PAROXETINE

B. ACTIVATED CHARCOAL

1. Activated charcoal effectively prevents gastrointestinal absorption of paroxetine (Greb et al, 1989).
2. CHARCOAL ADMINISTRATION

a. Consider administration of activated charcoal after a potentially toxic ingestion (Chyka & Seger, 1997). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

3. 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; and 1 gram/kilogram in infants up to 1 year old (USP DI, 2000; Chyka & Seger, 1997).

(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 (Barceloux et al, 1997).

b. ADVERSE EFFECTS/CONTRAINDICATIONS

(1) Complications: emesis, aspiration (Chyka & Seger, 1997). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
(2) Contraindications: unprotected airway, gastrointestinal tract not anatomically intact, therapy may increase the risk or severity of aspiration; ingestion of most hydrocarbons (Chyka & Seger, 1997).

6.5.3 TREATMENT

A. HYPOTENSION

1. SUMMARY

a. Infuse 10 to 20 milliliters/kilogram of isotonic fluid and place in Trendelenburg position. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

B. SEROTONIN SYNDROME

1. 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 may be useful. Diazepam: Adult: 5 to 10 milligrams IV every 5 to 10 minutes as needed, monitor for respiratory depression and need for intubation. Child: 0.25 milligram/kilogram IV every 5 to 10 minutes; monitor for respiratory depression and need for intubation.
c. Non-depolarizing paralytics may be used in severe cases.

2. HYPERTENSION

a. Monitor vital signs regularly. For mild/moderate asymptomatic hypertension, pharmacologic intervention may not be necessary. For hypertensive emergencies (emergent need to lower mean BP 30 percent within 30 minutes and achieve diastolic BP of 100 mmHg or less within one hour), nitroprusside is preferred.
b. NITROPRUSSIDE

(1) NITROPRUSSIDE/INDICATIONS

(a) Nitroprusside is preferred for hypertensive emergencies (emergent need to lower mean BP 30 percent within 30 minutes and achieve a diastolic BP of 100 mmHg or less within one hour).

(2) NITROPRUSSIDE/DOSE

(a) 0.1 to 5 microgram/kilogram/minute intravenous infusion; up to 10 micrograms/kilogram/minute may be required (AHA, 1992).

(3) NITROPRUSSIDE/SOLUTION PREPARATION

(a) Dilute a 50-milligram vial in 500 milliliters of dextrose 5 percent in water (100 micrograms/milliliter). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution.

(4) NITROPRUSSIDE/MAJOR ADVERSE REACTIONS

(a) Severe hypotension; cyanide toxicity; methemoglobinemia; lactic acidosis; chest pain or arrhthymias (high doses).

(5) NITROPRUSSIDE/MONITORING PARAMETERS

(a) Monitor blood pressure every 30 to 60 seconds at onset of drip; once stabilized, monitor every 30 minutes.

c. NITROGLYCERIN

(1) In theory, nitroglycerin may help alleviate the serotonin syndrome through nitric oxide mediated downregulation of serotonin.
(2) ADULT - Begin continuous infusion at 5 micrograms/minute and titrate to desired effect.
(3) CHILD - Begin infusion at 0.25 to 0.5 micrograms/kilogram/minute and titrate to desired effect.

3. HYPOTENSION

a. Administer 10 to 20 milliliters/kilogram 0.9% saline bolus and place patient in Trendelenburg position. Further fluid therapy should be guided by central venous pressure or right heart catheterization to avoid volume overload.
b. Control hyperthermia.
c. Pressor agents with dopaminergic effects may theoretically worsen serotonin syndrome and should be used with caution.
d. DOPAMINE

(1) PREPARATION: Add 200 or 400 milligrams to 250 milliliters of normal saline or dextrose 5% in water to produce 800 or 1600 micrograms per milliliter or add 400 milligrams to 500 milliliters of normal saline or dextrose 5% in water to produce 800 micrograms per milliliter.
(2) DOSE: Begin at 2 to 5 micrograms per kilogram per minute progressing in 5 to 10 micrograms per kilogram per minute increments as needed.
(3) CAUTION: If VENTRICULAR ARRHYTHMIAS occur, decrease rate of administration.

e. NOREPINEPHRINE

(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. HEMODIALYSIS

1. Because of the large volume of distribution and high degree of protein binding of paroxetine, hemodialysis would NOT be expected to be useful in overdose.

7.0 RANGE OF TOXICITY

7.1 SUMMARY

A. Overdose of 360 mg in an elderly adult resulted in excessive vomiting and SIADH with decreased serum sodium levels.
B. In a series of 35 patients, minimal or no effects developed after ingestion of 10 to 1000 mg.
C. Overdoses between 10 and 120 mg in 16 children < 5 years of age resulted in no symptoms.
D. Overdoses between 100 and 800 mg in adolescents aged 12 years up to 17 years old resulted in no symptoms in most of these cases.

7.2 THERAPEUTIC DOSE

7.2.1 ADULT

A. GENERAL

1. 10 to 50 mg/day

7.4 MAXIMUM TOLERATED EXPOSURE

A. CASE REPORTS

1. Anxiety was the only adverse effect reported in a 25-year-old male who ingested 400 milligrams (Gorman et al, 1993).
2. In a series of 35 patients, minimal or no effects developed after ingestion of 10 to 1000 mg (Myers et al, 1994).
3. A series of 11 children 5 years old or younger with paroxetine only ingestions of 10 to 120 milligrams were treated with ipecac or activated charcoal only. All remained asymptomatic (Myers et al, 1995; Myers & Krenzelok, 1997).
4. In a series of 11 children between 12 and 17 years old who ingested 100 to 800 milligrams of paroxetine, 9 received gastrointestinal decontamination and 2 did not (Myers et al, 1995; Myers & Krenzelok, 1997). Seven were asymptomatic and 4 developed minor symptoms.
5. Overdose of 360 mg in an elderly adult resulted in excessive vomiting and SIADH with decreased serum sodium levels (Johnsen & Hoejlyng, 1998).

7.5 SERUM/PLASMA/BLOOD CONCENTRATIONS

7.5.1 THERAPEUTIC CONCENTRATIONS

A. ADULT

1. A normal paroxetine peak steady state concentration, from clinical trials (30 milligrams/day), is reported to be 0.06 milligrams/liter (Goeringer et al, 2000).

7.5.2 TOXIC CONCENTRATIONS

A. ADULT

1. The lowest reported serum concentration, in the absence of other risk factors, resulting in death was 0.41 milligrams/liter for paroxetine (no other drugs involved) (Goeringer et al, 2000).
2. A high serum paroxetine concentration of 3.84 milligrams/liter is reported in a fatality involving a mixed drug ingestion (Goeringer et al, 2000).

8.0 KINETICS

8.1 ABSORPTION

A. ORAL

1. Paroxetine is slowly, but well absorbed after oral administration (Kaye et al, 1989). Because of slow absorption, symptoms of toxicity can be delayed (Vermeulen, 1998).

8.2 DISTRIBUTION

8.2.1 DISTRIBUTION SITES

A. PROTEIN BINDING

1. 95% (Kaye et al, 1989).

B. TISSUE/FLUID SITES

1. Postmortem tissue and fluid concentrations of paroxetine are as follows (Vermeulen, 1998):

§ CASE 1 PAROXETINE CONCENTRATION

§ --------------------------------------

§ Postmortem blood 4.0 mg/mL

§ Liver 110 mg/kg

§ Stomach contents 100 mg total

§ CASE 2

§ --------------------------------------

§ Postmortem blood 3.7 mg/mL

§ Liver 113 mg/kg

§ Urine 10.5 mg/L

§ CASE 3

§ --------------------------------------

§ Postmortem blood 1.4 mg/L

§ Liver 16 mg/kg

§ Stomach contents <1.0 mg

§ Urine <0.5 mg/L

8.2.2 DISTRIBUTION KINETICS

A. VOLUME OF DISTRIBUTION

1. 12 to 16 L/kg (Lund et al, 1979).

8.3 METABOLISM

8.3.1 METABOLISM SITES AND KINETICS

A. GENERAL

1. Hepatic metabolism with extensive first pass effect (Lund et al, 1979).

8.3.2 METABOLITES

A. GENERAL

1. Oxidized to an unstable catechol intermediate which is in part methylated and conjugated with glucuronide or sulfate (Kaye et al, 1989).

8.4 EXCRETION

8.4.1 KIDNEY

A. Urinary excretion of paroxetine is less than 2% of dose; 62% of dose excreted in the urine as metabolites (Kaye et al, 1989).

8.5 ELIMINATION HALF-LIFE

8.5.1 PARENT COMPOUND

A. GENERAL

1. Elimination half life after single dose in healthy adults 12 to 18 hours (Lund et al, 1979; Lund et al, 1982); shorter after IV dosing (10 to 15 hours). Half life is prolonged with higher doses or repeated dosing (Bayer et al, 1989; Lund et al 1979), in the elderly (10 to 44 hours) (Ghose, 1989; Lundmark et al, 1989), in patients with renal insufficiency (11 to 55 hours) (Doyle et al, 1989), and in patients with cirrhosis (17 to 312 hours) (Dalhoff et al, 1991).

9.0 PHARMACOLOGY/TOXICOLOGY

9.1 PHARMACOLOGIC MECHANISM

A. Paroxetine is a potent inhibitor of serotonin reuptake in pre-synaptic nerve terminals in the central nervous system. It has only weak anticholinergic effects (Mertens & Pintens, 1988).
B. Paroxetine is effective in the treatment of adult night terrors. It is suggested that the terror-suppressing action of paroxetine is a direct effect of its ability to increase 5-hydroxytryptamine (5-HT) concentrations in the brainstem by blocking reuptake (Wilson et al, 1997).

9.2 TOXICOLOGIC MECHANISM

A. ECCHYMOSES have been reported as an adverse effect of paroxetine. It is speculated that a decrease in serotonin uptake into platelets is associated with paroxetine treatment. Since serotonin is associated with platelet aggregation, it is thought that paroxetine may inhibit serotonin uptake in platelets, and theoretically, could contribute to abnormalities of aggregation (Cooper et al, 1998).

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