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NEFAZODONE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Nefazodone is an antidepressant belonging to the phenylpiperazine class and is structurally related to trazodone. Nefazodone has pharmacologic actions in both the serotonergic and noradrenergic systems.

Specific Substances

    1) 3H-1,2,4-triazol-3-one,2-(3-(4-(3-chlorophenyl)-1-
    2) piperazinyl)-propyl)-5-ethyl-2,4-dihydro-4-
    3) (2-phenoxyethyl)-,monohydrochloride
    4) 1-(3-(4-(m-chlorophenyl)-1-piperazinyl)propyl)-3-
    5) ethyl-4-(2-phenoxyethyl)-delta(2)-1,2,4-triazolin
    6) -5-one-monohydrochloride
    7) MJ 13754-1
    8) Nefazodone Hydrochloride
    9) Molecular Formula: C25-H32-Cl-N5-O2.HCl
    10) CAS 83366-66-9 (Nefazodone)
    11) CAS 82752-99-6 (Nefazodone Hydrochloride)
    1.2.1) MOLECULAR FORMULA
    1) C25H32ClN5O2-HCl

Available Forms Sources

    A) FORMS
    1) Nefazodone is available as 50, 100, 150, 200, and 250 milligram oral tablets (Prod Info Serzone(R), nefazodone hydrochloride, 2002).
    B) USES
    1) Nefazodone is indicated for the treatment of depression (DSM-III or DSM-IIIR category of major depressive disorder) (Prod Info Serzone(R), nefazodone hydrochloride, 2002).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH THERAPEUTIC USE
    1) WITH THERAPEUTIC USE
    a) Common adverse effects at therapeutic doses include headache, dizziness, light-headedness, somnolence, dry mouth, nausea, confusion and blurred vision. Liver failure has been reported following chronic therapy.
    B) WITH POISONING/EXPOSURE
    1) Experience with overdose is limited. Effects reported include nausea, vomiting, somnolence, hypotension, bradycardia, prolonged QT interval, and in one mixed ingestion with ethanol and methocarbamol, seizures. In another mixed overdose, increasing lethargy, significant bradycardia, hypotension, and decreased respiratory rate were noted.
    2) Trazodone is pharmacologically similar to nefazodone and might have similar effects in overdose. Effects commonly reported with trazodone overdose include CNS depression, nausea and vomiting. Coma is rare, but can be prolonged. Seizures and mild cardiovascular abnormalities (bradycardia and transient first degree heart block) have been described, but are rare.
    0.2.3) VITAL SIGNS
    A) WITH POISONING/EXPOSURE
    1) Hypotension, bradycardia and respiratory depression may occur with significant ingestions.
    0.2.5) CARDIOVASCULAR
    A) WITH POISONING/EXPOSURE
    1) Cardiovascular effects appear to be minimal, but may include hypotension, bradycardia and ECG abnormalities. Heart block and torsades de pointes have occurred with trazodone, which is structurally similar to nefazodone.
    0.2.6) RESPIRATORY
    A) WITH POISONING/EXPOSURE
    1) Respiratory depression has been reported in an overdose.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Therapeutic doses of nefazodone may produce somnolence, dizziness or asthenia.
    2) Seizures have occurred in a person treated with nefazodone who had a history of seizures.
    B) WITH POISONING/EXPOSURE
    1) CNS depression has been reported after overdose. Seizures have occurred with an overdose of nefazodone and other drugs.
    0.2.8) GASTROINTESTINAL
    A) WITH THERAPEUTIC USE
    1) Dry mouth, nausea, and constipation have been reported following therapeutic doses of nefazodone.
    B) WITH POISONING/EXPOSURE
    1) Overdoses have resulted in nausea and vomiting.
    0.2.9) HEPATIC
    A) WITH THERAPEUTIC USE
    1) Increases in liver function tests have been reported following therapeutic doses. Liver failure has been reported after 14 to 28 weeks of therapy.
    B) WITH POISONING/EXPOSURE
    1) Increases in liver function tests have been reported following overdoses of nefazodone.
    0.2.10) GENITOURINARY
    A) WITH POISONING/EXPOSURE
    1) Priapism might occasionally occur in overdose cases. This may be a very serious side effect requiring surgery.
    0.2.12) FLUID-ELECTROLYTE
    A) WITH THERAPEUTIC USE
    1) Peripheral edema has been reported in 3% of patients receiving therapeutic doses of nefazodone compared to 2% of placebo-treated patients.
    0.2.13) HEMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Rare cases of decreased hematocrit have been reported following therapeutic doses of nefazodone.
    0.2.14) DERMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Diaphoresis may be seen following therapeutic use.
    0.2.16) ENDOCRINE
    A) WITH THERAPEUTIC USE
    1) WITH THERAPEUTIC USE
    a) Plasma prolactin levels and cortisol may be increased following increased doses of nefazodone.
    0.2.18) PSYCHIATRIC
    A) WITH THERAPEUTIC USE
    1) Activation of mania/hypomania may occur following therapeutic nefazodone doses in bipolar or unipolar patients. Panic attacks have been reported.
    0.2.20) REPRODUCTIVE
    A) It is not known if nefazodone or its metabolites are excreted in human milk.
    B) A slight decrease in fertility occurred in rats at doses of 200 mg/kg/day.
    0.2.21) CARCINOGENICITY
    A) No significant increase in tumors occurred in rats or mice fed nefazodone for 2 years with daily doses approximately 3 to 6 times greater than the maximum human daily dose (Prod Info Serzone(R), nefazodone hydrochloride, 2002).
    0.2.22) OTHER
    A) Drug interactions include drugs which are metabolized by the cytochrome P450IIIA4 enzyme and highly protein bound drugs which may displace nefazodone or the other drugs.

Laboratory Monitoring

    A) Nefazodone plasma levels are not widely available and their clinical usefulness has not been determined.
    B) Following nefazodone overdose, monitor heart rate, ECG, blood pressure, liver function tests, neurologic and respiratory status.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) There is no specific antidote for nefazodone overdose other than decontamination and supportive care. Nefazodone overdose alone has not been reported to produce significant cardiotoxicity, patients generally do well with supportive care.
    B) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    C) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
    D) ATROPINE: ADULT DOSE: BRADYCARDIA: BOLUS: 0.5 mg IV may repeat every 3 to 5 min. Maximum: 3 mg. PEDIATRIC DOSE: 0.02 mg/kg IV/IO (0.04 to 0.06 mg/kg ET). Repeat once, if needed. Minimum dose: 0.1 mg. Maximum single dose: Child: 0.5 mg; Adolescent: 1 mg. Maximum total dose: Child: 1 mg; Adolescent: 2 mg.
    E) There is only a small risk for seizures in overdose, thus prophylactic treatment with anticonvulsants is not recommended.
    1) SEIZURES: Administer diazepam IV bolus (DOSE: ADULT: 5 to 10 mg) initially which may be repeated every 15 minutes PRN up to 30 mg. CHILD: 0.25 to 0.4 mg/kg/dose up to 10 mg/dose. If seizures cannot be controlled or recur, administer phenobarbital.
    F) PRIAPISM
    1) An immediate urological consult is necessary. Clinical history should include the use of other agents (ie, antihypertensives, antidepressants, illegal agents) that may also be contributing to priapism. In a patient with ischemic priapism the corpora cavernosa are often completely rigid and the patient complains of pain, while nonischemic priapism the corpora are typically tumescent, but not completely rigid and pain is not typical. Aspirate blood from the corpus cavernosum with a fine needle. Blood gas testing of the aspirated blood may be used to distinguish ischemic (typically PO2 less than 30 mmHg, PCO2 greater than 60 mmHg, and pH less than 7.25) and nonischemic priapism. Color duplex ultrasonography may also be useful. If priapism persists after aspiration, inject a sympathomimetic. PHENYLEPHRINE: Dose: Adult: For intracavernous injection, dilute phenylephrine with normal saline for a concentration of 100 to 500 mcg/mL and give 1 mL injections every 3 to 5 minutes for approximately 1 hour (before deciding that treatment is not successful). For children and patients with cardiovascular disease: Use lower concentrations in smaller volumes. NOTE: Treatment is less likely to be effective if done more than 48 hours after the development of priapism. Distal shunting (NOT first-line therapy) should only be considered after a trial of intracavernous injection of sympathomimetics.

Range Of Toxicity

    A) An overdose of 16,800 mg of nefazodone along with "a handful" of verapamil resulted in lethargy, significant bradycardia, hypotension, and decreased respiratory rate.
    B) An overdose of 13.5 grams of nefazodone, with no concomitant agents taken, resulted in no symptoms 2 hours after ingestion. The patient remained asymptomatic after decontamination.

Clinical Effects

Summary Of Exposure

    A) WITH THERAPEUTIC USE
    1) WITH THERAPEUTIC USE
    a) Common adverse effects at therapeutic doses include headache, dizziness, light-headedness, somnolence, dry mouth, nausea, confusion and blurred vision. Liver failure has been reported following chronic therapy.
    B) WITH POISONING/EXPOSURE
    1) Experience with overdose is limited. Effects reported include nausea, vomiting, somnolence, hypotension, bradycardia, prolonged QT interval, and in one mixed ingestion with ethanol and methocarbamol, seizures. In another mixed overdose, increasing lethargy, significant bradycardia, hypotension, and decreased respiratory rate were noted.
    2) Trazodone is pharmacologically similar to nefazodone and might have similar effects in overdose. Effects commonly reported with trazodone overdose include CNS depression, nausea and vomiting. Coma is rare, but can be prolonged. Seizures and mild cardiovascular abnormalities (bradycardia and transient first degree heart block) have been described, but are rare.

Vital Signs

    3.3.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Hypotension, bradycardia and respiratory depression may occur with significant ingestions.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Nefazodone has been shown to cause an elevation in body temperature, which may be mediated by the metabolite, mCPP (Walsh et al, 1993).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Amblyopia has been reported following therapeutic doses of nefazodone (Fontaine, 1992).
    2) Blurred vision has been reported with therapeutic use (Prod Info SERZONE(R) oral tablets, 2005).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Cardiovascular effects appear to be minimal, but may include hypotension, bradycardia and ECG abnormalities. Heart block and torsades de pointes have occurred with trazodone, which is structurally similar to nefazodone.
    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Minimal adverse cardiovascular effects have been reported in pre-marketing studies. Postural hypotension was reported in 2.8% of cases (Prod Info Serzone (R), 2002). A few cases of decreased pulse and supine blood pressure have occurred with therapeutic doses (Fontaine, 1993).
    2) WITH POISONING/EXPOSURE
    a) Acute overdose may result in significant hypotension, due to alpha-receptor blockade.
    b) CASE REPORT - Hypotension (lowest BP 70/30) developed in a 16-year-old female who ingested 24 nefazodone (100 mg). Hypotension (systolic BP less than 90 mmHg) persisted for 18 hours after ingestion but was never severe enough to require more than intravenous fluids (Isbister & Hackett, 2003).
    c) CASE REPORT - Hypotension (BP, 59/24 mm Hg) was reported 5 hours after ingestion of 16,800 mg nefazodone along with "a handful" of verapamil tablets in an adult. Following symptomatic therapy, the patient recovered (Catalano et al, 1999).
    d) CASE SERIES - In a case series of 1338 nefazodone overdoses, with no concomitant agents, bradycardia and hypotension occurred in 1.4% and 1.6% of all patients, respectively (Benson et al, 2000).
    B) BRADYCARDIA
    1) WITH THERAPEUTIC USE
    a) Nefazodone does not appear to produce tachycardia, even in patients with hypotension, and may lower baseline heart rate with therapeutic doses. Pre-marketing trials have shown a small incidence of modest reduction in resting pulse following therapeutic doses of nefazodone (Fontaine, 1993).
    b) Reports of cardiovascular/electrocardiographic toxicity of nefazodone have not always ruled out co-ingestants or underlying cardiac disease (Fontaine, 1993).
    c) Pre-marketing studies of nefazodone vs. placebo have shown a significant degree of ECG changes reflecting sinus bradycardia in nefazodone recipients (Prod Info Serzone(R), nefazodone hydrochloride, 2002).
    2) WITH POISONING/EXPOSURE
    a) Acute overdose may result in bradycardia.
    b) CASE REPORT - A 16-year-old female developed mild bradycardia (lowest heart rate 56 bpm) and hypotension after ingesting 24 nefazodone (100 mg). Bradycardia persisted for 30 hours but did not require specific therapy (Isbister & Hackett, 2003).
    c) CASE REPORT - In an overdose of 16,800 mg nefazodone along with "a handful" of verapamil, significant bradycardia (42 beats/minute) was reported in an adult (Catalano et al, 1999). ECG revealed normal sinus rhythm with a prolonged QT interval and occasional premature ventricular contractions.
    d) CASE SERIES - In a case series of 1338 nefazodone overdoses, with no concomitant agents, bradycardia and hypotension occurred in 1.4% and 1.6% of all patients, respectively (Benson et al, 2000).
    C) CONDUCTION DISORDER OF THE HEART
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT - A 16-year-old female developed moderate prolongation of the QT/QTc interval (460/444 msec) along with mild bradycardia and hypotension after ingesting 24 nefazodone (100 mg). The QTc interval remained greater than 440 msec for 24 hours (Isbister & Hackett, 2003).
    b) TRAZODONE - Nefazodone has been compared pharmacologically to trazodone (D'Amico et al, 1990), a drug which has occasionally produced cardiovascular effects in overdose, primarily when other drugs were also taken.
    c) Sporadic reports of hypotension, nonspecific ST-T wave changes, premature ventricular beats, torsades de pointes, right bundle-branch block, T wave inversion, bradycardia and AV block have been associated with trazodone overdoses (Lippman et al, 1982; (Gamble & Peterson, 1986) Henry & Ali, 1983; (Himmelhoch et al, 1984; Dubot et al, 1986; Augenstein et al, 1987; Irwin & Spar, 1983).
    d) Based on structural similarities, it is conceivable that cardiovascular effects associated with trazodone may also occur with nefazodone overdose.

Respiratory

    3.6.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Respiratory depression has been reported in an overdose.
    3.6.2) CLINICAL EFFECTS
    A) ACUTE RESPIRATORY INSUFFICIENCY
    1) WITH POISONING/EXPOSURE
    a) Overdose information is limited with nefazodone. Trazodone has produced respiratory arrest in rare overdose cases (Lippmann et al, 1982; Gamble & Peterson, 1986). The possibility of respiratory depression should be considered in cases of nefazodone overdose, as these drugs are pharmacologically similar (D'Amico et al, 1990).
    b) Respiratory depression, resulting in decreased oxygen saturation (O2, 83%), was reported in a 31-year-old female following the ingestion of 16,800 mg nefazodone and "a handful" of verapamil (Catalano et al, 1999).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Therapeutic doses of nefazodone may produce somnolence, dizziness or asthenia.
    2) Seizures have occurred in a person treated with nefazodone who had a history of seizures.
    B) WITH POISONING/EXPOSURE
    1) CNS depression has been reported after overdose. Seizures have occurred with an overdose of nefazodone and other drugs.
    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Pre-marketing clinical studies reported petit mal seizures in a patient with a history of petit mal seizures (Prod Info SERZONE(R) oral tablets, 2005).
    2) WITH POISONING/EXPOSURE
    a) A limited review of unpublished overdoses reported to the manufacturer identified seizures in one overdose case involving 2000 to 3000 mg nefazodone, methocarbamol and alcohol (Prod Info SERZONE(R) oral tablets, 2005).
    B) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH THERAPEUTIC USE
    a) Most common adverse effects following therapeutic doses of nefazodone have included somnolence, dizziness, and asthenia (Fontaine, 1992; D'Amico et al, 1990). These effects have tended to be dose related.
    2) WITH POISONING/EXPOSURE
    a) The incidence of CNS effects in cases of nefazodone overdose is limited. The possibility of CNS depression should be considered in severe overdoses. Manifestations of CNS depression, in general, can range from lethargy to coma.
    b) CASE REPORT - A 16-year-old female became drowsy and stumbled when walking after ingesting 24 nefazodone (100 mg) (Isbister & Hackett, 2003).
    c) CASE REPORT - In an overdose of 16,800 mg nefazodone along with "a handful" of verapamil, a 31-year-old female experienced increasing lethargy and slurred speech (Catalano et al, 1999).
    d) CASE REPORT - Five hours following an overdose of 3000 mg nefazodone alone, a 27-year-old woman developed somnolence. No other signs/symptoms were noted. She recovered with no sequelae (Gaffney et al, 1998).
    e) CASE SERIES - In a series of 1338 nefazodone overdoses, with no concomitant agents, patients were asymptomatic or developed minimal symptoms of nausea, vomiting, dizziness, and drowsiness (25% of all patients) (Benson et al, 2000).
    C) PSYCHOMOTOR AGITATION
    1) WITH THERAPEUTIC USE
    a) Agitation, anxiety and tremor have been reported in pre-marketing studies following therapeutic doses of nefazodone, but these effects were less than reported for other 5-HT uptake inhibitors (Fontaine, 1992).
    b) A clinical trial involving 90 patients reported improvement of depression-associated anxiety symptoms following nefazodone treatment (Fontaine et al, 1994). Fontaine (1993) reported a lower incidence of agitation in nefazodone treated patients (27 out of 1,022; 2.6%) as compared to placebo treated patients (30 out of 672; 4.5%).
    c) Discontinuation of nefazodone resulted in agitation in 1.2% of patients in clinical trials (Prod Info Serzone (R), 2002).
    2) WITH POISONING/EXPOSURE
    a) There is insufficient information concerning agitation and anxiety following nefazodone overdoses.
    D) CLOUDED CONSCIOUSNESS
    1) WITH THERAPEUTIC USE
    a) Confusion was reported in 7% of 393 patients treated with nefazodone in 6 to 8 week clinical trials. Confusion was reported in 2% of 394 patients in the placebo group (Prod Info SERZONE(R) oral tablets, 2005).
    E) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache was reported as frequently or more frequently in placebo treated patients compared to patients treated with nefazodone at 200 to 300 mg/day. The incidence of headache in nefazodone treated patients was not positively correlated with dose (D'Amico et al, 1990).
    F) SEROTONIN SYNDROME
    1) WITH THERAPEUTIC USE
    a) Discontinuation of drugs similar to nefazodone, followed by the use of a monoamine oxidase inhibitor (MAOI) have resulted in signs and symptoms of serotonin syndrome (mental status changes, agitation, myoclonus, hyper-reflexia, diaphoresis, shivering, tremor, diarrhea, fever or incoordination) (Prod Info SERZONE(R) oral tablets, 2005). Serotonin syndrome has resulted following therapeutic doses of nefazodone and mirtazapine (both partial serotonin antagonists) in two patients (McDaniel, 2001).
    1) Nefazodone should not be used with a MAOI, or within 14 days of discontinuing use of a MAOI. A period of at least 1 week should be awaited after discontinuing nefazodone before starting a MAOI (Prod Info SERZONE(R) oral tablets, 2005).
    b) Serotonin syndrome, associated with drug interactions between nefazodone and paroxetine or nefazodone and valproic acid, has been reported (John et al, 1997; Brazelton et al, 1997).
    G) ABNORMAL VISION
    1) WITH POISONING/EXPOSURE
    a) Akinetopsia (selective impairment of motion perception), with no other neurologic deficit, has been reported as a toxic effect of nefazodone. Following discontinuation or reduction of nefazodone dose, the symptoms resolved (Horton & Trobe, 1999).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Dry mouth, nausea, and constipation have been reported following therapeutic doses of nefazodone.
    B) WITH POISONING/EXPOSURE
    1) Overdoses have resulted in nausea and vomiting.
    3.8.2) CLINICAL EFFECTS
    A) PARASYMPATHOLYTIC POISONING
    1) WITH THERAPEUTIC USE
    a) Dry mouth (25%), nausea (22%), constipation (14%), and nausea with vomiting (2%) were reported in clinical trials (Prod Info SERZONE(R) oral tablets, 2005; Rickels et al, 1994).
    b) Other studies reported nausea in 15% of patients receiving doses of up to 300 mg daily and in 32% of those treated with up to 600 mg daily (D'Amico et al, 1990; Fontaine, 1992; Ansseau et al, 1994). Nausea has decreased with continued nefazodone use (D'Amico et al, 1990).
    c) One study reported that nefazodone has a lower propensity to cause anti-cholinergic adverse effects, such as dry mouth and constipation, compared to imipramine (Fontaine et al, 1994).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT - Following an overdose of 16,800 mg nefazodone along with "a handful" of verapamil, a 31-year-old experienced constipation and abdominal distention (Catalano et al, 1999).
    B) NAUSEA AND VOMITING
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES - In a series of 1338 nefazodone overdoses, with no concomitant agents, patients were asymptomatic or developed minimal symptoms of nausea, vomiting, dizziness, and drowsiness (25% of all patients) (Benson et al, 2000).

Hepatic

    3.9.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Increases in liver function tests have been reported following therapeutic doses. Liver failure has been reported after 14 to 28 weeks of therapy.
    B) WITH POISONING/EXPOSURE
    1) Increases in liver function tests have been reported following overdoses of nefazodone.
    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Increases in liver function tests, specifically, LDH, SGOT, and SGPT, were reported infrequently following therapeutic nefazodone doses. Hepatitis has been reported as a rare adverse event of nefazodone therapy (Prod Info SERZONE(R) oral tablets, 2005).
    2) WITH POISONING/EXPOSURE
    a) Hepatitis has been reported following overdoses (Catalano et al, 1999).
    B) HEPATIC FAILURE
    1) WITH THERAPEUTIC USE
    a) Cases of severe liver failure, resulting in death or liver transplant, have been reported in patients treated with nefazodone. This is a rare adverse effect, reported as one case of liver failure per 250,000 to 300,000 patient-years of nefazodone treatment (Prod Info SERZONE(R) oral tablets, 2005).
    b) Subfulminant liver failure due to severe hepatocellular injury from nefazodone, an idiosyncratic reaction, has been reported after 14 to 28 weeks of therapy in 3 separate cases (Aranda-Michel et al, 1999). Prominent centrilobular collapse and necrosis was evident in all 3 cases. A 4 to 6 week duration of jaundice preceded onset of hepatic encephalopathy.

Genitourinary

    3.10.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Priapism might occasionally occur in overdose cases. This may be a very serious side effect requiring surgery.
    3.10.2) CLINICAL EFFECTS
    A) PRIAPISM
    1) WITH POISONING/EXPOSURE
    a) Trazodone may cause priapism in overdose and might occur with nefazodone overdose. However, priapism is not expected to occur as frequently with nefazodone, due to a lesser degree of alpha-adrenergic blocking activity. If priapism does occur, it may be a serious adverse consequence requiring surgery (Ware et al, 1994). Patients with prolonged or inappropriate erections should be referred to a physician.

Hematologic

    3.13.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Rare cases of decreased hematocrit have been reported following therapeutic doses of nefazodone.
    3.13.2) CLINICAL EFFECTS
    A) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Pre-marketing clinical trials of nefazodone have shown rare cases of decreased hematocrit following therapeutic doses (Prod Info SERZONE(R) oral tablets, 2005).

Dermatologic

    3.14.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Diaphoresis may be seen following therapeutic use.
    3.14.2) CLINICAL EFFECTS
    A) EXCESSIVE SWEATING
    1) WITH THERAPEUTIC USE
    a) Sweating occurred in 2.6% (27 out of 1.022; placebo group 2.4%) of patients following therapeutic doses of nefazodone (Fontaine, 1993).
    B) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Rash and pruritus occurred in a small number of patients (2%) following therapeutic nefazodone doses (Prod Info SERZONE(R) oral tablets, 2005).

Endocrine

    3.16.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) WITH THERAPEUTIC USE
    a) Plasma prolactin levels and cortisol may be increased following increased doses of nefazodone.
    3.16.2) CLINICAL EFFECTS
    A) HYPERPROLACTINEMIA
    1) WITH THERAPEUTIC USE
    a) Oral nefazodone (50 to 200 mg) was associated with dose-related increases in plasma prolactin levels in one study involving healthy male volunteers. The drug did not significantly alter levels of corticotropin (ACTH), although a trend toward elevation of cortisol levels was reported (Walsh et al, 1993).

Reproductive

    3.20.1) SUMMARY
    A) It is not known if nefazodone or its metabolites are excreted in human milk.
    B) A slight decrease in fertility occurred in rats at doses of 200 mg/kg/day.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Nefazodone is classified as Pregnancy Category C by the FDA. No malformations were observed in rat or rabbit fetuses in reproductive studies, however, increased early pup mortality was reported at doses approximately 5 times the maximum human dose (Prod Info Serzone(R), nefazodone hydrochloride, 2002).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is not known if nefazodone or its metabolites are excreted in human milk (Prod Info Serzone(R), nefazodone hydrochloride, 2002).
    2) A temporal relationship between resolution of nefazodone adverse effects in a premature infant and cessation of breastfeeding was demonstrated. The mother had been taking nefazodone 300 mg/day. The infant exhibited signs/symptoms of drowsiness, lethargy, poor feeding and inability to maintain normal body temperature. The infant's symptoms resolved after breast feeding was stopped. The authors measured nefazodone and its metabolites in the breast milk. They determined the infant received an average of 0.45% of the maternal weight-adjusted nefazodone dose (Yapp et al, 2000).
    3) In a report of 2 breastfed infants whose mothers were taking nefazodone, but no other drugs, levels of nefazodone and its metabolites were measured in the milk. Levels of nefazodone were measured, but its major active metabolites were not found in the milk. In one infant, an exposure of 0.054 mg/kg or 2.2% of the weight-adjusted maternal dose was reported. In the other infant, an exposure of 0.028 mg/kg or 0.4% of the maternal dose was reported (Dodd et al, 2000).
    3.20.5) FERTILITY
    A) FERTILITY DECREASED FEMALE
    1) A slight decrease in fertility occurred in rats at doses of 200 mg/kg/day, which is approximately 3 times the maximum human daily dose. Lower doses did not decrease fertility (Prod Info Serzone(R), nefazodone hydrochloride, 2002).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) No significant increase in tumors occurred in rats or mice fed nefazodone for 2 years with daily doses approximately 3 to 6 times greater than the maximum human daily dose (Prod Info Serzone(R), nefazodone hydrochloride, 2002).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Nefazodone plasma levels are not widely available and their clinical usefulness has not been determined.
    B) Following nefazodone overdose, monitor heart rate, ECG, blood pressure, liver function tests, neurologic and respiratory status.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Quantitative determination of nefazodone plasma levels is not widely available and its clinical utility has not been determined.
    2) Following oral doses of 150 mg BID, plasma levels of approximately 1200 ng/mL were determined after 30 minutes in one female patient. Peak levels of the metabolites hydroxynefazodone and m-chlorophenylpiperazine (mCPP) were approximately 400 and 25 ng/mL, respectively, each occurring 2 hours following nefazodone administration (Franc et al, 1991).
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Although cardiovascular toxicity has been minimal in reports of overdose, ECG monitoring is recommended. There are insufficient data to determine the duration of monitoring required.
    2) MONITORING
    a) Monitor the chest x-ray in patients with significant exposure.
    b) Monitor blood gases and pulmonary function if respiratory or CNS depression is suspected.

Methods

    A) CHROMATOGRAPHY
    1) Franc et al (1991), describe a quantitative method utilizing high- performance liquid chromatography and ultraviolet detection for the determination of nefazodone and its metabolites, m-chlorophenylpiperazine (mCPP), p-hydroxynefazodone (PHN), and hydroxynefazodone (HO-NEF), in human plasma. However, the clinical utility of quantitative determination of nefazodone plasma levels has not yet been determined.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with suspected nefazodone poisoning should be monitored in view of a small possibility of cardiovascular and neurological disturbances.
    B) Although cardiovascular toxicity has been minimal in reports of overdose, ECG monitoring is recommended since reports of cardiotoxicity have occurred. There are insufficient data to determine the duration of monitoring required.

Monitoring

    A) Nefazodone plasma levels are not widely available and their clinical usefulness has not been determined.
    B) Following nefazodone overdose, monitor heart rate, ECG, blood pressure, liver function tests, neurologic and respiratory status.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) There is no specific treatment for nefazodone overdose other than supportive care. Nefazodone overdose alone has not prolonged QRS duration and there is no evidence that therapies used in tricyclic antidepressant overdose (hyperventilation, sodium bicarbonate) are useful.
    2) There is only a small risk for seizures in overdose, thus prophylactic treatment with anticonvulsants is not recommended. Hypotension has responded to intravenous fluids.
    B) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    C) BRADYCARDIA
    1) ATROPINE: It may be indicated if significant bradycardia or heart block are present.
    2) ATROPINE/DOSE
    a) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia in adults (Neumar et al, 2010).
    b) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg, giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE DOSE: Children: 0.5 milligram; adolescent: 1 mg.
    1) There is no minimum dose (de Caen et al, 2015).
    2) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).
    D) TORSADES DE POINTES
    1) Since nefazodone is pharmacologically related to trazodone, which is known to produce a dose-related prolongation of the QTc interval, ventricular arrhythmias, including torsades de pointes, are possible (Augenstein et al, 1987).
    2) SUMMARY
    a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
    b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).
    3) MAGNESIUM SULFATE
    a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
    b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
    c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
    d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).
    4) OVERDRIVE PACING
    a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).
    5) POTASSIUM REPLETION
    a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).
    6) ISOPROTERENOL
    a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
    b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
    c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    7) OTHER DRUGS
    a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).
    8) AVOID
    a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.
    E) SEIZURE
    1) SUMMARY - Attempt initial control with a benzodiazepine (diazepam or lorazepam). If seizures persist or recur administer phenobarbital.
    a) Monitor for respiratory depression, hypotension, dysrhythmias, and the need for endotracheal intubation.
    b) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or treat with intravenous dextrose ADULT: 100 milligrams IV, CHILD: 2 milliliters/kilogram 25% dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    7) Phenytoin should be avoided due to the potential effect of nefazodone on the QTc interval.
    F) PRIAPISM
    1) SUMMARY
    a) PRIAPISM: It is a medical emergency requiring immediate consult with a urologist.
    b) It has been suggested that administration of anticholinergics (i.e., benztropine) or beta-blockers may be effective in reversing trazodone-induced priapism, which is also theoretically possible, but NOT as likely, with nefazodone since it has less alpha-blocking activity. Clinical studies will be needed to verify efficacy (Fishbain, 1989; Ware et al, 1994).
    2) GUIDELINE ON THE MANAGEMENT OF PRIAPISM
    a) The following American Urological Association Guideline has been developed to evaluate and treat priapism (Montague et al, 2003):
    1) Ischemic priapism is characterized by little or no cavernous blood flow and abnormal cavernous blood gases (hypoxic, hypercarbic and acidotic).
    a) CLINICAL HISTORY: A clear history can determine the most effective treatment and should include the following:
    1) Duration of erection.
    2) Degree of pain (ischemic priapism is painful; nonischemic is not painful).
    3) Use of drug(s) associated with priapism (eg, antihypertensives, anticoagulants, antidepressants, illegal agents).
    4) Underlying disease (eg, sickle cell) or trauma.
    b) LABORATORY ANALYSIS: CBC, reticulocyte count, hemoglobin electrophoresis to rule out acute infection or underlying disease, psychoactive medication screening, and urine toxicology.
    c) PHYSICAL EXAMINATION: In a patient with ischemic priapism the corpora cavernosa are often completely rigid and painful while nonischemic priapism the corpora are typically tumescent, but not completely rigid, and is usually not painful.
    d) DIAGNOSTIC STUDIES: Blood gas testing and color duplex ultrasonography are the most reliable methods to distinguish between ischemic and nonischemic priapism.
    1) Ischemic finding: Blood aspirated from the corpus cavernosum is hypoxic and appears dark, and on blood gas testing typically has a PO2 of less than 30 mmHg and a PCO2 of greater than 60 mmHg and a pH of less than 7.25.
    2) Nonischemic finding: Blood is generally well oxygenated and appears bright red. Cavernosal blood gases are similar to normal arterial blood gas findings.
    3) Color Duplex Ultrasonography: Ischemic patient: Little or no blood flow in the cavernosal arteries.
    4) Penile Arteriography: An adjunctive study that has been mostly replaced by ultrasonography; it is often used only as part of an embolization procedure.
    e) TREATMENT: Ischemic priapism: Initial treatment usually includes therapeutic aspiration (with or without irrigation) followed by intracavernous injection of sympathomimetics (agents frequently used: epinephrine, norepinephrine, phenylephrine, ephedrine and metaraminol) as needed. Of these agents, resolution of ischemic effects occurred in 81% treated with epinephrine, 70% with metaraminol, 43% with norepinephrine and 65% with phenylephrine. To minimize adverse events, phenylephrine is an alpha1-selective adrenergic agonist is often selected because it produces no indirect neurotransmitter releasing action. Repeat sympathomimetic injection prior to considering surgical intervention.
    1) PHENYLEPHRINE: Dose: Adult: For intracavernous injection, dilute phenylephrine with normal saline for a concentration of 100 to 500 mcg/mL and 1 mL injections every 3 to 5 minutes for approximately 1 hour (before deciding that treatment is not successful). For children and patients with cardiovascular disease: Use lower concentrations in smaller volumes. NOTE: Treatment is less likely to be effective if done more than 48 hours after the development of priapism.
    2) DISTAL SHUNTING (NOT first -line therapy): Inserting a surgical shunt should ONLY be considered after a trial of intracavernous injection of sympathomimetics. A caveroglanular (corporoglanular) shunt is the preferred method to avoid complications.
    G) SEROTONIN SYNDROME
    1) SUMMARY
    a) Benzodiazepines are the mainstay of therapy. Cyproheptadine, a 5-HT antagonist, is also commonly used. Severe cases have been managed with benzodiazepine sedation and neuromuscular paralysis with non-depolarizing agents(Claassen & Gelissen, 2005).
    2) HYPERTHERMIA
    a) Control agitation and muscle activity. Undress patient and enhance evaporative heat loss by keeping skin damp and using cooling fans.
    b) MUSCLE ACTIVITY: Benzodiazepines are the drug of choice to control agitation and muscle activity. DIAZEPAM: ADULT: 5 to 10 mg IV every 5 to 10 minutes as needed, monitor for respiratory depression and need for intubation. CHILD: 0.25 mg/kg IV every 5 to 10 minutes; monitor for respiratory depression and need for intubation.
    c) Non-depolarizing paralytics may be used in severe cases.
    3) CYPROHEPTADINE
    a) Cyproheptadine is a non-specific 5-HT antagonist that has been shown to block development of serotonin syndrome in animals (Sternbach, 1991). Cyproheptadine has been used in the treatment of serotonin syndrome (Mills, 1997; Goldberg & Huk, 1992). There are no controlled human trials substantiating its efficacy.
    b) ADULT: 12 mg initially followed by 2 mg every 2 hours if symptoms persist, up to a maximum of 32 mg in 24 hours. Maintenance dose 8 mg orally repeated every 6 hours (Boyer & Shannon, 2005).
    c) CHILD: 0.25 mg/kg/day divided every 6 hours, maximum dose 12 mg/day (Mills, 1997).
    4) HYPERTENSION
    a) Monitor vital signs regularly. For mild/moderate asymptomatic hypertension, pharmacologic intervention is usually not necessary.
    5) HYPOTENSION
    a) Administer 10 to 20 mL/kg 0.9% saline bolus and place patient supine. Further fluid therapy should be guided by central venous pressure or right heart catheterization to avoid volume overload.
    b) Pressor agents with dopaminergic effects may theoretically worsen serotonin syndrome and should be used with caution. Direct acting agents (norepinephrine, epinephrine, phentolamine) are theoretically preferred.
    c) NOREPINEPHRINE
    1) PREPARATION: Add 4 mL of 0.1% solution to 1000 mL of dextrose 5% in water to produce 4 mcg/mL.
    2) INITIAL DOSE
    a) ADULT: 2 to 3 mL (8 to 12 mcg)/minute.
    b) ADULT or CHILD: 0.1 to 0.2 mcg/kg/min. Titrate to maintain adequate blood pressure.
    3) MAINTENANCE DOSE
    a) 0.5 to 1 mL (2 to 4 mcg)/minute.
    6) SEIZURES
    a) DIAZEPAM
    1) MAXIMUM RATE: Administer diazepam IV over 2 to 3 minutes (maximum rate: 5 mg/min).
    2) ADULT DIAZEPAM DOSE: 5 to 10 mg initially, repeat every 5 to 10 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 30 milligrams.
    3) PEDIATRIC DIAZEPAM DOSE: 0.2 to 0.5 mg/kg, repeat every 5 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 10 milligrams in children over 5 years or 5 milligrams in children under 5 years of age.
    4) RECTAL USE: If an intravenous line cannot be established, diazepam may be given per rectum (not FDA approved), or lorazepam may be given intramuscularly.
    b) LORAZEPAM
    1) MAXIMUM RATE: The rate of IV administration of lorazepam should not exceed 2 mg/min (Prod Info Ativan(R), 1991).
    2) ADULT LORAZEPAM DOSE: 2 to 4 mg IV. Initial doses may be repeated in 10 to 15 minutes, if seizures persist (Prod Info ATIVAN(R) injection, 2003).
    3) PEDIATRIC LORAZEPAM DOSE: 0.1 mg/kg IV push (range: 0.05 to 0.1 mg/kg; maximum dose 4 mg); may repeat dose in 5 to 10 minutes if seizures continue. It has also been given rectally at the same dose in children with no IV access (Sreenath et al, 2010; Chin et al, 2008; Wheless, 2004; Qureshi et al, 2002; De Negri & Baglietto, 2001; Mitchell, 1996; Appleton, 1995; Giang & McBride, 1988).
    c) RECURRING SEIZURES
    1) If seizures cannot be controlled with diazepam or recur, give phenobarbital or propofol.
    d) PHENOBARBITAL
    1) SERUM LEVEL MONITORING: Monitor serum levels over next 12 to 24 hours for maintenance of therapeutic levels (15 to 25 mcg/mL).
    2) ADULT PHENOBARBITAL LOADING DOSE: 600 to 1200 mg of phenobarbital IV initially (10 to 20 mg/kg) diluted in 60 mL of 0.9% saline given at 25 to 50 mg/minute.
    3) ADULT PHENOBARBITAL MAINTENANCE DOSE: Additional doses of 120 to 240 mg may be given every 20 minutes.
    4) MAXIMUM SAFE ADULT PHENOBARBITAL DOSE: No maximum safe dose has been established. Patients in status epilepticus have received as much as 100 mg/min until seizure control was achieved or a total dose of 10 mg/kg.
    5) PEDIATRIC PHENOBARBITAL LOADING DOSE: 15 to 20 mg/kg of phenobarbital intravenously at a rate of 25 to 50 mg/min.
    6) PEDIATRIC PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 5 to 10 mg/kg may be given every 20 minutes.
    7) MAXIMUM SAFE PEDIATRIC PHENOBARBITAL DOSE: No maximum safe dose has been established. Children in status epilepticus have received doses of 30 to 120 mg/kg within 24 hours. Vasopressors and mechanical ventilation were needed in some patients receiving these doses.
    8) NEONATAL PHENOBARBITAL LOADING DOSE: 20 to 30 mg/kg IV at a rate of no more than 1 mg/kg/min in patients with no preexisting phenobarbital serum levels.
    9) NEONATAL PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 2.5 mg/kg every 12 hours may be given; adjust dosage to maintain serum levels of 20 to 40 mcg/mL.
    10) MAXIMUM SAFE NEONATAL PHENOBARBITAL DOSE: Doses of up to 20 mg/kg/min up to a total of 30 mg/kg have been tolerated in neonates.
    11) CAUTION: Adequacy of ventilation must be continuously monitored in children and adults. Intubation may be necessary with increased doses.
    7) CHLORPROMAZINE
    a) Chlorpromazine is a 5-HT2 receptor antagonist that has been used to treat cases of serotonin syndrome (Graham, 1997; Gillman, 1996). Controlled human trial documenting its efficacy are lacking.
    b) ADULT: 25 to 100 mg intramuscularly repeated in 1 hour if necessary.
    c) CHILD: 0.5 to 1 mg/kg repeated as needed every 6 to 12 hours not to exceed 2 mg/kg/day.
    8) NOT RECOMMENDED
    a) BROMOCRIPTINE: It has been used in the treatment of neuroleptic malignant syndrome but is NOT RECOMMENDED in the treatment of serotonin syndrome as it has serotonergic effects (Gillman, 1997). In one case the use of bromocriptine was associated with a fatal outcome (Kline et al, 1989).

Enhanced Elimination

    A) EFFICACY
    1) There is no evidence that forced diuresis will enhance elimination, although it is suggested as a theoretical possibility by the manufacturer (Prod Info Serzone(R), nefazodone hydrochloride, 2002).
    2) Nefazodone is highly protein bound and largely excreted as metabolites. Although one metabolite is active, it is unknown if forced diuresis will be beneficial, and it is not recommended.

Range Of Toxicity

Summary

    A) An overdose of 16,800 mg of nefazodone along with "a handful" of verapamil resulted in lethargy, significant bradycardia, hypotension, and decreased respiratory rate.
    B) An overdose of 13.5 grams of nefazodone, with no concomitant agents taken, resulted in no symptoms 2 hours after ingestion. The patient remained asymptomatic after decontamination.

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) The minimum lethal dose of nefazodone in humans has not been determined.
    2) No deaths were reported in an analysis of 1338 nefazodone poisonings, with no concomitant agents taken. These patients did not develop life-threatening toxicity after an overdose. No dose response relationship was noted in 45 cases where ingested doses, up to 13.5 grams, were known; however, decontamination may have affected the outcome in some cases (Benson et al, 2000).
    3) Rare reports of fatalities have been noted in patients following nefazodone overdose; however, these overdoses predominantly occurred in combination with alcohol and/or other substances. No causal relationship to nefazodone has been established (Prod Info SERZONE(R) oral tablets, 2005).

Maximum Tolerated Exposure

    A) CASE REPORTS
    1) In premarketing clinical trials, seven overdoses were reported involving either nefazodone alone or in combination with other agents. Doses ranged from 1000 to 11,200 milligrams. Nausea, vomiting and somnolence were common effects. No deaths occurred (Prod Info SERZONE(R) oral tablets, 2005).
    2) Fontaine (1993) reported two patients attempting suicide with nefazodone overdose. One patient ingested 3,400 mg and the other ingested 3,600 mg. Neither ingestion was associated with life-threatening symptoms.
    3) Following an overdose of 16,800 mg nefazodone along with a handful of verapamil, a 31-year-old female developed increasing lethargy with slurred speech, significant bradycardia (pulse 42 bpm), hypotension (bp, 59/24 mm Hg), prolonged QT interval on ECG, and decreased respiratory rate resulting in decreased oxygen saturation (83%) (Catalano et al, 1999).
    4) In a case series of 1338 nefazodone overdoses, with no concomitant agents taken, no fatalities were reported. Patients either developed minimal signs/symptoms (nausea, vomiting, dizziness, and drowsiness) or remained asymptomatic (25% of all patients). Signs and symptoms were evident within 1 to 4 hours of ingestion and resolved within 8 to 24 hours of ingestion (Benson et al, 2000).
    5) Five hours following a nefazodone overdose of 3000 milligrams, a 27-year-old woman was asymptomatic except for somnolence. She recovered after hospital decontamination and was released (Gaffney et al, 1998).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) Following oral doses of 150 mg BID, plasma levels of approximately 1200 ng/mL were determined after 30 minutes in one female patient. Peak levels of the metabolites hydroxynefazodone and m-chlorophenylpiperazine (mCPP) were approximately 400 and 25 ng/mL, respectively, each occurring 2 hours following nefazodone administration (Franc et al, 1991).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) ADULT
    a) Approximately 5 hours following a 3000 mg ingestion of nefazodone, serum concentration was 5.5 mcg/mL in a 27-year-old woman. No concomitant overdoses were reported. Serum and urine toxicologic examinations revealed subtherapeutic amounts of norpropoxyphene and propoxyphene and undetermined concentrations of phentermine and phenylpropanolamine (Gaffney et al, 1998).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Nefazodone is a phenylpiperazine antidepressant agent that inhibits serotonin (5-HT) reuptake and also possesses 5-HT2 antagonist properties. Nefazodone has two major metabolites that contribute to its overall antidepressant activity and one minor metabolite. Nefazodone has weak alpha 1-adrenergic blocking activity with no significant affinity for alpha 2-adrenergic receptors (Eison et al, 1990).
    1) Nefazodone is pharmacologically similar to trazodone. It exhibits actions unlike those of tricyclic antidepressants or second-generation antidepressant agents (selective serotonin (5-HT) or norepinephrine uptake inhibitors, 5-HT1A partial agonists) (Fontaine, 1992; Eison et al, 1990).
    2) In vitro and ex vivo data suggest bimodal effects of nefazodone, characterized by inhibition of neuronal 5-HT reuptake and antagonism of 5-HT2 receptors (Eison et al, 1990; Sharpley et al, 1992; Fontaine, 1992). At least two metabolites of nefazodone also appear to be pharmacologically active: hydroxynefazodone possesses properties similar to nefazodone, whereas m-chlorophenylpiperazine (mCPP) exhibits direct central serotoninergic agonist activity and possibly some degree of 5-HT2 and 5-HT3 antagonism (Hamik & Peroutka, 1989; Sharpley et al, 1992; Garattini, 1985). mCPP is also a metabolite of trazodone (Garattini, 1985).
    3) The relative contribution of the serotonin-modulating actions of the parent compound and its metabolites to antidepressant (or toxic) effects remains to be determined. It is unclear if only one mechanism may be required for clinical efficacy (e.g., 5-HT2 antagonism alone) or if all mechanisms or a balance between them are responsible. It is speculated by some investigators that, combined with selective 5-HT reuptake inhibition, 5-HT2 receptor antagonism could facilitate 5-HT1A-mediated neurotransmission (Fontaine, 1992; Eison et al, 1990). This is supported to some degree by evidence of enhanced 5-HT1A-mediated behavioral responses during long-term nefazodone administration in animals (Eison et al, 1990).
    4) Nefazodone does not inhibit monoamine oxidase and possesses little or no affinity for alpha 1-adrenergic, alpha 2-adrenergic, histaminergic, dopaminergic, cholinergic, benzodiazepine, gamma-aminobutyric acid (GABA), or mu-opiate receptor binding sites (Eison et al, 1990; Sharpley et al, 1992).

Physicochemical

Physical Characteristics

    A) NEFAZODONE HYDROCHLORIDE is a nonhygroscopic, white crystalline solid that is freely soluble in chloroform, soluble in propylene glycol, and slightly soluble in polyethylene glycol and water (Prod Info SERZONE(R) oral tablets, 2005).

Molecular Weight

    A) 506.5 (Prod Info SERZONE(R) oral tablets, 2005)

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