Sertraline (Systemic)


VA CLASSIFICATION
Primary: CN603
Secondary: CN900

Commonly used brand name(s): Zoloft.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antidepressant—

antiobsessional agent—

antipanic agent—

Indications

Accepted

Depressive disorder, major (treatment)—Sertraline is indicated for the treatment of major depressive disorder {01} {07} {26}. Treatment of acute depressive episodes typically requires 6 to 12 months of antidepressant therapy {47}. Patients with recurrent or chronic depression may require long-term treatment {47}. Sertraline showed effective maintenance of antidepressant response for up to 52 weeks of treatment in a placebo-controlled trial {07}.

Obsessive-compulsive disorder (treatment)—Sertraline is indicated for the treatment of obsessions and compulsions in adults and children1 6 years of age and older with obsessive-compulsive disorder {07} {79}.

Panic disorder (treatment)—Sertraline is indicated for the treatment of panic disorder with or without agoraphobia {07} {26}.

Posttraumatic stress disorder (treatment)1—Sertraline is indicated for the treatment of posttraumatic stress disorder (PTSD) in adults. In placebo-controlled trials for up to 28 weeks, sertraline was shown to be effective in sustaining symptom improvement and preventing relapse of PTSD{84}.

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Naphthylamine derivative {01} {08} {09}. Chemically unrelated to tricyclic or tetracyclic antidepressants {01} {07}.
Molecular weight—
    Sertraline hydrochloride: 342.7 {48}
    Sertraline hydrochloride is slightly soluble in water and sparingly soluble in ethyl alcohol {07} {26}.

Mechanism of action/Effect:

Sertraline is a potent {08} {10} {19} {28} and selective {08} {09} {28} inhibitor of neuronal uptake of serotonin (5-hydroxytryptamine [5-HT]) {08} {09} {10} {19} {28}. It has only weak effects on neuronal uptake of norepinephrine {08} {19} and dopamine {08} {19}. Chronic administration of sertraline in animals has resulted in down-regulation of postsynaptic {11} {14} beta-adrenergic receptors {11} {19}. Sertraline's inhibition of serotonin reuptake enhances serotonergic transmission {05} {06} {19}, which results in subsequent inhibition of adrenergic activity in the locus ceruleus {15}. Specifically, sertraline depresses the firing of the raphe serotonin neurons; this, in turn, increases the activity of the locus ceruleus, with consequent desensitization of the postsynaptic beta-receptors and presynaptic alpha 2-receptors {11}.

Sertraline lacks affinity for adrenergic (alpha 1, alpha 2, or beta) receptors {28}, muscarinic {08} {28}-cholinergic receptors {01} {03} {26}, gamma aminobutyric acid (GABA) receptors {01} {26}, dopaminergic receptors {03} {11} {28}, histaminergic receptors {03} {05} {28}, serotonergic (5-HT 1A, 5-HT 1B, 5-HT 2) receptors {01} {28}, and benzodiazepine receptors {01} {26}. Sertraline does not inhibit monoamine oxidase {05} {06} {08}.


Other actions/effects:

Sertraline inhibits the isoenzyme cytochrome P450 2D6 (CYP2D6) {07}. When used in low {07} clinical {81} doses, sertraline probably inhibits CYP2D6 less than other selective serotonin reuptake inhibitors.

Sertraline blocks the uptake of serotonin into human platelets as well as into neurons {07} {26}. There have been rare reports of altered platelet function and of abnormal bleeding or purpura in patients taking sertraline {04} {07} {26}.

Sertraline has anorectic effects {01} {25}.

Absorption:

Slow {09} {15} {28} but consistent {09} {15}. Bioavailability and absorption rate are increased if sertraline is taken with food {07} {26}.

Distribution:

Both sertraline and its metabolites are extensively distributed into tissues {03}. In animal studies, the volume of distribution (Vol D) exceeded 20 liters/kilogram (L/kg) {03} {19} {28}.

Protein binding:

Very high (98%) {03} {28}. However, at concentrations up to and greater than those achieved during therapeutic dosing of sertraline, neither sertraline nor its major metabolite, N-desmethylsertraline, altered plasma protein binding of warfarin or propranolol in vitro {07}.

Biotransformation:

Undergoes extensive first-pass metabolism in the liver {07}. The primary initial pathway is N-demethylation {07} {28} to form N-desmethylsertraline {06} {08}, which is substantially less active than the parent compound {05} {06} {07}, exhibiting only about 1/8 of its activity {03} {11} {28}. Animal testing has shown that N-desmethylsertraline does not contribute appreciably to the pharmacologic activity {03} {06} or toxicity {05} {06} of the parent compound. Both sertraline and N-desmethylsertraline undergo oxidative deamination and subsequent reduction, hydroxylation, and glucuronide conjugation {07}.

Half-life:


Elimination:

Sertraline: 24 to 26 hours {07} {09} {26}.

N-desmethylsertraline: 62 to 104 hours {07} {26}.


Onset of action:

Antidepressant and antipanic effects—2 to 4 weeks {28} {53}.

Antiobsessional effects may take longer to achieve {42} {57}.

Time to peak concentration:

Time to reach mean peak plasma concentration (T max) following administration of 50 to 200 mg of sertraline once daily for 14 days ranged from 4.5 to 8.4 hours {07}. When sertraline was administered with food, T max fell from 8 hours to 5.5 hours post-dosing {07}.

Time to steady-state concentration

After once-daily dosing of sertraline in adult subjects, steady-state plasma concentrations were reached in about 7 days {15} {17}. Based on a 14-day kinetics study, steady state should be reached after 2 to 3 weeks in older patients {07}.

Peak plasma concentration

Mean peak plasma concentration (C max) and area under the plasma concentration–time curve (AUC) after a single dose of sertraline were proportional to dose over the range of 50 to 200 mg {07} {09}, demonstrating linear pharmacokinetics {07} {26} {28}. When sertraline was administered with food, C max increased by 25% and AUC increased slightly {07} {28}.

Elimination:


Renal—
        In two healthy male subjects, about 40 to 45% of an administered radioactive dose was recovered in the urine within 9 days {07}, with less than 0.2% recovered unchanged {02} {27}.



Fecal—
        In two healthy male subjects, about 40 to 45% of an administered radioactive dose was recovered in feces within 9 days {07}, including 12 to 14% unchanged sertraline {07}.



In dialysis—
        Due to large volume of distribution, dialysis is not believed to be effective {01}.



Precautions to Consider

Carcinogenicity

In lifetime carcinogenicity studies, there was a dose-related increase in the incidence of liver adenomas in male CD-1 mice receiving sertraline at doses of 10 to 40 mg per kg of body weight (mg/kg) per day (less than and equal to the maximum recommended human dose [MRHD] on a mg per square meter of body surface area [mg/m 2] basis). However, liver adenomas have a variable rate of spontaneous occurrence in the CD-1 mouse, and the significance of this finding to use in humans is unknown. No increase in liver adenomas was seen in Long-Evans rats or in female CD-1 mice receiving doses of up to 40 mg/kg. No increase in the incidence of hepatocellular carcinomas was seen in the studies. Female rats receiving 40 mg/kg (two times the MRHD on a mg/m 2 basis) had an increase in follicular adenomas of the thyroid, unaccompanied by thyroid hyperplasia. Rats receiving 10 to 40 mg/kg (0.5 to 2 times the MRHD on a mg/m 2 basis) showed an increase in uterine adenocarcinomas compared with placebo controls, but this effect was not clearly drug-related. {07} {26}

Mutagenicity

Sertraline had no genotoxic effects, with or without metabolic activation, based on the bacterial mutation assay, mouse lymphoma mutation assay, or tests for cytogenic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes {07} {26}.

Pregnancy/Reproduction
Fertility—
A decrease in fertility was seen in one of two studies in rats that received 80 mg/kg of sertraline per day (four times the MRHD on a mg/m 2 basis) {07}.

Pregnancy—
A prospective study compared birth outcomes of 267 pregnancies that were exposed to the selective serotonin reuptake inhibitors (SSRIs) sertraline (50 mg/day, range 25 to 250 mg/day), paroxetine (30 mg/day, range 10 to 60 mg/day), or fluvoxamine (50 mg/day, range 25 to 200 mg/day) with those of 267 pregnancies that were exposed to medications or medical treatments that are known to be nonteratogenic {74}. Sertraline was taken at some time during 147 of the SSRI-exposed pregnancies {74}. Based on interviews with the mothers 6 to 9 months after the births, no differences in the infants' gestational ages or mean birth weights, or in the rates of major malformations, spontaneous or elective abortions, or stillbirths were found between the two groups {74}. Also, no differences were found between infants exposed to SSRIs during the first trimester only and infants exposed to SSRIs throughout gestation {74}. The behavioral effects of in utero sertraline exposure were not examined {74}.

No teratogenic effects were demonstrated in studies in rats and rabbits receiving approximately four times the MRHD on a mg/m 2 basis. However, delayed ossification occurred in fetuses of rats and rabbits given sertraline dosages of 10 mg/kg per day (one half the MRHD on a mg/m 2 basis) and 40 mg/kg per day (four times the MRHD on a mg/m 2 basis), respectively, during the period of organogenesis. Also, an increase in pup stillbirths and pup deaths during the first 4 days of life and a decrease in pup weights were seen in rats when dams were given a sertraline dose of 20 mg/kg per day (equal to the MRHD on a mg/m 2 basis) through the last one third of gestation and through lactation. There was no effect on pup mortality at doses £ 10 mg/kg per day (one half the MRHD on a mg/m 2 basis). The decrease in pup survival was due to in utero exposure to sertraline. The clinical significance of these effects is unknown. {07}

FDA Pregnancy Category C {07}.


Labor and delivery—

The effect of sertraline on labor and delivery is not known {07} {26}.

Breast-feeding

Sertraline is distributed into breast milk {54}. Very low levels of sertraline and/or N-desmethylsertraline (< 2 nanograms/mL) were detected in the plasma of breast-fed infants of mothers who were receiving sertraline {56}. However, no adverse effects in the infants were seen during the short-term (< 2 years) follow-up {54} {56}.

Pediatrics

Sertraline has been tested in children 6 to 17 years of age and, in effective doses, has not been shown to cause different side effects or problems than it does in adults. However, the effects of long-term use of sertraline on the growth, development, and maturation of children and adolescents are unknown. Because of the anorectic effect of sertraline, body weight and growth should be monitored in children receiving long-term treatment. {07}


Geriatrics


No geriatrics-specific problems have been documented in studies done to date that included elderly patients {07} {27} {28}. However, in one study, clearance of sertraline in 16 elderly patients was about 40% lower than clearance in a group of younger subjects, indicating that steady-state will take 2 to 3 weeks to achieve in elderly patients {07}. A reduced initial dosage is recommended in elderly patients {20} {36} {38} {39} {40} {41} {43} {44}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Sertraline inhibits cytochrome P450 2D6 (CYP2D6) and a potential exists for clinically significant interactions with medications that are metabolized by this isoenzyme, particularly medications having a narrow therapeutic index, such as tricyclic antidepressants and the type 1C antiarrhythmics propafenone and flecainide. A lower dosage of these medications may be needed when they are used concomitantly with sertraline, and an increase in dosage may be necessary after discontinuation of sertraline following concomitant use. {07}
Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Alcohol    (although sertraline has not been shown to alter alcohol metabolism {03} {11} {19} and does not appear to potentiate cognitive and psychomotor effects of alcohol in normal subjects {16} {19}, concomitant use is not recommended {26})


» Antidepressants, tricyclic (TCAs)    (sertraline may inhibit the metabolism of TCAs {07} {77}; in a pharmacokinetic study in 18 healthy males, 50 mg per day of sertraline increased the mean area under the plasma concentration–time curve [AUC] and mean maximum plasma concentration [C max] of desipramine by 23% and 31%, respectively {23}; in 12 healthy males, 150 mg per day of sertraline increased the AUC and C max of desipramine by 54% and 22%, respectively, when desipramine was administered, and increased the AUC and C max of desipramine [a metabolite of imipramine] by 129% and 55%, respectively, when imipramine was administered {77}; imipramine AUC and C max were increased by 68% and 39%, respectively, in the second study {77}; TCA plasma concentration monitoring and dosage adjustments of the TCA and/or sertraline may be necessary {77})


» Astemizole {58} or
» Terfenadine {59}    (because sertraline inhibits cytochrome P450 enzymes and may increase plasma concentrations of these medications, thereby increasing the risk of cardiac arrhythmias, concurrent use is not recommended {58} {59})


Cimetidine    (AUC, C max, and mean half-life of sertraline were increased by 50%, 24%, and 26%, respectively, compared with placebo values, when a single dose of 100 mg of sertraline was administered on the second day of administration of 800 mg per day of cimetidine {07})


Diazepam    (after 21 days of dosing with sertraline or placebo, clearance of diazepam following a single intravenous dose was decreased from baseline by 32% in subjects administered sertraline and by 19% in subjects administered placebo {75}; however, the clinical significance of this interaction is unknown {07})


» Disulfiram    (sertraline oral concentrate contains 12% alcohol; concomitant use with disulfiram is contraindicated{83})


» Highly protein-bound medications, especially:
Digitoxin
Warfarin    (caution in concurrent use with sertraline is recommended because of possible displacement of either medication from protein-binding sites {07} {26}, leading to increased plasma concentrations of the free [unbound] medications and increased risk of adverse effects {07}; however, sertraline did not alter plasma protein binding of warfarin or propranolol in vitro {07})

    (after single oral doses of warfarin in six healthy males, the prothrombin time was increased and the protein binding of warfarin was decreased compared with both baseline and the placebo group values after 21 days of sertraline dosing that was escalated from 50 mg per day to 200 mg per day {76}; changes were small but statistically significant {76}; prothrombin time should be carefully monitored when sertraline therapy is initiated or stopped in patients taking warfarin {07} {26} {27})


Lithium    (although a placebo-controlled clinical trial in normal volunteers demonstrated no alteration in steady-state lithium levels or renal clearance of lithium {07} {33}, close monitoring of lithium concentrations is recommended {07} {26}; also, concurrent use may lead to an increased incidence of serotonin-associated side effects {26})


» Moclobemide    (because of the potentially fatal effects of concomitant use of sertraline and nonselective, irreversible monoamine oxidase [MAO] inhibitors, and the increased risk of development of the serotonin syndrome with concomitant use of sertraline and the selective, reversible MAO-A inhibitor moclobemide, concurrent use is not recommended; allowing a washout period of 3 to 7 days is advised between discontinuing moclobemide and initiating sertraline therapy, and allowing a washout period of 2 weeks is advised between discontinuing sertraline and initiating moclobemide therapy {82})


» Monoamine oxidase (MAO) inhibitors, including furazolidone, procarbazine, and selegiline    (concurrent use of MAO inhibitors with sertraline may result in hyperpyretic episodes, severe convulsions, hypertensive crises, or the serotonin syndrome; fatalities have occurred. Concomitant use of MAO inhibitors with sertraline is contraindicated. A wash-out period of at least 14 days should elapse between discontinuation of either medication [the MAO inhibitor or sertraline] and initiation of the other {07} {26} {27})


» Serotonergics or other medications or substances with serotonergic activity (see Appendix II )    (increased risk of developing the serotonin syndrome, a rare but potentially fatal hyperserotonergic state; symptoms typically occur shortly [hours to days] after the addition of a serotonergic agent to a regimen that includes other serotonin-enhancing drugs, such as sertraline, or an increase in dosage of a serotonergic agent; symptoms include agitation, diaphoresis, diarrhea, fever, hyperreflexia, incoordination, mental status changes [confusion, hypomania], myoclonus, shivering, or tremor; the syndrome usually resolves shortly after the discontinuation of the serotonergic agents {22})


Tolbutamide    (in a placebo-controlled study in 25 healthy male volunteers, clearance of tolbutamide following a single intravenous dose was decreased by 16% from baseline after 22 days of sertraline dosing that was escalated from 50 mg per day to 200 mg per day {07} {78}; blood glucose should be monitored, and the dosage of tolbutamide reduced if hypoglycemia occurs {02})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) or
Aspartate aminotransferase (AST [SGOT])    (values increased to ³ 3 times the upper limit of normal {26} have been reported infrequently {15} {17} {26} {28}; increases usually occur within 1 to 9 weeks of initiation of therapy {26} {28}, with values generally normalizing after sertraline is discontinued {26} {28})


Total cholesterol or
Triglycerides    (mean increases of 3% and 5%, respectively, have been reported {26})


Uric acid, serum    (mean decreases of approximately 7% have been reported {07} {26})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Hepatic function impairment    (in a single-dose study, mean elimination half-life of sertraline was prolonged from 22 hours in healthy subjects to 52 hours in patients with mild, stable cirrhosis {07}; peak concentrations and AUC were increased 1.7 and 4.4 times, respectively, in patients with hepatic impairment {07}; decreased dosage or less frequent dosing is recommended {07} {26})


Mania, history of    (activation of mania or hypomania was reported in approximately 0.4% of patients during premarketing testing of sertraline {07}, and occurs most frequently in patients with bipolar disorder {57})


Neurological impairment, including developmental delay    (risk of seizures may be increased {47})


Renal function impairment    (results of an open-label study showed no difference between pharmacokinetic parameters of sertraline in patients with renal impairment ranging from mild to severe [but not requiring regular hemodialysis] and those of a matched healthy group with no renal impairment {31}; however, since clinical experience with long-term sertraline treatment in patients with renal impairment is lacking, caution is recommended {07})


Seizure disorders    (seizures occurred in approximately 0.2% of subjects in clinical trials of sertraline for obsessive-compulsive disorder, with most cases occurring in patients with a pre-existing seizure disorder or a family history of seizure disorder {07}; as with other antidepressants, sertraline should be introduced with care {07} {26})


Sensitivity to sertraline {26}
Sensitivity to latex    (dropper dispenser for sertraline oral concentrate contains natural dry rubber{83})


Weight loss    (although the weight loss associated with sertraline use is usually about one to two pounds [0.4 to 0.9 kg], there have been rare reports of significant weight loss; significant weight loss may be undesirable in some patients {07})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Careful supervision of patients with suicidal tendencies    (recommended especially during early treatment phase before peak effectiveness of sertraline is achieved {07}; although sertraline has a wide margin of safety when taken in overdose {26} {71}, limiting the total amount of medication in the patient"s possession is recommended {07} {26})




Side/Adverse Effects

Note: Side effects may be dose-related {14} {17} {26} {27} and time-related {17}. Severity of side effects appears to lessen with decreased doses or after administration for longer than 2 weeks {17} {25}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Sexual dysfunction (decreased sexual desire or ability)

Note: Sexual dysfunction may include decreased libido, impotence, delayed ejaculation, or anorgasmia {07} {26} {29}. Delayed ejaculation is the most commonly seen form of sexual dysfunction associated with sertraline use {07} {26}.


Incidence less frequent or rare
    
Abnormal bleeding{04}{07} (red or purple spots on skin; nose bleeds)
    
akathisia{30}{45}{46} (inability to sit still; restlessness)
    
breast tenderness or enlargement{07}{49}
or galactorrhea{26}{51}{52} (unusual secretion of milk)—in females
    
extrapyramidal effects, dystonic{45} (unusual or sudden body or facial movements or postures)
    
fever{07}{26}
    
hyponatremia{60}{61}{62}{63}{64} (confusion; drowsiness; dryness of mouth; increased thirst; lack of energy; seizures)
    
mania or hypomania{18}{26}{27}{55} (fast talking and excited feelings or actions that are out of control)—may be more frequent in patients with bipolar disorder{57}
    
palpitation{03}{15}{17}{21} (fast or irregular heartbeat)
    
serotonin syndrome (diarrhea; fever; increased sweating; mood or behavior changes; overactive reflexes; racing heartbeat; restlessness; shivering or shaking)
    
skin rash, hives, or itching{07}{15}{17}{26}

Note: Hyponatremia is probably the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) {60} {61} {62} {63} {64}. Most cases have been in elderly patients {60} {62} {64} or in volume-depleted patients, such as patients taking diuretics {07} {26}.
The serotonin syndrome is most likely to occur shortly (within hours to days) after an increase in sertraline dosage or the addition of another serotonergic agent to the patient's regimen {22}. The syndrome may include cardiac arrhythmias, coma, disseminated intravascular coagulation, hypertension or hypotension, renal failure, respiratory failure, seizures, or severe hyperthermia {22}.




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Dizziness{15}{17}{28}
    
drowsiness{12}{13}{15}{16}{17}
    
gastrointestinal effects
including anorexia{07}{13}{15}{26} (decrease in appetite), diarrhea or loose stools{07}{15}{17}{26}
dryness of mouth{13}{15}{17}
nausea{13}{15}{17}
stomach or abdominal cramps, gas, or pain{13}{15}{17}
or weight loss{07}{15}{17}
    
headache{15}{17}{28}
    
increased sweating{15}{17}{19}
    
insomnia{15}{17}{28} (trouble in sleeping)
    
tiredness or weakness{13}{15}{17}{28}
    
tremor{15}{17}{19}{28} (trembling or shaking)

Note: Weight loss in patients in controlled trials was usually about one to two pounds [0.4 to 0.9 kg] {07}. Significant weight loss was reported rarely {07}.


Incidence less frequent
    
Anxiety{20}{21} , agitation{15}{17}{28} , or nervousness{07}{15}{26}
    
changes in vision{03}{15}{17} , including blurred vision{03}{15}{17}{28}
    
constipation{03}{15}{17}{28}
    
flushing or redness of skin, with feeling of warmth or heat{07}{26}
    
increased appetite{07}{26}
    
vomiting{13}{17}
    
yawning{07}



Those indicating the need for medical attention if they occur after medication is discontinued
    
Agitation{65}
    
anxiety{65}
    
dizziness{65}{66}{67}
    
gait instability{68}{69} (trouble in walking)
    
headache{65}{68}{69}{70}
    
increased sweating{65}
    
insomnia{65}{70} (trouble in sleeping)
    
nausea{65}
    
tremor{65} (trembling or shaking)
    
unusual tiredness{68}{69}{70}
    
vertigo{65}{68}{69} (feeling of constant movement of self or surroundings)

Note: Discontinuation symptoms are usually mild, and are often mistaken for influenza {81}.





Overdose
For specific information on the agents used in the management of sertraline overdose, see Charcoal, Activated (Oral-Local) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose

Note: Sertraline has a wide margin of safety in overdose {26} {71}. However, deaths have occurred in overdoses involving sertraline in combination with other drugs and/or alcohol {07} {26}.
Symptoms of overdose resemble the side/adverse effects occurring with therapeutic doses, but may be more intense {71} {72} or several symptoms may occur together {71}.
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Acute
    
Anxiety{07}
    
drowsiness{07}
    
electrocardiogram (ECG) changes{07}
    
mydriasis{07} (unusually large pupils)
    
nausea{07}
    
tachycardia{07} (unusually fast heartbeat)
    
vomiting{07}

Note: Some patients may develop the serotonin syndrome, a potentially fatal symptom complex, in response to acute overdose with sertraline {73}. The serotonin syndrome may be manifested by mental status changes, restlessness, myoclonus, hyperreflexia, diaphoresis, shivering, tremor, diarrhea, incoordination, and/or fever {22}.



Treatment of overdose
There is no specific antidote for sertraline {26} {50}. Treatment is essentially symptomatic and supportive {26} {50}.

To decrease absorption—Administering activated charcoal, which may be used with sorbitol, may be as effective as or more effective than emesis {07} {26} or gastric lavage {07} {26}.

Monitoring—Monitoring cardiac function and vital signs {07} {26}.

Supportive care—Establishing and maintaining airway {07} {26} {50}. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.

Note: Dialysis, forced diuresis, hemoperfusion, and exchange transfusions are unlikely to be of benefit {07} {26} {50} due to sertraline's large volume of distribution {07} {26} {50} and high degree of protein binding {28} {50}.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Sertraline (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to sertraline

Pregnancy—No difference in birth outcome was found between 267 SSRI-exposed pregnancies (147 to sertraline) and 267 pregnancies exposed to known nonteratogenic medications or procedures; behavioral effects were not studied





Breast-feeding—Distributed into breast milk; the long-term effects on nursing infants are unknown




Use in children—Body weight and growth should be monitored during long-term treatment because of anorectic effect






Use in the elderly—Clearance is reduced; reduced initial dosage is recommended



Contraindicated medications
Disulfiram

MAO inhibitors
Other medications, especially astemizole, digitoxin, moclobemide, serotonergics or other medications or substances with serotonergic activity, terfenadine, tricyclic antidepressants, and warfarin
Other medical problems, especially hepatic dysfunction

Proper use of this medication
» Compliance with therapy; not taking more or less medicine than prescribed

Taking with or without food, as directed by physician

» Four weeks or more of therapy may be required before antidepressant or antipanic effects are achieved; antiobsessional effects may take longer to achieve

» Proper dosing
Discussing with physician what to do about any missed doses since some patients take sertraline in the morning and other patients take sertraline in the evening

» Proper storage

Precautions while using this medication
Regular visits to physician to check progress of therapy

» Not taking sertraline with or within 14 days of taking an MAO inhibitor; not taking an MAO inhibitor within 14 days of taking sertraline

Avoiding use of alcoholic beverages

» Possible drowsiness, impairment of judgment, thinking, or motor skills; caution when driving or doing jobs requiring alertness or coordination until effects of medication are known {14} {15} {26} {31}

» Checking with physician before discontinuing sertraline; dosage tapering may be required


Side/adverse effects
Sexual dysfunction; abnormal bleeding; akathisia; breast tenderness or enlargement, or galactorrhea (in females); extrapyramidal effects, dystonic; fever; hyponatremia; mania or hypomania; serotonin syndrome; skin rash, hives, or itching

Possible discontinuation symptoms, including agitation, anxiety, dizziness, gait instability, headache, increased sweating, insomnia, nausea, tremor, unusual tiredness, or vertigo


General Dosing Information
Potentially suicidal patients, particularly those who may use alcohol excessively, should not have access to large quantities of this medication since they may continue to exhibit suicidal tendencies until significant improvement occurs {07}. Some clinicians recommend that the patient be supplied with the least amount of medication necessary for satisfactory patient management {07} {26}.

Activation of hypomania or mania has been reported in patients treated with sertraline {07} {26}. Risk is greatest in patients with a history of bipolar disorder {42}.

When discontinued, sertraline should be withdrawn gradually to help avoid the occurrence of discontinuation symptoms {65} {66} {69} {70}, including agitation {65}, anxiety {65}, dizziness {65} {66} {67}, gait instability {68} {69}, headache {65} {68} {69} {70}, increased sweating {65}, insomnia {65} {70}, nausea {65}, tremor {65}, unusual tiredness {68} {69} {70}, or vertigo {65} {68} {69}. Discontinuation symptoms are usually mild and are often mistaken for influenza {81}.

Diet/Nutrition
Sertraline may be taken with or without food {31} {32}. Some clinicians advise their patients to take this medication with food to lessen gastrointestinal side effects {35} {36} {37}.

For treatment of adverse effects
Serotonin syndrome—The serotonin syndrome usually resolves shortly after discontinuation of serotonergic medications. Treatment is essentially symptomatic and supportive. However, the nonspecific serotonergic receptor antagonists cyproheptadine and methysergide have been reported to be of some use in shortening the duration of the serotonin syndrome. {22}


Oral Dosage Forms

Note: The dosing and strengths of the dosage forms available are expressed in terms of sertraline base.

SERTRALINE HYDROCHLORIDE CAPSULES

Usual adult dose
Depression or
Obsessive-compulsive disorder
Oral, initially 50 mg (base) a day as a single morning or evening dose {07} {26}{83}. The dosage may be increased after several weeks in increments of 50 mg {02} {28}, with increases made at intervals of at least one week {07} {26}, as needed and tolerated.

Note: Some clinicians recommend an initial dosage of 25 mg a day for one to two days {20}.


Panic disorder or
Posttraumatic Stress Disorder 1
Oral, initially 25 mg (base) a day, as a single morning or evening dose {07} {26}{83}. After one week, the dosage should be increased to 50 mg (base) a day, as a single dose {07} {26}{83}. Further dosage increases may be made in increments of 50 mg {26}, at intervals of at least one week {07} {26}, as needed and tolerated{84}.


Note: Patients with hepatic function impairment should receive a lower dosage or less frequent dosing than patients with normal hepatic function {07} {26}{83}.


Usual adult prescribing limits
200 mg (base) a day {07} {26}{83}.

Usual pediatric dose
Depression or
Panic disorder or
Posttraumatic Stress Disorder
Safety and efficacy have not been established.{83}

Obsessive-compulsive disorder 1
Children 6 to 12 years of age: Oral, initially 25 mg (base) a day as a single morning or evening dose {07}{83}. Dosage may be increased at intervals of at least one week, as needed and tolerated {07}.

Children 13 to 17 years of age: Oral, initially 50 mg (base) a day as a single morning or evening dose {07}{83}. Dosage may be increased at intervals of at least one week, as needed and tolerated {07}.

Note: To avoid excessive dosing when the dosage is being increased, consideration should be given to the generally lower body weights of children as compared with adult body weights {07}{83}.



Usual pediatric prescribing limits
See Usual adult prescribing limits.

Usual geriatric dose
Depression or
Obsessive-compulsive disorder or
Panic disorder
Oral, initially 25 mg (base) a day, as a single morning or evening dose; dosage may be increased gradually as needed and tolerated {24}.


Strength(s) usually available
U.S.—
Not commercially available.

Canada—


25 mg (base) (Rx) [Zoloft (anhydrous lactose) (corn starch) (magnesium stearate) (sodium lauryl sulfate){26}]


50 mg (base) (Rx) [Zoloft (anhydrous lactose) (corn starch) (magnesium stearate) (sodium lauryl sulfate){26}]


100 mg (base) (Rx) [Zoloft (anhydrous lactose) (corn starch) (magnesium stearate) (sodium lauryl sulfate){26}]


150 mg (base) (Rx) [Zoloft (anhydrous lactose) (corn starch) (magnesium stearate) (sodium lauryl sulfate){26}]


200 mg (base) (Rx) [Zoloft (anhydrous lactose) (corn starch) (magnesium stearate) (sodium lauryl sulfate){26}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

Auxiliary labeling:
   • May cause dizziness or drowsiness.
   • Avoid alcoholic beverages.


SERTRALINE HYDROCHLORIDE ORAL CONCENTRATE

Usual adult dose
See Sertraline Hydrochloride Capsules .{83}

Usual adult prescribing limits
See Sertraline Hydrochloride Capsules .{83}

Usual pediatric dose
See Sertraline Hydrochloride Capsules .{83}

Usual pediatric prescribing limits
See Sertraline Hydrochloride Capsules.{83}

Strength(s) usually available
U.S.—


20 mg per mL (Rx) [Zoloft (alcohol) ( butylated hydroxytoluene) (glycerin) (menthol){83}]

Canada—
Not commercially available

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.{83}

Preparation of dosage form:
Mix the required amount of sertraline oral concentrate with 4 ounces of water, ginger ale, lemon/lime soda, lemonade or orange juice only. Solution should be ingested immediately after mixing.{83}
{83}
Auxiliary labeling:
   • May cause dizziness or drowsiness
   • Avoid alcoholic beverages


SERTRALINE HYDROCHLORIDE TABLETS

Usual adult dose
See Sertraline Hydrochloride Capsules .

Usual adult prescribing limits
See Sertraline Hydrochloride Capsules .

Usual pediatric dose
See Sertraline Hydrochloride Capsules .

Usual pediatric prescribing limits
See Sertraline Hydrochloride Capsules .

Usual geriatric dose
Depression or
Obsessive-compulsive disorder or
Panic disorder
Oral, initially 12.5 to 25 mg (base) a day, as a single morning or evening dose; dosage may be increased gradually as needed and tolerated {20} {36} {38} {39} {40} {41} {43} {44}.


Strength(s) usually available
U.S.—


25 mg (base) (Rx) [Zoloft (scored) ( dibasic calcium phosphate dihydrate) (FD&C Blue #2 aluminum lake) (hydroxypropyl cellulose) (hydroxypropyl methylcellulose) (magnesium stearate) (microcrystalline cellulose) (polyethylene glycol) (polysorbate 80) (sodium starch glycolate) ( titanium dioxide){07}]


50 mg (base) (Rx) [Zoloft (scored) ( dibasic calcium phosphate dihydrate) (FD&C Blue #2 aluminum lake) (hydroxypropyl cellulose) (hydroxypropyl methylcellulose) (magnesium stearate) (microcrystalline cellulose) (polyethylene glycol) (polysorbate 80) (sodium starch glycolate) ( titanium dioxide){07}]


100 mg (base) (Rx) [Zoloft (scored) ( dibasic calcium phosphate dihydrate) (hydroxypropyl cellulose) (hydroxypropyl methylcellulose) (magnesium stearate) (microcrystalline cellulose) (polyethylene glycol) ( polysorbate 80) (sodium starch glycolate) (synthetic yellow iron oxide) (titanium dioxide){07}]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

Auxiliary labeling:
   • May cause dizziness or drowsiness.
   • Avoid alcoholic beverages.



Revised: 09/14/2001



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