Side Effects of Serzone (nefazodone)

Serzone (nefazodone) is an antidepressant used to treat depression.

Many experts believe depression is caused by an imbalance among the amounts of neurotransmitters released in the brain. Serzone works by inhibiting the uptake by nerves of the neurotransmitters serotonin and norepinephrine, resulting in more serotonin and norepinephrine to transmit messages to other nerves.

Serzone is chemically unrelated to the serotonin reuptake inhibitors (SSRIs), the tricyclic antidepressants (TCAs), or the monoamine oxidase inhibitors (MAOIs). It is chemically related to the antidepressant trazodone and shares its actions. The brand name Serzone is no longer is available in the U.S.

Common side effects of Serzone include

• nausea,
• dizziness,
• insomnia,
• agitation,
• tiredness,
• dry mouth,
• constipation,
• lightheadedness,
• blurred vision, and
• confusion. 

Serious side effects of Serzone include

• prolonged penile erection (priapism),
• liver failure that may result in liver transplantation, and
• increased risk of suicidal thinking and behavior in children and adolescents with depression and other psychiatric disorders.

If antidepressants such as Serzone are discontinued abruptly, withdrawal symptoms may occur such as

• dizziness,
• headache,
• nausea,
• changes in mood, and
• changes in the sense of smell, taste, etc. 

Drug interactions of Serzone include monoamine oxidase inhibitors (MAOIs) because such combinations may lead to

• confusion,
• high blood pressure,
• tremor, and
• increased activity.

Serzone may increase the blood concentration of several drugs by reducing their removal by the liver. Through this mechanism Serzone may markedly increase the blood concentrations of triazolam and alprazolam, resulting in excessive sedation and impaired ability to perform tasks.

Serzone also may increase the blood concentration and possibly the side effects of eletriptan, eplerenone, pimozide, ranolazine, and silodosin. Carbamazepine may decrease Serzone blood levels and possibly its effectiveness by increasing Serzone's removal by the liver.

Conversely, Serzone may increase the levels of carbamazepine, possibly leading to toxicity, by decreasing the removal of carbamazepine by the liver.

If you are planning pregnancy, become pregnant, or think you may be pregnant, immediately discuss with your doctor the benefits and risks of using Serzone during pregnancy.

Serzone may be secreted in breast milk and may cause adverse effects in the nursing infant.  Consult your doctor before breastfeeding. 

The most commonly noted side effects associated with nefazodone are

• nausea,
• dizziness,
• insomnia,
• agitation,
• tiredness,
• dry mouth,
• constipation,
• lightheadedness,
• blurred vision, and
• confusion.

Rarely, nefazodone is associated with priapism or prolonged penile erection.

Compared with trazodone, nefazodone has a lesser risk of priapism (prolonged penile erection). Although the erection usually subsides eventually, occasionally blood clots form within the penis and cause serious damage to the penis. Nefazodone rarely may cause liver failure that may result in liver transplantation.

If antidepressants are discontinued abruptly, symptoms may occur such as dizziness, headache, nausea, changes in mood, or changes in the sense of smell, taste, etc. (Such symptoms even may occur when even a few doses of antidepressant are missed.) Therefore, it is recommended that the dose of antidepressant be reduced gradually when therapy is discontinued.

Antidepressants increased the risk of suicidal thinking and behavior in short-term studies in children and adolescents with depression and other psychiatric disorders.

Anyone considering the use of nefazodone or any other antidepressant in a child or adolescent must balance this risk of suicide with the clinical need. Patients who are started on therapy should be closely observed for clinical worsening, suicidal thoughts, or unusual changes in behavior.

Associated with Discontinuation of Treatment

Approximately 16% of the 3496 patients who received Serzone (nefazodone hydrochloride) in worldwide premarketing clinical trials discontinued treatment due to an adverse experience.

The more common (≥1%) events in clinical trials associated with discontinuation and considered to be drug related (ie, those events associated with dropout at a rate approximately twice or greater for Serzone (nefazodone) compared to placebo) included:

• nausea (3.5%),
• dizziness (1.9%),
• insomnia (1.5%),
• asthenia (1.3%), and
• agitation (1.2%).

Incidence in Controlled Trials

Commonly Observed Adverse Events in Controlled Clinical Trials

The most commonly observed adverse events associated with the use of Serzone (nefazodone) (incidence of 5% or greater) and not seen at an equivalent incidence among placebo-treated patients (ie, significantly higher incidence for Serzone (nefazodone) 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 (nefazodone) -Treated Patients

The table that follows enumerates adverse events that occurred at an incidence of 1% or more, and were more frequent than in the placebo group, among Serzone (nefazodone)-treated patients 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 600 mg/day.

This table shows the percentage of patients in each group who had at least one episode of an event at some time during their treatment. Reported adverse events were classified using standard COSTART-based Dictionary terminology.

The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials.

Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side-effect incidence rate in the population studied.

Treatment-Emergent Adverse Experience Incidence in 6- to 8-Week Placebo-Controlled Clinical Trials¹, Serzone (nefazodone) 300 to 600 mg/day Dose Range

		Percent of Patients
Body System	Preferred Term	Serzone (n=393)	Placebo (n=394)
Body as a Whole	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
	Increased appetite	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
	Vasodilatation2	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 vision3	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
	Vaginitis4	2	1
	Breast pain4	1	<1
1. Events reported by at least 1% of patients treated with Serzone (nefazodone) 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 (nefazodone) 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, emotional lability, sinusitis, rhinitis, dysmenorrhea4, dysuria.
2. Vasodilatation-flushing, feeling warm.
3. Abnormal vision-scotoma, visual trails.
4. Incidence adjusted for gender.

Dose Dependency of Adverse Events

The table that follows enumerates adverse events that were more frequent in the Serzone (nefazodone hydrochloride) dose range of 300 to 600 mg/day than in the Serzone (nefazodone) dose range of up to 300 mg/day.

This table shows only those adverse events for which there was a statistically significant difference (p≥0.05) in incidence between the Serzone (nefazodone) dose ranges as well as a difference between the high dose range and placebo.

Dose Dependency of Adverse Events in Placebo-Controlled Trials¹

		Percent of Patients
Body System	Preferred Term	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 nefazodone dose groups.

Visual Disturbances

• In controlled clinical trials, blurred vision occurred in 9% of nefazodone-treated patients compared to 3% of placebo-treated patients.
• In these same trials, abnormal vision, including scotomata and visual trails, occurred in 7% of nefazodone-treated patients compared to 1% of placebo-treated (see Treatment-Emergent Adverse Experience table, above).
• Dose-dependency was observed for these events in these trials, with none of the scotomata and visual trails at doses below 300 mg/day.
• However, scotomata and visual trails observed at doses below 300 mg/day have been reported in postmarketing experience with Serzone.

Vital Sign Changes

See prescribing information.

Weight Changes

In a pooled analysis of placebo-controlled premarketing studies, there were no differences between nefazodone and placebo groups in the proportions of patients meeting criteria for potentially important increases or decreases in body weight (a change of ≥7%).

Laboratory Changes

Of the serum chemistry, serum hematology, and urinalysis parameters monitored during placebo-controlled premarketing studies with nefazodone, a pooled analysis revealed a statistical trend between nefazodone and placebo for hematocrit, ie, 2.8% of nefazodone patients met criteria for a potentially important decrease in hematocrit (≤37% male or ≤32% female) compared to 1.5% of placebo patients (0.05p≤0.10).

Decreases in hematocrit, presumably dilutional, have been reported with many other drugs that block alpha₁-adrenergic receptors. There was no apparent clinical significance of the observed changes in the few patients meeting these criteria.

ECG Changes

Of the ECG parameters monitored during placebo-controlled premarketing studies with nefazodone, a pooled analysis revealed a statistically significant difference between nefazodone and placebo for sinus bradycardia, ie, 1.5% of nefazodone patients met criteria for a potentially important decrease in 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 observed changes in the few patients meeting these criteria.

Other Events Observed During the Premarketing Evaluation of Serzone (nefazodone)

• During its premarketing assessment, multiple doses of Serzone (nefazodone hydrochloride) were administered to 3496 patients in clinical studies, including more than 250 patients treated for at least one year.
• The conditions and duration of exposure to Serzone (nefazodone) varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, fixed-dose and titration studies.
• Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing.
• Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories.
• In the tabulations that follow, reported adverse events were classified using standard COSTART-based Dictionary terminology.
• The frequencies presented, therefore, represent the proportion of the 3496 patients exposed to multiple doses of Serzone (nefazodone) who experienced an event of the type cited on at least one occasion while receiving Serzone (nefazodone).
• All reported events are included except those already listed in the Treatment-Emergent Adverse Experience Incidence table, those events listed in other safety-related sections of this insert, those adverse experiences subsumed under COSTART terms that are either overly general or excessively specific so as to be uninformative, those events for which a drug cause was very remote, and those events which were not serious and occurred in fewer than two patients.
• It is important to emphasize that, although the events reported occurred during treatment with Serzone (nefazodone) , 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 those occurring on one or more occasions in at least 1/100 patients (only those not already listed 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 are those occurring in fewer than 1/1000 patients.

Body as a whole - Infrequent: allergic reaction, malaise, photosensitivity reaction, face edema, hangover effect, abdomen enlarged, hernia, pelvic pain, and halitosis. Rare: cellulitis.

Cardiovascular system - Infrequent: tachycardia, hypertension, syncope, ventricular extrasystoles, and angina pectoris. Rare: AV block, congestive heart failure, hemorrhage, pallor, and varicose vein.

Dermatological system - Infrequent: dry skin, acne, alopecia, urticaria, maculopapular rash, vesiculobullous rash, and eczema.

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, and ulcerative colitis.

Hemic and lymphatic system - Infrequent: ecchymosis, anemia, leukopenia, and lymphadenopathy.

Metabolic and nutritional system - Infrequent: weight loss, gout, dehydration, lactic dehydrogenase increased, SGOT increased, and SGPT increased. Rare: hypercholesteremia and hypoglycemia.

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, increased libido, suicide, and myoclonus. Rare: hyperkinesia, increased salivation, cerebrovascular accident, hyperesthesia, hypotonia, ptosis, and neuroleptic malignant syndrome.

Respiratory system - Frequent: dyspnea and bronchitis. Infrequent: asthma, pneumonia, laryngitis, voice alteration, epistaxis, hiccup. Rare: hyperventilation and yawn.

Special senses - Frequent: eye pain. Infrequent: dry eye, ear pain, abnormality of accommodation, diplopia, conjunctivitis, mydriasis, keratoconjunctivitis, hyperacusis, and photophobia. Rare: deafness, glaucoma, night blindness, and taste loss.

Urogenital system - Frequent: impotence. Infrequent: cystitis, urinary urgency, metrorrhagia, amenorrhea, polyuria, vaginal hemorrhage, breast enlargement, menorrhagia, urinary incontinence, abnormal ejaculation, hematuria, nocturia, and kidney calculus. Rare: uterine fibroids enlarged, uterine hemorrhage, anorgasmia, and oliguria. Adjusted for gender.

Postintroduction Clinical Experience

Postmarketing experience with Serzone (nefazodone) has shown an adverse experience profile similar to that seen during the premarketing evaluation of nefazodone. Voluntary reports of adverse events temporally associated with Serzone (nefazodone) have been received since market introduction that are not listed above and for which a causal relationship has not been established.

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;
• priapism;
• prolactin increased;
• rhabdomyolysis involving patients receiving the combination of Serzone (nefazodone) and lovastatin or simvastatin;
• serotonin syndrome;
• Stevens-Johnson syndrome; and
• thrombocytopenia.

Drugs Highly Bound to Plasma Protein

• Because nefazodone is highly bound to plasma protein, administration of Serzone (nefazodone) 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 prescribing information.

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 prescribing information.

Alcohol

• Although nefazodone did not potentiate the cognitive and psychomotor effects of alcohol in experiments with normal subjects, the concomitant use of Serzone (nefazodone) 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 C_max and up to 50-fold in AUC) and statistically significant decreases (about 50%) in plasma concentrations of the buspirone metabolite 1-pyrimidinylpiperazine.
• With 5-mg BID doses of buspirone, slight increases in AUC were observed for nefazodone (23%) and its metabolites hydroxynefazodone (17%) and mCPP (9%).
• Subjects receiving nefazodone 250 mg BID and buspirone 5 mg BID experienced lightheadedness, asthenia, dizziness, and somnolence, adverse events also observed with either drug alone.
• If the two drugs are to be used in combination, a low dose of buspirone (eg, 2.5 mg QD) is recommended. Subsequent dose adjustment of either drug should be based on clinical assessment.

Pimozide

• See prescribing information.

Fluoxetine

• When fluoxetine (20 mg QD) and nefazodone (200 mg BID) were administered at steady state there were no changes in the pharmacokinetic parameters for fluoxetine or its metabolite, norfluoxetine.
• Similarly, there were no changes in the pharmacokinetic parameters of nefazodone or HO-NEF; however, the mean AUC levels of the nefazodone metabolites mCPP and triazoledione increased by 3- to 6-fold and 1.3-fold, respectively.
• When a 200-mg dose of nefazodone was administered to subjects who had been receiving fluoxetine for 1 week, there was an increased incidence of transient adverse events such as headache, lightheadedness, nausea, or paresthesia, possibly due to the elevated mCPP levels.
• Patients who are switched from fluoxetine to nefazodone without an adequate washout period may experience similar transient adverse events. The possibility of this happening can be minimized by allowing a washout period before initiating nefazodone therapy and by reducing the initial dose of nefazodone.
• Because of the long half-life of fluoxetine and its metabolites, this washout period may range from one to several weeks depending on the dose of fluoxetine and other individual patient variables.

Phenytoin

• Pretreatment for 7 days with 200 mg BID of nefazodone had no effect on the pharmacokinetics of a single 300-mg oral dose of phenytoin.
• However, due to the nonlinear pharmacokinetics of phenytoin, the failure to observe a significant effect on the single-dose pharmacokinetics of phenytoin does not preclude the possibility of a clinically significant interaction with nefazodone when phenytoin is dosed chronically.
• However, no change in the initial dosage of phenytoin is considered necessary and any subsequent adjustment of phenytoin dosage should be guided by usual clinical practices.

Desipramine

• When nefazodone (150 mg BID) and desipramine (75 mg QD) were administered together there were no changes in the pharmacokinetics of desipramine or its metabolite, 2-hydroxy desipramine.
• There were also no changes in the pharmacokinetics of nefazodone or its triazoledione metabolite, but the AUC and C_max of mCPP increased by 44% and 48%, respectively, while the AUC of HO-NEF decreased by 19%.
• No changes in doses of either nefazodone or desipramine are necessary when the two drugs are given concomitantly.
• Subsequent dose adjustments should be made on the basis of clinical response.

Lithium

• In 13 healthy subjects the coadministration of nefazodone (200 mg BID) with lithium (500 mg BID) for 5 days (steady-state conditions) was found to be well tolerated.
• When the two drugs were coadministered, there were no changes in the steady-state pharmacokinetics of either lithium, nefazodone, or its metabolite HO-NEF; however, there were small decreases in the steady-state plasma concentrations of two nefazodone metabolites, mCPP and triazoledione, which are considered not to be of clinical significance.
• Therefore, no dosage adjustment of either lithium or nefazodone is required when they are coadministered.

Carbamazepine

• The coadministration of nefazodone (200 mg BID) for 5 days to 12 healthy subjects on carbamazepine who had achieved steady state (200 mg BID) was found to be well tolerated.
• Steady-state conditions for carbamazepine, nefazodone, and several of their metabolites were achieved by day 5 of coadministration.
• With coadministration of the two drugs there were significant increases in the steady-state C_max and AUC of carbamazepine (23% and 23%, respectively), while the steady-state C_max 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 C_max and AUC of nefazodone by 86% and 93%, respectively.
• Similar reductions in the C_max and AUC of HO-NEF were also observed (85% and 94%),while the reductions in C_max 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 (nefazodone), it is recommended that Serzone (nefazodone) not be used in combination with carbamazepine.

General Anesthetics

• Little is known about the potential for interaction between nefazodone and general anesthetics; therefore, prior to elective surgery, Serzone (nefazodone) should be discontinued for as long as clinically feasible.

Other CNS-Active Drugs

• The use of nefazodone in combination with other CNS-active drugs has not been systematically evaluated.
• Consequently, caution is advised if concomitant administration of Serzone (nefazodone hydrochloride) and such drugs is required.

Cimetidine

• When nefazodone (200 mg BID) and cimetidine (300 mg QID) were coadministered for one week, no change in the steady-state pharmacokinetics of either nefazodone or cimetidine was observed compared to each dosed alone.
• Therefore, dosage adjustment is not necessary for either drug when coadministered.

Theophylline

• When 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 the steady-state pharmacokinetics of either nefazodone or theophylline.
• FEV₁ measurements taken when theophylline and nefazodone were coadministered did not differ from baseline dosage (ie, when theophylline was administered alone).
• Therefore, dosage adjustment is not necessary for either drug when coadministered.

Cardiovascular-Active Drugs

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 phenotyped as CYP2D6 extensive metabolizers, C_max, C_min, and AUC of digoxin were increased by 29%, 27%, and 15%, respectively.
• Digoxin had no effects on the pharmacokinetics of nefazodone and its active metabolites.
• Because of the narrow therapeutic index of digoxin,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 mg BID) for 5.5 days to healthy male volunteers (n=18), including 3 poor and 15 extensive CYP2D6 metabolizers, resulted in 30% and 14% reductions in C_max and AUC of propranolol, respectively, and a 14% reduction in C_max for the metabolite, 4-hydroxypropranolol.
• The kinetics of nefazodone, hydroxynefazodone, and triazoledione were not affected by coadministration of propranolol.
• However, C_max, C_min, and AUC of m-chlorophenylpiperazine were increased by 23%, 54%, and 28%, respectively.
• No change in initial dose of either drug is necessary and dose adjustments should be made on the basis of clinical response.

HMG-CoA Reductase Inhibitors

• When single 40-mg doses of simvastatin or atorvastatin, both substrates of CYP3A4, were given to healthy adult volunteers who had received Serzone (nefazodone) 200 mg BID for 6 days, approximately 20-fold increases in plasma concentrations of simvastatin and simvastatin acid and 3- to 4-fold increases in plasma concentrations of atorvastatin and atorvastatin lactone were seen.
• These effects appear to be due to the inhibition of CYP3A4 by Serzone (nefazodone) because, in the same study, Serzone (nefazodone) had no significant effect on the plasma concentrations of pravastatin, which is not metabolized by CYP3A4 to a clinically significant extent.
• There have been rare reports of rhabdomyolysis involving patients receiving the combination of Serzone (nefazodone) and either simvastatin or lovastatin, also a substrate of CYP3A4.
• 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 (nefazodone) 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 are recommended.
• Since metabolic interactions are unlikely between Serzone (nefazodone) 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 Agents

• There have been reports of increased blood concentrations of cyclosporine and tacrolimus into toxic ranges when patients received these drugs concomitantly with Serzone (nefazodone).
• Both cyclosporine and tacrolimus are substrates of CYP3A4, and nefazodone is known to inhibit this enzyme.
• If either cyclosporine or tacrolimus is administered with Serzone (nefazodone), blood concentrations of the immunosuppressive agent should be monitored and dosage adjusted accordingly.

Pharmacokinetics of Nefazodone in 'Poor Metabolizers and Potential Interaction with Drugs that Inhibit and/or Are Metabolized by Cytochrome P450 Isozymes

CYP3A4 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 (nefazodone) 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 isozyme.

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.

DRUG ABUSE AND DEPENDENCE

Controlled Substance Class

• Serzone (nefazodone hydrochloride) is not a controlled substance.

Physical and Psychological Dependence

• In animal studies, nefazodone did not act as a reinforcer for intravenous self-administration in monkeys trained to self-administer cocaine, suggesting no abuse liability.
• In a controlled study of abuse liability in human subjects, nefazodone showed no potential for abuse.
• Nefazodone has not been systematically studied in humans for its potential for tolerance, physical dependence, or withdrawal.
• While the premarketing clinical experience with nefazodone did not reveal any tendency for a withdrawal syndrome or any drug-seeking behavior, it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed.
• Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of Serzone (nefazodone) (eg, development of tolerance, dose escalation, drug-seeking behavior).