FLUVOXAMINE

3. LORAZEPAM

a. MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 milligrams/minute (Prod Info Ativan(R), 1999).
b. ADULT LORAZEPAM DOSE: 2 to 8 milligrams intravenously. Initial doses may be repeated in 10 to 15 minutes if seizures persist (Prod Info, Ativan(R), 1999; AMA, 1991).
c. PEDIATRIC LORAZEPAM DOSE: 0.05 to 0.1 milligram/kilogram intravenously, (maximum 4 milligrams/dose) repeated twice at intervals of 10 to 15 minutes (Benitz & Tatro, 1995).

4. PHENOBARBITAL

a. 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.
b. ADULT PHENOBARBITAL MAINTENANCE DOSE: Additional doses of 120 to 240 milligrams may be given every 20 minutes.
c. 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.
d. PEDIATRIC PHENOBARBITAL LOADING DOSE: 15 to 20 milligrams per kilogram of phenobarbital intravenously at a rate of 25 to 50 milligrams per minute.
e. PEDIATRIC PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 5 to 10 milligrams per kilogram may be given every 20 minutes.
f. 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.
g. MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation.
h. 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.
i. 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.
j. 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.
k. CAUTIONS: Adequacy of ventilation must be continuously monitored in children and adults. Intubation may be necessary with increased doses.
l. SERUM LEVEL MONITORING: Monitor serum levels over next 12 to 24 hours for maintenance of therapeutic levels (20 to 40 micrograms per milliliter).

5. PHENYTOIN/FOSPHENYTOIN

a. Benzodiazepines and/or barbiturates are generally preferred to phenytoin or fosphenytoin in the treatment of drug or withdrawal induced seizures.
b. PHENYTOIN

(1) PHENYTOIN INTRAVENOUS PUSH VERSUS INTRAVENOUS INFUSION: Manufacturer does not recommend intravenous infusions due to lack of solubility and resultant precipitation, however infusions are commonly used.

(a) Administer phenytoin undiluted, by very slow intravenous push or dilute 50 milligrams per milliliter solution in 50 to 100 milliliters of 0.9 percent saline.

(2) PHENYTOIN ADMINISTRATION RATE: Rate of administration by either method should not exceed 0.5 milligram per kilogram per minute or 50 milligrams per minute.
(3) ADULT PHENYTOIN LOADING DOSE: 15 to 18 milligrams per kilogram of phenytoin initially. Rate of administration by very slow intravenous push or diluted to 50 milligrams per milliliter should not exceed 0.5 milligram per kilogram per minute or 50 milligrams per minute.
(4) ADULT PHENYTOIN MAINTENANCE DOSE: Manufacturers recommend a maintenance dose of 100 milligrams orally or intravenously every 6 to 8 hours. The goal is to maintain a serum concentration between 10 to 20 micrograms/milliliter.
(5) PEDIATRIC PHENYTOIN LOADING DOSE: 15 to 20 milligrams per kilogram or 250 milligrams/square meter of phenytoin. Rate of intravenous administration should not exceed 0.5 to 1.5 milligrams per kilogram per minute.
(6) PEDIATRIC PHENYTOIN MAINTENANCE DOSE: Repeat doses of 1.5 milligrams per kilogram may be given every 30 minutes to a maximum daily dose of 20 milligrams per kilogram.
(7) CAUTIONS: Administer phenytoin while monitoring ECG. Stop or slow infusion if arrhythmias or hypotension occur. Be careful not to extravasate. Follow each injection with injection of sterile saline through the same needle.
(8) SERUM LEVEL MONITORING: Monitor serum levels over next 12 to 24 hours for maintenance of therapeutic levels (10 to 20 micrograms per milliliter).

c. FOSPHENYTOIN

(1) ADULT DOSAGE AND ADMINISTRATION: The dose, concentration in dosing solutions, and infusion rate of fosphenytoin are expressed as phenytoin sodium equivalents.
(2) ADULT LOADING DOSE FOSPHENYTOIN: 15 to 20 milligrams/kilogram of phenytoin sodium equivalents at a rate of 100 to 150 milligrams phenytoin equivalent/minute.
(3) Fosphenytoin should not be infused at rates greater than 150 milligrams phenytoin equivalent/minute because of the risk of hypotension.
(4) CAUTIONS: Perform continuous monitoring of respiratory function, cardiac rhythm, and blood pressure throughout infusion and for at least 30 minutes thereafter.
(5) ADULT MAINTENANCE DOSING: 4 to 6 milligrams phenytoin equivalents/kilogram/day. Rate of administration should not exceed 150 milligrams phenytoin equivalent/minute.
(6) SERUM LEVEL MONITORING: Monitor serum phenytoin levels over the next 12 to 24 hours; therapeutic levels 10 to 20 microgram/milliliter. Do not obtain serum phenytoin concentrations until at least 2 hours after infusion is complete to allow for conversion of fosphenytoin to phenytoin.

D. 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. SUMMARY

1. No studies have addressed the utilization of extracorporeal elimination techniques in poisoning with this agent.

7.0 RANGE OF TOXICITY

7.1 SUMMARY

A. The therapeutic amount is 50 to 300 mg per day.
B. Doses of up to 6.5 grams have been survived. Coma has been reported in overdoses of 1.5 and 3 grams.

7.2 THERAPEUTIC DOSE

7.2.1 ADULT

A. GENERAL

1. Based on clinical trials, the dose should be between 50 to 300 milligrams daily when used for the treatment of obsessive-compulsive disorders or depression (Benfield & Ward, 1986). The dose is given once a day or given in 2 divided doses.
2. Starting the patient on 50 milligrams/day, then increasing the dose seems to decrease the amount of nausea and vomiting seen as a side effect (Conti et al, 1988; Martin et al, 1987; Goodman et al, 1989).

7.4 MAXIMUM TOLERATED EXPOSURE

A. CASE REPORTS

1. SUMMARY - Fluvoxamine has been involved in at least 41 cases of overdose, and although one patient died, the fluvoxamine was found in the stomach, and the death was attributed to the simultaneous ingestion of propranolol. The maximum amount ingested in this group was 6.5 grams (Banerjee, 1988).
2. A 74-year-old who ingested 3 grams of fluvoxamine and 250 mg of temazepam developed coma for 5 days (Banerjee, 1988).
3. In a study of 228 cases, the minimal toxic dose was 150 milligrams. Some patients who took up to 1000 milligrams had no symptoms (Azoyan et al, 1990).
4. A 58-year-old female ingested 5.5 grams fluvoxamine and developed severe sinus bradycardia. The patient recovered within 2 days following supportive care (Amital et al, 1994).

7.5 SERUM/PLASMA/BLOOD CONCENTRATIONS

7.5.2 TOXIC CONCENTRATIONS

A. GENERAL

1. No specific toxic blood level has been established, but a therapeutic level (normal steady state value that would occur after treatment with 100 milligrams/day) is 0.4 milligram/liter (Banerjee, 1988).

B. ADULT

1. CASE REPORT - A 32-year-old female ingested approximately 1500 milligrams fluvoxamine. A serum drug screening determined that her fluvoxamine level was 1.5 mg/L (therapeutic range 0.03 to 0.09 mg/L) (Gallerani et al, 1998).

8.0 KINETICS

8.1 ABSORPTION

A. ORAL

1. Fluvoxamine is almost total absorbed from the gastrointestinal tract following oral administration (DeBree et al, 1983).
2. RATE OF ABSORPTION - One study showed an absorption rate of 8.2 to 50 nanograms per milliliter of serum per hour (Azoyan et al, 1990).
3. Fluvoxamine undergoes zero-order kinetics for absorption (Azoyan et al, 1990).

8.2 DISTRIBUTION

8.2.1 DISTRIBUTION SITES

A. PROTEIN BINDING

1. Approximately 77% at plasma concentrations of 1 mg/L (Doogan, 1980; Benfield & Ward, 1986)

B. PEAK PLASMA LEVEL

1. After a 100 mg dose of fluvoxamine, peak plasma concentrations of 31 to 87 mcg/L were seen in 2 to 8 hours in one study (DeBree et al, 1983), but 6.5 to 24 hours in 8 of 228 cases and 17-50 hours in 4 others in this study (Azoyan et al, 1990). The peak plama level was not significantly altered with food (Wheeler et al, 1985).

8.2.2 DISTRIBUTION KINETICS

A. VOLUME OF DISTRIBUTION

1. 10 to 20 L/kg (Doogan, 1980)

8.3 METABOLISM

8.3.1 METABOLISM SITES AND KINETICS

A. GENERAL

1. Metabolized in the liver.

a. Oxidative demethylation of the aliphatic methoxyl group of the parent compound accounts for approximately 65% of fluvoxamine's metabolites (Overmars et al, 1983).
b. Lesser proportions are produced by degradation at the primary amino group (15%), at both the methoxyl and amino groups (20%), or by removal of the entire ethanolamine group (10%).

2. 94% of an administered dose of fluvoxamine is excreted in the urine as metabolites, over 48 hours (Doogan, 1980; DeBree et al, 1983).

8.3.2 METABOLITES

A. GENERAL

1. Administration of a single dose of radiolabelled fluvoxamine produced at least 11 metabolites in human urine. Nine of the 11 have been identified by mass spectrometry and account for 85% of the total urinary radioactivity (Overmars et al, 1983).
2. The major metabolite is produced by oxidative demethylation of the aliphatic methoxyl group of the parent compound and is not pharmacologically active (Doogan, 1980).

8.4 EXCRETION

8.4.1 KIDNEY

A. The kidney appears to be the sole excretory organ for fluvoxamine (Doogan, 1980).
B. After a single, radiolabelled dose was given to volunteers, a mean of 94% of the administered dose appeared in the urine over 48 hours (Doogan, 1980; DeBree et al, 1983). No unchanged drug was found in the urine (Doogan, 1980; Overmars et al, 1983).
C. CLEARANCE - 19.6 mL/min (first 7 hours) and 16.6 mL/min (next 16.5 hours) (Azoyan et al, 1990)

8.5 ELIMINATION HALF-LIFE

8.5.1 PARENT COMPOUND

A. GENERAL

1. 16.9 hours in healthy volunteers given enteric coated tablets (Siddiqui et al, 1985)
2. 23.2 hours in depressed patients given enteric coated tablets (Siddiqui et al, 1985)
3. DeBree et al (1983) found the mean elimination half-life of fluvoxamine's terminal phase to be 14.6 hours.
4. Azoyan et al (1990) found elimination to be biphasic with the first half-life being about 12.3 hours and second being about 30 hours.

9.0 PHARMACOLOGY/TOXICOLOGY

9.1 PHARMACOLOGIC MECHANISM

A. Fluvoxamine is a compound in the series of 2-aminoethyl oximethers of aralkylketones. It has no structural similarities to tricyclic antidepressants. It acts as antidepressant.
B. Fluvoxamine is a potent selective inhibitor of presynaptic serotonin (5-hydroxytryptamine) uptake and has little or no effect on the catecholamine system (Classen et al, 1977).
C. In vitro and in vivo experiments demonstrated that fluvoxamine fails to facilitate noradrenergic neurotransmission, similar to other specific inhibitors of serotonin uptake (Bradford, 1984; Claassen, 1983).
D. Unlike the tricyclic antidepressants, fluvoxamine demonstrates a very low in vitro affinity for alpha-1, alpha-2, beta-1, dopamine-2, histamine-1, serotonin-1, serotonin-2, or muscarinic receptors (Richelson & Nelson, 1984; Benfield & Ward, 1986).
E. In vitro and in vivo studies have not demonstrated any monoamine oxidase inhibitor activity (Lapierre et al, 1983; Benfield & Ward, 1986).

10.0 PHYSICOCHEMICAL

10.1 PHYSICAL CHARACTERISTICS

A. Fluvoxamine maleate exists as crystals.

10.3 MOLECULAR WEIGHT

A. 318.35

12.0 REFERENCES

12.2 GENERAL BIBLIOGRAPHY
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4. Azoyan PH, Garrier R, Chataigner D et al: Toxicokinetics of fluvoxamine in overdose (abstract). EAPCCT International Congress 1990; Milano, Sept 25-28.
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15. Classen V: Review of the animal pharmacology and pharmacokinetics of fluvoxamine. Br J Clin Pharmacol 1983; 15(Suppl 3):349S-355S.
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17. Crome P & Ali C: Clinical features and management of self-poisoning with newer antidepressants. Med Toxicol 1986; 1:411-420.