SERTRALINE

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).

11. CASE REPORT - Serotonin syndrome (dilated pupils, hyperactivity, hyperreflexia, unsteady ataxic gait, tremor, fever) was reported in a 24-month-old female 12 hours after an ingestion of 10 50-mg tablets (500 mg) of sertraline. No other medications were ingested. Symptoms resolved 40 minutes after one dose of cyproheptadine 1 mg orally (Horowitz & Mullins, 1999).

6.11 ENHANCED ELIMINATION

A. SUMMARY

1. Sertraline has a high degree of protein binding, and a large volume of distribution, so forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be beneficial.

7.0 RANGE OF TOXICITY

7.1 SUMMARY

A. Minimum lethal human exposure is unknown.
B. Overdoses in adults of 700 to 2100 milligrams have not resulted in serious symptoms. Ingestion of 4 grams resulted in seizures in an adolescent.
C. Overdose of 400 and 500 milligrams in two children has resulted in serotonin syndrome.

7.2 THERAPEUTIC DOSE

7.2.1 ADULT

A. GENERAL

1. NORMAL ORAL DOSE -

a. Initial doses are 50 milligrams daily as a single dose in the morning or the evening. The dosage may be increased at intervals of at least 1 week to a maximum recommended dosage of 200 milligrams daily (Prod Info Zoloft(R), 1992).
b. Recommended maximum is 200 milligrams daily (Prod Info Zoloft(R), 1992).

2. DOSE IN GERIATRIC PATIENTS -

a. No specific dosage adjustments have been recommended for sertraline use in geriatric patients.
b. Sertraline plasma clearance was reported to be 40 percent lower in a group of 16 elderly patients treated with a dose of 100 milligrams daily for 14 days.
c. A decreased clearance of desmethylsertraline was noted in older males but not in females (Prod Info Zoloft(R), 1992).

7.3 MINIMUM LETHAL EXPOSURE

A. GENERAL/SUMMARY

1. The minimum lethal human dose to this agent has not been delineated.

7.4 MAXIMUM TOLERATED EXPOSURE

A. GENERAL/SUMMARY

1. ADULTS - At the time of this review, NO serious effects have been reported following several cases of overdose with sertraline. Doses ingested have ranged from 700 to 2100 milligrams. All patients have recovered without sequelae (Klein-Schwartz & Anderson, 1996).

B. CASE REPORTS

1. A 23-year-old female with depression took an overdose of 750 to 1000 milligrams. She was lavaged, observed, and treated symptomatically. She recovered without sequelae (Prod Info Zoloft(R), 1992).
2. A 43-year-old female took 1400 milligrams with unknown amounts of alcohol, temazepam, and mefenamic acid. She was observed overnight and discharged without sequelae the next day (Prod Info Zoloft(R), 1992).
3. A 28-year-old male ingested 2100 milligrams with other (unknown) medication. He was lavaged and observed. No sequelae were noted (Prod Info Zoloft(R), 1992).
4. A 9-year-old child developed prolonged tachycardia, hypertension, hallucinations, coma, hyperthermia, tremors, and skin flushing after ingesting an unknown amount or sertraline. He recovered without sequelae with supportive care (Kaminski et al, 1994).
5. Following the ingestion of 4 grams sertraline, a 14-year-old female developed delayed (4.5 hours post-ingestion) onset of a grand mal seizure. A second seizure occurred 5.5 hours after the ingestion. Treatment with anticonvulsants was not given, and the girl recovered (Meier & Lam, 1998).
6. Serotonin syndrome is reported in a 5-year-old girl following the ingestion of at least 400 mg sertraline. Symptoms gradually resolved over 7 days (Pao & Tipnis, 1997).
7. Serotonin syndrome was reported in a 24-month-old female after an unintentional ingestion of 10 50-milligram tablets (500 milligrams) of sertraline. No other medications were ingested. Symptoms resolved 40 minutes after one dose of cyproheptadine 1 milligram orally (Horowitz & Mullins, 1999).
8. A sertraline ingestion of between 250 and 300 milligrams produced only minimal symptoms of initial lethargy and possible fever in a 22-month-old female (Catalano et al, 1998).

7.5 SERUM/PLASMA/BLOOD CONCENTRATIONS

7.5.1 THERAPEUTIC CONCENTRATIONS

A. CONCENTRATION LEVEL

1. Therapeutic sertraline serum levels are reported to range from 16 to 78 nanograms/milliliter (Meier & Lam, 1998).
2. Steady-state plasma levels in patients taking 100 to 300 milligrams/day have ranged from 0.02 to 0.21 milligrams/liter of sertraline (Goeringer et al, 2000).
3. Normal range for steady-state concentration in persons receiving therapeutic doses is reported to be 30 to 200 nanograms/milliliter (Carson et al, 2000).

7.5.2 TOXIC CONCENTRATIONS

A. CONCENTRATION LEVEL

1. Saletu et al (1986) found a mean peak plasma sertraline concentration of 54.5 nanograms/milliliter 4 hours after a single 100-milligram oral dose.
2. After single 200 and 400 milligram doses, the mean peak plasma levels were 105.4 and 253.2 nanograms/milliliter, respectively, at 6 hours post-dosing.
3. The lowest postmortem sertraline serum concentration, in the absence of other risk factors, resulting in death was 1.5 milligrams/liter (Goeringer et al, 2000).
4. Carson et al (2000) reported a post-mortem quantitative blood concentration of 620 nanograms/milliliter in an 18-year-old who probably ingested about 9 tablets. Death was due to a severe asthma attack associated with sertraline overdose.
5. PEDIATRIC - Serum concentrations after an unknown quantity of sertraline was ingested were as follows: 9 hours post-ingestion, 68 ng/mL; 26.5 hours post- ingestion, 32 ng/mL; 50.5 hours post-ingestion, <10 ng/mL. This patient exhibited signs and symptoms of a serotonin syndrome (Kaminski et al, 1994).
6. PEDIATRIC - At 72 hours post-ingestion of at least 400 mg in a 5-year-old girl, serum sertraline level was reported to be 99 nanograms/milliliter, which decreased to 14 nanograms/milliliter at 168 hours after ingestion (Pao & Tipnis, 1997).
7. PEDIATRIC - Serum sertraline levels >1000 nanograms/milliliter were reported in a 14-year-old girl following a 4000 milligram sertraline overdose (Meier & Lam, 1998).

7.7 LD50/LC50

A. ANIMAL DATA

§ References: Davies & Klowe, 1998

§ LD50 - (ORAL) MALE MOUSE: 350 mg/kg

§ LD50 - (ORAL) FEMALE MOUSE: 300 mg/kg

§ LD50 - (ORAL) MALE RAT: 1000 mg/kg

§ LD50 - (ORAL) FEMALE RAT: 750 mg/kg

§ LD50 - (IP) MALE MOUSE: 50 mg/kg

§ LD50 - (IP) MALE RAT: 50 mg/kg

8.0 KINETICS

8.1 ABSORPTION

A. ORAL

1. Sertraline is slowly and completely absorbed; peak plasma concentrations are reached approximately 6 to 8 hours after oral dosing (Doogan & Caillard, 1988; Prod Info Zoloft(R), 1992).
2. FOOD EFFECTS -

a. Single dose studies of sertraline absorption with and without food indicate that the presence of food produces:

(1) A slightly higher area under the plasma concentration time curve (AUC),
(2) A 25% increase in mean peak plasma concentrations,
(3) And a decreased time to peak plasma concentrations from a mean of 8 hours to a mean of 5.5 hours post-dose (Prod Info Zoloft(R), 1992).

8.2 DISTRIBUTION

8.2.1 DISTRIBUTION SITES

A. PROTEIN BINDING

1. 98 to 99% (Jefferis, 1992; Doogan & Caillard, 1988)

B. PEAK PLASMA LEVEL

1. Peak plasma levels are obtained about 4.5 to 8 hours after an oral dose (Jefferis, 1992; Prod Info Zoloft(R), 1992; Doogan & Caillard, 1988; Saletu et al, 1986).
2. Peak plasma concentrations of the inactive or weakly active metabolite desmethylsertraline are reportedly reached 8 to 12 hours after oral dosing (Doogan & Caillard, 1988).

8.2.2 DISTRIBUTION KINETICS

A. VOLUME OF DISTRIBUTION

1. The volume of distribution of sertraline has been estimated as 20 L/kg (Doogan & Caillard, 1988).

B. STEADY STATE LEVELS

1. Steady state levels are obtained after about one week of once a day dosing (2 to 3 weeks in the elderly) (Jefferis, 1992).

8.3 METABOLISM

8.3.1 METABOLISM SITES AND KINETICS

A. GENERAL

1. Sertraline undergoes extensive first-pass metabolism (Prod Info Zoloft(R), 1992).
2. Sertraline is mainly metabolized via N-demethylation to desmethylsertraline, which is inactive or weakly active; it is reportedly 8 times less active than the parent compound.

a. Both these compounds are further metabolized to their corresponding ketones and then hydroxylated. The alpha-hydroxy ketone metabolite is excreted in the urine and feces (Doogan & Caillard, 1988).

3. Peak plasma concentrations of the inactive or weakly active metabolite desmethylsertraline are reportedly reached 8 to 12 hours after oral dosing (Doogan & Caillard, 1988).

8.3.2 METABOLITES

A. GENERAL

1. The principal metabolite of sertraline is desmethylsertraline; this compound is 8 times less potent than sertraline, and has been shown to be inactive in behavioral models.

a. Other minor metabolites, presumably inactive, are alcohols and oximes (Doogan & Caillard, 1988).

2. Desmethylsertraline exhibits 5- to 9-fold time and dose dependent increases in the area under the plasma concentration time curve, mean peak plasma concentration, and mean minimum plasma concentration over the first 14 days of administration (Prod Info Zoloft(R), 1992).

8.4 EXCRETION

8.4.1 KIDNEY

A. The alpha-hydroxy ketone metabolite of sertraline is excreted in the urine and feces (Doogan & Caillard, 1988).
B. In studies of radiolabeled sertraline, 40 to 45% of an administered dose is recovered in the urine in 9 days, none as unchanged sertraline (Prod Info Zoloft(R), 1992).
C. ELDERLY - Excretion rates in an elderly group of patients were approximately 40% lower than that seen in a younger group (Jefferis, 1992).

8.4.2 FECES

A. The alpha-hydroxy ketone metabolite of sertraline is excreted in the urine and feces (Doogan & Caillard, 1988).