the older patients. With multiple doses, however, differences weremuch smaller, 10–20%. A similar result was seen for gender, with a higher Cmax andAUC 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 ResultsStudies in Outpatients with DepressionDuring its premarketing development, the efficacy of SERZONE was evaluated at doseswithin the therapeutic range in five well-controlled, short-term (6–8 weeks) clinicalinvestigations. These trials enrolled outpatients meeting DSM-III or DSM-IIIR criteriafor major depression. Among these trials, two demonstrated the effectiveness ofSERZONE, 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 400mg/day], on a BID schedule) and placebo. The second trial was an 8-week dose-titrationstudy 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 studiesdemonstrated SERZONE, at doses titrated between 300 mg to 600 mg/day (therapeuticdose 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 DepressedMood item, Clinical Global Impressions (CGI) Severity score, and CGI Improvementscore. Significant differences were also found for certain factors of the HDRS (e.g.,anxiety factor, sleep disturbance factor, and retardation factor). In the two supportivestudies, SERZONE was titrated up to 500 or 600 mg/day (mean modal doses of 462mg/day and 363 mg/day). In the fifth study, the differentiation in response rates betweenSERZONE and placebo was not statistically significant. Three additional trials wereconducted 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 differentialresponsiveness on the basis of sex. There were too few elderly patients in these trials toreveal 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’suse under conditions not evaluated fully at the time initial marketing approval wasgranted.
Studies in “Inpatients”Two studies were conducted to evaluate SERZONE’s effectiveness in hospitalizeddepressed patients. These were 6-week, dose-titration trials comparing SERZONE (up to600 mg/day) and placebo, on a BID schedule. In one study, SERZONE was superior toplacebo. In this study, the mean modal dose of SERZONE was 503 mg/day, and 85% ofthese inpatients were melancholic; at baseline, patients were distributed at the higher endof 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 ratesbetween SERZONE and placebo was not statistically significant. This result may beexplained by the “high” rate of spontaneous improvement among the patients randomizedto placebo.
Studies of “Relapse Prevention in Patients Recently Recovered (Clinically) fromDepression”Two studies were conducted to assess SERZONE’s capacity to maintain a clinicalremission 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 thisstudy, 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 relapserate (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 patientsadmitted for evaluation did not suffer relapses at a high enough incidence to provide ameaningful test of SERZONE’s efficacy for this use.
Comparisons of Clinical Trial ResultsHighly variable results have been seen in the clinical development of all antidepressantdrugs. Furthermore, in those circumstances when the drugs have not been studied in thesame controlled clinical trial(s), comparisons among the findings of studies evaluating theeffectiveness of different antidepressant drug products are inherently unreliable. Becauseconditions of testing (e.g., patient samples, investigators, doses of the treatmentsadministered and compared, outcome measures, etc.) vary among trials, it is virtuallyimpossible to distinguish a difference in drug effect from a difference due to one or moreof the confounding factors just enumerated.
INDICATIONS AND USAGESERZONE (nefazodone hydrochloride) is indicated for the treatment of depression.
The efficacy of SERZONE in the treatment of depression 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
A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for atleast 2 weeks). It must include either depressed mood or loss of interest or pleasure and atleast five of the following nine symptoms: depressed mood, loss of interest in usualactivities, 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 depression 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 (i.e., 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.
Coadministration of terfenadine, astemizole, cisapride, pimozide, or carbamazepine with
SERZONE (nefazodone hydrochloride) is contraindicated (see WARNINGS and
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
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 asufficient dosage reduction, the coadministration of triazolam and SERZONE should beavoided for most patients, including the elderly.
Hepatotoxicity (See BOXED WARNING.)
Cases of life-threatening hepatic failure have been reported in patients treated with

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
(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.

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

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 TriazolobenzodiazepinesInteraction studies of nefazodone with two triazolobenzodiazepines, i.e., triazolam andalprazolam, metabolized by cytochrome P450 3A4, have revealed substantial andclinically important increases in plasma concentrations of these compounds whenadministered 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, 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
AlprazolamWhen alprazolam (1 mg BID) and nefazodone (200 mg BID) were coadministered,steady-state peak concentrations, AUC and half-life values for alprazolam increased byapproximately 2-fold. Nefazodone plasma concentrations were unaffected by alprazolam.
If alprazolam is coadministered with SERZONE, a 50% reduction in the initialalprazolam 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
be an inhibitor of CYP3A4. Consequently, it is recommended that nefazodone not
be used in combination with either terfenadine, astemizole, cisapride, or pimozide
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.
Consequently, it is recommended that SERZONE not be used in combination with
Hepatotoxicity (See BOXED WARNING.)
Postural HypotensionA pooled analysis of the vital signs monitored during placebo-controlled premarketingstudies 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 timeduring treatment (systolic blood pressure ≤90 mmHg and a change from baseline of ≥20mmHg). While there was no difference in the proportion of nefazodone and placebopatients having adverse events characterized as ‘syncope’ (nefazodone, 0.2%; placebo,0.3%), the rates for adverse events characterized as ‘postural hypotension’ were asfollows: 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 posturalhypotension in association with nefazodone use. SERZONE should be used with cautionin patients with known cardiovascular or cerebrovascular disease that could beexacerbated 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/HypomaniaDuring 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-treatedpatients. In patients classified as bipolar the rate of manic episodes was 1.6% fornefazodone, 5.1% for the combined tricyclic-treated groups, and 0% for placebo-treatedpatients. Activation of mania/hypomania is a known risk in a small proportion of patientswith major affective disorder treated with other marketed antidepressants. As with allantidepressants, SERZONE (nefazodone hydrochloride) should be used cautiously inpatients with a history of mania.
SuicideThe possibility of a suicide attempt is inherent in depression and may persist untilsignificant remission occurs. Close supervision of high-risk patients should accompanyinitial drug therapy. Prescriptions for SERZONE should be written for the smallestquantity of tablets consistent with good patient management in order to reduce the risk ofoverdose.
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
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 IllnessSERZONE has not been evaluated or used to any appreciable extent in patients with arecent history of myocardial infarction or unstable heart disease. Patients with thesediagnoses were systematically excluded from clinical studies during the product’spremarketing testing. Evaluation of electrocardiograms of 1153 patients who receivednefazodone in 6- to 8-week, double-blind, placebo-controlled trials did not indicate thatnefazodone is associated with the development of clinically important ECGabnormalities. However, sinus bradycardia, defined as heart rate ≤50 bpm and a decreaseof at least 15 bpm from baseline, was observed in 1.5% of nefazodone-treated patientscompared to 0.4% of placebo-treated patients (p≤0.05). Because patients with a recenthistory of myocardial infarction or unstable heart disease were excluded from clinicaltrials, 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 PatientsPhysicians are advised to discuss the following issues with patients for whom theyprescribe SERZONE: HepatotoxicityPatients should be informed that SERZONE therapy has been associated with liverabnormalities ranging from asymptomatic reversible serum transaminase increases tocases of liver failure resulting in transplant and/or death. At present, there is no way topredict who is likely to develop liver failure. Ordinarily, patients with active liver diseaseshould not be treated with SERZONE. Patients should be advised to be alert for signs ofliver dysfunction (jaundice, anorexia, gastrointestinal complaints, malaise, etc.) and toreport them to their doctor immediately if they occur.
Time to Response/ContinuationAs with all antidepressants, several weeks on treatment may be required to obtain the fullantidepressant effect. Once improvement is noted, it is important for patients to continuedrug treatment as directed by their physician.
Interference With Cognitive and Motor PerformanceSince any psychoactive drug may impair judgment, thinking, or motor skills, patientsshould be cautioned about operating hazardous machinery, including automobiles, untilthey are reasonably certain that SERZONE therapy does not adversely affect their abilityto engage in such activities.
PregnancyPatients should be advised to notify their physician if they become pregnant or intend tobecome pregnant during therapy.
Patients 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 withXANAX®1, concomitant use with HALCION®1 should be avoided for most patientsincluding the elderly, and concomitant use with SELDANE®2, HISMANAL®3, PROPULSID®3, ORAP®4, or TEGRETOL 5 is contraindicated (see
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 arelated allergic phenomenon.
Visual Disturbances
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.)
Laboratory Tests
There are no specific laboratory tests recommended.
Drug Interactions
Drugs Highly Bound to Plasma Protein
Because nefazodone is highly bound to plasma protein (see CLINICAL
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 Drugs
Monoamine 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%).
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) wereadministered at steady state there were no changes in the pharmacokinetic parameters forfluoxetine or its metabolite, norfluoxetine. Similarly, there were no changes in thepharmacokinetic parameters of nefazodone or HO-NEF; however, the mean AUC levelsof 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 whohad been receiving fluoxetine for 1 week, there was an increased incidence of transientadverse events such as headache, lightheadedness, nausea, or paresthesia, possibly due tothe elevated mCPP levels. Patients who are switched from fluoxetine to nefazodonewithout an adequate washout period may experience similar transient adverse events. Thepossibility of this happening can be minimized by allowing a washout period beforeinitiating nefazodone therapy and by reducing the initial dose of nefazodone. Because ofthe long half-life of fluoxetine and its metabolites, this washout period may range fromone to several weeks depending on the dose of fluoxetine and other individual patientvariables.
Phenytoin—Pretreatment for 7 days with 200 mg BID of nefazodone had no effect on thepharmacokinetics of a single 300-mg oral dose of phenytoin. However, due to thenonlinear pharmacokinetics of phenytoin, the failure to observe a significant effect on thesingle-dose pharmacokinetics of phenytoin does not preclude the possibility of aclinically significant interaction with nefazodone when phenytoin is dosed chronically.
However, no change in the initial dosage of phenytoin is considered necessary and anysubsequent adjustment of phenytoin dosage should be guided by usual clinical practices.
Desipramine—When nefazodone (150 mg BID) and desipramine (75 mg QD) wereadministered together there were no changes in the pharmacokinetics of desipramine orits metabolite, 2-hydroxy desipramine. There were also no changes in thepharmacokinetics of nefazodone or its triazole-dione metabolite, but the AUC and Cmax ofmCPP increased by 44% and 48%, respectively, while the AUC of HO-NEF decreasedby 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 thebasis of clinical response.
Lithium—In 13 healthy subjects the coadministration of nefazodone (200 mg BID) withlithium (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-statepharmacokinetics of either lithium, nefazodone, or its metabolite HO-NEF; however,there were small decreases in the steady-state plasma concentrations of two nefazodonemetabolites, mCPP and triazole-dione, which are considered not to be of clinicalsignificance. Therefore, no dosage adjustment of either lithium or nefazodone is requiredwhen 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-dione were more modest (13% and
44% for the former and 28% and 57% for the latter). Due to the potential for
coadministration of carbamazepine to result in insufficient plasma nefazodone and
hydroxynefazodone concentrations for achieving an antidepressant effect for SERZONE,
it is recommended that SERZONE not be used in combination with carbamazepine (see
General Anesthetics—Little is known about the potential for interaction betweennefazodone and general anesthetics; therefore, prior to elective surgery, SERZONEshould be discontinued for as long as clinically feasible.
Other CNS-Active Drugs—The use of nefazodone in combination with other CNS-activedrugs has not been systematically evaluated. Consequently, caution is advised ifconcomitant administration of SERZONE (nefazodone hydrochloride) and such drugs isrequired.
CimetidineWhen nefazodone (200 mg BID) and cimetidine (300 mg QID) were coadministered forone week, no change in the steady-state pharmacokinetics of either nefazodone orcimetidine was observed compared to each dosed alone. Therefore, dosage adjustment isnot necessary for either drug when coadministered.
TheophyllineWhen nefazodone (200 mg BID) was given to patients being treated with theophylline(600-1200 mg/day) for chronic obstructive pulmonary disease, there was no change in thesteady-state pharmacokinetics of either nefazodone or theophylline. FEV1 measurementstaken when theophylline and nefazodone were coadministered did not differ frombaseline dosage (i.e., when theophylline was administered alone). Therefore, dosageadjustment is not necessary for either drug when coadministered.
Cardiovascular-Active DrugsDigoxin—When nefazodone (200 mg BID) and digoxin (0.2 mg QD) werecoadministered for 9 days to healthy male volunteers (n=18) who were phenotyped asCYP2D6 extensive metabolizers, Cmax, Cmin, and AUC of digoxin were increased by29%, 27%, and 15%, respectively. Digoxin had no effects on the pharmacokinetics ofnefazodone and its active metabolites. Because of the narrow therapeutic index ofdigoxin, caution should be exercised when nefazodone and digoxin are coadministered;plasma level monitoring for digoxin is recommended.
Propranolol—The coadministration of nefazodone (200 mg BID) and propranolol (40 mgBID) for 5.5 days to healthy male volunteers (n=18), including 3 poor and 15 extensiveCYP2D6 metabolizers, resulted in 30% and 14% reductions in Cmax and AUC ofpropranolol, respectively, and a 14% reduction in Cmax for the metabolite, 4-hydroxypropranolol. The kinetics of nefazodone, hydroxynefazodone, and triazole-dionewere not affected by coadministration of propranolol. However, Cmax, Cmin, and AUC ofm-chlorophenylpiperazine were increased by 23%, 54%, and 28%, respectively. Nochange in initial dose of either drug is necessary and dose adjustments should be made onthe basis of clinical response.
HMG-CoA Reductase Inhibitors—When single 40-mg doses of simvastatin oratorvastatin, both substrates of CYP3A4, were given to healthy adult volunteers who hadreceived SERZONE 200 mg BID for 6 days, approximately 20-fold increases in plasmaconcentrations of simvastatin and simvastatin acid and 3- to 4-fold increases in plasmaconcentrations of atorvastatin and atorvastatin lactone were seen. These effects appear tobe due to the inhibition of CYP3A4 by SERZONE because, in the same study,SERZONE had no significant effect on the plasma concentrations of pravastatin, which isnot metabolized by CYP3A4 to a clinically significant extent.
There have been rare reports of rhabdomyolysis involving patients receiving the combination of SERZONE and either simvastatin or lovastatin, also a substrate of
CYP3A4 (see ADVERSE REACTIONS: Postintroduction Clinical Experience).
Rhabdomyolysis has been observed in patients receiving HMG-CoA reductase inhibitors
administered alone (at recommended dosages) and in particular, for certain drugs in this
class, when given in combination with inhibitors of the CYP3A4 isozyme.
Caution should be used if SERZONE is administered in combination with HMG-CoA reductase inhibitors that are metabolized by CYP3A4, such as simvastatin, atorvastatin,and lovastatin, and dosage adjustments of these HMG-CoA reductase inhibitors arerecommended. Since metabolic interactions are unlikely between SERZONE and HMG-CoA reductase inhibitors that undergo little or no metabolism by the CYP3A4 isozyme,such as pravastatin or fluvastatin, dosage adjustments should not be necessary.
Immunosuppressive AgentsThere have been reports of increased blood concentrations of cyclosporine andtacrolimus into toxic ranges when patients received these drugs concomitantly withSERZONE. Both cyclosporine and tacrolimus are substrates of CYP3A4, and nefazodoneis known to inhibit this enzyme. If either cyclosporine or tacrolimus is administered withSERZONE, blood concentrations of the immunosuppressive agent should be monitoredand dosage adjusted accordingly. Pharmacokinetics of Nefazodone in ‘Poor Metabolizers’ and Potential Interaction withDrugs that Inhibit and/or Are Metabolized by Cytochrome P450 IsozymesCYP3A4 Isozyme—Nefazodone has been shown in vitro to be an inhibitor of CYP3A4.
This is consistent with the interactions observed between nefazodone and triazolam, alprazolam, buspirone, atorvastatin, and simvastatin, drugs metabolized by this isozyme.
Consequently, caution is indicated in the combined use of nefazodone with any drugs
known to be metabolized by CYP3A4. In particular, the combined use of nefazodone
with triazolam should be avoided for most patients, including the elderly. The combined
use of nefazodone with terfenadine, astemizole, cisapride, or pimozide is contraindicated
CYP2D6 Isozyme—A subset (3% to 10%) of the population has reduced activity of the
drug-metabolizing enzyme CYP2D6. Such individuals are referred to commonly as “poor
metabolizers” of drugs such as debrisoquin, dextromethorphan, and the tricyclic
antidepressants. The pharmacokinetics of nefazodone and its major metabolites are not
altered in these “poor metabolizers.” Plasma concentrations of one minor metabolite
(mCPP) are increased in this population; the adjustment of SERZONE dosage is not
required when administered to “poor metabolizers.” Nefazodone and its metabolites have
been shown in vitro to be extremely weak inhibitors of CYP2D6. Thus, it is not likely
that nefazodone will decrease the metabolic clearance of drugs metabolized by this
CYP1A2 Isozyme—Nefazodone and its metabolites have been shown in vitro not to
inhibit CYP1A2. Thus, metabolic interactions between nefazodone and drugs
metabolized by this isozyme are unlikely.
Electroconvulsive Therapy (ECT)There are no clinical studies of the combined use of ECT and nefazodone.
Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenesisThere is no evidence of carcinogenicity with nefazodone. The dietary administration ofnefazodone 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 humandaily dose on a mg/m2 basis, produced no increase in tumors.
MutagenesisNefazodone 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 mammalianmutation assay in Chinese hamster ovary cells, an in vivo cytogenetics assay in rat bonemarrow cells, and a rat dominant lethal study.
Impairment of FertilityA 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 at100 mg/kg/day (approximately 1.5 times the maximum human daily dose on a mg/m2basis).
PregnancyTeratogenic Effects—Pregnancy Category CReproduction studies have been performed in pregnant rabbits and rats at daily doses upto 200 and 300 mg/kg, respectively (approximately 6 and 5 times, respectively, themaximum human daily dose on a mg/m2 basis). No malformations were observed in theoffspring as a result of nefazodone treatment. However, increased early pup mortalitywas seen in rats at a dose approximately five times the maximum human dose, anddecreased pup weights were seen at this and lower doses, when dosing began duringpregnancy 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 beused during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery
The effect of SERZONE on labor and delivery in humans is unknown.
Nursing Mothers
It is not known whether SERZONE or its metabolites are excreted in human milk.
Because many drugs are excreted in human milk, caution should be exercised when
SERZONE is administered to a nursing woman.
Pediatric UseSafety and effectiveness in individuals below 18 years of age have not been established.
Geriatric UseOf the approximately 7000 patients in clinical studies who received SERZONE for thetreatment 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 oflaboratory tests, no overall differences in safety between elderly and younger patientswere observed in clinical studies. Efficacy in the elderly has not been demonstrated inplacebo-controlled trials. Other reported clinical experience has not identified differencesin responses between elderly and younger patients, but greater sensitivity of some olderindividuals 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.
ADVERSE REACTIONSAssociated with Discontinuation of TreatmentApproximately 16% of the 3496 patients who received SERZONE (nefazodonehydrochloride) in worldwide premarketing clinical trials discontinued treatment due to anadverse experience. The more common (≥1%) events in clinical trials associated withdiscontinuation and considered to be drug related (i.e., those events associated withdropout at a rate approximately twice or greater for SERZONE compared to placebo)included: nausea (3.5%), dizziness (1.9%), insomnia (1.5%), asthenia (1.3%), andagitation (1.2%).
Incidence in Controlled TrialsCommonly Observed Adverse Events in Controlled Clinical TrialsThe most commonly observed adverse events associated with the use of SERZONE(incidence of 5% or greater) and not seen at an equivalent incidence among placebo-treated patients (i.e., significantly higher incidence for SERZONE compared to placebo,p≤0.05), derived from the table below, were: somnolence, dry mouth, nausea, dizziness,constipation, asthenia, lightheadedness, blurred vision, confusion, and abnormal vision.
Adverse Events Occurring at an Incidence of 1% or More Among SERZONE-TreatedPatientsThe table that follows enumerates adverse events that occurred at an incidence of 1% ormore, and were more frequent than in the placebo group, among SERZONE-treatedpatients who participated in short-term (6- to 8-week) placebo-controlled trials in which patients were dosed with SERZONE (nefazodone hydrochloride)to ranges of 300 to 600mg/day. This table shows the percentage of patients in each group who had at least oneepisode of an event at some time during their treatment. Reported adverse events wereclassified 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 patientcharacteristics and other factors differ from those which prevailed in the clinical trials.
Similarly, the cited frequencies cannot be compared with figures obtained from otherclinical investigations involving different treatments, uses, and investigators. The citedfigures, however, do provide the prescribing physician with some basis for estimating therelative contribution of drug and nondrug factors to the side-effect incidence rate in thepopulation studied.
Treatment-Emergent Adverse Experience Incidence in 6- to 8-Week Placebo-Controlled Clinical Trials1 Percent of Patients
Body System
Urinary retention
1 Events reported by at least 1% of patients treated with SERZONE and more frequent than the placebo group are included; incidence is rounded to the nearest 1% (<1% indicates an incidence less than 0.5%).
Events for which the SERZONE incidence was equal to or less than placebo are not listed in the table,but included the following: abdominal pain, pain, back pain, accidental injury, chest pain, neck pain,palpitation, migraine, sweating, flatulence, vomiting, anorexia, tooth disorder, weight gain, edema,myalgia, cramp, agitation, anxiety, depression, hypesthesia, CNS stimulation, dysphoria, emotionallability, sinusitis, rhinitis, dysmenorrhea4, dysuria.
2 Vasodilatation—flushing, feeling warm.
3 Abnormal vision—scotoma, visual trails.
4 Incidence adjusted for gender.
Dose Dependency of Adverse EventsThe table that follows enumerates adverse events that were more frequent in theSERZONE (nefazodone hydrochloride) dose range of 300 to 600 mg/day than in theSERZONE dose range of up to 300 mg/day. This table shows only those adverse eventsfor which there was a statistically significant difference (p≤0.05) in incidence betweenthe SERZONE dose ranges as well as a difference between the high dose range andplacebo.
Dose Dependency of Adverse Events in Placebo-Controlled Trials1 Percent of Patients
Events for which there was a statistically significant difference (p≤0.05) between the nefazodonedose groups.
Visual DisturbancesIn controlled clinical trials, blurred vision occurred in 9% of nefazodone-treated patientscompared to 3% of placebo-treated patients. In these same trials, abnormal vision,including scotomata and visual trails, occurred in 7% of nefazodone-treated patientscompared 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 thescotomata 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 SERZONE. (See PRECAUTIONS: Information for Patients.)
Vital Sign Changes
(See PRECAUTIONS: Postural Hypotension.)
Weight ChangesIn a pooled analysis of placebo-controlled premarketing studies, there were nodifferences between nefazodone and placebo groups in the proportions of patientsmeeting criteria for potentially important increases or decreases in body weight (a changeof ≥7%).
Laboratory ChangesOf the serum chemistry, serum hematology, and urinalysis parameters monitored duringplacebo-controlled premarketing studies with nefazodone, a pooled analysis revealed astatistical trend between nefazodone and placebo for hematocrit, i.e., 2.8% of nefazodonepatients met criteria for a potentially important decrease in hematocrit (≤37% male or ≤32% female) compared to 1.5% of placebo patients (0.05<p≤0.10). Decreases inhematocrit, presumably dilutional, have been reported with many other drugs that blockalpha1-adrenergic receptors. There was no apparent clinical significance of the observedchanges in the few patients meeting these criteria.
ECG ChangesOf the ECG parameters monitored during placebo-controlled premarketing studies withnefazodone, a pooled analysis revealed a statistically significant difference betweennefazodone and placebo for sinus bradycardia, i.e., 1.5% of nefazodone patients metcriteria for a potentially important decrease in heart rate (≤50 bpm and a decrease of ≥15bpm) compared to 0.4% of placebo patients (p<0.05). There was no obvious clinicalsignificance of the observed changes in the few patients meeting these criteria.
Other Events Observed During the Premarketing Evaluation of SERZONEDuring its premarketing assessment, multiple doses of SERZONE (nefazodonehydrochloride) were administered to 3496 patients in clinical studies, including more than250 patients treated for at least one year. The conditions and duration of exposure toSERZONE 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 recordedby clinical investigators using terminology of their own choosing. Consequently, it is notpossible to provide a meaningful estimate of the proportion of individuals experiencingadverse events without first grouping similar types of untoward events into a smallernumber 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 SERZONEwho experienced an event of the type cited on at least one occasion while receivingSERZONE. All reported events are included except those already listed in the Treatment-Emergent Adverse Experience Incidence table, those events listed in other safety-relatedsections of this insert, those adverse experiences subsumed under COSTART terms thatare either overly general or excessively specific so as to be uninformative, those eventsfor which a drug cause was very remote, and those events which were not serious andoccurred in fewer than two patients.
It is important to emphasize that, although the events reported occurred during treatment with SERZONE, they were not necessarily caused by it.
Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are thoseoccurring on one or more occasions in at least 1/100 patients (only those not alreadylisted in the tabulated results from placebo-controlled trials appear in this listing);infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events arethose occurring in fewer than 1/1000 patients.
Body as a wholeInfrequent: allergic reaction, malaise, photosensitivity reaction, faceedema, hangover effect, abdomen enlarged, hernia, pelvic pain, and halitosis. Rare:cellulitis.
Cardiovascular systemInfrequent: tachycardia, hypertension, syncope, ventricularextrasystoles, and angina pectoris. Rare: AV block, congestive heart failure, hemorrhage,pallor, and varicose vein. Dermatological systemInfrequent: dry skin, acne, alopecia, urticaria, maculopapularrash, vesiculobullous rash, and eczema.
Gastrointestinal systemFrequent: gastroenteritis. Infrequent: eructation, periodontalabscess, 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, andlymphadenopathy.
Metabolic and nutritional systemInfrequent: weight loss, gout, dehydration, lacticdehydrogenase increased, SGOT increased, and SGPT increased. Rare:hypercholesteremia and hypoglycemia.
Musculoskeletal systemInfrequent: arthritis, tenosynovitis, muscle stiffness, andbursitis. Rare: tendinous contracture.
Nervous systemInfrequent: vertigo, twitching, depersonalization, hallucinations,suicide attempt, apathy, euphoria, hostility, suicidal thoughts, abnormal gait, thinkingabnormal, attention decreased, derealization, neuralgia, paranoid reaction, dysarthria,increased libido, suicide, and myoclonus. Rare: hyperkinesia, increased salivation,cerebrovascular accident, hyperesthesia, hypotonia, ptosis, and neuroleptic malignantsyndrome.
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 ofaccommodation, diplopia, conjunctivitis, mydriasis, keratoconjunctivitis, hyperacusis,and photophobia. Rare: deafness, glaucoma, night blindness, and taste loss.
Urogenital systemFrequent: impotence.a Infrequent: cystitis, urinary urgency,metrorrhagiaa, amenorrheaa, polyuria, vaginal hemorrhagea, breast enlargementa,menorrhagiaa, urinary incontinence, abnormal ejaculationa, hematuria, nocturia, andkidney calculus. Rare: uterine fibroids enlargeda, uterine hemorrhagea, anorgasmia, andoliguria.
aAdjusted for gender.
Postintroduction Clinical ExperiencePostmarketing experience with SERZONE has shown an adverse experience profilesimilar to that seen during the premarketing evaluation of nefazodone. Voluntary reportsof adverse events temporally associated with SERZONE have been received since marketintroduction that are not listed above and for which a causal relationship has not beenestablished. These include: Anaphylactic reactions; angioedema; convulsions (including grand mal seizures); galactorrhea; gynecomastia (male); hyponatremia; liver necrosis and liver failure, in
some cases leading to liver transplantation and/or death (see WARNINGS); priapism
(see PRECAUTIONS); prolactin increased; rhabdomyolysis involving patients receiving
the combination of SERZONE and lovastatin or simvastatin (see PRECAUTIONS);
serotonin syndrome; Stevens-Johnson syndrome; and thrombocytopenia.
DRUG ABUSE AND DEPENDENCEControlled Substance ClassSERZONE (nefazodone hydrochloride) is not a controlled substance.
Physical and Psychological DependenceIn animal studies, nefazodone did not act as a reinforcer for intravenous self-administration in monkeys trained to self-administer cocaine, suggesting no abuseliability. In a controlled study of abuse liability in human subjects, nefazodone showed nopotential for abuse.
Nefazodone has not been systematically studied in humans for its potential for tolerance, physical dependence, or withdrawal. While the premarketing clinicalexperience with nefazodone did not reveal any tendency for a withdrawal syndrome orany drug-seeking behavior, it is not possible to predict on the basis of this limitedexperience the extent to which a CNS-active drug will be misused, diverted, and/orabused once marketed. Consequently, physicians should carefully evaluate patients for ahistory of drug abuse and follow such patients closely, observing them for signs ofmisuse or abuse of SERZONE (e.g., development of tolerance, dose escalation, drug-seeking behavior).
OVERDOSAGEHuman ExperienceIn premarketing clinical studies, there were seven reports of nefazodone overdose aloneor in combination with other pharmacological agents. The amount of nefazodone ingestedranged from 1000 mg to 11,200 mg. Commonly reported symptoms from overdose ofnefazodone included nausea, vomiting, and somnolence. One nonstudy participant took2000–3000 mg of nefazodone with methocarbamol and alcohol; this person reportedlyexperienced a convulsion (type not documented). None of these patients died.
In postmarketing experience, overdose with SERZONE alone and in combination with alcohol and/or other substances has been reported. Commonly reported symptomswere similar to those reported from overdose in premarketing experience. While therehave been rare reports of fatalities in patients taking overdoses of nefazodone,predominantly in combination with alcohol and/or other substances, no causalrelationship to nefazodone has been established.
Overdosage ManagementTreatment should consist of those general measures employed in the management ofoverdosage with any antidepressant.
Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended.
Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tubewith appropriate airway protection, if needed, may be indicated if performed soon afteringestion, or in symptomatic patients.
Activated charcoal should be administered. Due to the wide distribution of nefazodone in body tissues, forced diuresis, dialysis, hemoperfusion, and exchangetransfusion are unlikely to be of benefit. No specific antidotes for nefazodone are known.
In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional informationon the treatment of any overdose. Telephone numbers for certified poison control centersare listed in the Physicians’ Desk Reference (PDR).
DOSAGE AND ADMINISTRATIONInitial TreatmentThe recommended starting dose for SERZONE (nefazodone hydrochloride) is 200mg/day, administered in two divided doses (BID). In the controlled clinical trialsestablishing the antidepressant efficacy of SERZONE, the effective dose range wasgenerally 300 to 600 mg/day. Consequently, most patients, depending on tolerability andthe need for further clinical effect, should have their dose increased. Dose increasesshould occur in increments of 100 mg/day to 200 mg/day, again on a BID schedule, atintervals of no less than 1 week. As with all antidepressants, several weeks on treatmentmay be required to obtain a full antidepressant response.
Dosage for Elderly or Debilitated PatientsThe recommended initial dose for elderly or debilitated patients is 100mg/day,administered in two divided doses (BID) These patients often have reducednefazodone 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-stateplasma levels do not change with age, the final target dose based on a careful assessmentof 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 SERZONE. 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 SERZONE 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
.) The safety of SERZONE 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 InhibitorAt least 14 days should elapse between discontinuation of an MAOI and initiation oftherapy with SERZONE. In addition, at least 7 days should be allowed after stoppingSERZONE before starting an MAOI.
HOW SUPPLIEDSERZONE® (nefazodone hydrochloride) tablets are hexagonal tablets imprinted withBMS and the strength (i.e., 100 mg) on one side and the identification code number onthe other. The 100 mg and 150 mg tablets are bisect scored on both tablet faces. The 50mg, 200 mg, and 250 mg tablets are unscored.
U.S. Patent Nos. 4,338,317 and 6,008,222
Store at room temperature, below 40º C (104º F) and dispense in a tight container.
REFERENCES1. HALCION® and XANAX® are registered trademarks of Pharmacia & Upjohn.
2. SELDANE® is a registered trademark of Hoechst Marion Roussel Inc. (now Aventis 3. HISMANAL® and PROPULSID® are registered trademarks of Janssen 4. ORAP® is a registered trademark of Gate Pharmaceuticals, a division of Teva 5. TEGRETOL is a registered trademark of Novartis Pharmaceuticals Corporation.
Princeton, NJ 08543 USA
  • DRUG: Serzone (nefazodone hydrochloride) 50 mg, 100 mg. 150 mg, 200 mg\, and 250 mg Tablets
  • Senior Regulatory Project Manager
  • Supervisory Regulatory Health Officer


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