Professional Information
Nefazodone (Systemic)
 |
VA CLASSIFICATION
Primary: CN609
Commonly used brand name(s): Serzone.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
Category:
Antidepressant—
Indications
Accepted
Depressive disorder, major (treatment)—Nefazodone is indicated for the treatment of depression {01}{03}.
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Structurally related to trazodone {01}; structurally unrelated to selective serotonin reuptake inhibitors, tricyclic, tetracyclic, or monoamine oxidase inhibitors {01}{03}.
Chemical group—
Phenylpiperazine {01}{03}.
Molecular weight—
Nefazodone hydrochloride: 506.5 {01}
Mechanism of action/Effect:
The mechanism of action of nefazodone is unknown {01}. However, nefazodone inhibits neuronal uptake of serotonin and norepinephrine {01}. Nefazodone occupies central 5-HT 2 receptors at nanomolar concentrations, where it acts as an antagonist {01}. It has also been shown to antagonize alpha 1-adrenergic receptors, a property which may be associated with postural hypotension {01}.
In in vitro studies, nefazodone has not demonstrated significant affinity for alpha 2-adrenergic, beta-adrenergic, 5-HT 1A, cholinergic, dopaminergic, or benzodiazepine receptors {01}{03}.
Absorption:
Rapid and complete {01}{03}. However, due to extensive metabolism, absolute bioavailability is low (about 20%) and variable {01}{03}. Food delays absorption and decreases the bioavailability by approximately 20% {01}{03}.
Distribution:
Nefazodone is widely distributed in body tissues, including the central nervous system (CNS) {01}{03}. The volume of distribution of nefazodone in humans ranges from 0.22 to 0.87 liters per kilogram (L/kg) {01}{03}.
Protein binding:
Very high (>99%) {01}{03}.
Biotransformation:
Nefazodone is extensively metabolized after oral administration by N-dealkylation and aliphatic and aromatic hydroxylation {01}{03}. Three metabolites have been identified in the plasma: hydroxynefazodone (HO-NEF), meta-chlorophenylpiperazine (mCPP), and a triazole-dione metabolite. HO-NEF has a pharmacological profile qualitatively and quantitatively similar to that of nefazodone. Meta-chlorophenylpiperazine (mCPP) has some similarities to nefazodone, but also has agonist activity at some serotonergic receptor subtypes. The pharmacological profile of the triazole-dione metabolite has not been well characterized.{01}{03} Several other metabolites have been identified but not tested for pharmacological activity. {01}
Half-life:
2 to 4 hours {01}{03}.
Onset of action:
Full antidepressant effect may take several weeks to achieve {01}{03}.
Time to peak concentration:
Approximately 1 to 3 hours {01}{03}.
Plasma concentrations
Both nefazodone and HO-NEF exhibit nonlinear kinetics for both dose and time, with area under the plasma concentration–time curve (AUC) and peak plasma concentrations (C max) increasing more than proportionally with dose increases {01}{03}.
Steady-state plasma concentrations
Attained within 4 to 5 days after initiation of twice-daily dosing or upon dosage increase or decrease {01}{03}. In studies involving 29 patients with renal function impairment (creatinine clearances ranging from 7 to 60 mL/min/1.73 m 2), no effect on steady-state plasma concentrations was observed {01}. In a study of patients with liver cirrhosis, the AUC values for nefazodone and HO-NEF at steady-state were approximately 25% greater than those observed in normal volunteers {01}. In studies comparing single 300 mg doses of nefazodone in younger and older patients, AUC and C max were increased up to two-fold in older patients. However, with multiple doses, increases were only 10 to 20% greater in the older patients. Similarly, women exhibited a higher AUC and C max after single doses of nefazodone, but no differences after multiple dosing. {01}
Elimination:
Following oral administration of radiolabeled nefazodone, approximately 50% to 65% of administered radioactivity was excreted in the urine and about 20% to 40% in feces {01}{03}.
Precautions to Consider
Cross-sensitivity and/or related problems
Patients sensitive to other phenylpiperazine antidepressants (e.g., trazodone) may be sensitive to nefazodone also {01}.
Carcinogenicity/Tumorigenicity
There is no evidence of carcinogenicity with nefazodone {01}. No increased incidence of tumors was demonstrated after two years of administration of nefazodone to rats and mice at daily doses of up to 200 and 800 mg per kg of body weight (mg/kg), respectively. (These doses correlate to approximately 3 and 6 times, respectively, the maximum human daily dose on a mg per square meter of body surface area [mg/m 2] basis.) {01} No evidence of teratogenicity was exhibited by rats or rabbits in studies of nefazodone given at 16 to 25 times the maximum human daily dose of 600 mg.{03}
Mutagenicity
Nefazodone has been shown to have no genotoxic effects based on the following assays: bacterial mutation assays, a DNA repair assay in cultured rat hepatocytes, a mammalian mutation assay in Chinese hamster ovary cells, an in vivo cytogenetics assay in rat bone marrow cells, and a rat dominant lethal study {01}.
Pregnancy/Reproduction
Fertility—
A fertility study in rats showed a slight decrease in fertility when nefazodone was administered at a dose of 200 mg/kg per day (approximately 3 times the maximum human daily dose on a mg/m 2 basis); however, this effect was not demonstrated at a dose of 100 mg/kg per day (approximately 1.5 times the maximum human daily dose on a mg/m 2 basis) {01}.
Pregnancy—
There are no adequate and well-controlled studies in pregnant women {01}.
No malformations attributable to nefazodone were observed in the offspring of rabbits and rats receiving daily doses up to 200 and 300 mg/kg, respectively (approximately 6 and 5 times, respectively, the maximum human daily dose on a mg/m 2 basis). Increased early pup mortality was seen in rats at a dose approximately five times the maximum human dose, and decreased pup weights were seen at this and lower doses, when dosing began during pregnancy and continued until weaning; the cause of these deaths is unknown. The no-effect dose for rat pup mortality was 1.3 times the human dose on a mg/m 2 basis. {01}
FDA Pregnancy Category C {01}.
Labor and delivery—
The effect of nefazodone on labor and delivery in humans is unknown {01}.
Breast-feeding
It is not known if nefazodone or its metabolites are distributed into human breast milk {01}. Nefazodone and 2 of its active metabolites (hydroxynefazodone and meta-chlorophenylpiperazine) are distributed into the milk of lactating rats.{03}
Pediatrics
No information is available on the relationship of age to the effects of nefazodone in pediatric patients. Safety and efficacy in children up to 18 years of age have not been established. {01}{03}
Geriatrics
The relationship of age to the effects of nefazodone has not been systematically studied in geriatric patients. However, peak plasma concentrations and AUC were 10% to 20% higher in patients 65 years of age and older compared with patients less than 65 years of age, after multiple doses of nefazodone.{03} , Therefore, decreases in initial dosing in geriatric patients are recommended. {01}{03}
Pharmacogenetics
About 3 to 10% of the population have reduced activity of the drug-metabolizing enzyme cytochrome P450 2D6 (CYP2D6) and are referred to as poor metabolizers of drugs such as debrisoquin, dextromethorphan, and the tricyclic antidepressants. The pharmacokinetics of nefazodone and its major metabolite HO-NEF are not altered in this population, but plasma concentrations of the mCPP metabolite are increased. However, dosage adjustment of nefazodone in poor metabolizers is not necessary. {01}
Dental
Because nefazodone has the potential to decrease or inhibit salivary flow, it may contribute to the development of caries, periodontal disease, oral candidiasis, and discomfort.
Surgical
Since little is known about the potential for interaction between nefazodone and general anesthetics, nefazodone should be discontinued for as long as clinically feasible prior to elective surgery {01}.
Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
Note: Nefazodone has been shown in vitro to be an inhibitor of cytochrome P450 3A4 (CYP3A4), and caution is indicated in the combined use of nefazodone with any drugs known to be metabolized by CYP3A4 {01}(e.g., some calcium channel antagonists, cyclosporine, clarithromycin, erythromycin, ketoconazole, itraconazole, lovastatin, simvastatin, atorvastatin, midazolam, or vinblastine).{03} Rhabdomyolysis involving patients receiving the combination of nefazodone and simvastatin or lovastatin has been reported in post-marketing clinical studies.{04}
Nefazodone and its metabolites have been shown in vitro to be extremely weak inhibitors of CYP2D6; therefore, it is unlikely that nefazodone will decrease the metabolic clearance of drugs metabolized by this isoenzyme {01}{03}.
Nefazodone and its metabolites have been shown in vitro not to inhibit CYP1A2; metabolic interactions between nefazodone and drugs metabolized by this isoenzyme are unlikely {01}{03}.
Because of nefazodone's high degree of binding to plasma proteins, concurrent administration with another highly protein-bound medication may displace that agent and cause increased free concentrations of that agent, potentially resulting in adverse effects. Conversely, displacement of nefazodone by other highly protein-bound medications may result in adverse effects. {01}{03}
Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Alcohol or
CNS-active medications (although nefazodone did not potentiate the cognitive and psychomotor effects of alcohol in normal subjects, the concomitant use of nefazodone with alcohol in depressed patients is not advised{03})
(the use of nefazodone in combination with other CNS-active agents has not been systematically evaluated; caution is advised)
» Alprazolam or
» Triazolam (triazolobenzodiazepines metabolized by CYP3A4 have demonstrated significantly increased plasma concentrations when administered concomitantly with nefazodone; initial alprazolam dosage should be reduced by 50%;{03} initial triazolam dosage should be reduced by 75%, and many patients [e.g., the elderly] should not receive triazolam and nefazodone concurrently; coadministration of nefazodone potentiated the effects of triazolam on psychomotor performance tests)
Antihypertensives (potential hypotensive effects of these medications can enhance hypotensive effects of nefazodone{03})
» Astemizole or
» Cisapride or
» Terfenadine (as an inhibitor of CYP3A4, nefazodone can block the metabolism of these medications, resulting in increased plasma concentrations, which are associated with QT prolongation; rare cases of cardiovascular adverse effects, including death, principally due to torsades de pointes, have been reported with other inhibitors of CYP3A4; concomitant use with nefazodone is contraindicated {01} {02}{03})
Digoxin (coadministration of nefazodone and digoxin to male volunteers who were phenotyped as extensive metabolizers of CYP2D6 substrates resulted in elevated plasma concentrations of digoxin; because of digoxin's narrow therapeutic index, caution should be exercised and monitoring of digoxin plasma concentrations is recommended {01}{03})
Fluoxetine (concomitant administration of fluoxetine significantly increases the AUC of the nefazodone metabolite meta-chlorophenylpiperazine by approximately 3 to 6 fold; patients who are transferred from fluoxetine to nefazodone should have an intervening wash-out period of 4 to 8 weeks {03})
Haloperidol (concomitant administration of a single oral 5-mg dose of haloperidol with nefazodone [200 mg twice a day] at steady-state resulted in a 35% decrease in apparent clearance of haloperidol with no significant increase in peak concentrations or time to peak concentration; pharmacodynamic effects of haloperidol were generally not altered significantly; the clinical significance of decreased clearance is unknown, but dosage adjustments of haloperidol may be necessary during coadministration {01}{03})
» Monoamine oxidase (MAO) inhibitors (serious and sometimes fatal reactions have occurred in patients receiving an MAO inhibitor in combination with antidepressants with pharmacological properties similar to those of nefazodone; reactions have included hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes including extreme agitation progressing to delirium and coma; some cases presented with features resembling neuroleptic malignant syndrome, such as severe hyperthermia and seizures, sometimes fatal )
(the effects of nefazodone combined with MAO inhibitors have not been evaluated in humans or animals; however, because nefazodone is an inhibitor of both serotonin and norepinephrine reuptake, concomitant use is not recommended; in addition, at least 14 days should elapse between discontinuation of an MAO inhibitor and initiation of therapy with nefazodone; at least 7 days should elapse between discontinuation of nefazodone and initiation of therapy with an MAO inhibitor {01}{03})
Propranolol (coadministration of propranolol and nefazodone to healthy male volunteers [3 poor and 15 extensive CYP2D6 metabolizers] resulted in significant decreases in AUC and C max of propranolol and in C max of the metabolite 4-hydroxypropranolol; the kinetics of nefazodone, HO-NEF, and the triazole-dione metabolite were unaffected; however, the peak and nadir plasma concentrations and AUC of mCPP were increased; no change in the initial dose of either drug is necessary, and dosage adjustments should be made on the basis of clinical response {01})
Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
With diagnostic test results
Electrocardiogram (ECG) (during premarketing studies, a statistically significant difference in the incidence of sinus bradycardia was observed in 1.5% of patients receiving nefazodone as compared with 0.4% of patients receiving placebo who met the defined criteria of a potentially important decrease in heart rate: £ 50 bpm and a decrease of ³ 15 bpm; there was no obvious clinical significance of the observed changes in these patients)
With physiology/laboratory test values
Growth hormone concentration and
Prolactin concentration (nefazodone has been associated with dose-dependent increases in plasma prolactin and growth hormone concentrations in healthy male volunteers; mean plasma prolactin concentrations were double baseline values [but still within the normal range] at 150 minutes after a single 200-mg dose; mean plasma concentrations of growth hormone were increased approximately 15-fold over baseline values at 150 minutes after single doses of 100 to 200 mg; however, when nefazodone was given as 100-mg doses two times a day for 7 days, plasma concentrations declined to normal range within the dosing interval; endocrine effects of nefazodone in females have not been studied{03})
Hematocrit (during premarketing studies, a potentially important decrease in hematocrit [£ 37% in males or £ 32% in females] was reported in 2.8% of patients receiving nefazodone as compared to 1.5% of patients receiving placebo; decreases in hematocrit, presumably dilutional, have been reported with other medications that block alpha 1-adrenergic receptors; there was no apparent clinical significance of the observed changes in these patients )
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
Risk-benefit should be considered when the following medical problems exist
» Cardiovascular disease, including angina, ischemic stroke, or history of myocardial infarction or
» Cerebrovascular disease (may be exacerbated by potential hypotensive effects of nefazodone {03})
» Dehydration or
» Hypovolemia (nefazodone-induced hypotension may be exacerbated{03})
Drug abuse or dependence, or history of (patients with a history of drug abuse should be observed closely for signs of misuse or abuse, as with any new central nervous system [CNS] drug)
» Hepatic function impairment{04} (plasma concentrations of nefazodone and its metabolites may be increased; cases of life-threatening hepatic failure have been reported following both short- and long-term therapy with nefazodone; although injury has been rare and usually has been reversible, hepatic failure and death have been reported; nefazodone should be used with caution in patients with hepatic function impairment but should not be initiated in patients exhibiting clinical evidence of active liver disease or elevated serum baseline transaminase levels. Patients should be advised to be alert for signs and symptoms of liver dysfunction (jaundice, anorexia, gastrointestinal complaints, malaise) and to report them to their doctor immediately if they occur. There is no evidence that pre-existing liver disease increases the likelihood of developing liver failure; however, baseline abnormalities can complicate patient monitoring. Nefazodone should be discontinued if transaminase values become greater than three times the upper limit of normal or if jaundice develops{04})
» Mania or hypomania, history of (condition may be activated{03})
» Seizures, history of (although not documented to occur with nefazodone, as with other antidepressants, the condition potentially may be exacerbated{03})
» Sensitivity to nefazodone or other phenylpiperazine antidepressants
Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
Careful supervision of depressed patients with suicidal tendencies (recommended especially during early treatment phase before peak effectiveness of nefazodone is achieved; prescribing the smallest number of tablets necessary for good patient management is recommended to decrease the risk of overdose {01}{03})
Alanine aminotransferase (ALT [SGPT]){01} and
Aspartate aminotransferase (AST [SGOT]){01} (in postintroduction clinical experience, elevations greater than three times the upper limit of normal were observed in nefazodone-treated patients. These patients should be presumed to be at increased risk for liver injury. Accordingly, such patients should not be considered for re-treatment.{04})
Side/Adverse Effects
Note: Rare occurrences of priapism have been associated with use of nefazodone; in some of the reported cases, surgical intervention was required.{03} If priapism occurs, the medication should be immediately discontinued and the physician consulted. If the condition persists for longer than 24 hours, a urologist should be consulted to determine appropriate management. {01}{03}
Note: Cases of life-threatening hepatic failure have been reported following both short- and long-term therapy with nefazodone; although injury has been rare, hepatic failure and death have been reported; nefazodone should not be initiated in patients with active liver disease or elevated serum baseline transaminase levels.{04}
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence more frequent
Abnormal gait or ataxia (clumsiness or unsteadiness)
abnormal vision, including blurred vision
scotoma
visual trails
or visual field defects (changes in vision){03}
hypotension or postural hypotension {03}(lightheadedness or fainting)
skin rash or itching
tinnitus (ringing in the ears)
Note: Abnormal vision and tinnitus appear to be dose-related.
Incidence less frequent
Bronchitis (shortness of breath, tightness in chest, or wheezing)
dyspnea (troubled breathing)
eye pain
gastroenteritis (diarrhea; nausea; stomach pain)
Incidence rare
Allergic reactions, including photosensitivity (increased sensitivity to sun), facial edema (swelling of face), and urticaria (hives)
anemia (unusual tiredness or weakness)
arthritis, bursitis, tenosynovitis, or muscle stiffness (joint or muscle pain or stiffness)
asthma
cardiovascular effects, including angina pectoris (chest pain), hypertension
syncope (fainting), or tachycardia (fast heartbeat)
CNS effects, including abnormal thinking
apathy
decreased concentration
depersonalization
derealization
hostility or paranoid reaction (mood or mental changes), dysarthria ( problems in speaking), euphoria (unusual feeling of well-being ), hallucinations (seeing, hearing, or feeling things that are not there), mania or hypomania (talking, feeling, and acting with excitement and activity you cannot control)
neuralgia (nerve pain), or twitching
ear pain or hyperacusis (increased sense of hearing)
ecchymosis (unusual bleeding or bruising)
eye problems, including dryness of eyes
abnormality of accommodation (blurred vision ), diplopia (double vision), conjunctivitis or keratoconjunctivitis (red or irritated eyes), mydriasis ( large pupils), photophobia (sensitivity of eyes to light )
gastrointestinal bleeding ( bloody or black, tarry stools; vomiting of blood or material that looks like coffee grounds)
{03}
gout (joint pain; lower back or side, or stomach pain)
leukopenia (fever, chills, or sore throat)
lymphadenopathy (swollen glands)
menstrual problems, including amenorrhea
menorrhagia
metrorrhagia
or vaginal hemorrhage (menstrual changes)
mouth ulcers or stomatitis (irritation or soreness of mouth)
pelvic pain
rectal hemorrhage (bleeding from the rectum)
sexual dysfunction, including increased or decreased libido
impotence
priapism (prolonged, painful, inappropriate penile erection ){03}, or abnormal ejaculation (change in sexual desire or performance)
urinary effects, including cystitis
urinary urgency
polyuria
hematuria
nocturia
urinary incontinence (problems with urination), or kidney calculus (kidney stones)
Incidence not determined
— Observed during clinical practice with nefazodone; estimates of frequency cannot be determined{04}
Angioedema (large, hive-like swelling on face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs)
convulsions, including grand mal seizures (muscle spasm or jerking of all extremities; sudden loss of consciousness)
hyponatremia (increased thirst; confusion; decreased urine output; muscle pain or cramps)
liver failure ( light-colored stools or dark urine; gastrointestinal complaints; lack of appetite; unusual tiredness)
rhabdomyolysis, in combination with lovastatin or simvastatin (dark-colored urine; fever; muscle pain or stiffness; unusual tiredness or weakness)
serotonin syndrome (agitation; diarrhea; sweating; poor coordination )
Stevens-Johnson syndrome (blistering, peeling, loosening of skin; itching red skin lesions, often with a purple center; unusual tiredness or weakness )
thrombocytopenia (black, sticky stools; pain, warmth, or burning in fingers, toes and legs; sore throat; dizziness )
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
Abnormal dreams {03}
agitation
confusion {03}
constipation {03}
diarrhea {03}
dizziness {03}
drowsiness
dryness of mouth {03}
dyspepsia (heartburn)
fever or chills {03}
flushing or a feeling of warmth
headache {03}
increased appetite
increased cough
insomnia {03}(trouble in sleeping)
memory impairment {03}
nausea {03}
paresthesias {03}(tingling, burning, or prickly sensations)
peripheral edema (swelling of arms or legs)
pharyngitis (sore throat)
tremor
vomiting {03}
Note: Confusion, constipation, dizziness, drowsiness, and nausea are dose-related.
Incidence less frequent or rare
Abdominal pain (pain in stomach or abdomen){03}
arthralgia (joint pain)
asthenia (loss of strength or energy; muscle pain or weakness){03}
breast pain
increased thirst
Incidence not determined
— Observed during clinical practice with nefazodone; estimates of frequency cannot be determined{04}
galactorrhea (unexpected or excess milk flow from breasts)
gynecomastia, male (swelling of the breasts or breast soreness in males)
Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center {01} (see Poison Control Center Listing).
Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute effects
Bradycardia {03}
hypotension {01}{03}
nausea {01}{03}
somnolence {01}{03}
vomiting {01}{03}
Note: Overdosage of nefazodone may cause an increase in incidence or severity of any of the reported adverse reactions {01}.
Treatment of overdose
Note: The possibility of multiple drug involvement should be considered in managing overdose {01}{03}.
There is no specific antidote for nefazodone {01}{03}. Treatment is essentially symptomatic and supportive {01}{03}.
To decrease absorption—Gastric lavage should be initiated in any patient suspected of having taken an overdose of nefazodone {01}{03}.
Supportive care—Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation.
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Nefazodone (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):
Before using this medication
» Conditions affecting use, especially:
Sensitivity to nefazodone or trazodone
Pregnancy—In studies in rats, increased early pup mortality was seen at a dose approximately five times the maximum human dose, and decreased pup weights were seen at this and lower doses, when dosing began during pregnancy and continued until weaning; the cause of these deaths is unknown
Contraindicated medications
Astemizole, cisapride, and terfenadine
Other medications, especially alprazolam, monoamine oxidase (MAO) inhibitors, and triazolam
Other medical problems, especially cardiovascular or cerebrovascular disease, dehydration or hypovolemia, hepatic function impairment, history of mania or hypomania, or history of seizures
Proper use of this medication
» Compliance with therapy; not taking more or less medicine than prescribed
» Several weeks of treatment may be required before antidepressant effects are achieved
» Proper dosing
Taking as soon as possible; continuing on regular schedule with next dose; not doubling doses
» Proper storage
Precautions while using this medication
Regular visits to physician to check progress of therapy
» Not taking astemizole, cisapride, or terfenadine because of possible life-threatening cardiac arrhythmias
» Not taking an MAO inhibitor with or less than 7 days after taking nefazodone; not taking nefazodone less than 14 days after taking an MAO inhibitor
» Avoiding use of alcoholic beverages; not taking other CNS-active agents unless prescribed by physician
» Possible blurred vision, drowsiness, impairment of judgment, thinking, or motor skills; caution when driving or doing jobs requiring alertness
» Possible dizziness or lightheadedness; caution when getting up suddenly from a lying or sitting position
» Possible dryness of mouth; using sugarless gum or candy, ice, or saliva substitute for relief; checking with physician or dentist if dry mouth continues for more than 2 weeks
Side/adverse effects
Signs of potential side effects, especially abnormal gait or ataxia; abnormal vision; angioedema, convulsions (including grand mal seizures), hypotension or postural hypotension, skin rash or itching, tinnitus, bronchitis, dyspnea, eye pain, gastroenteritis, allergic reactions, anemia, arthritis, bursitis, tenosynovitis, or muscle stiffness, asthma, cardiovascular effects, CNS effects, ear pain or hyperacusis, ecchymosis, eye problems, gastrointestinal bleeding, gout, hyponatremia, leukopenia, liver failure, lymphadenopathy, menstrual problems, mouth ulcers or stomatitis, pelvic pain, rectal hemorrhage, rhabdomyolysis, in combination with lovastatin or simvastatin, serotonin syndrome, sexual dysfunction, including priapism, Stevens-Johnson syndrome, thrombocytopenia and urinary effects
General Dosing Information
There is no body of evidence from controlled trials to indicate how long a depressed patient should be treated with nefazodone. It is generally agreed, however, that pharmacological treatment for acute episodes of depression should continue for up to six months or longer. It is unknown whether the dose of antidepressant needed to induce remission is identical to the dose needed to maintain euthymia. {01}
Potentially suicidal patients should not have access to large quantities of this medication since depressed patients, particularly those who may use alcohol excessively, may continue to exhibit suicidal tendencies until significant improvement occurs. Some clinicians recommend that the patient be supplied with the smallest quantity of medication necessary for satisfactory patient management. {01}{03}
Activation of hypomania or mania has been reported in depressed patients treated with nefazodone {01}{03}.
Patients should be advised to be alert for signs and symptoms of liver dysfunction (jaundice, anorexia, gastrointestinal symptoms, malaise, etc.) and to report them to their doctor immediately if they occur.{04}
Oral Dosage Forms
NEFAZODONE HYDROCHLORIDE TABLETS
Usual adult dose
Antidepressant
Oral, initially 100 to 200 mg a day, administered in two divided doses. The dosage may be increased, as needed and tolerated, in increments of 100 to 200 mg a day at intervals of no less than one week. The effective dosage range in clinical trials was generally 300 to 600 mg a day. {01}{03}
Note: For dosage for debilitated patients, see Usual geriatric dose. In patients with liver disease, therapy should be initiated at one-half the usual dose, with titration based on therapeutic response.{03} In patients with severe renal impairment, doses on the lower end of the dosage range are advised.{03}
Usual pediatric dose
Safety and efficacy in children up to 18 years of age have not been established {01}{03}.
Usual geriatric dose
Antidepressant
Oral, initially 100 mg a day administered in two divided doses. Since these patients may have reduced nefazodone clearance and/or increased sensitivity to the CNS side effects, the subsequent titration rate of nefazodone dosage may need to be modified. Final dosage determination should be based on the patient's clinical response; since steady-state plasma levels do not change with age, the target dose may be similar in healthy younger and older patients. {01}{03}
Strength(s) usually available
U.S.—
50 mg (Rx) [Serzone (microcrystalline cellulose) (povidone) (sodium starch glycolate ) (colloidal silicon dioxide) ( magnesium stearate) (iron oxides)]
100 mg (Rx) [Serzone (scored) (microcrystalline cellulose) (povidone) ( sodium starch glycolate) (colloidal silicon dioxide ) (magnesium stearate) ( iron oxides)]
150 mg (Rx) [Serzone (scored) (microcrystalline cellulose) (povidone) ( sodium starch glycolate) (colloidal silicon dioxide ) (magnesium stearate) ( iron oxides)]
200 mg (Rx) [Serzone (microcrystalline cellulose) (povidone) (sodium starch glycolate ) (colloidal silicon dioxide) ( magnesium stearate) (iron oxides)]
250 mg (Rx) [Serzone (microcrystalline cellulose) (povidone) (sodium starch glycolate ) (colloidal silicon dioxide) ( magnesium stearate) (iron oxides)]
Canada—
50 mg (Rx) [Serzone (colloidal silicon dioxide) (magnesium stearate) (microcrystalline cellulose) (povidone) ( red ferric oxide) (sodium starch glycolate)]{03}
100 mg (Rx) [Serzone (scored) ( colloidal silicon dioxide) (magnesium stearate) (microcrystalline cellulose) (povidone ) (sodium starch glycolate)]{03}
150 mg (Rx) [Serzone (scored) (colloidal silicon dioxide) (magnesium stearate) (microcrystalline cellulose) (povidone ) (red ferric oxide) ( sodium starch glycolate) (yellow ferric oxide)]{03}
200 mg (Rx) [Serzone (colloidal silicon dioxide) (magnesium stearate) (microcrystalline cellulose) (povidone) ( sodium starch glycolate) (yellow ferric oxide)]{03}
Packaging and storage:
Store below 40 °C (104 °F) unless otherwise specified by manufacturer. Dispense in a tight container. {01}
Auxiliary labeling:
• Avoid alcoholic beverages.
• May cause dizziness or drowsiness.
Developed: 09/27/1995
Revised: 01/04/2002
References
- Serzone package insert (Bristol-Myers Squibb—US), Rev 1/1995, Rec 4/7/1995.
- Serzone package insert (Bristol-Myers Squibb—US), Rev 5/1998, Rec 5/1998.
- Product Information: Serzone®, nefazodone. Bristol-Myers Squibb, Canada. In: Welbanks L (ed): Compendium of Pharmaceuticals and Specialties, 35th ed. Canadian Pharmaceutical Association, Ottawa, Ontario, Canada, 2000. p.1455–1457.
- Product Information: Serzone®, nefazodone. Bristol-Myers Squibb, Princeton, NJ, (PI revised 11/2001) reviewed 12/2001.
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