NEFAZODONE

c. RECURRING SEIZURES: If seizures cannot be controlled with diazepam or recur, give phenobarbital.
d. PHENOBARBITAL

(1) SERUM LEVEL MONITORING: Monitor serum levels over next 12 to 24 hours for maintenance of therapeutic levels (15 to 25 micrograms per milliliter).
(2) ADULT PHENOBARBITAL LOADING DOSE: 600 to 1200 milligrams of phenobarbital intravenously initially (10 to 20 milligrams per kilogram) diluted in 60 milliliters of 0.9 percent saline given at 25 to 50 milligrams per minute.
(3) ADULT PHENOBARBITAL MAINTENANCE DOSE: Additional doses of 120 to 240 milligrams 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 milligrams/minute until seizure control was achieved or a total dose of 10 milligrams/kilogram.
(5) PEDIATRIC PHENOBARBITAL LOADING DOSE: 15 to 20 milligrams per kilogram of phenobarbital intravenously at a rate of 25 to 50 milligrams per minute.
(6) PEDIATRIC PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 5 to 10 milligrams per kilogram 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 milligrams/kilogram within 24 hours. Vasopressors and mechanical ventilation were needed in some patients receiving these doses.
(8) INDICATIONS FOR INTUBATION: Intubation should be considered after total doses of greater than 20 milligrams/kilogram.
(9) NEONATAL PHENOBARBITAL LOADING DOSE: 20 to 30 milligrams/kilogram intravenously at a rate of no more than 1 milligram/kilogram per minute in patients with no preexisting phenobarbital serum levels.
(10) NEONATAL PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 2.5 milligrams/kilogram every 12 hours may be given; adjust dosage to maintain serum levels of 20 to 40 micrograms/milliliter.
(11) MAXIMUM SAFE NEONATAL PHENOBARBITAL DOSE: Doses of up to 20 milligrams/kilogram/minute up to a total of 30 milligrams/kilogram have been tolerated in neonates.
(12) CAUTIONS: Adequacy of ventilation must be continuously monitored in children and adults. Intubation may be necessary with increased doses.
5. 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 - 4 to 8 milligrams orally repeated every 1 to 4 hours until therapeutic response is observed or maximum of 32 milligrams administered (Mills, 1997).
c. CHILD - 0.25 milligram/kilogram/day divided every 6 hours, maximum dose 12 milligrams/day (Mills, 1997).

6. NITROGLYCERIN

a. In theory nitroglycerin may help alleviate the serotonin syndrome through nitric oxide mediated downregulation of serotonin. It has been used in human cases with apparent benefit (Brown et al, 1996). There are no human trials substantiating its efficacy
b. ADULT - Begin continuous infusion at 5 micrograms/minute and titrate to desired effect.
c. CHILD - Begin infusion at 0.25 to 0.5 microgram/kilogram/minute and titrate to desired effect.

7. PROPRANOLOL

a. Propranolol is a 5-HT1A receptor antagonist (Sternbach, 1991). Propranolol has been used in human cases of serotonin syndrome with apparent benefit (Guze & Baxter, 1986; Dursun et al, 1997). There are no controlled human trials substantiating its efficacy.
b. PROPRANOLOL/ADULT DOSE

(1) 1 milligram/dose intravenously, administered no faster than 1 milligram/minute repeated every 2 to 5 minutes until desired response is seen or a maximum of 5 milligrams has been given.

c. PROPRANOLOL/PEDIATRIC DOSE

(1) 0.01 to 0.1 milligram/kilogram/dose over 10 minutes. Maximum 1 milligram/dose (Benitz & Tatro, 1988).

8. 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 milligrams intramuscularly repeated in one hour if necessary.
c. CHILD - 0.5 to 1 milligram/kilogram repeated as needed every 6 to 12 hours not to exceed 2 milligrams/kilogram/day.

9. OTHER

a. Other agents which have been used to treat serotonin syndrome include methysergide and mirtazapine (Mills, 1997; Hoes, 1996).

10. NOT RECOMMENDED

a. BROMOCRIPTINE - Is 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).

6.11 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 Nefazodone (Serzone(R), 1995).
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.

7.0 RANGE OF TOXICITY

7.1 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.

7.2 THERAPEUTIC DOSE

7.2.1 ADULT

A. GENERAL

1. Initial recommended dose is 100 mg twice daily, which may be titrated up to a maximum dose of 600 mg per day in divided doses (Prod Info Serzone(R), 1995).
2. Elderly or debilitated patients should be started on 50 mg twice daily, which may be titrated up to a maximum of 600 mg per day in divided doses, depending on assessment of the patients clinical response (Prod Info Serzone(R), 1995).

7.3 MINIMUM LETHAL EXPOSURE

A. GENERAL/SUMMARY

1. The minimum lethal dose of nefazodone in humans has not been determined.

7.4 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), 1995).
2. In premarketing clinical trials, seven overdoses were reported involving either nefazodone alone or in combination with other agents. The maximum tolerated dose was 11,200 milligrams in an adult survivor (Prod Info Serzone(R), 1995).
3. 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.
4. 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 (hr, 42 beats/minute), 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).

7.5 SERUM/PLASMA/BLOOD CONCENTRATIONS

7.5.1 THERAPEUTIC CONCENTRATIONS

A. GENERAL

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).

8.0 KINETICS

8.1 ABSORPTION

A. ORAL

1. Following oral administration, nefazodone is almost completely absorbed. It is subject to extensive first-pass metabolism, resulting in approximately 20% variable bioavailability.

a. Food delays absorption and decreases bioavailability by about 20%, which is believed to be clinically insignificant.

8.2 DISTRIBUTION

8.2.1 DISTRIBUTION SITES

A. PROTEIN BINDING

1. Nefazodone appears to be highly and loosely protein-bound (>99%) (Prod Info Serzone(R), 1995).

B. TISSUE/FLUID SITES

1. Nefazodone is widely distributed throughout body tissues, including the central nervous system.

8.2.2 DISTRIBUTION KINETICS

A. VOLUME OF DISTRIBUTION

1. The volume of distribution ranges from 0.22 to 0.87 liters (Prod Info Serzone(R), 1995).

8.3 METABOLISM

8.3.1 METABOLISM SITES AND KINETICS

A. GENERAL

1. Extensive metabolism occurs in the liver, where nefazodone is metabolized to three active metabolites, whose activity and half-lives vary (Eison et al, 1990; Shukla et al, 1987; Prod Info Serzone(R), 1995).

a. Nefazodone is extensively metabolized by n-dealkylation and aliphatic and aromatic hydroxylation.

8.3.2 METABOLITES

A. GENERAL

1. Nefazodone is metabolized in the liver to three active metabolites: hydroxy- nefazodone (OH-nefazodone), desethyl hydroxynefazodone (triazole dione), and m-chlorophenylpiperazine (mCPP) (Franc et al, 1991; Shukla, 1987; Eison et al, 1990).

a. Hydroxy-nefazodone is considered to have significant clinical activity similar to the parent drug (Hamik & Peroutka, 1989; Sharpley et al, 1992). The triazole dione metabolite is approximately one-seventh as potent as the parent compound at the 5-HT2 receptor, but does not block 5-HT reuptake. The minor metabolite, mCPP, has very little clinically relevant activity (Shukla, 1987; Eison et al, 1990; Prod Info Serzone(R), 1995).

8.4 EXCRETION

8.4.1 KIDNEY

A. Less than 1% of an administered dose is excreted unchanged in the urine (Prod Info Serzone(R), 1995).
B. Following oral administration of radiolabelled nefazodone, approximately 55% of the administered radioactivity was detected in the urine (Prod Info Serzone(R), 1995).

8.4.2 FECES

A. Following oral administration of radiolabelled nefazodone, approximately 20 to 30% of the radioactivity was detected in the feces (Prod Info Serzone(R), 1995).

8.5 ELIMINATION HALF-LIFE

8.5.1 PARENT COMPOUND

A. GENERAL

1. Data from one patient suggest an elimination half-life of 3.5 hours for nefazodone (Franc et al, 1991).
2. Nefazodone half-life increased both with dose (50 mg/day - 0.96 hour to 300 mg/day - 2.4 hours) and with time (2.4 hours on day 1 with 300 mg/day to 4.8 hours on day 13 with 300 mg/day) (Shukla et al, 1987).
3. Following oral administration of radiolabelled nefazodone, the mean half-life of total label ranged between 11 and 24 hours (Prod Info Serzone(R), 1995).
4. Shea et al (1988) have found significantly higher half-lives of nefazodone and its metabolites in elderly patients and hepatically impaired patients, suggesting decreased metabolic clearance.

8.5.2 METABOLITE

A. GENERAL

1. The elimination half-lives of OH-nefazodone, mCPP and triazole dione are 2 to 4 hours, 4 to 9 hours, and 18 to 33 hours, respectively (Balon, 1994; Prod Info Serzone(R), 1995).
2. Shukla et al (1987) report data which supports first order kinetics for mCPP, which had a mean half-life of 4.5 hours. OH-nefazodone appeared to exhibit formation rate limited disposition.

9.0 PHARMACOLOGY/TOXICOLOGY

9.1 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).

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13.0 AUTHOR INFORMATION

13.1 CONTRIBUTOR(S) TO THIS DOCUMENT

A. Original publication: 04/95
B. Most recent revision: 03/99

§ C. List of contributors:

§ 1. Katherine M. Hurlbut, MD

§ 2. POISINDEX(R) Editorial Staff

D. Specialty Board: CNS DRUGS

Refer to the POISINDEX EDITORIAL BOARD section for more information. (MG1894)

End of Document