TRAZODONE

(1) PREPARATION: Add 4 milliliters of 0.1 percent solution to 1000 milliliters of dextrose 5% in water to produce 4 micrograms/milliliter.
(2) INITIAL DOSE

(a) ADULTS: 2 to 3 milliliters (8 to 12 micrograms)/minute
(b) ADULT AND CHILD: 0.1 to 0.2 microgram/kilogram/minute. Titrate to maintain adequate blood pressure.

(3) MAINTENANCE DOSE

(a) 0.5 to 1 milliliter (2 to 4 micrograms)/minute
4. SEIZURES

a. DIAZEPAM

(1) MAXIMUM RATE: Administer diazepam intravenously over 2 to 3 minutes (maximum rate = 5 milligrams/minute).
(2) ADULT DIAZEPAM DOSE: 5 to 10 milligrams 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 milligram per kilogram, 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 intravenous administration of lorazepam should not exceed 2 milligrams/minute (Prod Info Ativan(R), 1991).
(2) ADULT LORAZEPAM DOSE: 4 to 8 milligrams intravenously. Initial doses may be repeated in 10 to 15 minutes if seizures persist (AMA, 1991).
(3) PEDIATRIC LORAZEPAM DOSE: 0.05 to 0.1 milligram/kilogram intravenously, repeated twice at intervals of 15 to 20 minutes (Benitz & Tatro, 1988; Giang & McBride, 1988).

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. DIURESIS

1. There is no evidence that forced diuresis will enhance elimination, although it is suggested as a theoretical possibility by the manufacturer (Pers Comm, 1987).
2. Trazodone 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. There is minimal experience in overdose in children. Accidental ingestion of 200 mg in a 6-year-old child did not result in toxicity.
B. Ingestions in adults of 2 to 3 g without co-ingestants have produced respiratory arrest, however effects were limited to drowsiness and ataxia after 4 to 5 g in other cases.
C. Post mortem blood concentrations of trazodone below 9.0 mg/L are rarely associated with fatalities due solely to trazodone.

7.2 THERAPEUTIC DOSE

7.2.1 ADULT

A. GENERAL

1. 150 milligrams/day to 400 milligrams/day is the usual adult dose (Baselt, 2000). A maximum dose of 600 milligrams/day should generally not be exceeded (Prod Info Desyrel(R), 1987). Doses up to 800 milligrams/day have been used in severe depression (Brogden et al, 1981).

7.3 MINIMUM LETHAL EXPOSURE

A. CASE REPORTS

1. TRAZODONE ALONE - Of 820 trazodone overdose cases reported in 1985 to the American Association of Poison Control Centers, one death in a 64-year-old patient was noted from trazodone alone, and 3 deaths from multiple ingestants (Litovitz et al, 1986).
2. TRAZODONE WITH COINGESTANTS - Nine deaths have been described following ingestion of 400 to 3650 milligrams of trazodone in combination with other drugs, including one case where alcohol was the only co-ingestant (Gamble & Peterson, 1986).
3. A reported fatal case was due to drowning (Demorest, 1983).

7.4 MAXIMUM TOLERATED EXPOSURE

A. CASE REPORTS

1. PEDIATRIC

a. Accidental ingestion of 200 milligrams in a 6-year-old child did not result in signs or symptoms (Ali & Henry, 1986).
b. A 10-year-old who ingested an unspecified amount had abdominal pain only.

2. INFANT

a. In 4 children aged 1.2 to 2 years, ingestion of 50 to 500 milligrams of trazodone resulted in no complications (Gamble & Peterson, 1986).

3. ADULT

a. Ingestion of 2 to 3 grams has produced respiratory arrest (Flomenbaum & Price, 1986; Gamble & Peterson, 1986).
b. Drowsiness and ataxia have been reported after 4 to 5 grams (Henry et al, 1984).
c. Bradycardia and hypotension were reported after 1 gram (Dubot et al, 1986).

7.5 SERUM/PLASMA/BLOOD CONCENTRATIONS

7.5.2 TOXIC CONCENTRATIONS

A. GENERAL

1. A normal upper therapeutic blood concentration of trazodone is reported to be 2.0 milligrams/liter. Fatalities due to trazodone alone are rarely seen with post mortem blood concentrations below 9.0 milligrams/liter (Georinger et al, 2000).
2. Peak plasma levels after single therapeutic doses have ranged from 700 to 1070 nanograms/milliliter after 50 milligrams and 2500 nanograms/milliliter after 200 milligrams (Catanese & Lisciane, 1970; Ankier, 1981; Putzolu et al, 1976).
3. Levels as high as 15,000 and 19,000 nanograms/milliliter have been described after overdoses of 4 to 5 grams. Blood levels as high as 28 micrograms/milliliter (28,000 nanograms/milliliter) have been reported to the manufacturer (Pers Comm, 1987).

a. In these 2 patients drowsiness and ataxia were the only manifestations of toxicity.

4. Coma was described in a patient with a level of 4,200 nanograms/milliliter 18 hours after admission and in a patient with a level of 8,200 nanograms/milliliter 20 hours after admission (Henry et al, 1984). Both of these had co-ingestants which may have contributed to coma.
5. A post mortem blood level of 32.91 milligrams/liter of trazodone has been reported in an acute trazodone, fluoxetine and ethanol overdose in a 32-year-old which resulted in death (Goeringer et al, 2000).

7.7 LD50/LC50

A. ANIMAL DATA

§ LD50 - (IV) MOUSE: 91 mg/kg (RTECS, 2000)

§ LD50 - (ORAL) MOUSE: 610 mg/kg (RTECS, 2000)

§ LD50 - (IM) MOUSE: 475 mg/kg (RTECS, 2000)

§ LD50 - (IP) MOUSE: 210 mg/kg (RTECS, 2000)

§ LD50 - (ORAL) RAT: 690 mg/kg (RTECS, 2000)

§ LD50 - (IV) RAT: 91 mg/kg (RTECS, 2000)

§ LD50 - (IM) RAT: >1 gm/kg (RTECS, 2000)

§ LD50 - (IP) RAT: 178 mg/kg (RTECS, 2000)

7.8 CALCULATIONS

A. SI UNIT CONVERSION

1. To convert traditional units (nanograms/milliliter) into SI units (nanomoles/liter), multiply traditional units by 2.689.
2. To convert SI units (nanomoles/liter) into traditional units (nanograms/milliliter), divide SI units by 2.689.

8.0 KINETICS

8.1 ABSORPTION

A. ROUTE OF EXPOSURE

1. ORAL - Trazodone is rapidly and completely absorbed, with peak levels occurring in 1/2 to 2 hours (Sweetman, 2000; Rawls, 1982; Georgotas et al, 1982); absorption is affected by food.

8.2 DISTRIBUTION

8.2.1 DISTRIBUTION SITES

A. PROTEIN BINDING

1. In vitro, trazodone is reportedly 89% to 95% protein bound (Sweetman, 2000; Rawls, 1982; Georgotas et al, 1982).

B. TISSUE/FLUID SITES

1. POSTMORTEM - Martin & Pounder (1992) report tissue concentrations from post-mortem examinations in 2 patients who overdosed on trazodone. Case 1 patient is estimated to have taken 1.16 grams and case 2 patient, 1.01 grams trazodone.

a. MUSCLE - Case 1: 7.3 mcg/G; Case 2: 9.0 mcg/G
b. LEFT LUNG - Case 1: 13.3 mcg/G; Case 2: 35.3 mcg/G
c. RIGHT LUNG - Case 1: 12.9 mcg/G; Case 2: 40.1 mcg/G
d. HEART - Case 1: 30.9 mcg/G; Case 2: 28.9 mcg/G
e. KIDNEYS - Case 1: 34.7 mcg/G; Case 2: 39.6 mcg/G
f. LIVER - Case 1: 73.7 mcg/G; Case 2: 82.4 mcg/G
g. FAT - Case 1: 18.5 mcg/G; Case 2: 16.5 mcg/G
h. BRAIN - Case 1: 48.6 mcg/G; Case 2: 20.9 mcg/G

2. POSTMORTEM - Trazodone exhibits postmortem redistribution. The mean heart/femoral blood concentration ratio in 4 reported postmortem cases was 1.5 (Goeringer et al, 2000).
3. BREAST MILK - Sweetman (2000) reports small amounts distributed into breast milk.

8.2.2 DISTRIBUTION KINETICS

A. VOLUME OF DISTRIBUTION

1. Martin & Pounder (1992) report a volume of distribution of 1.27 L/kg following a 25 mg intravenous dose, and 1.5 L/kg following a 50 mg oral dose in females. In male subjects a 25 mg intravenous dose produced a volume of distribution of 0.89 L/kg, and 1.15 L/kg following a 50 mg oral dose.

8.3 METABOLISM

8.3.1 METABOLISM SITES AND KINETICS

A. GENERAL

1. Trazodone is extensively metabolized in the liver by N-oxidation and hydroxylation (Sweetman, 2000; Rawls, 1982; Georgotas et al, 1982).

8.3.2 METABOLITES

A. GENERAL

1. Four basic metabolites have been identified. The N-oxide, the diol, hydroxy derivatives and conjugated compounds (Baiocchi et al, 1974).
2. The major metabolite in animals is m-chlorophenyl piperazine (m-CPP), which is an active metabolite that achieves higher concentrations in the brain than in plasma in animals (Sweetman, 2000; Brogden et al, 1981).
3. m-CPP has also been demonstrated to be a minor metabolite (representing 0.15% of the dose) in healthy human volunteers given a single oral dose of trazodone 150 mg (Caccia et al, 1982).
4. M-CPP appears to act as an antagonist of trazodone, and is a direct central serotonergic agonist at postsynaptic receptors. It is not clear whether trazodone or m-CPP is responsible for both antidepressant and/or toxic effects (Garattini, 1985).

8.4 EXCRETION

8.4.1 KIDNEY

A. Seventy-five percent is excreted renally, mostly as metabolites. Less than 1% is excreted unchanged in the urine (Sweetman, 2000; Brogden et al, 1981).

8.4.2 FECES

A. 21.1% of a 25 mg post-prandial PO dose is excreted in the feces in 95 to 96 hours (Jaunch et al, 1976). Excretion in feces is via biliary elimination (Sweetman, 2000).

8.4.3 BILE

A. Twenty percent of the dose is excreted in the bile.

8.5 ELIMINATION HALF-LIFE

8.5.1 PARENT COMPOUND

A. THERAPEUTIC DOSE

1. Rawls (1982) and Sweetman (2000), reporting manufacturer's data, indicated a biphasic T1/2 for trazodone (T1/2 of 3 to 6 hours for the first 3 to 10 hours following ingestion, followed by a T1/2 of 5 to 9 hours for the subsequent 10 to 36 hours), following administration of therapeutic doses.

B. OVERDOSE

1. The elimination was linear after overdose with high initial levels (7453 ng/ml), with a half-life of 8.8 hours (Hassan & Miller, 1985).

8.5.2 METABOLITE

A. GENERAL

1. The active metabolite m-CPP has a longer half-life than the parent compound in rats (Caccia et al, 1981).
2. The half-life of m-CPP in human volunteers was 4.2 hours, compared to 3.5 hours for the parent compound (Caccia et al, 1982).

9.0 PHARMACOLOGY/TOXICOLOGY

9.1 PHARMACOLOGIC MECHANISM

A. Trazodone, an atypical tetracyclic antidepressant, possesses both antidepressant and anxiolytic and hypnotic activities. It is a powerful antagonist of the 5HT2A receptor and it has some selective inhibition of reuptake of serotonin. The metabolite (m-CPP) is a potent postsynaptic serotonin agonist. It is sometimes referred to as a serotonin antagonist reuptake inhibitor (SARIs) (Goeringer et al, 2000).

9.2 TOXICOLOGIC MECHANISM

A. Trazodone had 150 to 800 times less in vitro anticholinergic activity than tricyclic antidepressants, and had no in vivo activity in mice (Taylor et al, 1980).
B. Intravenous doses of 1 to 30 mg/kg of trazodone in anesthetized dogs produced a dose-related decrease in heart rate and blood pressure, but had no significant effect on ECG intervals (Gomoll & Byrne, 1979).
C. Hypotension may be due to alpha receptor blockade. Alpha1 blockade activity is 5 times greater than alpha2 blockade (Van Zwieten, 1977).
D. Hepatic injury due to therapeutic trazodone (either acute or chronic) may be an idiosyncratic, possible immune, mechanism of injury. The exact basis for this reaction is unknown. Since the drug bears structural similarity to the fluorobutyrophenone antipsychotics such as haloperidol, and the major metabolite of trazodone is m-chlor,4-phenylpiperazine, similar to phenothiazines, it may share similar mechanisms of hepatic toxicity (Fernandes et al, 2000).

10.0 PHYSICOCHEMICAL

10.1 PHYSICAL CHARACTERISTICS

A. This compound exists as an off-white, odorless, crystalline powder with a bitter taste. It is sparingly soluble to soluble in water and is sparingly soluble in alcohol and in chloroform (Sweetman, 2000).

10.2 PH

A. pH of 3.9 to 4.5 is reported with a 1% solution in water (Sweetman, 2000).

10.3 MOLECULAR WEIGHT

A. 371.91 (trazodone) (RTECS,2000)
B. 408.3 (trazodone hydrochloride) (Sweetman, 2000)

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