Zoloft - Treatment for Major Depressive Disorder

ZOLOFT (sertraline hydrochloride)

Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Zoloft or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Zoloft is not approved for use in pediatric patients except for patients with obsessive compulsive disorder (OCD). (See Warnings: Clinical Worsening and Suicide Risk, Precautions: Information for Patients, and Precautions: Pediatric Use)

Zoloft Description
Zoloft® (sertraline hydrochloride) is a selective serotonin reuptake inhibitor (SSRI) for oral administration. It has a molecular weight of 342.7. Sertraline hydrochloride has the following chemical name: (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride. The empirical formula C₁₇H₁₇NCl₂•HCl is represented by the following structural formula:

Sertraline hydrochloride is a white crystalline powder that is slightly soluble in water and isopropyl alcohol, and sparingly soluble in ethanol.

Zoloft is supplied for oral administration as scored tablets containing sertraline hydrochloride equivalent to 25, 50 and 100 mg of sertraline and the following inactive ingredients: dibasic calcium phosphate dihydrate, D & C Yellow #10 aluminum lake (in 25 mg tablet), FD & C Blue #1 aluminum lake (in 25 mg tablet), FD & C Red #40 aluminum lake (in 25 mg tablet), FD & C Blue #2 aluminum lake (in 50 mg tablet), hydroxypropyl cellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, synthetic yellow iron oxide (in 100 mg tablet), and titanium dioxide.

Zoloft oral concentrate is available in a multidose 60 mL bottle. Each mL of solution contains sertraline hydrochloride equivalent to 20 mg of sertraline. The solution contains the following inactive ingredients: glycerin, alcohol (12%), menthol, butylated hydroxytoluene (BHT). The oral concentrate must be diluted prior to administration (see PRECAUTIONS, Information for Patients and DOSAGE AND ADMINISTRATION).

Zoloft - Clinical Pharmacology

Pharmacodynamics
The mechanism of action of sertraline is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin (5HT). Studies at clinically relevant doses in man have demonstrated that sertraline blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that sertraline is a potent and selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro studies have shown that sertraline has no significant affinity for adrenergic (alpha1, alpha2, beta), cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5HT1A, 5HT1B, 5HT2), or benzodiazepine receptors; antagonism of such receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects for other psychotropic drugs. The chronic administration of sertraline was found in animals to down regulate brain norepinephrine receptors, as has been observed with other drugs effective in the treatment of major depressive disorder. Sertraline does not inhibit monoamine oxidase.

Pharmacokinetics

Systemic Bioavailability
In man, following oral once-daily dosing over the range of 50 to 200 mg for 14 days, mean peak plasma concentrations (Cmax) of sertraline occurred between 4.5 to 8.4 hours post-dosing. The average terminal elimination half-life of plasma sertraline is about 26 hours. Based on this pharmacokinetic parameter, steady-state sertraline plasma levels should be achieved after approximately one week of once-daily dosing. Linear dose-proportional pharmacokinetics were demonstrated in a single dose study in which the Cmax and area under the plasma concentration time curve (AUC) of sertraline were proportional to dose over a range of 50 to 200 mg. Consistent with the terminal elimination half-life, there is an approximately two-fold accumulation, compared to a single dose, of sertraline with repeated dosing over a 50 to 200 mg dose range. The single dose bioavailability of sertraline tablets is approximately equal to an equivalent dose of solution.

In a relative bioavailability study comparing the pharmacokinetics of 100 mg sertraline as the oral solution to a 100 mg sertraline tablet in 16 healthy adults, the solution to tablet ratio of geometric mean AUC and Cmax values were 114.8% and 120.6%, respectively. 90% confidence intervals (CI) were within the range of 80–125% with the exception of the upper 90% CI limit for Cmax which was 126.5%.

The effects of food on the bioavailability of the sertraline tablet and oral concentrate were studied in subjects administered a single dose with and without food. For the tablet, AUC was slightly increased when drug was administered with food but the Cmax was 25% greater, while the time to reach peak plasma concentration (Tmax) decreased from 8 hours post-dosing to 5.5 hours. For the oral concentrate, Tmax was slightly prolonged from 5.9 hours to 7.0 hours with food.

Metabolism
Sertraline undergoes extensive first pass metabolism. The principal initial pathway of metabolism for sertraline is N-demethylation. N-desmethylsertraline has a plasma terminal elimination half-life of 62 to 104 hours. Both in vitro biochemical and in vivo pharmacological testing have shown N-desmethylsertraline to be substantially less active than sertraline. Both sertraline and N-desmethylsertraline undergo oxidative deamination and subsequent reduction, hydroxylation, and glucuronide conjugation. In a study of radiolabeled sertraline involving two healthy male subjects, sertraline accounted for less than 5% of the plasma radioactivity. About 40–45% of the administered radioactivity was recovered in urine in 9 days. Unchanged sertraline was not detectable in the urine. For the same period, about 40–45% of the administered radioactivity was accounted for in feces, including 12–14% unchanged sertraline.

Desmethylsertraline exhibits time-related, dose dependent increases in AUC (0–24 hour), Cmax and Cmin, with about a 5–9 fold increase in these pharmacokinetic parameters between day 1 and day 14.

Protein Binding
In vitro protein binding studies performed with radiolabeled 3H-sertraline showed that sertraline is highly bound to serum proteins (98%) in the range of 20 to 500 ng/mL. However, at up to 300 and 200 ng/mL concentrations, respectively, sertraline and N-desmethylsertraline did not alter the plasma protein binding of two other highly protein bound drugs, viz., warfarin and propranolol (see PRECAUTIONS).

Pediatric Pharmacokinetics
Sertraline pharmacokinetics were evaluated in a group of 61 pediatric patients (29 aged 6–12 years, 32 aged 13–17 years) with a DSM-III-R diagnosis of major depressive disorder or obsessive-compulsive disorder. Patients included both males (N=28) and females (N=33). During 42 days of chronic sertraline dosing, sertraline was titrated up to 200 mg/day and maintained at that dose for a minimum of 11 days. On the final day of sertraline 200 mg/day, the 6–12 year old group exhibited a mean sertraline AUC (0–24 hr) of 3107 ng-hr/mL, mean Cmax of 165 ng/mL, and mean half-life of 26.2 hr. The 13–17 year old group exhibited a mean sertraline AUC (0–24 hr) of 2296 ng-hr/mL, mean Cmax of 123 ng/mL, and mean half-life of 27.8 hr. Higher plasma levels in the 6–12 year old group were largely attributable to patients with lower body weights. No gender associated differences were observed. By comparison, a group of 22 separately studied adults between 18 and 45 years of age (11 male, 11 female) received 30 days of 200 mg/day sertraline and exhibited a mean sertraline AUC (0–24 hr) of 2570 ng-hr/mL, mean Cmax of 142 ng/mL, and mean half-life of 27.2 hr. Relative to the adults, both the 6–12 year olds and the 13–17 year olds showed about 22% lower AUC (0–24 hr) and Cmax values when plasma concentration was adjusted for weight. These data suggest that pediatric patients metabolize sertraline with slightly greater efficiency than adults. Nevertheless, lower doses may be advisable for pediatric patients given their lower body weights, especially in very young patients, in order to avoid excessive plasma levels (see DOSAGE AND ADMINISTRATION).

Age
Sertraline plasma clearance in a group of 16 (8 male, 8 female) elderly patients treated for 14 days at a dose of 100 mg/day was approximately 40% lower than in a similarly studied group of younger (25 to 32 y.o.) individuals. Steady-state, therefore, should be achieved after 2 to 3 weeks in older patients. The same study showed a decreased clearance of desmethylsertraline in older males, but not in older females.

Liver Disease
As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of sertraline. In patients with chronic mild liver impairment (N=10, 8 patients with Child-Pugh scores of 5–6 and 2 patients with Child-Pugh scores of 7–8) who received 50 mg sertraline per day maintained for 21 days, sertraline clearance was reduced, resulting in approximately 3-fold greater exposure compared to age-matched volunteers with no hepatic impairment (N=10). The exposure to desmethylsertraline was approximately 2-fold greater compared to age-matched volunteers with no hepatic impairment. There were no significant differences in plasma protein binding observed between the two groups. The effects of sertraline in patients with moderate and severe hepatic impairment have not been studied. The results suggest that the use of sertraline in patients with liver disease must be approached with caution. If sertraline is administered to patients with liver impairment, a lower or less frequent dose should be used (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Renal Disease
Sertraline is extensively metabolized and excretion of unchanged drug in urine is a minor route of elimination. In volunteers with mild to moderate (CLcr=30–60 mL/min), moderate to severe (CLcr=10–29 mL/min) or severe (receiving hemodialysis) renal impairment (N=10 each group), the pharmacokinetics and protein binding of 200 mg sertraline per day maintained for 21 days were not altered compared to age-matched volunteers (N=12) with no renal impairment. Thus sertraline multiple dose pharmacokinetics appear to be unaffected by renal impairment (see PRECAUTIONS).

Indications and Usage for Zoloft

Major Depressive Disorder
Zoloft (sertraline hydrochloride) is indicated for the treatment of major depressive disorder in adults.

The efficacy of Zoloft in the treatment of a major depressive episode was established in six to eight week controlled trials of adult outpatients whose diagnoses corresponded most closely to the DSM-III category of major depressive disorder (see Clinical Trials under CLINICAL PHARMACOLOGY).

A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation.

The antidepressant action of Zoloft in hospitalized depressed patients has not been adequately studied.

The efficacy of Zoloft in maintaining an antidepressant response for up to 44 weeks following 8 weeks of open-label acute treatment (52 weeks total) was demonstrated in a placebo-controlled trial. The usefulness of the drug in patients receiving Zoloft for extended periods should be reevaluated periodically (see Clinical Trials under CLINICAL PHARMACOLOGY).

Obsessive-Compulsive Disorder
Zoloft is indicated for the treatment of obsessions and compulsions in patients with obsessive-compulsive disorder (OCD), as defined in the DSM-III-R; i.e., the obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning.

The efficacy of Zoloft was established in 12-week trials with obsessive-compulsive outpatients having diagnoses of obsessive-compulsive disorder as defined according to DSM-III or DSM-III-R criteria (see Clinical Trials under CLINICAL PHARMACOLOGY).

Obsessive-compulsive disorder is characterized by recurrent and persistent ideas, thoughts, impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable.

The efficacy of Zoloft in maintaining a response, in patients with OCD who responded during a 52-week treatment phase while taking Zoloft and were then observed for relapse during a period of up to 28 weeks, was demonstrated in a placebo-controlled trial (see Clinical Trials under CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to use Zoloft for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

Panic Disorder
Zoloft is indicated for the treatment of panic disorder in adults, with or without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks.

The efficacy of Zoloft was established in three 10–12 week trials in adult panic disorder patients whose diagnoses corresponded to the DSM-III-R category of panic disorder (see Clinical Trials under CLINICAL PHARMACOLOGY).

Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.

The efficacy of Zoloft in maintaining a response, in adult patients with panic disorder who responded during a 52-week treatment phase while taking Zoloft and were then observed for relapse during a period of up to 28 weeks, was demonstrated in a placebo-controlled trial (see Clinical Trials under CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to use Zoloft for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

Posttraumatic Stress Disorder (PTSD)
Zoloft (sertraline hydrochloride) is indicated for the treatment of posttraumatic stress disorder in adults.

The efficacy of Zoloft in the treatment of PTSD was established in two 12-week placebo-controlled trials of adult outpatients whose diagnosis met criteria for the DSM-III-R category of PTSD (see Clinical Trials under CLINICAL PHARMACOLOGY).

PTSD, as defined by DSM-III-R/IV, requires exposure to a traumatic event that involved actual or threatened death or serious injury, or threat to the physical integrity of self or others, and a response which involves intense fear, helplessness, or horror. Symptoms that occur as a result of exposure to the traumatic event include reexperiencing of the event in the form of intrusive thoughts, flashbacks or dreams, and intense psychological distress and physiological reactivity on exposure to cues to the event; avoidance of situations reminiscent of the traumatic event, inability to recall details of the event, and/or numbing of general responsiveness manifested as diminished interest in significant activities, estrangement from others, restricted range of affect, or sense of foreshortened future; and symptoms of autonomic arousal including hypervigilance, exaggerated startle response, sleep disturbance, impaired concentration, and irritability or outbursts of anger. A PTSD diagnosis requires that the symptoms are present for at least a month and that they cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

The efficacy of Zoloft in maintaining a response in adult patients with PTSD for up to 28 weeks following 24 weeks of open-label treatment was demonstrated in a placebo-controlled trial. Nevertheless, the physician who elects to use Zoloft for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

Premenstrual Dysphoric Disorder (PMDD)
Zoloft is indicated for the treatment of premenstrual dysphoric disorder (PMDD) in adults.

The efficacy of Zoloft in the treatment of PMDD was established in 2 placebo-controlled trials of female adult outpatients treated for 3 menstrual cycles who met criteria for the DSM-III-R/IV category of PMDD (see Clinical Trials under CLINICAL PHARMACOLOGY).

The essential features of PMDD include markedly depressed mood, anxiety or tension, affective lability, and persistent anger or irritability. Other features include decreased interest in activities, difficulty concentrating, lack of energy, change in appetite or sleep, and feeling out of control. Physical symptoms associated with PMDD include breast tenderness, headache, joint and muscle pain, bloating and weight gain. These symptoms occur regularly during the luteal phase and remit within a few days following onset of menses; the disturbance markedly interferes with work or school or with usual social activities and relationships with others. In making the diagnosis, care should be taken to rule out other cyclical mood disorders that may be exacerbated by treatment with an antidepressant.

The effectiveness of Zoloft in long-term use, that is, for more than 3 menstrual cycles, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use Zoloft for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

Social Anxiety Disorder
Zoloft (sertraline hydrochloride) is indicated for the treatment of social anxiety disorder, also known as social phobia in adults.

The efficacy of Zoloft in the treatment of social anxiety disorder was established in two placebo-controlled trials of adult outpatients with a diagnosis of social anxiety disorder as defined by DSM-IV criteria (see Clinical Trials under CLINICAL PHARMACOLOGY).

Social anxiety disorder, as defined by DSM-IV, is characterized by marked and persistent fear of social or performance situations involving exposure to unfamiliar people or possible scrutiny by others and by fears of acting in a humiliating or embarrassing way. Exposure to the feared social situation almost always provokes anxiety and feared social or performance situations are avoided or else are endured with intense anxiety or distress. In addition, patients recognize that the fear is excessive or unreasonable and the avoidance and anticipatory anxiety of the feared situation is associated with functional impairment or marked distress.

The efficacy of Zoloft in maintaining a response in adult patients with social anxiety disorder for up to 24 weeks following 20 weeks of Zoloft treatment was demonstrated in a placebo-controlled trial. Physicians who prescribe Zoloft for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see Clinical Trials under CLINICAL PHARMACOLOGY).

Contraindications

All Dosage Forms of Zoloft
Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated (see WARNINGS). Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS).

Zoloft is contraindicated in patients with a hypersensitivity to sertraline or any of the inactive ingredients in Zoloft.

Oral Concentrate
Zoloft oral concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol content of the concentrate.

Warnings

Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18–24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION—Discontinuation of Treatment with Zoloft, for a description of the risks of discontinuation of Zoloft).

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Zoloft should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Screening Patients for Bipolar Disorder
A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Zoloft is not approved for use in treating bipolar depression.

Cases of serious sometimes fatal reactions have been reported in patients receiving Zoloft (sertraline hydrochloride), a selective serotonin reuptake inhibitor (SSRI), in combination with a monoamine oxidase inhibitor (MAOI). Symptoms of a drug interaction between an SSRI and an MAOI include: hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes that include confusion, irritability, and extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued an SSRI and have been started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore, Zoloft should not be used in combination with an MAOI, or within 14 days of discontinuing treatment with an MAOI. Similarly, at least 14 days should be allowed after stopping Zoloft before starting an MAOI.

The concomitant use of Zoloft with MAOIs intended to treat depression is contraindicated (see CONTRAINDICATIONS and WARNINGS – Potential for Interaction with Monoamine Oxidase Inhibitors).

Serotonin Syndrome
The development of a potentially life-threatening serotonin syndrome may occur in treatment with SNRIs and SSRIs, including Zoloft, particularly with concomitant use of serotonergic drugs (including triptans) and with drugs which impair metabolism of serotonin (including MAOIs). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

If concomitant treatment of SNRIs and SSRIs, including Zoloft, with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see PRECAUTIONS – Drug Interactions).

The concomitant use of SNRIs and SSRIs, including Zoloft, with serotonin precursors (such as tryptophan) is not recommended (see PRECAUTIONS – Drug Interactions).

More detailed information on Zoloft

ZOLOFT (sertraline hydrochloride)

Zoloft is also used to treat the following:

• Premenstrual dysphoric disorder (PMDD), a condition marked by a depressed mood, anxiety or tension, emotional instability, and anger or irritability in the two weeks preceding menstruation.
• Obsessive-compulsive disorder (unwanted thoughts that won't go away and an irresistible urge to keep repeating certain actions, such as hand-washing or counting).
• Panic disorder (unexpected attacks of overwhelming anxiety, accompanied by fear of their return).
• Social anxiety disorder (extreme shyness in social situations that interferes with an individual's work and social life).
• Post-traumatic stress disorder (re-experiencing a dangerous or life-threatening event through intrusive thoughts, flashbacks, and intense psychological distress).

Zoloft belongs to a class of drugs called selective serotonin re-uptake inhibitors (SSRIs). Serotonin is one of the chemical messengers believed to govern moods. Ordinarily, it is quickly reabsorbed after its release at the junctures between nerves. Re-uptake inhibitors such as Zoloft slow this process, thereby boosting the levels of serotonin available in the brain.

Most important fact about Zoloft
Do not take Zoloft within 2 weeks of taking any drug classified as an MAO inhibitor. Drugs in this category include the antidepressants Marplan, Nardil, and Parnate. When serotonin boosters such as Zoloft are combined with MAO inhibitors, serious and sometimes fatal reactions can occur. In addition, you should not combine Zoloft with the drug pimozide (Orap).

How should you take Zoloft?
Take Zoloft exactly as prescribed: once a day, in either the morning or the evening.
Zoloft is available in capsule and oral concentrate forms. To prepare Zoloft oral concentrate, use the dropper provided. Measure out the amount of concentrate prescribed by your doctor and mix it with 4 ounces of water, ginger ale, lemon/lime soda, lemonade, or orange juice. (Do not mix the concentrate with any other type of beverage.) Drink the mixture immediately; do not prepare it in advance for later use. At times, a slight haze may appear after mixing, but this is normal.
Improvement with Zoloft may not be seen for several days to a few weeks. You should expect to keep taking it for at least several months.
Zoloft may make your mouth dry. For temporary relief suck a hard candy, chew gum, or melt bits of ice in your mouth.

If you miss a dose...
Take the forgotten dose as soon as you remember. If several hours have passed, skip the dose. Never try to "catch up" by doubling the dose.

Storage instructions...
Store at room temperature.

What side effects may occur?
Side effects cannot be anticipated. If any develop or change in intensity, inform your doctor as soon as possible. Only your doctor can determine if it is safe for you to continue taking Zoloft.

More common side effects may include:
Abdominal pain, agitation, anxiety, constipation, decreased sex drive, diarrhea or loose stools, difficulty with ejaculation, dizziness, dry mouth, fatigue, gas, headache, decreased appetite, increased sweating, indigestion, insomnia, nausea, nervousness, pain, rash, sleepiness, sore throat, tingling or pins and needles, tremor, vision problems, vomiting

Many people lose a pound or two of body weight while taking Zoloft. This usually poses no problem but may be a concern if your depression has already caused you to lose a great deal of weight.

In a few people, Zoloft may trigger the grandiose, inappropriate, out-of-control behavior called mania or the similar, but less dramatic, "hyper" state called hypomania.

Why should Zoloft not be prescribed?
Do not use Zoloft while taking an MAO inhibitor or the drug pimozide (Orap) (see "Most important fact about Zoloft"). Avoid Zoloft if it causes an allergic-type reaction.

Special warnings about Zoloft
In clinical studies, antidepressants increased the risk of suicidal thinking and behavior in children and adolescents with depression and other psychiatric disorders. Anyone considering the use of Zoloft or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Zoloft is only approved for treating obsessive-compulsive disorder in children 6 years and older.
Additionally, the progression of major depression is associated with a worsening of symptoms and/or the emergence of suicidal thinking or behavior in both adults and children, whether or not they are taking antidepressants. Individuals being treated with Zoloft and their caregivers should watch for any change in symptoms or any new symptoms that appear suddenly--especially agitation, anxiety, hostility, panic, restlessness, extreme hyperactivity, and suicidal thinking or behavior--and report them to the doctor immediately. Be especially observant at the beginning of treatment or whenever there is a change in dose.
Use Zoloft cautiously and under close medical supervision if you have a history of kidney or liver disorders, heart disease, seizures, or bleeding problems. Your doctor may limit your dosage if you have one of these conditions.
Zoloft could cause weight loss in children. The manufacturer recommends regular monitoring of weight and growth during long-term treatment in children.
SSRI antidepressants could potentially cause stomach bleeding, especially when combined with nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve), and ketoprofen (Orudis KT). Consult your doctor before combining Zoloft with NSAIDs or blood-thinning medications.
Like all antidepressants, Zoloft could trigger a manic episode. Let the doctor know if you've ever had this problem.
Zoloft has not been found to impair the ability to drive or operate machinery. Nevertheless, the manufacturer recommends caution until you know how the drug affects you.
If you are sensitive to latex, use caution when handling the dropper provided with the oral concentrate.

Possible food and drug interactions when taking Zoloft
Remember that Zoloft must never be combined with pimozide (Orap) or an MAO inhibitor (see "Most important fact about Zoloft").
You should not drink alcoholic beverages while taking Zoloft. Use over-the-counter remedies with caution. Although none is known to interact with Zoloft, interactions remain a possibility.
If Zoloft is taken with certain other drugs, the effects of either could be increased, decreased, or altered. It is especially important to check with your doctor before combining Zoloft with the following:

Antidepressants that boost serotonin such as Paxil and Prozac
Other antidepressants, including tricyclics such as Elavil and Pamelor
Cimetidine (Tagamet)
Diazepam (Valium)
Digitoxin (Crystodigin)
Flecainide (Tambocor)
Lithium (Eskalith, Lithobid)
Over-the-counter drugs such as cold remedies
Propafenone (Rythmol)
Sumatriptan (Imitrex)
Tolbutamide (Orinase)
Warfarin (Coumadin)

If you are using the oral concentrate form of Zoloft, do not take disulfiram (Antabuse)

Special information if you are pregnant or breastfeeding
The effects of Zoloft during pregnancy have not been adequately studied. If you are pregnant or plan to become pregnant, inform your doctor immediately. Zoloft should be taken during pregnancy only if it is clearly needed. It is not known whether Zoloft appears in breast milk. Caution is advised when using Zoloft during breastfeeding.

Recommended dosage

ADULTS
Depression or Obsessive Compulsive Disorder

The usual starting dose is 50 milligrams once a day, taken either in the morning or in the evening. The doctor may increase your dose depending upon your response. The maximum dose is 200 milligrams in a day.

Premenstrual Dysphoric Disorder
Doses may be prescribed throughout the menstrual cycle or limited to the 2 weeks preceding menstruation. The starting dose is 50 milligrams a day. If this proves insufficient, the doctor will increase the dose in 50-milligram steps at the start of each new menstrual cycle up to a maximum of 100 milligrams per day in the 2-week regimen or 150 milligrams per day in the full-cycle regimen. (During the first 3 days of the 2-week regimen, doses are always limited to 50 milligrams.)

Panic Disorder, Post-traumatic Stress Disorder, and Social Anxiety Disorder
During the first week, the usual dose is 25 milligrams once a day. After that, the dose increases to 50 milligrams once a day. Depending on your response, you're the doctor may continue to increase your dose up to a maximum of 200 milligrams a day.

CHILDREN 6 TO 17 YEARS OLD

Obsessive-Compulsive Disorder
The starting dose for children aged 6 to 12 is 25 milligrams and for adolescents aged 13 to 17, 50 milligrams. The doctor will adjust the dose as necessary.

Safety and effectiveness have not been established for children under 6.

DOSAGE ADJUSTMENT
The doctor will need to reduce the dosage if you have liver disease.

Overdosage: Any medication taken in excess can have serious consequences. An overdose of Zoloft can be fatal. If you suspect an overdose, seek medical attention immediately.

• Common symptoms of Zoloft overdose include:
  Agitation, dizziness, nausea, rapid heartbeat, sleepiness, tremor, vomiting

Other possible symptoms include coma, stupor, fainting, convulsions, delirium, hallucinations, mania, high or low blood pressure, and slow, rapid, or irregular heartbeat