SERZONE(r) (nefazodonehydrochloride) is an antidepressant for oral administration with a chemical struc- ture unrelated to selective serotonin reuptake inhibitors, tricyclics, tetracyclics, or monoamine oxidase inhibitors (MAOI). Nefazodonehydrochloride is a synthetically derivedphenylpiperazineantidepressant.Thechemical namefor 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 correspondsto a molecular weight of 506.5. The structural formula is:
C2H5
N One trial wasa 6-week dose-titrationstudy comparingSERZONE in two doseranges(upto 300mg/dayand up to 600mg/day[meanmodal dosefor this groupwas about 400mg/day], on a BID schedule) andplacebo. The secondtrial was an 8-week dose-titration study comparing SERZONE (up to 600 mg/day; meanmodal dosewas 375 mg/day), imipramine (up to 300 mg/day), and placebo, all on a BID schedule. Both studies demonstrated SERZONE, at dosestitrated between 300 mg to 600 mg/day (therapeutic doserange), to be superior to placeboonat least threeof thefollowing four measures: 17-ItemHamiltonDepressionRatingScale orHDRS(total score),HamiltonDepressedMood item,ClinicalGlobal Impressions(CGI)Severity score, andCGI Improvement score.Significant differenceswerealsofoundfor certain factors of theHDRS(e.g.,anxiety factor, sleepdisturbancefactor, andretardation factor). In thetwo supportivestudies,SERZONEwas titratedup to 500 or 600 mg/day(meanmodal dosesof 462 mg/dayand 363 mg/day). In the fifth study, the differentiation in responserates betweenSERZONE and placebo was not statistically significant. Three additional trials were conducted using subtherapeutic dosesof SERZONE. Overall, approximately two thirds of patients in thesetrials were women, andan analysis of theeffects of gender on outcomedid not suggest any differential responsivenesson thebasis of sex. There were too few elderly patients in thesetrials to reveal possible age-related differences in response. Since its initial marketing as an antidepressant drug product, additional clinical investigations of SERZONE
N
CH2CH2CH2 N N
O
HCl
Cl
havebeenconducted.ThesestudiesexploredSERZONE's useunder conditionsnot evaluated fully at the time initial marketing approval was granted.
Studies in "Inpatients"
Two studies were conducted to evaluateSERZONE's effectivenessin hospitalizeddepressedpatients.These were 6-week, dose-titration trials comparingSERZONE(up to 600mg/day)andplacebo, ona BID schedule. Nefazodonehydrochloride is a nonhygroscopic, white crystalline solid. It is freely soluble in chloroform, soluble in propyleneglycol, andslightly soluble in polyethyleneglycol andwater. SERZONE is supplied as hexagonal tablets containing 50 mg, 100mg, 150mg, 200mg, or 250mg of nefa- zodonehydrochloride 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.
The mechanism of action of nefazodone, as with other antidepressants, is unknown. Preclinical studies have shown that nefazodoneinhibits neuronal uptake of serotonin andnorepinephrine. Nefazodoneoccupiescentral 5-HT2 receptors at nanomolar concentrations, andacts asanantagonist at this receptor. Nefazodonewas shown to antagonize alpha1-adrenergic receptors, a property which maybe asso- ciated with postural hypotension. In vitro binding studies showed that nefazodonehadno significant affinity for the following receptors: alpha2 andbeta adrenergic, 5-HT1A, cholinergic, dopaminergic, or benzodiazepine.
Nefazodonehydrochloride is rapidly and completely absorbedbut is subject to extensive metabolism, so that its absolute bioavailability is low, about 20%, andvariable. Peak plasmaconcentrationsoccur at about onehour and the half-life of nefazodoneis 2-4 hours. Both nefazodoneand its pharmacologically similar metabolite, hydroxynefazodone, exhibit nonlinear kinetics for both doseand time, withAUCandCmax increasingmore thanproportionally with doseincreasesandmore than expected uponmultiple 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 nefazodoneand hydroxynefazodone increasedby about 4-fold with an increasein dosefrom 200 to 400mg per day; C max increasedby about 3- fold with thesamedoseincrease. In a multiple-dosestudy involvingBIDdosingwith 25, 50, 100, and150mg, theaccumulation ratios for nefazodoneandhydroxynefazodoneAUC, after 5 daysof BID dosing relative to the first dose, rangedfromapproximately 3 to 4 at the lower doses(50-100mg/day)andfrom5 to 7 at thehigher doses(200-300 mg/day); there were also approximately 2- to 4-fold increasesin Cmax after 5 daysof BID dosing relative to the first dose, suggestingextensiveandgreater thanpredictedaccumulationof nefazodone and its hydroxymetabolite with multiple dosing. Steady-state plasmanefazodoneandmetabolite concentra- tionsare attainedwithin 4 to 5 daysof initiation of BID dosing or upondoseincreaseor decrease. Nefazodoneis extensively metabolizedafter oral administrationbyn-dealkylationandaliphatic andaromatic hydroxylation, andlessthan1%of administerednefazodoneis excretedunchangedin urine.Attempts to char- acterize three metabolites identified in plasma, hydroxynefazodone(HO-NEF), meta-chlorophenylpiperazine (mCPP), anda triazole-dionemetabolite, have beencarried out.TheAUC(expressedas a multiple of theAUC for nefazodonedosedat 100mgBID) andelimination half-lives for thesethreemetabolites were as follows:
| AUCMultiples andT 1/2 for ThreeMetabolites of Nefazodone(100mg BID) | ||
| Metabolite | AUCMultiple | T 1/2 |
| HO-NEF | 0.4 | 1.5 - 4 h |
| mCPP | 0.07 | 4 - 8 h |
| Triazole-dione | 4.0 | 18 h |
HO-NEF possessesa 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. Thepharmacological profile of the triazole-dionemetabolite hasnot yet beenwell characterized. In addition to theabovecompounds, several other metabolites were present in plasmabut havenot beentested for pharmacological activity. After oral administrationof radiolabelednefazodone, themeanhalf-life of total label rangedbetween11 and 24 hours. Approximately 55% of the administered radioactivity was detected in urine and about 20-30% in feces.
Distribution
--Nefazodoneis widely distributed in body tissues, including the central nervoussystem (CNS). In humansthevolumeof distribution of nefazodonerangesfrom 0.22 to 0.87 L/kg.
Protein Binding--At concentrations of 25-2500ng/mL nefazodoneis extensively (>99%) boundto human plasmaproteins in vitro.Theadministrationof 200mgBIDof nefazodonefor 1 week did not increasethe frac- tionof unboundwarfarin in subjects whoseprothrombin timeshadbeenprolongedbywarfarin therapy to 120- 150%of the laboratory control (seePRECAUTIONS section,DrugInteractions subsection). While nefazodone did not alter the in vitro protein binding of chlorpromazine, desipramine, diazepam, diphenylhydantoin, lido- caine, prazosin, propranolol, or verapamil, it is unknown whether displacement of either nefazodoneor these drugsoccurs in vivo.There wasa 5% decreasein theprotein bindingof haloperidol; this is probably of noclin- ical significance.
Effect of Food
--Fooddelays the absorption of nefazodoneand decreasesthe bioavailability of nefazodone by approximately 20%.
Renal Disease--In studies involving 29 renally impaired patients, renal impairment (creatinine clear- ances ranging from 7 to 60 mL/min/1.73m2) had no effect on steady-state nefazodoneplasmaconcen- trations.
Liver Disease
--In a multiple-dosestudy of patients with liver cirrhosis, theAUCvalues for nefazodoneand HO-NEF at steady state were approximately 25% greater than thoseobserved in normal volunteers.
Age/Gender Effects--After single dosesof 300mg to younger (18-45 years)andolder patients (>65 years), Cmax andAUC for nefazodoneand hydroxynefazodonewere up to twice as high in the older patients. With multiple doses, however, differences were much smaller, 10-20%. A similar result was seenfor gender, with a higher Cmax andAUCin womenafter single dosesbut no difference after multiple doses. Treatment withSERZONEshould be initiatedat half theusual dosein elderly patients, especially women(see DOSAGE AND ADMINISTRATION section), but the therapeutic dose range is similar in younger and older patients.
Studies in Outpatients with Depression
During its premarketing development, the efficacy of SERZONE was evaluated at doseswithin the thera- peutic range in five well-controlled, short-term (6-8 weeks) clinical investigations. These trials enrolled outpatients meetingDSM-IIIor DSM-IIIRcriteria for major depression.Amongthesetrials, two demonstrated the effectivenessof SERZONE, and two providedadditional support for that conclusion. In onestudy, SERZONE was superior to placebo. In this study, the meanmodal doseof SERZONE was 503 mg/day, and85% of theseinpatients 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 responserates betweenSERZONE and placebo was not statistically significant.This result maybeexplainedby the "high" rate of spontaneousimprovement among the patients randomized to placebo.
Studies of "RelapsePrevention in Patients Recently Recovered (Clinically) fromDepression"
Two studies were conducted to assessSERZONE's capacity to maintain a clinical remission in acutely depressedpatients who were judgedto have respondedadequately (HDRStotal score <=10)after a 16-week period of open treatment with SERZONE (titration up to 600 mg/day). In onestudy, 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 (HDRStotal score >=18) for patients taking SERZONE compared to thoseon placebo. The secondstudy was of appro- priate designandpower, but thesample of patients admitted for evaluationdid not suffer relapsesat a high enoughincidenceto provide a meaningful test of SERZONE's efficacy for this use.
Comparisonsof Clinical Trial Results
Highly variable results havebeenseenin theclinical development of all antidepressant drugs. Furthermore, in those circumstances when the drugs have not been studied in the same controlled clinical trial(s), comparisonsamong the findings of studies evaluating the effectivenessof different antidepressant drug products are inherently unreliable. Becauseconditionsof testing(e.g., patient samples, investigators, doses of the treatments administered and compared, outcome measures, etc.) vary among trials, it is virtually impossible to distinguisha difference in drugeffect froma difference dueto oneor more of theconfounding factors just enumerated.
SERZONE (nefazodonehydrochloride) is indicated for the treatment of depression. Theefficacy of SERZONE in the treatment of depressionwasestablishedin 6-8 week controlled trials of out- patients and in a 6-week controlled trial of depressedinpatients whosediagnosescorrespondedmost closely to theDSM-IIIor DSM-IIIR category of major depressive disorder (see CLINICALPHARMACOLOGY section). A major depressiveepisodeimplies a prominent and relatively persistent depressedor dysphoric moodthat usually interferes with daily functioning (nearly every day for at least 2 weeks). It must include either depressedmoodor 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 hyper- somnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicideattempt or suicidal ideation. Theefficacy of SERZONE in reducing relapsein patients with major depressionwho were judgedto havehad a satisfactory clinical responseto 16weeks of open-label SERZONE treatment for anacute depressiveepisode has beendemonstrated in a randomized placebo-controlled trial (see CLINICAL PHARMACOLOGY section). Althoughremitted patients were followed for as longas 36 weeks in thestudy cited (i.e., 52 weeks total), the physician who elects to useSERZONE for extendedperiodsshould periodically reevaluate the long-term use- fulnessof the drug for the individual patient.
Coadministration of terfenadine, astemizole, cisapride, pimozide, or carbamazepine with SERZONE (nefa- zodonehydrochloride) is contraindicated (see WARNINGS andPRECAUTIONS sections). SERZONE is contraindicated in patients with knownhypersensitivity to nefazodoneor other phenylpiperazine antidepressants. The coadministration of triazolam andnefazodonecausesa significant increasein the plasmalevel of tria- zolam (see WARNINGS and PRECAUTIONS sections), and a 75% reduction in the initial triazolam dosage is recommendedif the two drugsare to begiventogether. Becausenot all commercially available dosage forms of triazolam permit a sufficient dosage reduction, the coadministration of triazolam andSERZONE should be avoided for most patients, including theelderly.
Interaction studies of nefazodonewith two triazolobenzodiazepines, i.e., triazolam andalprazolam, metab- olized by cytochrome P450 3A4, have revealed substantial and clinically important increases in plasma concentrationsof thesecompoundswhen administered concomitantly with nefazodone.
Triazolam
Whena single oral 0.25-mg doseof triazolam was coadministered with nefazodone(200mgBID) at steady state, triazolamhalf-life andAUCincreased4-fold andpeak concentrations increased1.7-fold. Nefazodone plasmaconcentrations were unaffected by triazolam. Coadministration of nefazodone potentiated the effects of triazolam on psychomotor performancetests. If triazolam is coadministered with SERZONE, a 75% reduction in the initial triazolam dosage is recommended. Becausenot 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 andPRECAUTIONS sections).
Alprazolam
When alprazolam (1 mg BID) and nefazodone(200 mg BID) were coadministered, steady-state peak concentrations, AUC and half-life values for alprazolam increased by approximately 2-fold. Nefazodone plasma concentrations were unaffected by alprazolam. If alprazolam is coadministered with SERZONE, a 50% reduction in the initial alprazolam dosage is recommended. No dosage adjustment is required for SERZONE.
(see
and
sections).
The coadministration of carbamazepine 200 mg BID with nefazodone200 mg BID, at steady state for both drugs, resulted in almost 95% reductions in AUCs for nefazodoneand hydroxynefazodone, likely resulting in insufficient plasmanefazodoneand hydroxynefazodoneconcentrations for achieving an antidepressant effect for SERZONE.Consequently, it is recommendedthat SERZONEnot beusedin combinationwith carba- mazepine (see CONTRAINDICATIONS andPRECAUTIONS sections).
Postural Hypotension
A pooled analysis of the vital signs monitored during placebo-controlled premarketing studies revealed that 5.1% of nefazodonepatients compared to 2.5% of placebo patients (p<=0.01) met criteria for a potentially important decreasein bloodpressure at sometimeduring treatment (systolic bloodpressure <=90 mmHg and a change from baseline of >=20 mmHg). While there was no difference in the proportion of nefazodoneand placebo patients having adverse events characterized as 'syncope' (nefazodone, 0.2%; placebo, 0.3%), the rates for adverseevents characterizedas 'postural hypotension' were as follows: nefazodone(2.8%), tricyclic antidepressants (10.9%), SSRI (1.1%), andplacebo(0.8%).Thus, theprescriber should beaware that there is somerisk of postural hypotension in association with nefazodoneuse. SERZONE should beusedwith caution in patients with known cardiovascular or cerebrovascular diseasethat could be exacerbated by hypotension (history of myocardial infarction, angina, or ischemic stroke) andconditions that would predisposepatients to hypotension (dehydration, hypovolemia, and treatment with antihypertensivemedication).
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 proportionof patients with major affectivedisorder treated with other marketedantidepressants.As with all antidepressants, SERZONE (nefazodonehydrochloride)should be usedcautiously in patients with a history of mania.
Suicide
The possibility of a suicide attempt is inherent in depression and may persist until significant remission occurs. Close supervision of high-risk patients should accompany initial drug therapy. Prescriptions for SERZONE should be written for the smallest quantity of tablets consistent with goodpatient management in order to reduce the risk of overdose.
Seizures
During premarketing testing, a recurrence of a petit mal seizure was observed in a patient receiving nefa- zodonewho hada history of suchseizures. In addition, onenonstudy participant reportedly experienced a convulsion (type not documented) following a multiple-drug overdose (see OVERDOSAGE section). Rare occurrences of convulsions (including grand mal seizures) following nefazodoneadministration have been reported since market introduction. A causal relationship to nefazodonehas not been established (see ADVERSEREACTIONS section).
Priapism
While priapism did not occur during premarketing experience with nefazodone, rare reports of priapism havebeenreceivedsincemarket introduction.A causal relationship to nefazodonehasnot beenestablished (see ADVERSE REACTIONS section). If patients present with prolonged or inappropriate erections, they should discontinuetherapy immediately andconsult their physicians. If thecondition persists for more than 24 hours, a urologist should be consulted to determine appropriate management.
Use in Patients with Concomitant Illness
SERZONE has not beenevaluated or used to any appreciable extent in patients with a recent history of myocardial infarctionor unstable heart disease.Patients with thesediagnoseswere systematically excluded from clinical studies during the product's premarketing testing. Evaluation of electrocardiograms of 1153 patients who receivednefazodonein 6- to 8-week, double-blind, placebo-controlled trials did not indicate that nefazodoneis associated with the development of clinically important ECG abnormalities. 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 patients compared to 0.4% of placebo-treated patients (p <=0.05). Because patients with a recent history of myocardial infarction or unstable heart diseasewere excluded from clinical trials, suchpatients should be treated with caution. In patients with cirrhosis of the liver, theAUCvaluesof nefazodoneandHO-NEF were increasedby approx- imately 25%.
Physiciansare advised to discussthe following issueswith patients for whom theyprescribeSERZONE:
Time to Response/Continuation
As with all antidepressants, several weeks on treatment maybe 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.
InterferenceWith CognitiveandMotor Performance
Since any psychoactive drug may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that SERZONE therapy doesnot adversely affect their ability to engage in suchactivities.
Pregnancy
Patients should be advised to notify their physician if they becomepregnant or intend to becomepregnant during therapy.
Nursing
Patients should be advised to notify their physician if theyare breast-feeding an infant (see
PRECAUTIONS
section, NursingMothers subsection).
Concomitant Medication
Patients should be advised to inform their physicians if theyare 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(r)1, concomitant use with HALCION(r)1 should be avoided for most patients including theelderly, andconcomitant usewith SELDANE(r)2, HISMANAL(r)3, PROPULSID(r)3, ORAP(r)4, or TEGRETOL(r)5 is contraindicated (seeCONTRAINDICATIONS andWARNINGS sections).
Alcohol
Patients should be advised to avoid alcohol while taking SERZONE.
Allergic Reactions
Patients should be advised to notify their physician if they develop a rash, hives, or a related allergic phenomenon.
There are no specific laboratory tests recommended.
DrugsHighly Boundto PlasmaProtein
Because nefazodone is highly bound to plasma protein (see CLINICAL PHARMACOLOGY section, Pharmacokinetics subsection), administration of SERZONE to a patient taking another drug that is highly protein boundmay cause increasedfree concentrations of the other drug, potentially resulting in adverse events. Conversely, adverse effects could result from displacement of nefazodoneby 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 nefazodonedid decrease the subjects' exposure to S-warfarin by 12%, the lack of effects on the prothrombin and bleeding times indi- cates this modest change is not clinically significant. Although these results suggest no adjustments in warfarin dosage are required when nefazodoneis administered to patients stabilized on warfarin, such patients should be monitored as required by standard medical practices.
CNS-ActiveDrugs
MonoamineOxidaseInhibitors--See WARNINGS section. Haloperidol--Whena single oral 5-mg doseof haloperidol was coadministered with nefazodone(200 mg BID) at steady state, haloperidol apparent clearance decreasedby 35% with nosignificant increasein 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 changesin thepharmacokinetic parameters for nefazodone. Dosageadjustment of haloperidol maybenecessary 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--SeeCONTRAINDICATIONS andWARNINGS sections. Alcohol--Althoughnefazodonedid not potentiate thecognitiveandpsychomotor effects of alcohol in exper- iments with normal subjects, the concomitant use of SERZONE and alcohol in depressedpatients 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 buspironeconcentrations(increasesup to 20-fold in Cmaxandup to 50-fold inAUC) andstatistically signif- icant decreases(about 50%) in plasmaconcentrationsof thebuspironemetabolite 1-pyrimidinylpiperazine. With 5-mg BID dosesof buspirone, slight increasesin AUC were observed for nefazodone(23%) and its metabolites hydroxynefazodone(17%) and mCPP (9%). The side effect profile for subjects receiving buspirone 2.5 mg BID and nefazodone250 mg BID was similar to that for subjects receiving either drug alone. Subjects receiving buspirone 5 mg BID and nefazodone250 mg BID experienced side effects such as lightheadedness, asthenia, dizziness, andsomnolence. If the two drugsare to be usedin combination, a low dose of buspirone (e.g., 2.5 mg BID) is recommended. Subsequent dose adjustment of either drug should be basedon clinical assessment. Pimozide--SeeCONTRAINDICATIONS, WARNINGS, andPRECAUTIONS: Pharmacokineticsof Nefazodonein 'Poor Metabolizers' and Potential Interaction with Drugs that Inhibit and/or Are Metabolized by Cytochrome P450 Isozymes. Fluoxetine--When fluoxetine (20 mgQD) and nefazodone(200mg 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 nefazodoneor HO-NEF; however, themeanAUClevels of the nefazodonemetabolites mCPPand triazole-dione increasedby 3- to 6-fold and 1.3-fold, respectively. When a 200-mg doseof nefazodonewas administered to subjects who had been receiving fluoxetine for 1 week, there was an increased incidenceof transient adverse events such as headache, lightheadedness, nausea, or paresthesia, possibly dueto theelevatedmCPPlevels. Patients who are switched from fluoxetine to nefazodonewithout an adequate washout period may experience similar transient adverse events. The possibility of this happening can be minimizedby allowing a washout period before initiating nefazodonetherapy and by reducing the initial doseof nefazodone. Becauseof the long half-life of fluoxetine and its metabolites, this washout period may range from one to several weeks depending on the doseof fluoxetine andother individual patient variables. Phenytoin--Pretreatment for 7 dayswith 200 mg BID of nefazodonehadno effect on the pharmacokinetics of a single 300-mg oral doseof phenytoin. However, due to the nonlinear pharmacokinetics of phenytoin, the failure to observea significant effect on thesingle-dosepharmacokineticsof phenytoin doesnot precludethe possibility of a clinically significant interactionwith nefazodonewhenphenytoin is dosedchronically.However, no change in the initial dosage of phenytoin is considered necessary and any subsequent adjustment of phenytoin dosage should be guidedby usual clinical practices. Desipramine--When nefazodone(150 mg BID) and desipramine (75 mg QD) were administered together there were no changesin the pharmacokinetics of desipramine or its metabolite, 2-hydroxy desipramine. There were alsono changesin thepharmacokinetics of nefazodoneor its triazole-dionemetabolite, but the AUCandCmax of mCPPincreasedby 44% and 48%, respectively, while theAUCof HO-NEF decreasedby 19%. No changesin dosesof either nefazodoneor desipramineare necessary when the two drugsare given concomitantly. Subsequent doseadjustments should be madeon the basis of clinical response. Lithium--In 13 healthysubjects thecoadministrationof nefazodone(200mgBID) with lithium(500mgBID) for 5 days(steady-state conditions) was found to be well tolerated. When the two drugs were coadminis- tered, there were no changes in the steady-state pharmacokinetics of either lithium, nefazodone, or its metaboliteHO-NEF; however, there were small decreasesin thesteady-state plasmaconcentrationsof two nefazodonemetabolites, mCPPand triazole-dione, which are considered not to be of clinical significance. Therefore, nodosageadjustment of either lithiumor nefazodoneis required when theyare coadministered. Carbamazepine--The coadministration of nefazodone(200 mg BID) for 5 days to 12 healthy subjects on carbamazepine who hadachievedsteady state (200mg BID) was found to be well tolerated. Steady-state conditionsfor carbamazepine, nefazodone, andseveral of their metaboliteswere achievedbyday5 of coad- ministration. With coadministration of the two drugs there were significant increases in the steady-state Cmax andAUCof carbamazepine (23% and 23%, respectively), while the steady-state Cmax and theAUCof the carbamazepine metabolite, 10,11 epoxycarbamazepine, decreasedby 21% and 20%, respectively. The coadministration of the two drugs significantly reduced the steady-state Cmax andAUCof nefazodoneby 86% and 93%, respectively. Similar reductions in theCmax andAUCof HO-NEF were also observed (85% and 94%), while the reductions in Cmax andAUCof mCPPand triazole-dionewere more modest (13% and 44% for the former and 28% and 57% for the latter). Due to the potential for coadministration of carba- mazepine to result in insufficient plasmanefazodoneand hydroxynefazodoneconcentrations for achieving an antidepressant effect for SERZONE, it is recommendedthat SERZONE not be usedin combination with carbamazepine (see CONTRAINDICATIONS andWARNINGS sections). General Anesthetics--Little is known about the potential for interaction between nefazodoneand general anesthetics; therefore, prior to elective surgery, SERZONE should be discontinued for as long as clinically feasible. Other CNS-ActiveDrugs--Theuseof nefazodonein combination with other CNS-activedrugshasnot been systematically evaluated.Consequently, caution is advisedif concomitant administrationof SERZONE(nefa- zodonehydrochloride)and suchdrugs is required.
Cimetidine
Whennefazodone(200mgBID) andcimetidine(300mgQID) were coadministered for oneweek, nochange in the steady-state pharmacokinetics of either nefazodoneor cimetidine was observed compared to each dosedalone. Therefore, dosage adjustment is not necessary for either drug when coadministered.
Theophylline
Whennefazodone(200 mg BID) was given to patients being treated with theophylline (600-1200mg/day) for chronic obstructive pulmonary disease, there was no change in the steady-state pharmacokinetics of either nefazodoneor theophylline. FEV1 measurements taken when theophylline and nefazodonewere coadministered did not differ from baseline dosage (i.e., when theophylline was administered alone). Therefore, dosage adjustment is not necessary for either drug when coadministered.
Cardiovascular-ActiveDrugs
Digoxin--When nefazodone(200 mg BID) and digoxin (0.2 mg QD) were coadministered for 9 days to healthy male volunteers (n=18) who were phenotypedasCYP2D6 extensive metabolizers, Cmax, Cmin, and AUCof digoxin were increasedby 29%, 27%, and 15%, respectively. Digoxin had no effects on the phar- macokinetics of nefazodoneand its activemetabolites. Becauseof thenarrow therapeutic indexof digoxin, caution should beexercisedwhen nefazodoneanddigoxin are coadministered; plasmalevel monitoring for digoxin is recommended. Propranolol--The coadministration of nefazodone(200 mg BID) and propranolol (40 mg BID) for 5.5 days to healthymale volunteers (n=18), including3 poor and15extensiveCYP2D6 metabolizers, resulted in 30% and 14% reductions in Cmax and AUC of propranolol, 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 of m-chlorophenylpiperazine were increasedby 23%, 54%, and 28%, respectively. No change in initial dose of either drug is necessary and doseadjustments should be madeon the basis of clinical response. HMG-CoA ReductaseInhibitors--Whensingle 40-mg dosesof simvastatin or atorvastatin, both substrates of CYP3A4, were given to healthy adult volunteers who had received SERZONE 200 mg BID for 6 days, approximately 20-fold increasesin plasmaconcentrationsof simvastatin andsimvastatin acid and3- to 4- fold increasesin plasmaconcentrations of atorvastatin and atorvastatin lactone were seen. Theseeffects appear to be due to the inhibition of CYP3A4 by SERZONE because, in the samestudy, SERZONE had no significant effect on theplasmaconcentrationsof pravastatin, which is not metabolizedbyCYP3A4 to a clin- ically significant extent. There have beenrare 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 section). Rhabdomyolysis has beenobserved in patients receiving HMG-CoA reductase inhibitors administered alone(at recommendeddosages)and in particular, for certain drugs in this class, when given in combination with inhibitors of theCYP3A4 isozyme. Caution should be usedif 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 theseHMG-CoA reductase inhibitors are recommended. Since metabolic interactions are unlikely between SERZONE and HMG-CoA reductase inhibitors that undergo little or no metabolism by the CYP3A4 isozyme, suchas pravastatin or fluvastatin, dosageadjustments should not be necessary.
ImmunosuppressiveAgents
There havebeenreports of increasedbloodconcentrationsof cyclosporineand tacrolimus into toxic ranges when patients received thesedrugs concomitantly with SERZONE. Both cyclosporine and tacrolimus are substrates of CYP3A4, andnefazodoneis known to inhibit this enzyme. If either cyclosporine or tacrolimus is administered with SERZONE, bloodconcentrationsof the immunosuppressiveagent should bemonitored and dosage adjusted accordingly.
Pharmacokinetics of Nefazodonein 'Poor Metabolizers' andPotential Interaction with Drugs that Inhibit and/or Are MetabolizedbyCytochromeP450 Isozymes
CYP3A4 Isozyme--Nefazodonehasbeenshown in vitro to bean inhibitor of CYP3A4.This is consistent with the interactions observed between nefazodoneand triazolam, alprazolam, buspirone, atorvastatin, and simvastatin, drugsmetabolizedby this isozyme. Consequently, caution is indicated in the combineduseof nefazodonewith any drugs known to be metabolized by CYP3A4. In particular, the combineduseof nefa- zodonewith triazolamshould beavoidedfor most patients, including theelderly.Thecombineduseof nefa- zodonewith terfenadine, astemizole, cisapride, or pimozide is contraindicated (see CONTRAINDICATIONS andWARNINGS sections). CYP2D6 Isozyme--A subset (3% to 10%) of the population has reduced activity of the drug-metabolizing enzymeCYP2D6. Such individuals are referred to commonly as "poor metabolizers" of drugssuchasdebriso- quin, dextromethorphan, and the tricyclic antidepressants. Thepharmacokinetics of nefazodoneand its major metabolites are not altered in these "poor metabolizers." Plasma concentrations of one minor metabolite (mCPP) are increasedin this population; the adjustment of SERZONE dosage is not required when adminis- tered to "poor metabolizers." Nefazodoneand its metabolites havebeenshown in vitro to beextremely weak inhibitors of CYP2D6. Thus, it is not likely that nefazodonewill decrease the metabolic clearance of drugs metabolizedby this isozyme. CYP1A2 Isozyme--Nefazodoneand its metabolites have beenshown in vitro not to inhibit CYP1A2. Thus, metabolic interactions betweennefazodoneand drugsmetabolizedby this isozymeare unlikely.
ElectroconvulsiveTherapy (ECT)
There are no clinical studies of the combineduseof ECT and nefazodone. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis There is no evidenceof carcinogenicity with nefazodone. The dietary administration of nefazodoneto rats and mice for 2 years at daily dosesof up to 200 mg/kg and 800 mg/kg, respectively, which are approxi- mately 3 and 6 times, respectively, the maximum human daily dose on a mg/m 2 basis, produced no increasein tumors.
Mutagenesis
Nefazodonehas beenshown to have no genotoxic effects basedon the following assays: bacterial muta- tion assays, a DNA repair assay in cultured rat hepatocytes, a mammalian mutation assay in Chinese hamster ovary cells, an in vivo cytogeneticsassayin rat bonemarrow cells, anda rat dominant lethal study.
Impairment of Fertility
A fertility study in rats showed a slight decreasein fertility at 200 mg/kg/day(approximately three times the maximum humandaily dose on a mg/m2 basis) but not at 100 mg/kg/day (approximately 1.5 times the maximumhumandaily doseon a mg/m2 basis).
Teratogenic Effects--Pregnancy Category C
Reproduction studies have beenperformed in pregnant rabbits and rats at daily dosesup to 200 and 300 mg/kg, respectively (approximately 6 and5 times, respectively, themaximumhumandaily doseona mg/m 2 basis). No malformations were observed in the offspring as a result of nefazodonetreatment. However, increasedearly pupmortality wasseenin rats at a doseapproximately five timesthemaximumhumandose, and decreasedpup weights were seenat this and lower doses, when dosing beganduring pregnancy and continueduntil weaning. The causeof thesedeaths is not known. The no-effect dosefor rat pup mortality was1.3 timesthehumandoseona mg/m2 basis.There are noadequate andwell-controlledstudies in preg- nant women. Nefazodoneshould beusedduring pregnancy only if thepotential benefit justifies thepotential risk to the fetus.
The effect of SERZONE (nefazodonehydrochloride)on labor and delivery in humansis unknown.
It is not known whether SERZONE or its metabolites are excreted in humanmilk. Becausemany drugsare excreted in humanmilk, caution should be exercisedwhenSERZONE is administered to a nursing woman.
Pediatric Use
Safety andeffectivenessin individuals below 18 years of age have not beenestablished.
Of the approximately 7000patients in clinical studies who receivedSERZONE for the treatment of depres- sion, 18% were 65 years and older, while 5% were 75 years and older. Basedon monitoring of adverse events, vital signs, electrocardiograms, and results of laboratory tests, no overall differences in safety betweenelderly andyounger patients were observedin clinical studies. Efficacy in theelderly hasnot been demonstrated in placebo-controlled trials. Other reported clinical experience hasnot identified differences in responsesbetweenelderly andyounger patients, but greater sensitivity of someolder individuals cannot be ruled out. Due to the increasedsystemic exposure to nefazodoneseenin single-dosestudies in elderly patients (see CLINICAL PHARMACOLOGY section, Pharmacokinetics subsection), treatment should be initiated at half the usual dose, but titration upward should take place over the samerange as in younger patients (see DOSAGEANDADMINISTRATION section).Theusual precautionsshould beobservedin elderly patients who have concomitant medical illnessesor who are receiving concomitant drugs.
Associated with Discontinuation of Treatment
Approximately 16% of the 3496patients who receivedSERZONE (nefazodonehydrochloride) in worldwide premarketing clinical trials discontinuedtreatment dueto anadverseexperience.Themore common( >=1%) events in clinical trials associated with discontinuationandconsidered to bedrug related (i.e., thoseevents associated with dropout 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%).
Incidencein Controlled Trials
Commonly ObservedAdverseEvents in ControlledClinical Trials
The most commonly observed adverse events associated with the use of SERZONE (incidenceof 5% or greater) and not seenat an equivalent incidenceamongplacebo-treated patients (i.e., significantly higher incidencefor SERZONEcompared to placebo, p<=0.05), derivedfrom the table below, were: somnolence, dry mouth, nausea, dizziness, constipation, asthenia, lightheadedness, blurred vision, confusion, andabnormal vision.
AdverseEvents Occurring at an Incidenceof 1% or MoreAmongSERZONE-TreatedPatients
The table that follows enumerates adverse events that occurred at an incidenceof 1% or more, and were more frequent than in the placebogroup, amongSERZONE-treated patients who participated in short-term (6- to 8-week) placebo-controlled trials in which patients were dosed with SERZONE (nefazodone hydrochloride) to rangesof 300 to 600 mg/day. This table shows the percentage of patients in each group who had at least one episodeof an event at sometime during their treatment. Reported adverse events were classified using standard COSTART-basedDictionary terminology. Theprescriber should beaware that thesefigures cannot beusedto predict the incidenceof sideeffects in the course of usual medical practice where patient characteristics andother factors differ from thosewhich prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators.Thecited figures, however, do provide the prescribing physician with somebasis for estimating the relative contribution of drug and nondrug factors to the side-effect incidencerate in the population studied. Treatment-Emergent AdverseExperience Incidencein 6- to 8-Week Placebo-ControlledClinical Trials1, SERZONE 300 to 600 mg/dayDoseRange
| Body System | PreferredTerm | SERZONE (n=393) | Placebo (n=394) |
| Body as aWhole | Headache | 36 | 33 |
| Asthenia | 11 | 5 | |
| Infection | 8 | 6 | |
| Flu syndrome | 3 | 2 | |
| Chills | 2 | 1 | |
| Fever | 2 | 1 | |
| Neck rigidity | 1 | 0 | |
| Cardiovascular | Postural hypotension | 4 | 1 |
| Hypotension | 2 | 1 | |
| Dermatological | Pruritus | 2 | 1 |
| Rash | 2 | 1 | |
| Gastrointestinal | Dry mouth | 25 | 13 |
| Nausea | 22 | 12 | |
| Constipation | 14 | 8 | |
| Dyspepsia | 9 | 7 | |
| Diarrhea | 8 | 7 | |
| Increasedappetite | 5 | 3 | |
| Nausea& vomiting | 2 | 1 | |
| Metabolic | Peripheral edema | 3 | 2 |
| Thirst | 1 | < 1 | |
| Musculoskeletal | Arthralgia | 1 | < 1 |
| Nervous | Somnolence | 25 | 14 |
| Dizziness | 17 | 5 | |
| Insomnia | 11 | 9 | |
| Lightheadedness | 10 | 3 | |
| Confusion | 7 | 2 | |
| Memory impairment | 4 | 2 | |
| Paresthesia | 4 | 2 | |
| Vasodilatation 2 | 4 | 2 | |
| Abnormal dreams | 3 | 2 | |
| Concentration decreased | 3 | 1 | |
| Ataxia | 2 | 0 | |
| Incoordination | 2 | 1 | |
| Psychomotor retardation | 2 | 1 | |
| Tremor | 2 | 1 | |
| Hypertonia | 1 | 0 | |
| Libido decreased | 1 | < 1 | |
| Respiratory | Pharyngitis | 6 | 5 |
| Cough increased | 3 | 1 | |
| Special Senses | Blurred vision | 9 | 3 |
| Abnormal vision 3 | 7 | 1 | |
| Tinnitus | 2 | 1 | |
| Taste perversion | 2 | 1 | |
| Visual field defect | 2 | 0 | |
| Urogenital | Urinary frequency | 2 | 1 |
| Urinary tract infection | 2 | 1 | |
| Urinary retention | 2 | 1 | |
| Vaginitis 4 | 2 | 1 | |
| Breast pain 4 | 1 | < 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% indicatesan incidencelessthan0.5%).Events for which the SERZONE incidencewas 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, agita- tion, anxiety, depression, hypesthesia, CNS stimulation, dysphoria, emotional lability, sinusitis, rhinitis, dysmenorrhea4, dysuria.
Vasodilatation--flushing, feeling warm.
Abnormal vision--scotoma, visual trails.
Incidenceadjusted for gender.
DoseDependency of AdverseEvents
The table that follows enumerates adverse events that were more frequent in the SERZONE (nefazodone hydrochloride)doserangeof 300 to 600mg/daythanin theSERZONEdoserangeof up to 300mg/day.This table shows only thoseadverse events for which there was a statistically significant difference (p <=0.05) in incidencebetween the SERZONE dose rangesas well as a difference between the high dose range and placebo. DoseDependency of AdverseEvents in Placebo-ControlledTrials1 Percent of Patients
| Body System | PreferredTerm | SERZONE 300-600 mg/day (n = 209) | SERZONE <= 300 mg/day (n = 211) | Placebo (n = 212) |
| Gastrointestinal | Nausea | 23 | 14 | 12 |
| Constipation | 17 | 10 | 9 | |
| Nervous | Somnolence | 28 | 16 | 13 |
| Dizziness | 22 | 11 | 4 | |
| Confusion | 8 | 2 | 1 | |
| Special Senses | Abnormal vision | 10 | 0 | 2 |
| Blurred vision | 9 | 3 | 2 | |
| Tinnitus | 3 | 0 | 1 |
1 Events for which there was a statistically significant difference (p <=0.05)between the nefazodonedose groups.
Vital SignChanges
(See PRECAUTIONS section, Postural Hypotension subsection.)
Weight Changes
In a pooled analysis of placebo-controlled premarketing studies, there were no differences between nefa- zodoneandplacebogroupsin theproportionsof patients meetingcriteria for potentially important increases or decreasesin body weight (a changeof >=7%).
Laboratory Changes
Of theserumchemistry, serumhematology, andurinalysis parameters monitored during placebo-controlled premarketing studies with nefazodone, a pooled analysis revealed a statistical trend between nefazodone and placebo for hematocrit, i.e., 2.8% of nefazodonepatients met criteria for a potentially important decreasein hematocrit (<=37%male or <=32% female) compared to 1.5%of placebopatients (0.05 ECGChanges
Of the ECG parameters monitored during placebo-controlled premarketing studies with nefazodone, a pooled analysis revealed a statistically significant difference between nefazodoneand placebo for sinus bradycardia, i.e., 1.5% of nefazodonepatients met criteria for a potentially important decreasein heart rate (<=50 bpm and a decrease of >=15 bpm) compared to 0.4% of placebo patients (p<0.05).
There was no obvious clinical significance of the observedchangesin the few patients meeting thesecriteria.
Other Events Observed During the Premarketing Evaluation of SERZONE
During its premarketing assessment, multiple dosesof SERZONE (nefazodonehydrochloride)were admin- istered to 3496patients in clinical studies, including more than 250 patients treated for at least one year.
Theconditionsanddurationof exposure toSERZONEvariedgreatly, andincluded(in overlappingcategories) openanddouble-blind studies, uncontrolled and controlled studies, inpatient andoutpatient studies, fixed- doseand titration studies.
Untoward events associated with this exposure were recordedby clinical inves- tigators using terminology of their own choosing.
Consequently, it is not possible to provide a meaningful estimate of theproportion of individuals experiencing adverseevents without first grouping similar typesof untoward events into a smaller number of standardizedevent 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 exposedto multiple dosesof SERZONE who experienced an event of the typecited on at least oneoccasion while receiving SERZONE.
All reported events are included except those already listed in the Treatment- EmergentAdverseExperience Incidencetable, thoseevents listed inother safety-relatedsectionsof this insert, thoseadverse experiences subsumedunder COSTART terms that are either overly general or excessively specific so as to be uninformative, thoseevents for which a drug causewas very remote, and thoseevents which were not seriousandoccurred in fewer than two patients.
It is important to emphasize that, althoughthe events reported occurred during treatment with SERZONE, theywere not necessarily causedby it.
Events are further categorizedby body system and listed in order of decreasing frequency according to the following definitions: frequent adverseevents are thoseoccurring on oneor more occasions in at least 1/100 patients (only thosenot already listed in the tabulated results from placebo-controlled trials appear in this listing);
infrequent adverse events are thoseoccurring in 1/100 to 1/1000 patients;
rare events are those occurring in fewer than1/1000patients.
Body as a whole--
Infrequent:allergic reaction, malaise, photosensitivity reaction, face edema, hangover effect, abdomenenlarged, hernia, pelvic pain, andhalitosis.
Rare:cellulitis.
Cardiovascular system--
Infrequent:tachycardia, hypertension, syncope, ventricular extrasystoles, andangina pectoris.
Rare:AV block, congestive heart failure, hemorrhage, pallor, andvaricosevein.
Dermatological system--
Infrequent:dry skin, acne, alopecia, urticaria, maculopapular rash, vesiculobullous rash, andeczema.
Gastrointestinal system--
Frequent:gastroenteritis.
Infrequent:eructation, periodontal abscess, abnormal liver function tests, gingivitis, colitis, gastritis, mouth ulceration, stomatitis, esophagitis, peptic ulcer, and rectal hemorrhage.
Rare:glossitis, hepatitis, dysphagia, gastrointestinal hemorrhage, oral moniliasis, andulcerative colitis.
Hemic and lymphatic system--
Infrequent:ecchymosis, anemia, leukopenia, and lymphadenopathy.
Metabolic andnutritional system--
Infrequent:weight loss, gout, dehydration, lactic dehydrogenaseincreased, SGOT increased, andSGPT increased.
Rare:hypercholesteremia andhypoglycemia.
Musculoskeletal system--
Infrequent:arthritis, tenosynovitis, muscle stiffness, and bursitis.
Rare:tendinous contracture.
Nervous system--
Infrequent:vertigo, twitching, depersonalization, hallucinations, suicide attempt, apathy, euphoria, hostility, suicidal thoughts, abnormal gait, thinking abnormal, attention decreased, derealization, neuralgia, paranoid reaction, dysarthria, increasedlibido, suicide, andmyoclonus.
Rare:hyperkinesia, increased salivation, cerebrovascular accident, hyperesthesia, hypotonia, ptosis, andneuroleptic malignant syndrome.
Respiratory system--
Frequent:dyspneaandbronchitis.
Infrequent:asthma, pneumonia, laryngitis, voicealter- ation, epistaxis, hiccup.
Rare:hyperventilation andyawn.
Special senses--
Frequent:eye pain.
Infrequent:dry eye, ear pain, abnormality of accommodation, diplopia, conjunctivitis, mydriasis, keratoconjunctivitis, hyperacusis, andphotophobia.
Rare:deafness, glaucoma, night blindness, and taste loss.
Urogenital system--
Frequent:impotencea.
Infrequent:cystitis, urinary urgency, metrorrhagiaa, amenorrheaa, polyuria, vaginal hemorrhagea, breast enlargementa, menorrhagiaa, urinary incontinence, abnormal ejacula- tiona, hematuria, nocturia, and kidneycalculus.
Rare:uterine fibroids enlargeda, uterine hemorrhagea, anor- gasmia, andoliguria.
a
Adjusted for gender.
Postintroduction Clinical Experience
Postmarketing experience with SERZONE has shown an adverse experience profile similar to that seen during the premarketing evaluation of nefazodone.
Voluntary reports of adverse events temporally associ- ated with SERZONE havebeenreceivedsincemarket introduction that are not listed aboveand for which a causal relationship hasnot beenestablished.
Theseinclude: Rare occurrences of convulsions(including grandmal seizures) andpriapism (see PRECAUTIONS section);
Rare reports of rhabdomyolysis involving patients receiving the combination of SERZONEand lovastatin or simvastatin (see PRECAUTIONS section);
Rare reports of liver necrosis and liver failure, in somecasesleading to liver transplantation and/or death.
DRUGABUSE ANDDEPENDENCE
Controlled SubstanceClass
SERZONE (nefazodonehydrochloride) is not a controlled substance.
Physical andPsychological Dependence
In animal studies, nefazodonedid not act as a reinforcer for intravenousself-administration in monkeys trained to self-administer cocaine, suggesting no abuse liability.
In a controlled study of abuse liability in humansubjects, nefazodoneshowed no potential for abuse.
Nefazodonehasnot beensystematically studied in humansfor its potential for tolerance, physical depend- ence, or withdrawal.While the premarketing clinical experience with nefazodonedid not reveal any tendency for a withdrawal syndromeor any drug-seekingbehavior, it is not possible to predict on thebasis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abusedonce marketed.
Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuseor abuseof SERZONE (e.g., development of tolerance, doseescalation, drug-seeking behavior).
In premarketing clinical studies, there were sevenreports of nefazodoneoverdosealoneor in combination with other pharmacological agents. The amount of nefazodoneingested rangedfrom 1000 mg to 11,200 mg. Commonly reported symptoms from overdoseof nefazodoneincludednausea, vomiting, and somno- lence. One nonstudy participant took 2000-3000mg of nefazodonewith methocarbamol and alcohol; this personreportedly experienced a convulsion (typenot documented). Noneof thesepatients died. In postmarketing experience, overdosewith SERZONE alone and in combination with alcohol and/or other substances hasbeenreported. Commonly reported symptomswere similar to thosereported from overdose in premarketing experience. While there have beenrare reports of fatalities in patients taking overdosesof nefazodone, predominantly in combination with alcohol and/or other substances, no causal relationship to nefazodonehasbeenestablished.
Treatment should consist of thosegeneral measures employed in themanagement of overdosage 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 tube with appropriate airway protection, if needed, may be indi- cated if performedsoonafter ingestion, or in symptomatic patients. Activatedcharcoal should beadministered.Dueto thewidedistributionof nefazodonein body tissues, forced diuresis, dialysis, hemoperfusion, andexchangetransfusionare unlikely to beof benefit.No specific antidotes for nefazodoneare known. In managingoverdosage, consider thepossibility of multiple drug involvement.Thephysicianshould consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poisoncontrol centers are listed in the Physicians' Desk Reference (PDR).
The recommendedstarting dosefor SERZONE (nefazodonehydrochloride) is 200 mg/day, administered in two divideddoses(BID). In thecontrolled clinical trials establishing theantidepressant efficacy of SERZONE, the effective dose range was generally 300 to 600 mg/day. Consequently, most patients, depending on tolerability and theneedfor further clinical effect, should have their doseincreased. Dose increasesshould occur in increments of 100 mg/day to 200 mg/day, again on a BID schedule, at intervals of no less than 1 week. As with all antidepressants, several weeks on treatment may be required to obtain a full antide- pressant response.
The recommendedinitial dosefor elderly or debilitated patients is 100mg/day, administered in two divided doses(BID). Thesepatients often have reduced nefazodoneclearance and/or increasedsensitivity to the sideeffects of CNS-activedrugs. It mayalsobeappropriate to modify the rate of subsequent dosetitration. As steady-state plasmalevels donot changewith age, the final target dosebasedon a careful assessment of the patient's clinical responsemaybe similar in healthy younger andolder patients.
There is no body of evidenceavailable from controlled trials to indicate how long the depressedpatient should be treated with SERZONE. It is generally agreed, however, that pharmacological treatment for acute episodesof depression should continue for up to 6 months or longer. Whether the doseof antidepressant neededto induceremission is identical to the doseneededto maintain euthymia is unknown. Systematic evaluation of the efficacy of SERZONE hasshown that efficacy is maintained for periodsof 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 dosewas that associated with responseduring acute treatment. (SeeCLINICALPHARMACOLOGY section.) Thesafety of SERZONE in long-term useis supported by data from both double-blind and open-label trials involving more than 250 patients treated for at least oneyear.
At least 14 daysshould elapsebetweendiscontinuationof anMAOI and initiationof therapy with SERZONE. In addition, at least 7 daysshould be allowed after stopping SERZONE before starting an MAOI.
SERZONE(r) (nefazodonehydrochloride) tablets are hexagonal tablets imprinted with BMSand the strength (i.e., 100mg)on onesideand the identification codenumber on theother. The 100mg and150mg tablets are bisect scored on both tablet faces. The 50 mg, 200 mg, and 250 mg tablets are unscored.
NDCCODE DESCRIPTION
NDC 0087-0031-47 50 mg light pink tablet, bottle of 60 NDC 0087-0032-31 100 mg white tablet, bottle of 60 NDC 0087-0039-31 150 mg peachtablet, bottle of 60 NDC 0087-0033-31 200 mg light yellow tablet, bottle of 60 NDC 0087-0041-31 250 mg white tablet, bottle of 60 U.S. Patent No. 4,338,317 Store at room temperature, below 40oC (104oF) and dispensein a tight container.
HALCION(r) andXANAX(r) are registered trademarks of theUpjohnCompany.
SELDANE(r) is a registered trademark of Merrell Pharmaceuticals, Incorporated, a subsidiary of Hoechst MarionRoussel.
HISMANAL(r) andPROPULSID(r) are registered trademarks of JanssenPharmaceutica, Incorporated.
ORAP(r) is a registered trademark of Gate Pharmaceuticals, a division of TevaPharmaceuticals USA.
TEGRETOL(r) is a registered trademark of Novartis Corporation.
Bristol-Myers Squibb Company
Princeton, NJ 08543 U.S.A.
RevisedJune 2000 Printed in USA 0032DIM-15 P4460-13 D5-B001-08-00