Nefazodone

470.014

470.01

59H4FCV1TF

760344

DTXSID2023357

Crystals from 2-propanol/heptane

N - Nervous system

51.6

4.7

Solid

1.23±0.1 g/cm3(Predicted)

83.5 °C

DMSO: ~11 mg/mL at 60 °C

Store at 20 deg to 25 °C (68 deg to 77 °F). /Nefazodone hydrochloride/|Keep container tightly closed in a dry and well-ventilated place. /Nefazodone hydrochloride/

5.20X10-11 mm Hg at 25 °C (est)

Henry's Law constant = 1.53X10-17 atm-cu m/mol at 25 °C (est)

211.7 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]

Hydroxyl radical reaction rate constant = 2.74X10-10 cu cm/molec-sec at 25 °C (est)

3

S22-S24/25

Stable under recommended storage conditions. /Nefazodone hydrochloride/

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contaminated packaging: Dispose of as unused product. /Nefazodone hydrochloride/

Incompatible materials: Strong oxidizing agents. /Nefazodone hydrochloride/

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including nefazodone hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Nefazodone hydrochloride/

Eye/face protection: Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /Nefazodone hydrochloride/|Skin protection: Handle with gloves. /Nefazodone hydrochloride/|Body Protection: Choose body protection in relation to its type, to the concentration and amount of dangerous substances, and to the specific work-place. /Nefazodone hydrochloride/|Respiratory protection: Respiratory protection is not required. Where protection from nuisance levels of dusts are desired, use type N95 (US) or type P1 (EN 143) dust masks. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /Nefazodone hydrochloride/

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. /Nefazodone hydrochloride/|Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary. /Nefazodone hydrochloride/

Hazardous decomposition products formed under fire conditions: - Carbon oxides, Nitrogen oxides (NOx), Hydrogen chloride gas. /Nefazodone hydrochloride/

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Avoid dust formation. Avoid breathing vapors, mist or gas. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Sweep up and shovel. Keep in suitable, closed containers for disposal. /Nefazodone hydrochloride/

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Avoid dust formation. Avoid breathing vapors, mist or gas. Environmental precautions: Do not let product enter drains.|Precautions for safe handling: Provide appropriate exhaust ventilation at places where dust is formed. Normal measures for preventive fire protection. /Nefazodone hydrochloride/|Appropriate engineering controls: General industrial hygiene practice. /Nefazodone hydrochloride/|Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. /Nefazodone hydrochloride/|SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Cases of life-threatening hepatic failure have been reported in patients treated with nefazodone.|IDENTIFICATION AND USE: Nefazodone is a solid. It is used as an antidepressive agent. HUMAN STUDIES: In postmarketing experience, overdose with nefazodone alone and in combination with alcohol and/or other substances has been reported. While there have been rare reports of fatalities in patients taking overdoses of nefazodone, predominantly in combination with alcohol and/or other substances, no causal relationship to nefazodone has been established. In premarketing clinical studies, there were seven reports of nefazodone overdose alone or in combination with other pharmacological agents. None of these patients died. The amount of nefazodone ingested ranged from 1000 mg to 11,200 mg. Commonly reported symptoms from overdose of nefazodone included nausea, vomiting, and somnolence. One patient took 2000 to 3000 mg of nefazodone with methocarbamol and alcohol, and this person reportedly experienced a convulsion. Nefazodone therapy has been associated with liver abnormalities ranging from asymptomatic reversible serum transaminase increases to cases of liver failure resulting in transplant and/or death. At present, there is no way to predict who is likely to develop liver failure. Ordinarily, patients with active liver disease should not be treated with nefazodone. The drug does not increase the rates of major human malformations during pregnancy above the baseline rate of 1% to 3%. ANIMAL STUDIES: There is no evidence of carcinogenicity with nefazodone. The dietary administration of nefazodone to rats and mice for 2 years at daily doses of up to 200 mg/kg and 800 mg/kg, respectively, produced no increase in tumors. Reproduction studies have been performed in pregnant rabbits and rats at daily doses up to 200 and 300 mg/kg, respectively (approximately 6 and 5 times, respectively. No malformations were observed in the offspring as a result of nefazodone treatment. However, increased early pup mortality, and decreased pup weights were seen in rats. A fertility study in rats showed a slight decrease in fertility at 200 mg/kg/day. 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.

Liver test abnormalities occur in a proportion of patients on nefazodone, but elevations are usually modest and usually do not require dose modification or discontinuation. Soon after its general availability, nefazodone was linked to several instances of acute, clinically apparent liver injury, some of which were fatal. The onset of injury varied from 6 weeks to 8 months and the pattern of serum enzyme elevations was typically hepatocellular. Autoimmune (autoantibodies) and immunoallergic features (rash, fever, eosinophilia) were uncommon. Liver biopsy usually demonstrated an acute hepatitis with cholestasis and variable degrees of centrolobular (zone 3) necrosis. Systematic reviews suggested that the incidence of hepatic failure due to nefazodone is 1 per 250,000 to 300,000 patient-years of exposure. Because of this complication, nefazodone was withdrawn from use in many countries. Nefazodone, however, can be effective in patients with otherwise resistant forms of severe depression. For this reason, it remains available in the United States with the recommendation that it be used only if other antidepressants have been found to be ineffective and after full disclosure and discussion of the risks. It has a “black box” warning for hepatotoxicity.

Simvastatin is a hydroxymethyl glutaryl coenzyme A reductase inhibitor commonly used to treat patients with hyperlipidemia. It is a safe and effective medication in most patients when used appropriately. A serious side effect known as rhabdomyolysis may rarely occur in patients who take simvastatin, especially at higher doses and with agents that interact and increase the level of simvastatin in the blood. We describe the case of a patient with rhabdomyolysis that occurred after the patient's simvastatin was titrated to 80 mg at approximately the same time that his antidepressant medication was switched to nefazodone. We found only two other similar cases in the literature, both of which were presented as letters to the editor in two different journals. We present this case to add to the literature and to assist practitioners by raising their awareness of this interaction so that it can be monitored.|This study was conducted to determine the potential for an interaction between nefazodone, a new antidepressant, and alprazolam after single- and multiple-dose administration in a randomized, double-blind, parallel-group, placebo-controlled study in 48 healthy male volunteers. A group of 12 subjects received either placebo twice daily, 1 mg of alprazolam twice daily, 200 mg of nefazodone twice daily, or the combination of 1 mg of alprazolam and 200 mg of nefazodone twice daily for 7 days. Serial blood samples were collected after dosing on day 1 and day 7 and before the morning dose on days 4, 5, and 6 for the determination of alprazolam and its metabolites alpha-hydroxyalprazolam (AOH) and 4-hydroxyalprazolam (4OH) and nefazodone and its metabolites hydroxynefazodone (HO-nefazodone), m-chlorophenylpiperazine (mCPP), and a triazole dione metabolite (dione) by validated high-performance liquid chromatography methods. Steady-state levels in plasma were reached by day 4 for alprazolam, 4OH, nefazodone, HO-nefazodone, mCPP, and dione. Noncompartmental pharmacokinetic analysis showed that at steady state, alprazolam Cmax and AUCtau values significantly increased approximately twofold and 4OH Cmax and AUCtau values significantly decreased by 40 and 26%, respectively, when nefazodone was coadministered with alprazolam. There was no effect of alprazolam on the single-dose or steady-state pharmacokinetics of nefazodone, HO-nefazodone, or dione after the coadministration of alprazolam and nefazodone. However, the mean steady-state mCPP Cmax and AUCtau significantly increased by approximately threefold and t1/2 values significantly increased by approximately twofold after the coadministration of alprazolam and nefazodone in comparison to those when nefazodone was given alone. Competitive inhibition between alprazolam and nefazodone metabolism at cytochrome P450 3A4 may be responsible for the pharmacokinetic interaction when alprazolam and nefazodone were coadministered. No adjustment of nefazodone dosage is required when nefazodone and alprazolam are coadministered. Because alprazolam concentrations in plasma are increased in the presence of nefazodone, a reduction in alprazolam dosage is recommended when the two agents are coadministered.|Tacrolimus (FK-506) is an important immunosuppressive agent most often given for maintenance immunosuppression to prevent acute cellular organ rejection. A 57-year-old woman with end-stage renal disease presumed secondary to chronic glomerulonephritis underwent a living related renal allograft transplantation. She tolerated the surgery well and was discharged on postoperative day 5. She was stabilized with prednisone, azathioprine, and tacrolimus. Two years after transplantation, nefazodone 50 mg twice/day orally was prescribed due to depression. After 1 week of nefazodone therapy the patient experienced headache, confusion, and "gray areas" in her vision, without abnormal ophthalmologic findings. Her serum creatinine was elevated to 2.2 mg/dL (baseline 1.5 mg/dL), and trough tacrolimus level was markedly elevated (> 30 ng/mL). Both tacrolimus and nefazodone are metabolized by the cytochrome P450 (CYP) 3A4 system. We suspect that nefazodone inhibits metabolism of tacrolimus. Coadministration of antidepressant agents such as nefazodone, or any other drug that inhibits the CYP3A4 isoenzyme subfamily, should be anticipated to interfere with tacrolimus metabolism. Monitoring blood concentrations of tacrolimus is vital, and appropriate dosage adjustments are required when the two drugs are administered concurrently to avoid serious interactions such as nephrotoxicity and neurotoxicity.|Depression is a significant post-transplant complication often necessitating drug therapy. Many of the newer selective serotonin reuptake inhibitor (SSRI) antidepressants are metabolized by the same cytochrome P450IIIA isoenzyme system that is responsible for the metabolism of cyclosporine, and these agents pose an interactive risk in transplant patients. We have observed nearly a 10-fold increase in whole blood cyclosporine concentrations in a cardiac transplant patient shortly after the addition of nefazodone antidepressant therapy. We suggest there is a clinically significant drug-drug interaction between nefazodone and cyclosporine due to inhibition of cytochrome P-450 IIIA4 isoenzymes by nefazodone.|For more Interactions (Complete) data for Nefazodone (26 total), please visit the HSDB record page.

Nefazodone should be used with caution in patients with known cardiovascular or cerebrovascular disease that could be exacerbated by hypotension (history of myocardial infarction, angina, or ischemic stroke) and conditions that would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medication).|As with all antidepressants, nefazodone should be used cautiously in patients with a history of mania.

Greater than 99% (in vitro, human plasma proteins).

Nefazodone's production and administration as a medication(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1.0X10+5(SRC), determined from a structure estimation method(2), indicates that nefazodone is expected to be immobile in soil(SRC). Volatilization of nefazodone from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.5X10-17 atm-cu m/mole(SRC), developed using a fragment constant estimation method(3). Nefazodone is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 5.2X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2018).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1.0X10+5(SRC), determined from a structure estimation method(2), indicates that nefazodone is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.5X10-17 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(65), an estimated BCF of 9(SRC), from an estimated log Kow of 5.00(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2018).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), nefazodone, which has aan estimated vapor pressure of 5.2X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase. Particulate-phase nefazodone may be removed from the air by wet and dry deposition(SRC). Nefazodone does not contain chromophores that absorb at wavelengths >290 nm(3) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

Nefazodone is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(1). Nefazodone does not contain chromophores that absorb at wavelengths >290 nm(1) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 9 was calculated in fish for nefazodone(SRC), using an estimated log Kow of 5.00(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of nefazodone can be estimated to be 1.0X10+5(SRC). According to a classification scheme(2), this estimated Koc value suggests that nefazodone is expected to be immobile in soil. Freundlich adsorption isotherms for nefazodone in primary sludge, secondary long sludge and secondary short sludge were reported as 2.7, 0.96 and 3.0X10-2 L/g, respectively. The average Kd value at pH 6-8 was 6.4(3).

The Henry's Law constant for nefazodone is estimated as 1.5X10-17 atm-cu m/mole(SRC) developed using a fragment constant estimation method(1). This Henry's Law constant indicates that nefazodone is expected to be essentially nonvolatile from water and moist surfaces(2). Nefazodone is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 5.2X10-11 mm Hg(SRC), determined from a fragment constant method(1).

Occupational exposure to nefazodone may occur through inhalation and dermal contact with this compound at workplaces where nefazodone is produced or used. The general public is not likely to be exposed to nefazodone unless by direct medical treatment. (SRC)

For the treatment of depression.|FDA Label

Nefazodone is a serotoninergic modulating antidepressant that is used in therapy of depression, aggressive behavior and panic disorder. Nefazodone therapy has been associated with transient, usually asymptomatic elevations in serum aminotransferase levels and has been linked to several instances of clinically apparent acute liver injury some of which have been fatal.

Antidepressant Agents

Antidepressive Agents, Second-Generation|/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Nefazodone is included in the database.|Nefazodone hydrochloride tablets are indicated for the treatment of depression. When deciding among the alternative treatments available for this condition, the prescriber should consider the risk of hepatic failure associated with nefazodone hydrochloride treatment. In many cases, this would lead to the conclusion that other drugs should be tried first. /Included in US product label/

/BOXED WARNING/ Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of nefazodone hydrochloride tablets or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Nefazodone hydrochloride tablets are not approved for use in pediatric patients.|/BOXED WARNING/ Cases of life-threatening hepatic failure have been reported in patients treated with nefazodone hydrochloride tablets. The reported rate in the United States is about 1 case of liver failure resulting in death or transplant per 250,000 to 300,000 patient-years of nefazodone hydrochloride treatment. The total patient-years is a summation of each patient's duration of exposure expressed in years. For example, 1 patient-year is equal to 2 patients each treated for 6 months, 3 patients each treated for 4 months, etc. Ordinarily, treatment with nefazodone hydrochloride tablets should not be initiated in individuals with active liver disease or with elevated baseline serum transaminases. There is no evidence that pre-existing liver disease increases the likelihood of developing liver failure, however, baseline abnormalities can complicate patient monitoring. Patients should be advised to be alert for signs and symptoms of liver dysfunction (jaundice, anorexia, gastrointestinal complaints, malaise, etc.) and to report them to their doctor immediately if they occur. Nefazodone hydrochloride tablets should be discontinued if clinical signs or symptoms suggest liver failure. Patients who develop evidence of hepatocellular injury such as increased serum AST or serum ALT levels >/= 3 times the upper limit of NORMAL, while on nefazodone hydrochloride tablets should be withdrawn from the drug. These patients should be presumed to be at increased risk for liver injury if nefazodone hydrochloride is reintroduced. Accordingly, such patients should not be considered for re-treatment.|The most commonly observed adverse events associated with the use of nefazodone (incidence of 5% or greater) and not seen at an equivalent incidence among placebo-treated patients (i.e., significantly higher incidence for nefazodone compared to placebo, p /= 1%) events in clinical trials associated with discontinuation and considered to be drug related (i.e., those events associated with dropout at a rate approximately twice or greater for nefazodone compared to placebo) included: nausea (3.5%), dizziness (1.9%), insomnia (1.5%), asthenia (1.3%), and agitation (1.2%).|For more Drug Warnings (Complete) data for Nefazodone (17 total), please visit the HSDB record page.

Nefazodone, an antidepressant synthetically derived phenylpiperazine, is used to treat major depression. Although it is structurally similar to trazodone, nefazodone has a mechanism of action different from other antidepressants and, hence, lacks the risk for major cardiovascular toxicity seen with tricyclics and insomnia and inhibition of REM sleep seen with the selective serotonin reuptake inhibitors.

A structurally and mechanistically diverse group of drugs that are not tricyclics or monoamine oxidase inhibitors. The most clinically important appear to act selectively on serotonergic systems, especially by inhibiting serotonin reuptake. (See all compounds classified as Antidepressive Agents, Second-Generation.)|Drugs that bind to but do not activate SEROTONIN 5-HT2 RECEPTORS, thereby blocking the actions of SEROTONIN or SEROTONIN 5-HT2 RECEPTOR AGONISTS. Included under this heading are antagonists for one or more specific 5-HT2 receptor subtypes. (See all compounds classified as Serotonin 5-HT2 Receptor Antagonists.)|Drugs that selectively block or suppress the plasma membrane transport of SEROTONIN and NORADRENALINE into axon terminals and are used as ANTIDEPRESSIVE AGENTS. (See all compounds classified as Serotonin and Noradrenaline Reuptake Inhibitors.)

Nefazodone is rapidly and completely absorbed. Its absolute bioavailability is low (about 20%).|Nefazodone is extensively metabolized after oral administration by n-dealkylation and aliphatic and aromatic hydroxylation, and less than 1% of administered nefazodone is excreted unchanged in urine.|0.22 to 0.87 L/kg|/MILK/ In two ... subjects, one taking 50 mg twice daily and the other 50 mg in the morning and 100 mg in the evening, the trough plasma levels were <50 ng/mL, whereas the paired milk concentrations were 687 and 213 ng/mL, respectively.|/MILK/ ... In one woman taking 200 mg twice daily /of nefazodone/, the paired concentrations of nefazodone in milk and plasma (trough) were 57 and 617 ng/mL, respectively. the milk:plasma ratio was 0.09.|/MILK/ Nefazodone is excreted into breast milk.|/MILK/ The purpose of this study was/ to investigate whether adverse effects in a premature neonate could be attributed to nefazodone exposure via breast milk. The breast-fed white infant (female, 2.1 kg, 36 weeks corrected gestational age) of a 35-year-old woman (60 kg) taking nefazodone 300 mg/day was admitted to the hospital because she was drowsy, lethargic, unable to maintain normal body temperature, and was feeding poorly. A diagnosis of exposure to nefazodone via breast milk was considered only after other more likely diagnoses had been excluded. ... The maternal plasma and milk concentration-time profiles for nefazodone and its metabolites, triazoledione, HO-nefazodone, and m-chlorphenylpiperazine, were quantified by HPLC. The calculated infant dose for nefazodone and its active metabolites (as nefazodone equivalents) via the milk was only 0.45% of the weight-adjusted maternal nefazodone daily dose. ...|For more Absorption, Distribution and Excretion (Complete) data for Nefazodone (7 total), please visit the HSDB record page.

Hepatic.|... A 16-year-old female took 2.4 g of nefazodone. ... The terminal elimination half-life for nefazodone was 8.3 hours, and its metabolite hydroxy(OH)-nefazodone was 14.6 hours. BP-time curves demonstrated an 18-hour period of hypotension. There was a significant correlation between systolic BP and OH-nefazodone (R2 = 0.602). HR remained between 56 and 66 bpm for 30 hours despite hypotension. QT was significantly correlated with nefazodone (R2 = 0.911) and OH-nefazodone (R2 = 0.797), but no significant relationship between QTc and drug concentrations. ...|The purpose of this study was/ to investigate whether adverse effects in a premature neonate could be attributed to nefazodone exposure via breast milk. The breast-fed white infant (female, 2.1 kg, 36 weeks corrected gestational age) of a 35-year-old woman (60 kg) taking nefazodone 300 mg/day was admitted to the hospital because she was drowsy, lethargic, unable to maintain normal body temperature, and was feeding poorly. ... The maternal plasma and milk concentration-time profiles for nefazodone and its metabolites, triazoledione, HO-nefazodone, and m-chlorphenylpiperazine, were quantified by HPLC. The calculated infant dose for nefazodone and its active metabolites (as nefazodone equivalents) via the milk was only 0.45% of the weight-adjusted maternal nefazodone daily dose. ...|The utility of multivariate analysis in in vitro metabolite identification studies was examined with nefazodone, an antidepressant drug with a well-established metabolic profile. The chromatographic conditions were purposefully chosen to reflect those utilized in high-throughput screening for microsomal stability of new chemical entities. Molecular ion, retention time information on groups of human liver microsomal samples with/without nefazodone was evaluated by principal component analysis (PCA). Resultant scores and loadings plots from the PCA revealed the segregation and the ions of interest that designated the drug and its corresponding metabolites. Subsequent acquisition of tandem mass spectrometry (MS/MS) spectra for targeted ions permitted the interrogation and interpretation of spectra to identify nefazodone and its metabolites. A comparison of nefazodone metabolites identified by PCA versus those found by traditional metabolite identification approaches resulted in very good correlation when utilizing similar analytical methods. Fifteen metabolites of nefazodone were identified in beta-nicotinamide adenine dinucleotide phosphate (NADPH)-supplemented human liver microsomal incubations, representing nearly all primary metabolites previously reported. Of the 15 metabolites, eight were derived from the N-dealkylation and N-dephenylation of the N-substituted 3-chlorophenylpiperazine motif in nefazodone, six were derived from mono- and bis-hydroxylation, and one was derived from the Baeyer Villiger oxidation of the ethyltriazolone moiety in nefazodone.|Nefazodone is extensively metabolized after oral administration by n-dealkylation and aliphatic and aromatic hydroxylation, and less than 1% of administered nefazodone is excreted unchanged in urine. Attempts to characterize three metabolites identified in plasma, hydroxynefazodone (HO-NEF), meta-chlorophenylpiperazine (mCPP), and a triazole-dione metabolite, have been carried out.|This paper describes the complete profiling and characterization of in vitro metabolites of the antidepressant agent nefazodone (NEF) generated by human liver microsome (HLM). Two new metabolic pathways (biotransformation) for NEF have been discovered by the characterization of three new metabolites, including two new metabolites (M24, M25) formed due to the N-dealkylation reaction that occurred between the triazolone and propyl units, and one new metabolite (M26) formed due to the O-dearylation reaction that occurred on the phenoxyethyl unit. These metabolites were initially detected by a 4000 Q-Trap instrument and then confirmed by exact mass measurement using an LTQ-Orbitrap. Both instruments proved to be capable of providing complete in vitro metabolite information in a single liquid chromatography/tandem mass spectrometry (LC/MS/MS) analysis, although each had its advantages and disadvantages. One noticeable disadvantage of the 4000 Q-Trap was the reduced quality of isotopic pattern in the enhanced mass scan (EMS) spectrum when it was used as survey scan to trigger multiple dependent product ion scans. The problem was especially exacerbated for minor metabolites with low signal intensity. On the other hand, the LTQ-Orbitrap maintained excellent isotopic pattern when used as a full scan survey scan. Twenty-six metabolites were detected and identified. The formation of these new metabolites was also confirmed by analyzing duplicate incubations at different time points.|Nefazodone has known human metabolites that include 1-(3-Chlorophenyl)piperazine, 5-Ethyl-4-(2-phenoxyethyl)-2-(3-hydroxypropyl)-2H-1,2,4-triazol-3(4H)-one, Hydroxynefazodone, and P-Hydroxynefazodone.

2-4 hours|... A 16-year-old female took 2.4 g of nefazodone. ... The terminal elimination half-life for nefazodone was 8.3 hours, and its metabolite hydroxy(OH)-nefazodone was 14.6 hours.|... In a 4-way crossover design, 16 subjects received clinically relevant doses of venlafaxine, nefazodone, or sertraline for 8 days or fluoxetine for 11 days. Treatments were separated by a 7- to 14-day washout period and fluoxetine was always the last antidepressant taken. ... Nefazodone was also the only antidepressant that caused a significant change in alprazolam (ALPZ) disposition, decreasing its area under the concentration-versus-time curve (AUC; P < 0.01), and increasing its elimination half-life (16.4 vs. 12.3 hours; P < 0.05) compared with values at baseline. ...|... the half-life of nefazodone is 2 to 4 hours.

Within the serotonergic system, nefazodone acts as an antagonist at type 2 serotonin (5-HT₂) post-synaptic receptors and, like fluoxetine-type antidepressants, inhibits pre-synaptic serotonin (5-HT) reuptake. These mechanisms increase the amount of serotonin available to interact with 5-HT receptors. Within the noradrenergic system, nefazodone inhibits norepinephrine uptake minimally. Nefazodone also antagonizes alpha(1)-adrenergic receptors, producing sedation, muscle relaxation, and a variety of cardiovascular effects. Nefazodone's affinity for benzodiazepine, cholinergic, dopaminergic, histaminic, and beta or alpha(2)-adrenergic receptors is not significant.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/|Emergency and supportive measures. 1. Maintain an open airway and assist ventilation if needed. Administer supplemental oxygen. 2. Treat coma, hypotension, hypertension, and seizures if they occur. 3. For mild serotonin syndrome, benzodiazepines can be used for control of agitation and tremor. Severe serotonin syndrome with hyperthermia requires hospitalization and aggressive cooling measures, which often include neuromuscular paralysis and endotracheal intubation. ... /Antidepressants, general (noncyclic)/|For more Antidote and Emergency Treatment (Complete) data for Nefazodone (8 total), please visit the HSDB record page.

/SIGNS AND SYMPTOMS/ Cases of life-threatening hepatic failure have been reported in patients treated with nefazodone hydrochloride tablets. The reported rate in the United States is about 1 case of liver failure resulting in death or transplant per 250,000 to 300,000 patient-years of nefazodone hydrochloride treatment. The total patient-years is a summation of each patient's duration of exposure expressed in years. For example, 1 patient-year is equal to 2 patients each treated for 6 months, 3 patients each treated for 4 months, etc. Ordinarily, treatment with nefazodone hydrochloride tablets should not be initiated in individuals with active liver disease or with elevated baseline serum transaminases. There is no evidence that pre-existing liver disease increases the likelihood of developing liver failure, however, baseline abnormalities can complicate patient monitoring. Patients should be advised to be alert for signs and symptoms of liver dysfunction (jaundice, anorexia, gastrointestinal complaints, malaise, etc.) and to report them to their doctor immediately if they occur. Nefazodone hydrochloride tablets should be discontinued if clinical signs or symptoms suggest liver failure. Patients who develop evidence of hepatocellular injury such as increased serum AST or serum ALT levels = 3 times the upper limit of NORMAL, while on nefazodone hydrochloride tablets should be withdrawn from the drug. These patients should be presumed to be at increased risk for liver injury if nefazodone hydrochloride is reintroduced. Accordingly, such patients should not be considered for re-treatment.|/SIGNS AND SYMPTOMS/ In postmarketing experience, overdose with nefazodone alone and in combination with alcohol and/or other substances has been reported. Commonly reported symptoms were similar to those reported from overdose in premarketing experience. While there have been rare reports of fatalities in patients taking overdoses of nefazodone, predominantly in combination with alcohol and/or other substances, no causal relationship to nefazodone has been established.|/SIGNS AND SYMPTOMS/ In premarketing clinical studies, there were seven reports of nefazodone overdose alone or in combination with other pharmacological agents. The amount of nefazodone ingested ranged from 1000 mg to 11,200 mg. Commonly reported symptoms from overdose of nefazodone included nausea, vomiting, and somnolence. One nonstudy participant took 2000 to 3000 mg of nefazodone with methocarbamol and alcohol; this person reportedly experienced a convulsion (type not documented). None of these patients died.|/SIGNS AND SYMPTOMS/ Patients should be informed that nefazodone therapy has been associated with liver abnormalities ranging from asymptomatic reversible serum transaminase increases to cases of liver failure resulting in transplant and/or death. At present, there is no way to predict who is likely to develop liver failure. Ordinarily, patients with active liver disease should not be treated with nefazodone. Patients should be advised to be alert for signs of liver dysfunction (jaundice, anorexia, gastrointestinal complaints, malaise, etc.) and to report them to their doctor immediately if they occur.|For more Human Toxicity Excerpts (Complete) data for Nefazodone (17 total), please visit the HSDB record page.

Apo-Nefazodone

Table: Nefazodone Hydrochloride Preparations [Table#8470]

Pharmaceuticals