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sertraline hcl 100 mg tablet (generic zoloft)

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Uses

Major Depressive Disorder

Sertraline is used in the treatment of major depressive disorder. 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). According to DSM-IV criteria, a major depressive episode includes at least 5 of the following 9 symptoms (with at least one of the symptoms being either depressed mood or loss of interest or pleasure): depressed mood most of the day as indicated by subjective report (e.g., feels sad or empty) or observation made by others; markedly diminished interest or pleasure in all, or almost all, activities most of the day; significant weight loss (when not dieting) or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite; insomnia or hypersomnia; psychomotor agitation or retardation (observable by others, not merely subjective feelings of restlessness or being slowed down); fatigue or loss of energy; feelings of worthlessness or excessive or inappropriate guilt (not merely self-reproach or guilt about being sick); diminished ability to think or concentrate or indecisiveness (either by subjective account or as observed by others); and recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide attempt or specific plan for committing suicide.

Treatment of major depressive disorder generally consists of an acute phase (to induce remission), a continuation phase (to preserve remission), and a maintenance phase (to prevent recurrence). Various interventions (e.g., psychotherapy, antidepressant drug therapy, electroconvulsive therapy [ECT]) are used alone or in combination to treat major depressive episodes. Treatment should be individualized and the most appropriate strategy for a particular patient is determined by clinical factors such as severity of depression (e.g., mild, moderate, severe), presence or absence of certain psychiatric features (e.g., suicide risk, catatonia, psychotic or atypical features, alcohol or substance abuse or dependence, panic or other anxiety disorder, cognitive dysfunction, dysthymia, personality disorder, seasonal affective disorder), and concurrent illness (e.g., asthma, cardiac disease, dementia, seizure disorder, glaucoma, hypertension). Demographic and psychosocial factors as well as patient preference also are used to determine the most effective treatment strategy.

While use of psychotherapy alone may be considered as an initial treatment strategy for patients with mild to moderate major depressive disorder (based on patient preference and presence of clinical features such as psychosocial stressors), combined use of antidepressant drug therapy and psychotherapy may be useful for initial treatment of patients with moderate to severe major depressive disorder with psychosocial issues, interpersonal problems, or a comorbid axis II disorder. In addition, combined use of antidepressant drug therapy and psychotherapy may be beneficial in patients who have a history of poor compliance or only partial response to adequate trials of either antidepressant drug therapy or psychotherapy alone.

Antidepressant drug therapy can be used alone for initial treatment of patients with mild major depressive disorder (if preferred by the patient) and usually is indicated alone or in combination with psychotherapy for initial treatment of patients with moderate to severe major depressive disorder (unless ECT is planned). ECT is not generally used for initial treatment of uncomplicated major depression, but is recommended as first-line treatment for severe major depressive disorder when it is coupled with psychotic features, catatonic stupor, severe suicidality, food refusal leading to nutritional compromise, or other situations when a rapid antidepressant response is required. ECT also is recommended for patients who have previously shown a positive response or a preference for this treatment modality and can be considered for patients with moderate or severe depression who have not responded to or cannot receive antidepressant drug therapy. In certain situations involving depressed patients unresponsive to adequate trials of several individual antidepressant agents, adjunctive therapy with another agent (e.g., buspirone, lithium) or concomitant use of a second antidepressant agent (e.g., bupropion) has been used; however, such combination therapy is associated with an increased risk of adverse reactions, may require dosage adjustments, and (if not contraindicated) should be undertaken only after careful consideration of the relative risks and benefits.(See Drug Interactions: Serotonergic Drugs, Drug Interactions: Tricyclic and Other Antidepressants, and Drug Interactions: Lithium.)

The efficacy of sertraline for the acute treatment of major depression has been established by 2 placebo-controlled studies in adult outpatients who met DSM-III criteria for major depression. In the first study of 8 weeks' duration, sertraline was administered with flexible dosing in a range of 50-200 mg daily; the mean daily dosage for patients completing the study was 145 mg daily. In the second study of 6 weeks' duration, sertraline was administered in fixed doses of 50, 100, and 200 mg daily. Overall, these 2 studies demonstrated that sertraline was superior to placebo in improving scores on the Hamilton Depression Rating Scale and the Clinical Global Impression Severity and Improvement Scales. However, the second study was not readily interpretable regarding whether there was a dose-response relationship for the drug's efficacy.

In a third study, depressed outpatients who had responded by the end of an initial 8-week open treatment phase to sertraline 50-200 mg daily were randomized to continue sertraline in the same dosage range or placebo for 44 weeks in a double-blind manner. The mean daily dosage of sertraline in those who completed this long-term study was 70 mg daily, and the relapse rate in the sertraline-treated patients was substantially lower than in those who received placebo.

An analysis of these 3 controlled studies for possible gender-related effects on treatment outcome did not suggest any difference in efficacy based on the gender of the patient.

While the optimum duration of sertraline therapy has not been established, many experts state that acute depressive episodes require several months or longer of sustained antidepressant therapy. In addition, some clinicians recommend that long-term antidepressant therapy be considered in certain patients at risk for recurrence of depressive episodes (such as those with highly recurrent unipolar depression). The efficacy of sertraline in maintaining an antidepressant response for up to 1 year without increased toxicity has been demonstrated in a controlled setting. The manufacturers state that the usefulness of the drug in patients receiving prolonged therapy should be reevaluated periodically.(See Dosage and Administration: Dosage.)

The manufacturers state that the drug's antidepressant efficacy in hospital settings has not been adequately studied to date.

As with certain other antidepressants, the possibility that sertraline may precipitate hypomanic or manic attacks in patients with bipolar or other major affective disorder should be considered. Sertraline is not approved for use in treating bipolar depression in adults.

Considerations in Choosing an Antidepressant

A variety of antidepressant drugs is available for the treatment of major depressive disorder, including selective serotonin-reuptake inhibitors (SSRIs; e.g., citalopram, escitalopram, fluoxetine, paroxetine, sertraline), selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs; e.g., desvenlafaxine, duloxetine, venlafaxine), tricyclic antidepressants (e.g., amitriptyline, amoxapine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine), monoamine oxidase (MAO) inhibitors (e.g., phenelzine, tranylcypromine), and other antidepressants (e.g., bupropion, maprotiline, nefazodone, trazodone, vilazodone). Most clinical studies have shown that the antidepressant effect of usual dosages of sertraline in patients with depression is greater than that of placebo and comparable to that of usual dosages of tricyclic antidepressants (e.g., amitriptyline), other SSRIs (e.g., fluoxetine), and other antidepressants (e.g., nefazodone). In geriatric patients with major depression, sertraline appears to be as effective as amitriptyline. The onset of action of sertraline appears to be comparable to that of tricyclic antidepressants.

In general, response rates in patients with major depression are similar for currently available antidepressants, and the choice of antidepressant agent for a given patient depends principally on other factors such as potential adverse effects, safety or tolerability of these adverse effects in the individual patient, psychiatric and medical history, patient or family history of response to specific therapies, patient preference, quantity and quality of available clinical data, cost, and relative acute overdose safety. No single antidepressant can be recommended as optimal for all patients because of substantial heterogeneity in individual responses and in the nature, likelihood, and severity of adverse effects. In addition, patients vary in the degree to which certain adverse effects and other inconveniences of drug therapy (e.g., cost, dietary restrictions) affect their preferences.

In the large-scale Sequenced Treatment Alternatives to Relieve Depression (STAR*D) effectiveness trial, patients with major depressive disorder who did not respond to or could not tolerate therapy with one SSRI (citalopram) were randomized to switch to extended-release (''sustained-release'') bupropion, sertraline, or extended-release venlafaxine as a second step of treatment (level 2). Remission rates as assessed by the 17-item Hamilton Rating Scale for Depression (HRSD-17) and the Quick Inventory of Depressive Symptomatology--Self Report (QIDS-SR-16) were approximately 21 and 26% for extended-release bupropion, 18 and 27% for sertraline, and 25 and 25% for extended-release venlafaxine therapy, respectively; response rates as assessed by the QIDS-SR-16 were 26, 27, and 28% for extended-release bupropion, sertraline, and extended-release venlafaxine therapy, respectively. These results suggest that after unsuccessful initial treatment of depressed patients with an SSRI, approximately 25% of patients will achieve remission after therapy is switched to another antidepressant and that either another SSRI (e.g., sertraline) or an agent from another class (e.g., bupropion, venlafaxine) may be reasonable alternative antidepressants in patients not responding to initial SSRI therapy.

Patient Tolerance Considerations

Because of differences in the adverse effect profile between SSRIs and tricyclic antidepressants, particularly less frequent anticholinergic effects, cardiovascular effects, and weight gain with SSRIs, these drugs may be preferred in patients in whom such effects are not tolerated or are of potential concern. The decreased incidence of anticholinergic effects associated with sertraline and other SSRIs compared with tricyclic antidepressants is a potential advantage, since such effects may result in discontinuance of the drug early during therapy in unusually sensitive patients. In addition, some anticholinergic effects may become troublesome during long-term tricyclic antidepressant therapy (e.g., persistent dry mouth may result in tooth decay). Although SSRIs share the same overall tolerability profile, certain patients may tolerate one drug in this class better than another. In an open study, most patients who had discontinued fluoxetine therapy because of adverse effects subsequently tolerated sertraline therapy. Antidepressants other than SSRIs may be preferred in patients in whom certain adverse GI effects (e.g., nausea, anorexia), nervous system effects (e.g., anxiety, nervousness, insomnia), and/or weight loss are not tolerated or are of concern, since such effects appear to occur more frequently with this class of drugs.

Pediatric Considerations

The clinical presentation of depression in children and adolescents can differ from that in adults and generally varies with the age and developmental stages of the child. Younger children may exhibit behavioral problems such as social withdrawal, aggressive behavior, apathy, sleep disruption, and weight loss; adolescents may present with somatic complaints, self esteem problems, rebelliousness, poor performance in school, or a pattern of engaging in risky or aggressive behavior.

Only limited data are available to date from controlled clinical studies evaluating various antidepressant agents in children and adolescents, and many of these studies have methodologic limitations (e.g., nonrandomized or uncontrolled, small sample size, short duration, nonspecific inclusion criteria). However, there is some evidence that the response to antidepressants in pediatric patients may differ from that seen in adults, and caution should be used in extrapolating data from adult studies when making treatment decisions for pediatric patients. Results of several studies evaluating tricyclic antidepressants (e.g., amitriptyline, desipramine, imipramine, nortriptyline) in preadolescent and adolescent patients with major depression indicate a lack of overall efficacy in this age group. Based on the lack of efficacy data regarding use of tricyclic antidepressants and MAO inhibitors in pediatric patients and because of the potential for life-threatening adverse effects associated with the use of these drugs, many experts consider selective serotonin-reuptake inhibitors, including sertraline, the drugs of choice when antidepressant therapy is indicated for the treatment of major depressive disorder in children and adolescents. However, the US Food and Drug Administration (FDA) states that, while efficacy of fluoxetine has been established in pediatric patients, efficacy of other newer antidepressants (i.e., sertraline, citalopram, desvenlafaxine, duloxetine, escitalopram, fluvoxamine, mirtazapine, nefazodone, paroxetine, venlafaxine) was not conclusively established in clinical trials in pediatric patients with major depressive disorder. In addition, FDA now warns that antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder and other psychiatric disorders.(See Cautions: Pediatric Precautions.) FDA currently states that anyone considering using an antidepressant in a child or adolescent for any clinical use must balance the potential risk of therapy with the clinical need.(See Cautions: Precautions and Contraindications.)

Geriatric Considerations

The response to antidepressants in depressed geriatric patients without dementia is similar to that reported in younger adults, but depression in geriatric patients often is not recognized and is not treated. In geriatric patients with major depressive disorder, selective serotonin-reuptake inhibitors (SSRIs) appear to be as effective as tricyclic antidepressants (e.g., amitriptyline) but generally are associated with fewer overall adverse effects than these other agents. Geriatric patients appear to be especially sensitive to anticholinergic (e.g., dry mouth, constipation, vision disturbance), cardiovascular, orthostatic hypotensive, and sedative effects of tricyclic antidepressants. The low incidence of anticholinergic effects associated with sertraline and other SSRIs compared with tricyclic antidepressants also is a potential advantage in geriatric patients, since such effects (e.g., constipation, dry mouth, confusion, memory impairment) may be particularly troublesome in these patients. However, SSRI therapy may be associated with other troublesome adverse effects (e.g., nausea and vomiting, agitation and akathisia, parkinsonian adverse effects, sexual dysfunction, weight loss, hyponatremia). Some clinicians state that SSRIs such as sertraline may be preferred for treating depression in geriatric patients in whom the orthostatic hypotension associated with many antidepressants (e.g., tricyclics) potentially may result in injuries (such as severe falls). However, despite the fewer cardiovascular and anticholinergic effects associated with SSRIs, these drugs did not show any advantage over tricyclic antidepressants with regard to hip fracture in a case-control study. In addition, there was little difference in the rates of falls between nursing home residents receiving SSRIs and those receiving tricyclic antidepressants in a retrospective study. Therefore, all geriatric individuals receiving either type of antidepressant should be considered at increased risk of falls and appropriate measures should be taken. In addition, clinicians prescribing SSRIs in geriatric patients should be aware of the many possible drug interactions associated with these drugs, including those involving metabolism of the drugs through the cytochrome P-450 system.(See Drug Interactions.)

Patients with dementia of the Alzheimer's type (Alzheimer's disease, presenile or senile dementia) often present with depressive symptoms, such as depressed mood, appetite loss, insomnia, fatigue, irritability, and agitation. Most experts recommend that patients with dementia of the Alzheimer's type who present with clinically important and persistent depressive symptoms be considered as candidates for pharmacotherapy even if they fail to meet the criteria for a major depressive syndrome. The goals of such therapy are to improve mood, functional status (e.g., cognition), and quality of life. Treatment of depression also may reduce other neuropsychiatric symptoms associated with depression in patients with dementia, including aggression, anxiety, apathy, and psychosis. Although patients may present with depressed mood alone, the possibility of more extensive depressive symptomatology should be considered. Therefore, patients should be evaluated and monitored carefully for indices of major depression, suicidal ideation, and neurovegetative signs since safety measures (e.g., hospitalization for suicidality) and more vigorous and aggressive therapy (e.g., relatively high dosages, multiple drug trials) may be needed in some patients.

Although placebo-controlled trials of antidepressants in depressed patients with concurrent dementia have shown mixed results, the available evidence and experience with the use of antidepressants in patients with dementia of the Alzheimer's type and associated depressive manifestations indicate that depressive symptoms (including depressed mood alone and with neurovegetative changes) in such patients are responsive to antidepressant therapy. In some patients, cognitive deficits may partially or fully resolve during antidepressant therapy, but the extent of response will be limited to the degree of cognitive impairment that is directly related to depression. SSRIs such as sertraline, citalopram, escitalopram, fluoxetine, or paroxetine are generally considered as first-line agents in the treatment of depressed patients with dementia since they are better tolerated than some other antidepressants (e.g., tricyclic antidepressants, monoamine oxidase inhibitors). Some possible alternative agents to SSRIs include bupropion, mirtazapine, and venlafaxine. Some geriatric patients with dementia and depression may be unable to tolerate the antidepressant dosages needed to achieve full remission. When a rapid antidepressant response is not critical, some experts therefore recommend a very gradual dosage increase to increase the likelihood that a therapeutic dosage of the SSRI or other antidepressant will be reached and tolerated. In a randomized, placebo-controlled study in a limited number of patients with major depression and Alzheimer's disease, sertraline was found to be superior to placebo; depression reduction in this study was accompanied by lessened behavior disturbance and improved activities of daily living but not improved cognition.

Cardiovascular Considerations

The relatively low incidence of adverse cardiovascular effects, including orthostatic hypotension and conduction disturbances, associated with sertraline and most other SSRIs may be advantageous in patients in whom the cardiovascular effects associated with tricyclic antidepressants may be hazardous. Patients with a recent history of myocardial infarction or unstable cardiovascular disease were excluded from premarketing clinical studies with sertraline. However, the cardiovascular safety of sertraline (50-200 mg daily for 24 weeks; mean dosage of 89 mg daily) was evaluated in a postmarketing, double-blind, placebo-controlled study in adult outpatients with major depressive disorder and a recent history of myocardial infarction or unstable angina pectoris requiring hospitalization but who were otherwise free of life-threatening medical conditions. When therapy was initiated during the acute phase of recovery (within 30 days after a myocardial infarction or hospitalization for unstable angina), sertraline therapy did not differ from placebo on the following cardiovascular end points at week 16: left ventricular ejection fraction and total cardiovascular events (angina, chest pain, edema, palpitations, syncope, postural dizziness, chronic heart failure, myocardial infarction, tachycardia, bradycardia, blood pressure changes). Although not statistically significant, approximately 20% fewer major cardiovascular events involving death or requiring hospitalization (e.g., for myocardial infarction, chronic heart failure, stroke, angina) occurred in the sertraline-treated patients compared with those receiving placebo.(See Cautions: Cardiovascular Effects and also see Cautions: Precautions and Contraindications.)

Sedative Considerations

Because sertraline and other SSRIs are generally less sedating than some other antidepressants (e.g., tricyclics), some clinicians state that these drugs may be preferable in patients who do not require the sedative effects associated with many antidepressant agents; however, an antidepressant with more prominent sedative effects (e.g., trazodone) may be preferable in certain patients (e.g., those with insomnia).

Suicidal Risk Considerations

Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. However, there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidal thinking and behavior (suicidality) in certain patients during the early phases of treatment. FDA states that antidepressants increased the risk of suicidality in short-term studies in children, adolescents, and young adults (18-24 years of age) with major depressive disorder and other psychiatric disorders.(See Cautions: Pediatric Precautions.) An increased suicidality risk was not demonstrated with antidepressants compared with placebo in adults older than 24 years of age and a reduced risk was observed in adults 65 years of age or older. It currently is unknown whether the suicidality risk extends to longer-term antidepressant use (i.e., beyond several months); however, there is substantial evidence from placebo-controlled maintenance trials in adults with major depressive disorder that antidepressants can delay the recurrence of depression. Because the risk of suicidality in depressed patients may persist until substantial remission of depression occurs, appropriate monitoring and close observation of all patients who are receiving antidepressant therapy is recommended.(See Cautions: Precautions and Contraindications.)

Other Considerations

Sertraline has been effective in patients with moderate to severe depression.

In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) level 2 trial, patients with major depressive disorder who did not respond to or could not tolerate therapy with citalopram (another SSRI) were randomized to receive either extended-release (''sustained-release'') bupropion or buspirone therapy in addition to citalopram. Although both extended-release bupropion and buspirone were found to produce similar remission rates, extended-release bupropion produced a greater reduction in the number and severity of symptoms and a lower rate of drug discontinuance than buspirone in this large-scale, effectiveness trial. These results suggest that augmentation of SSRI therapy with extended-release bupropion may be useful in some patients with refractory depression.

Sertraline has been effective in patients with depression and concurrent human immunodeficiency virus (HIV) infection and depression with anxiety.

In a double-blind, placebo-controlled study, both sertraline and imipramine were found to be more effective than placebo in reducing the depressive symptoms and improving psychosocial functioning in patients with dysthymia without concurrent major depression; moreover, fewer patients treated with sertraline than those treated with imipramine or placebo discontinued therapy because of adverse effects. The results of several other studies, both controlled and uncontrolled, also suggest that sertraline may be effective in patients with dysthymia. Because dysthymia is a chronic condition and requires prolonged antidepressant therapy, the good tolerability demonstrated in clinical studies to date may be advantageous. Sertraline also has been used in the treatment of anger attacks associated with atypical depression and dysthymia in a limited number of patients.

Obsessive-Compulsive Disorder

Sertraline is used in the treatment of obsessive-compulsive disorder when the obsessions or compulsions cause marked distress, are time consuming (take longer than 1 hour daily), or interfere substantially with the patient's normal routine, occupational or academic functioning, or usual social activities or relationships. Obsessions are recurrent and persistent ideas, thoughts, impulses, or images that, at some time during the disturbance, are experienced as intrusive and inappropriate (i.e., ''ego dystonic'') and that cause marked anxiety or distress but that are not simply excessive worries about real-life problems. Compulsions are repetitive, intentional behaviors (e.g., hand washing, ordering, checking) or mental acts (e.g., praying, counting, repeating words silently) performed in response to an obsession or according to rules that must be applied rigidly (e.g., in a stereotyped fashion). Although the behaviors or acts are aimed at preventing or reducing distress or preventing some dreaded event or situation, they either are not connected in a realistic manner with what they are designed to neutralize or prevent or are clearly excessive. At some time during the course of the disturbance, the patient, if an adult, recognizes that the obsessions or compulsions are excessive or unreasonable; children may not make such a recognition.

The efficacy of sertraline for the management of obsessive-compulsive disorder has been established in several multicenter, placebo-controlled studies, including one study of 8 weeks' duration and 2 studies of 12 weeks' duration in adults and one study of 12 weeks' duration in children and adolescents 6-17 years of age. Patients in these studies had moderate to severe obsessive-compulsive disorder with mean baseline total scores on the Yale-Brown Obsessive-Compulsive Scale (YBOCS) of 23-25 in adults and 22 in children and adolescents (measured in the Children's Yale-Brown Obsessive-Compulsive Scale [CY-BOCS]). In the 8-week study with flexible dosing, adult patients received sertraline in dosages ranging from 50-200 mg daily; the mean dosage for those completing the study was 186 mg daily. Total scores on the YBOCS decreased by an average of approximately 4 points in sertraline-treated patients and 2 points in patients receiving placebo; this difference was statistically significant.

In a fixed-dose study of 12 weeks' duration involving sertraline dosages of 50, 100, and 200 mg daily, adult patients receiving 50 and 200 mg of the drug daily experienced substantially greater reductions in the YBOCS total score than those receiving placebo (approximately 6 to approximately 3 points, respectively). In a 12-week study with flexible dosing in the range of 50-200 mg daily, the mean sertraline dosage in adult patients completing the study was 185 mg daily. YBOCS total scores in the sertraline-treated patients were reduced by a mean of approximately 7 points, which was better than the mean reduction of approximately 4 points reported in the placebo-treated patients.

In a 12-week study with flexible dosing, sertraline therapy was initiated at dosages of 25 or 50 mg daily in children 6-12 years of age or adolescents 13-17 years of age, respectively. Subsequent dosage was titrated according to individual tolerance over the first 4 weeks to a maximum dosage of 200 mg daily; the mean dosage for those completing the study was 178 mg daily. The drug produced substantially greater reductions in scores in the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS), the National Institute of Mental Health Global Obsessive-Compulsive Scale (NIMH-OC), and the Clinical Global Impressions (CGI) Improvement Scale; total scores on the CY-BOCS decreased by an average of approximately 7 units in sertraline-treated patients and 3 units in patients receiving placebo. An analysis of these controlled studies for possible age- and gender-related effects on treatment outcome did not suggest any difference in efficacy based on either the age or gender of the patient.

In addition, in an uncontrolled 6-week study with flexible dosing (50-200 mg daily) in children or adolescents 6-17 years of age with obsessive-compulsive disorder or major depression, those with a diagnosis of obsessive-compulsive disorder had mean baseline total scores on the CY-BOCS, NIMH-OC, and CGI of about 24.9, 10.2, and 5.2, respectively. Sertraline produced substantial reductions in all 3 of the scales; total scores on CY-BOCS, NIMH-OC, and CGI decreased to 12.9, 6.7, and 3.4, respectively. In another uncontrolled, 6-week study employing a sertraline dosage that was escalated from 25 to 200 mg daily over 3 weeks, the drug combined with behavioral therapy was effective in a limited number of adolescents 13-17 years of age with obsessive-compulsive disorder refractory to other therapies; total scores on the CY-BOCS at the end of the study decreased by 11 points (from 25.4 to 14.4).

Results from comparative studies to date suggest sertraline and other selective serotonin-reuptake inhibitors (SSRIs; e.g., fluoxetine, fluvoxamine, paroxetine) are as effective or somewhat less effective than clomipramine and more effective than tricyclic antidepressants (e.g., amitriptyline, desipramine, imipramine, nortriptyline) in the management of obsessive-compulsive disorder. In a pooled analysis of separate short-term (10-13 weeks) studies comparing clomipramine, fluoxetine, fluvoxamine, or sertraline with placebo, clomipramine was calculated as being more effective (as determined by measures on the YBOC scale) than SSRIs, although all drugs were superior to placebo. Like clomipramine, SSRIs reduce but do not completely eliminate obsessions and compulsions.

Many clinicians consider an SSRI (e.g., sertraline, fluoxetine, fluvoxamine, paroxetine) or clomipramine to be the drugs of choice for the pharmacologic treatment of obsessive-compulsive disorder. The decision whether to initiate therapy with an SSRI or clomipramine often is made based on the adverse effect profile of these drugs. For example, some clinicians prefer clomipramine in patients who may not tolerate the adverse effect profile of SSRIs (nausea, headache, overstimulation, sleep disturbances) while SSRIs may be useful alternatives in patients unable to tolerate the adverse effects (anticholinergic effects, cardiovascular effects, sedation) associated with clomipramine therapy. Consideration of individual patient characteristics (age, concurrent medical conditions), pharmacokinetics of the drug, potential drug interactions, and cost of therapy may also influence clinicians when selecting between SSRIs and clomipramine as first-line therapy in patients with obsessive-compulsive disorder. Although not clearly established, it has been suggested that the mechanism of action of sertraline and other potent serotonin-reuptake inhibitors (e.g., clomipramine, fluoxetine, fluvoxamine, paroxetine) used in the management of obsessive-compulsive disorder may be related to their serotonergic activity.

Panic Disorder

Sertraline is used in the treatment of panic disorder with or without agoraphobia. 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 clinically important change in behavior related to the attacks.

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

The efficacy of sertraline for the management of panic disorder has been established by 3 double-blind, placebo-controlled studies in adult outpatients who met DSM-III-R criteria for panic disorder with or without agoraphobia. The first 2 studies were of 10 weeks' duration and used a flexible dosing schedule. Sertraline therapy was initiated in a dosage of 25 mg daily for the first week and then dosage was escalated to 50-200 mg daily depending on clinical response and tolerability. The mean sertraline dosages for completers were 131 and 144 mg daily for the first 2 studies. Overall, these 2 studies demonstrated that sertraline was superior to placebo in decreasing the frequency of panic attacks and in improving scores on the Clinical Global Impression Severity of Illness and Global Improvement Scales. The difference between sertraline and placebo in reduction in the number of full panic attacks per week compared with baseline was approximately 2 in both studies.

The third study was a fixed-dose study of 12 weeks' duration. Sertraline was given in dosages of 50, 100, and 200 mg daily. The patients receiving sertraline demonstrated a substantially greater reduction in panic attack frequency than patients receiving placebo. However, the results of this study were not readily interpretable regarding a dose-response relationship for efficacy in this condition.

An analysis of these 3 controlled studies for possible age-, race-, or gender-related effects on treatment outcome did not suggest any difference in efficacy based on these patient characteristics.

Panic disorder can be treated with cognitive and behavioral psychotherapy and/or pharmacologic therapy. There are several classes of drugs that appear to be effective in the pharmacologic management of panic disorder, including tricyclic antidepressants, MAO inhibitors (e.g., phenelzine), selective serotonin-reuptake inhibitors (SSRIs; e.g., citalopram, fluoxetine, paroxetine, sertraline), and benzodiazepines (e.g., alprazolam, clonazepam). When choosing among the available drugs, clinicians should consider their acceptance and tolerability by patients; their ability to reduce or eliminate panic attacks, reduce clinically important anxiety and disability secondary to phobic avoidance, and ameliorate other common comorbid conditions (such as depression); and their ability to prevent relapse during long-term therapy. Because of their better tolerability when compared with other agents (such as the tricyclic antidepressants and benzodiazepines), the lack of physical dependence problems commonly associated with benzodiazepines, and efficacy in panic disorder with comorbid conditions (e.g., depression, other anxiety disorders such as obsessive-compulsive disorder, alcoholism), many clinicians prefer SSRIs as first-line therapy in the management of panic disorder. If SSRI therapy is ineffective or not tolerated, use of a tricyclic antidepressant or a benzodiazepine is recommended.

Sertraline has improved chronic idiopathic urticaria associated with panic disorder in at least one patient, but further study is needed to determine whether serotonin is involved in the pathogenesis of urticaria and whether SSRIs are effective in this condition.

Posttraumatic Stress Disorder

Sertraline is used in the treatment of posttraumatic stress disorder (PTSD). PTSD is an anxiety disorder that involves the development of certain characteristic symptoms following personal exposure to an extreme traumatic stressor. According to DSM-IV, PTSD requires exposure to a traumatic event(s) that involved actual or threatened death or serious injury, or threat to the physical integrity of self or others, and the response to the event must involve intense fear, helplessness, or horror (in children the response may be expressed by disorganized or agitated behavior). PTSD is characterized by persistent symptoms of reexperiencing the trauma (e.g., intrusive distressing recollections of the event; recurrent distressing dreams of the event; acting or feeling as if the event were recurring including illusions, hallucinations, or flashbacks; intense distress at exposure to internal or external cues that symbolize or resemble an aspect of the event; physiologic reactivity on exposure to internal or external cues that symbolize or resemble an aspect of the event), persistent avoidance of stimuli associated with the trauma and numbing of general responsiveness (e.g., efforts to avoid thoughts, feelings, or conversations related to the event; efforts to avoid activities, places, or people that arouse recollections of the event; inability to recall an important aspect of the event; markedly diminished interest or participation in significant activities; feeling of detachment or estrangement from others; restricted emotions and/or range of affect not present before the event; sense of a foreshortened future), and persistent symptoms of increased arousal (e.g., difficulty sleeping; irritability/outbursts of anger; difficulty concentrating; hypervigilance; exaggerated startle response). According to DSM-IV, a PTSD diagnosis requires the presence of 1 or more symptoms of reexperiencing, 3 or more symptoms of avoidance, and 2 or more symptoms of increased arousal, all of which must be present for at least one month and cause clinically important distress or impairment in social, occupational, or other important areas of functioning. PTSD, like other anxiety disorders, rarely occurs alone, and patients with PTSD often present with comorbid disorders (e.g., major depressive disorder, substance abuse disorders, panic disorder, generalized anxiety disorders, obsessive-compulsive disorder, social phobia); it is unknown whether these comorbid disorders precede or follow the onset of PTSD.

Psychotherapy alone or in combination with pharmacotherapy generally is considered the treatment of choice for PTSD. Pharmacologic therapy may be indicated in addition to psychotherapy for initial treatment of PTSD in patients who have comorbid disorders (e.g., major depressive disorder, bipolar disorder, other anxiety disorders) and also may be indicated in those who do not respond to initial treatment with psychotherapy alone. If pharmacotherapy is indicated in patients with PTSD, selective serotonin-reuptake inhibitors (SSRIs; e.g., sertraline, fluoxetine, paroxetine) usually are considered the drugs of choice (except in patients with bipolar disorder who require treatment with mood stabilizing agents).

The efficacy of sertraline for the management of PTSD has been established in 2 placebo-controlled studies of 12 weeks' duration in adult outpatients (76% women) who met DSM-III-R criteria for chronic PTSD (duration of symptoms 3 months or longer). The mean duration of PTSD for these patients was approximately 12 years and 44% of patients had secondary depressive disorders. Sertraline therapy was initiated at a dosage of 25 mg daily for the first week and then dosage was escalated (using a flexible dosage schedule) to 50-200 mg daily based on clinical response and tolerability. The mean sertraline dosage for patients who completed studies 1 and 2 was 146 mg and 151 mg daily, respectively. Overall, these 2 studies showed that sertraline was superior to placebo in improving scores on the Clinician-Administered PTSD Scale Part 2 total severity scale (a measure of the intensity and frequency of all 3 PTSD diagnostic symptom clusters [reexperiencing/intrusion, avoidance/numbing, and hyperarousal]), Impact of Event Scale (a patient rated measurement of the intrusion and avoidance symptoms), and the Clinical Global Impressions Severity of Illness and Global Improvement Scales.

However, in 2 additional placebo-controlled studies of similar design and duration, the difference in response to treatment on key assessment scales between patients receiving sertraline and those receiving placebo was not statistically significant. In one study of mostly female patients who met the DSM-III-R criteria for PTSD related to sexual/physical trauma, those receiving placebo experienced substantially greater improvement on the Impact of Event Scale than those receiving sertraline therapy. Although this study enrolled a higher proportion of patients with comorbid anxiety disorders and a higher proportion of patients receiving placebo with a successful response to previous psychotropic therapies than the studies demonstrating efficacy of the drug, it is unknown whether these factors alone account for the high placebo response in the study.

Efficacy of sertraline for the management of PTSD related to war or combat was evaluated in a study involving primarily white men in a VA medical center outpatient setting (mean duration of PTSD approximately 18 years). At the end of this study, patients receiving sertraline did not differ from those receiving placebo on any of the key efficacy assessment scales (e.g., Clinician-Administered PTSD scale, Davidson Self-Rating Trauma scale, Impact of Event Scale). In addition, the mean change from baseline for both treatment groups in this study was of a lesser magnitude than those of patients receiving placebo in the other reported studies. The lack of response to sertraline treatment in these combat veterans is consistent with controlled studies evaluating other selective serotonin-reuptake inhibitors (e.g., fluoxetine, brofaromine [not commercially available in the US]) in Vietnam veterans with PTSD. Some experts suggest that patients with combat- or war-related PTSD may be less responsive to treatment than patients with PTSD related to other traumatic events (e.g., sexual assault, accidents, natural disasters) because of some factor inherent in combat- or war-related trauma. However, other experts suggest that the poor treatment response in studies evaluating use in veterans may be the result of sampling error since veterans receiving treatment at VA hospitals may constitute a self-selected group of patients with chronic PTSD who have multiple impairments (comorbid disorders, substance abuse) that make them less responsive to treatment.

Since PTSD is a more common disorder in women than men, the majority (76%) of patients in reported studies were women. A retrospective analysis of pooled data has shown a substantial difference between sertraline and placebo on key efficacy assessment scales (e.g., Clinician-Administered PTSD scale, Impact of Event Scale, Clinical Global Impressions Severity of Illness Scale) in women (regardless of a baseline diagnosis of comorbid depression), but essentially no effect in the limited number of men studied. The clinical importance of this apparent gender effect is unknown; however, only limited data are available to date regarding use of SSRIs in men who have PTSD related to noncombat-related trauma (e.g., sexual assault, accidents, natural disasters). There are insufficient data to date to determine whether race or age has any effect on the efficacy of sertraline in the management of PTSD.

For additional information on the use of SSRIs in the treatment of PTSD, .

Premenstrual Dysphoric Disorder

Sertraline is used in the treatment of premenstrual dysphoric disorder (previously late luteal phase dysphoric disorder). DSM-IV criteria for premenstrual dysphoric disorder (PMDD) require that in most menstrual cycles of the previous year at least 5 of the following 11 symptoms must have been present for most of the time during the last week of the luteal phase (with at least one of the symptoms being one of the first 4 listed): marked depressed mood, feelings of hopelessness, or self-deprecating thoughts; marked anxiety, tension, feelings of being ''keyed up'' or on ''edge''; marked affective lability (e.g., feeling suddenly sad or tearful or increased sensitivity to rejection); persistent and marked anger or irritability or increased interpersonal conflicts; decreased interest in usual activities (e.g., work, school, friends, hobbies); a subjective sense of difficulty in concentrating; lethargy, easy fatigability, or marked lack of energy; marked change in appetite, overeating, or specific food cravings; hypersomnia or insomnia; a subjective sense of being overwhelmed or out of control; and other physical symptoms, such as breast tenderness or swelling, headaches, joint or muscle pain, or a sensation of ''bloating'' or weight gain. Such symptoms should begin to remit within a few days of the onset of menses (follicular phase) and are always absent in the week following menses. The presence of this cyclical pattern of symptoms must be confirmed by at least 2 consecutive months of prospective daily symptom ratings. PMDD should be distinguished from the more common premenstrual syndrome (PMS) by prospective daily ratings and the strict criteria listed above.

The efficacy of sertraline for the management of PMDD has been established in 2 randomized, placebo-controlled studies over 3 menstrual cycles in adult women who met DSM-III-R or DSM-IV criteria for PMDD. In these studies, flexible dosages (range: 50-150 mg daily) of sertraline administered continuously throughout the menstrual cycle or during the luteal phase only (i.e., for 2 weeks prior to the onset of menses) were shown to be substantially more effective than placebo in improving scores from baseline on the Daily Record of Severity of Problems (DRSP), the Clinical Global Impression of Severity of Illness (CGI-S) and Improvement (CGI-I), and/or the Hamilton Depression Rating Scales (HAMD-17). The mean dosage of sertraline in patients completing these trials was 102 or 74 mg daily for those receiving continuous or luteal-phase dosing of the drug, respectively.

When given in a flexible dosage of 50-150 mg daily in a separate double-blind, placebo-controlled study, sertraline was substantially better than placebo in improving symptoms (depressive symptoms, physical symptoms, anger/irritability) and functional impairment associated with this disorder. The beneficial effect of the drug was apparent by the first treatment cycle. In an open study comparing sertraline and desipramine in the treatment of premenstrual dysphoric disorder, sertraline and possibly desipramine were found to be effective; however, sertraline was better tolerated than desipramine. Additional controlled studies are needed to determine whether the efficacy of the drug is sustained during longer-term, maintenance therapy in women with this condition. In addition, efficacy of sertraline used in conjunction with oral contraceptives for the treatment of PMDD has not been determined since patients receiving oral contraceptives were excluded from most clinical studies to date.

Social Phobia

Sertraline is used in the treatment of social phobia (social anxiety disorder). According to DSM-IV, social phobia is characterized by a marked and persistent fear of one or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others. Exposure to the feared situation almost invariably provokes anxiety, which may approach the intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or distress. The avoidance, fear, or anxious anticipation of encountering the social or performance situation interferes significantly with the person's daily routine, occupational or academic functioning, or social activities or relationships, or there is marked distress about having the phobias. Lesser degrees of performance anxiety or shyness generally do not require psychotherapy or pharmacologic treatment.

The efficacy of sertraline in the treatment of social phobia has been established in 2 multicenter, placebo-controlled studies in adult outpatients who met DSM-IV criteria for social phobia. In one study of 12 weeks' duration, 47% of patients receiving flexible dosages of sertraline (50-200 mg daily; mean dosage of 144 mg daily) were characterized as responders (defined as a score of 1 or 2 on the Clinical Global Impressions [CGI] Global Improvement Scale) compared with 26% of those receiving placebo (intent-to-treat analysis). Sertraline also was found to be superior to placebo on the Liebowitz Social Anxiety Scale (LSAS), a 24-item clinician administered measure of fear, anxiety, and avoidance of social and performance situation, and on most secondary efficacy measures, including the Duke Brief Social Phobia Scale (BSPS) total score, fear and avoidance subscales of BSPS, and fear/anxiety and avoidance subscales of LSAS. These results were similar to those seen in a flexible-dose study of 20 weeks' duration, in which a score of 1 (''very much improved'') or 2 (''much improved'') on the CGI Global Improvement Scale was attained by the end of the treatment period by 53 or 29% of patients receiving sertraline (50-200 mg daily; mean dosage of 147 mg daily) or placebo, respectively (intent-to-treat analysis). Sixty-five patients in this study subsequently were enrolled in a separate controlled study, including 50 patients who had responded to sertraline in the initial study and then were randomized to receive either continued treatment with sertraline or placebo in the subsequent study and 15 patients who had responded to placebo in the initial study and continued to receive placebo in the subsequent study. Based on an intent-to-treat analysis, 4% of patients who continued treatment with sertraline, 36% of patients randomized to receive placebo, and 27% of those who continued treatment with placebo relapsed (defined as an increase of 2 or more points from baseline in the CGI Severity of Illness score or discontinuance of the study drug because of lack of efficacy) at the end of the 24-week treatment period. Similar to results of pivotal, short-term clinical studies, sertraline also was shown to be substantially more effective than placebo on the CGI Severity of Illness Scale, Marks Fear Questionnaire (MFQ) Social Phobia subscale, and BSPS total score.

Subgroup analysis of short-term, controlled studies in adult outpatients with social anxiety disorder did not reveal any evidence of gender-related differences in treatment outcome. There was insufficient information to determine the effect of race or age on treatment outcome. Safety and efficacy of sertraline for the treatment of social phobia in children or adolescents have not been established to date.

Premature Ejaculation

Like some other serotonin-reuptake inhibitors, sertraline has been used with some success in the treatment of premature ejaculation. In a placebo-controlled study, sertraline produced substantial improvements compared with placebo in time to ejaculation, number of successful attempts at intercourse, and incidence of ejaculation during foreplay, as well as overall clinical judgment of improvement. In addition, the drug was well tolerated in most patients. A trial with drug therapy may be particularly useful in patients who fail or refuse behavioral or psychotherapeutic treatment or when partners are unwilling to cooperate with such therapy.

Other Uses

Sertraline has been used in a limited number of patients with various types of headache with variable results; however, its use in this condition may be limited by frequent adverse effects.

Dosage and Administration

Administration

Sertraline is administered orally. The drug usually is administered once daily in the morning or evening. The extent of GI absorption of sertraline reportedly may be increased slightly, the peak concentration increased by about 25%, and the time to peak concentration after a dose decreased from about 8 to 5.5 hours when the drug is administered with food, but such changes do not appear to be clinically important.

When sertraline hydrochloride concentrate for oral solution (Zoloft) is used, doses of the drug should be measured carefully using the calibrated dropper provided by the manufacturer. The appropriate dose of the oral solution should be diluted in 120 mL of water, ginger ale, lemon/lime soda, lemonade, or orange juice before administration. The diluted solution containing sertraline hydrochloride should be mixed and administered immediately and should not be allowed to stand before administration. A slight haze may occasionally appear in the diluted oral solution, but the manufacturer states that this is normal.

Dosage

Dosage of sertraline hydrochloride is expressed in terms of sertraline.

Patients receiving sertraline should be monitored for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustment.(See Cautions: Precautions and Contraindications.)

Because withdrawal effects may occur with discontinuance of sertraline, other selective serotonin-reuptake inhibitors (SSRIs), and selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), abrupt discontinuance of these drugs should be avoided whenever possible. In addition, patients may experience a worsening of psychiatric status when the drug is discontinued abruptly. When sertraline therapy is discontinued, the dosage should be reduced gradually (e.g., over a period of several weeks) and the patient monitored for possible withdrawal symptoms. If intolerable symptoms occur following a dosage reduction or upon discontinuance of therapy, the drug may be reinstituted at the previously prescribed dosage. Subsequently, the clinician may continue decreasing the dosage, but at a more gradual rate. (See Cautions: Nervous System Effects and see Chronic Toxicity.)

The manufacturers recommend that an interval of at least 2 weeks elapse when switching a patient from a monoamine oxidase (MAO) inhibitor to sertraline or when switching from sertraline to an MAO inhibitor. For additional information on potentially serious drug interactions that may occur between sertraline and MAO inhibitors or other serotonergic agents, see Cautions: Precautions and Contraindications and also see Drug Interactions: Serotonergic Drugs.

Clinical experience regarding the optimal timing of switching from other drugs used in the treatment of major depressive disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, premenstrual dysphoric disorder, and social anxiety disorder to sertraline therapy is limited. Therefore, the manufacturers recommend that care and prudent medical judgment be exercised when switching from other drugs to sertraline, particularly from long-acting agents (such as fluoxetine). Because some adverse reactions resembling serotonin syndrome have developed when fluoxetine therapy was discontinued abruptly and sertraline therapy was initiated immediately afterward, a washout period appears to be advisable when transferring a patient from fluoxetine to sertraline therapy. However, the appropriate duration of the washout period when switching from one selective serotonin-reuptake inhibitor to another has not been clearly established. Pending further experience in patients being transferred from therapy with another antidepressant to sertraline, it generally is recommended that the previous antidepressant be discontinued according to the recommended guidelines for the specific antidepressant prior to initiation of sertraline therapy.(See Drug Interactions: Serotonergic Drugs and see Drug Interactions: Tricyclic and Other Antidepressants.)

Major Depressive Disorder

For the management of major depressive disorder in adults, the recommended initial dosage of sertraline is 50-100 mg once daily. If no clinical improvement is apparent, dosage may be increased at intervals of not less than 1 week up to a maximum of 200 mg daily. Clinical experience with the drug to date suggests that many patients will respond to 50-100 mg of the drug once daily. While a relationship between dose and antidepressant effect has not been established, efficacy of the drug was demonstrated in clinical trials employing 50-200 mg daily.

While the optimum duration of sertraline therapy has not been established, many experts state that acute depressive episodes require several months or longer of sustained antidepressant therapy. In addition, some clinicians recommend that long-term antidepressant therapy be considered in certain patients at risk for recurrence of depressive episodes (such as those with highly recurrent unipolar depression). Whether the dose of sertraline required to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown. Systematic evaluation of sertraline has shown that its antidepressant efficacy is maintained for periods of up to 1 year in patients receiving 50-200 mg daily (mean dose of 70 mg daily). The usefulness of the drug in patients receiving prolonged therapy should be reevaluated periodically.

Obsessive-Compulsive Disorder

For the management of obsessive-compulsive disorder in adults and adolescents 13-17 years of age, the recommended initial dosage of sertraline is 50 mg once daily. In children 6-12 years of age, the recommended initial dosage of sertraline is 25 mg once daily. If no clinical improvement is apparent, dosage may be increased at intervals of not less than 1 week up to a maximum of 200 mg daily. However, it should be considered that children usually have a lower body weight than adults and particular care should be taken to avoid excessive dosage in children. While a relationship between dose and efficacy in obsessive-compulsive disorder has not been established, efficacy of the drug was demonstrated in clinical trials employing 50-200 mg daily in adults and 25-200 mg daily in children and adolescents.

While the optimum duration of sertraline therapy required to prevent recurrence of obsessive-compulsive symptoms has not been established to date, the manufacturer and many experts state that this disorder is chronic and requires several months or longer of sustained therapy. Whether the dose of sertraline required to induce remission is identical to the dose needed to maintain and/or sustain remission in patients with this disorder is unknown. Systematic evaluation of sertraline has shown that its efficacy in the management of obsessive-compulsive disorder is maintained for periods of up to 28 weeks in patients receiving 50-200 mg daily. The usefulness of the drug in patients receiving prolonged therapy should be reevaluated periodically.

Panic Disorder

For the management of panic disorder in adults, the recommended initial dosage of sertraline is 25 mg once daily. After 1 week, the dosage should be increased to 50 mg once daily. If no clinical improvement is apparent, dosage may then be increased at intervals of not less than 1 week up to a maximum of 200 mg daily.

While the optimum duration of sertraline therapy required to prevent recurrence of panic disorder has not been established to date, the manufacturer and many experts state that this disorder is chronic and requires several months or longer of sustained therapy. Whether the dose of sertraline required to induce remission is identical to the dose needed to maintain and/or sustain remission in patients with this disorder is unknown. Systematic evaluation of sertraline has shown that its efficacy in the management of panic disorder is maintained for periods of up to 28 weeks in patients receiving 50-200 mg daily. The usefulness of the drug in patients receiving prolonged therapy should be reevaluated periodically.

Posttraumatic Stress Disorder

For the management of posttraumatic stress disorder (PTSD) in adults, the recommended initial dosage of sertraline is 25 mg once daily. After 1 week, dosage should be increased to 50 mg once daily. If no clinical improvement is apparent, dosage may then be increased at intervals of not less than 1 week up to a maximum of 200 mg daily.

While the optimum duration of sertraline therapy required to prevent recurrence of PTSD has not been established to date, this disorder is chronic and it is reasonable to continue therapy in responding patients. Whether the dose of sertraline required to induce remission is identical to the dose needed to maintain and/or sustain remission in patients with this disorder is unknown. Systematic evaluation of sertraline has shown that its efficacy in the management of posttraumatic stress disorder is maintained for periods of up to 28 weeks in patients receiving 50-200 mg daily. The usefulness of the drug in patients receiving prolonged therapy should be reevaluated periodically.

Premenstrual Dysphoric Disorder

For the treatment of premenstrual dysphoric disorder (previously late luteal phase dysphoric disorder), the recommended initial dosage of sertraline is 50 mg daily given continuously throughout the menstrual cycle or given during the luteal phase only (i.e., starting 2 weeks prior to the anticipated onset of menstruation and continuing through the first full day of menses). If no clinical improvement is apparent, dosage may be increased in 50-mg increments at the onset of each new menstrual cycle up to a maximum of 150 mg daily when administered continuously or 100 mg daily when administered during the luteal phase only. If a dosage of 100 mg daily has been established with luteal phase dosing, dosages should be increased gradually over the first 3 days of each luteal phase dosing period. While a relationship between dose and effect in premenstrual dysphoric disorder (PMDD) has not been established, efficacy of the drug was demonstrated in clinical trials employing 50-150 mg daily.

The optimum duration of sertraline therapy required to treat PMDD has not been established to date. The manufacturer states that the efficacy of sertraline therapy beyond 3 menstrual cycles has not been demonstrated in controlled studies. However, because women commonly report that symptoms of PMDD worsen with age until relieved by the onset of menopause, the manufacturer recommends that long-term sertraline therapy be considered in responding women. Dosage adjustments, which may include transfers between dosing regimens (e.g., continuous versus luteal phase dosing), may be needed to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment.

Social Phobia

For the management of social phobia in adults, the recommended initial dosage of sertraline is 25 mg once daily. After 1 week, the dosage should be increased to 50 mg once daily. If no clinical improvement is apparent, dosage may then be increased at intervals of not less than 1 week up to a maximum of 200 mg daily.

While the optimum duration of sertraline therapy required to prevent recurrence of social phobia symptoms has not been established to date, the manufacturer states that this disorder is chronic and requires several months or longer of sustained therapy. Whether the dose of sertraline required to induce remission is identical to the dose needed to maintain and/or sustain remission in patients with this disorder is unknown. Systematic evaluation of sertraline has shown that its efficacy in the management of social phobia is maintained for periods of up to 24 weeks following 20 weeks of therapy at dosages of 50-200 mg daily. Dosages should be adjusted so that the patient is maintained on the lowest effective dosage, and patients should be reassessed periodically to determine the need for continued therapy.

Premature Ejaculation

For the management of premature ejaculation, sertraline has been given in a dosage of 25-50 mg daily. Alternatively, patients have taken sertraline on an ''as needed'' basis using doses of 25-50 mg daily.

Dosage in Geriatric Patients

Major Depressive Disorder

For the management of depressive symptoms associated with dementia of the Alzheimer's type in geriatric patients, some experts recommend an initial sertraline dosage of 12.5-25 mg once daily. The dosage may then be gradually increased at intervals of 1-2 weeks up to a maximum dosage of 150-200 mg once daily.

Dosage in Renal and Hepatic Impairment

The manufacturers state that, based on the pharmacokinetics of sertraline, there is no need for dosage adjustment in patients with renal impairment. Because sertraline does not appear to be removed substantially by dialysis, supplemental doses of the drug probably are unnecessary after dialysis.

Because sertraline is metabolized extensively by the liver, hepatic impairment can affect the elimination of the drug.(See Pharmacokinetics: Elimination.) Therefore, the manufacturers recommend that sertraline be administered with caution and in a reduced dosage or less frequently in patients with hepatic impairment.

Treatment of Pregnant Women during the Third Trimester

Because some neonates exposed to sertraline and other SSRIs or SNRIs late in the third trimester of pregnancy have developed severe complications, consideration may be given to cautiously tapering sertraline therapy in the third trimester prior to delivery if the drug is administered during pregnancy.(See Pregnancy, under Cautions: Pregnancy, Fertility, and Lactation.)

Cautions

The adverse effect profile of sertraline is similar to that of other selective serotonin-reuptake inhibitors (SSRIs) (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine). Because sertraline is a highly selective serotonin-reuptake inhibitor with little or no effect on other neurotransmitters, the incidence of some adverse effects commonly associated with tricyclic antidepressants, such as anticholinergic effects (dry mouth, constipation), certain cardiovascular effects (e.g., orthostatic hypotension), drowsiness, and weight gain, is lower in patients receiving sertraline. However, certain adverse GI (e.g., nausea, diarrhea, anorexia) and nervous system (e.g., tremor, insomnia) effects appear to occur more frequently with sertraline and other SSRIs than with tricyclic antidepressants.

Overall, the adverse effect profile of sertraline in adults with depression, obsessive-compulsive disorder, or panic disorder appears to be similar. In controlled studies, the most common adverse effects occurring more frequently in adults receiving sertraline than in those receiving placebo included GI effects such as nausea, diarrhea or loose stools, dyspepsia, and dry mouth; nervous system effects such as somnolence, dizziness, insomnia, and tremor; sexual dysfunction in males (principally ejaculatory delay); and sweating. Discontinuance of sertraline therapy was required in about 15% of adults in clinical trials, principally because of adverse psychiatric (e.g., somnolence, insomnia, agitation, tremor), other nervous system (e.g., dizziness, headache), GI (e.g., nausea, diarrhea or loose stools, anorexia), or male sexual dysfunction (e.g., ejaculatory delay) effects or because of fatigue.

Nervous System Effects

Headache is the most common adverse nervous system effect of sertraline, occurring in approximately 26% of patients receiving the drug in controlled clinical trials; headache occurred in 23% of those receiving placebo in these trials. Somnolence or drowsiness occurred in about 14% of patients receiving sertraline in controlled clinical trials. Headache or somnolence each required discontinuance of therapy in about 2% of patients. Fatigue has been reported in approximately 12% of patients receiving the drug in clinical trials and required discontinuance of therapy in about 1% of patients; this effect was reported in 8% of those receiving placebo in these trials.

Dizziness occurred in about 13% of patients receiving sertraline in controlled clinical trials and required discontinuance of therapy in less than 1% of patients. Insomnia occurred in about 22% of patients receiving the drug in controlled clinical trials. However, because insomnia is a symptom also associated with depression, relief of insomnia and improvement in sleep patterns may occur when clinical improvement in depression becomes apparent during antidepressant therapy. In clinical trials, about 2% of patients discontinued sertraline because of insomnia.

Tremor occurred in about 9%, nervousness in about 6%, anxiety (which occasionally may be severe [e.g., panic]) in about 4%, paresthesia in about 3%, and agitation in about 6% of patients receiving sertraline in controlled clinical trials. Tremor, agitation, and nervousness resulted in discontinuance of sertraline in about 1% of patients while anxiety resulted in discontinuance in less than 1% of patients in clinical trials. Agitation and anxiety may subside with continued therapy. Hypoesthesia, hypertonia, or malaise occurred in at least 1% of patients receiving sertraline in clinical trials. Impaired concentration, dystonia, or twitching occurred in approximately 0.1-1% of patients receiving sertraline, although these adverse effects have not been definitely attributed to the drug.

The incidence of seizures during sertraline therapy appears to be similar to or less than that observed during therapy with most other currently available antidepressants. Seizures occurred in less than 0.1% of patients receiving sertraline in clinical trials.(See Cautions: Precautions and Contraindications.)

Hypomania and mania have been reported in approximately 0.4% of patients receiving sertraline in controlled clinical trials, which is similar to the incidence reported in patients receiving active control agents (i.e., other antidepressants). In at least 2 patients, hypomanic symptoms occurred after they were receiving sertraline 200 mg daily for approximately 9 weeks. In both patients, the adverse reaction was obviated by a reduction in sertraline dosage.(See Cautions: Precautions and Contraindications.) Such reactions have occurred in patients receiving other antidepressant agents and may be caused by antidepressant-induced functional increases in catecholamine activity within the CNS, resulting in a ''switch'' from depressive to manic behavior. There is some evidence that patients with bipolar disorder may be more likely to experience antidepressant-induced hypomanic or manic reactions than patients without evidence of this disorder. In addition, limited evidence suggests that such reactions may occur more frequently in bipolar depressed patients receiving tricyclics and tetracyclics (e.g., maprotiline, mianserin [not commercially available in the US]) than in those receiving SSRIs (e.g., citalopram, escitalopram, fluoxetine, paroxetine, sertraline). However, further studies are needed to confirm these findings.

Asthenia has been reported in at least 1% of patients receiving sertraline; however, a causal relationship to the drug has not been established. Confusion, migraine, abnormal coordination, abnormal gait, hyperesthesia, ataxia, depersonalization, hallucinations, hyperkinesia, hypokinesia, nystagmus, vertigo, abnormal dreams, aggressive reaction, amnesia, apathy, paroniria, delusion, depression or aggravated depression, emotional lability, euphoria, abnormal thinking, or paranoid reaction have been reported in 0.1-1% of patients receiving the drug, although these adverse effects have not been definitely attributed to sertraline.

Adverse nervous system effects reported in less than 0.1% of patients receiving sertraline include dysphoria, choreoathetosis, dyskinesia, coma, dysphonia, hyporeflexia, hypotonia, ptosis, somnambulism, and illusion; these effects have not been definitely attributed to the drug. Although a causal relationship has not been established, psychosis, extrapyramidal symptoms, and oculogyric crisis have been reported during postmarketing surveillance. Forgetfulness, panic attacks, and unspecified pain also have been reported rarely, although a causal relationship to sertraline has not been established. Sertraline also has been reported to precipitate or exacerbate ''flashbacks'' in patients who previously had used lysergic acid diethylamide (LSD).

Serotonin syndrome and neuroleptic malignant syndrome (NMS)-like reactions have been reported in patients receiving sertraline, other SSRIs, and selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs).(See Cautions: Precautions and Contraindications, Drug Interactions: Serotonergic Drugs, and Acute Toxicity.)

Extrapyramidal reactions, including akathisia, stuttering (which may be a speech manifestation of akathisia), bilateral jaw stiffness, and torticollis, have been reported rarely with sertraline use, and such reactions appear to be a class effect of SSRIs and dose related. Reactions occurring early during therapy with these drugs may be secondary to preexisting parkinsonian syndrome and/or concomitant therapy.

Withdrawal Reactions

Withdrawal symptoms, including dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania, have been reported upon discontinuance of sertraline, other SSRIs, and SNRIs, particularly when discontinuance of these drugs is abrupt. While these reactions are generally self-limiting, there have been reports of serious discontinuance symptoms. Therefore, patients should be monitored for such symptoms when discontinuing sertraline therapy. A gradual reduction in the dosage rather than abrupt cessation is recommended whenever possible. (See Dosage and Administration: Dosage.)

A withdrawal syndrome has been reported in less than 0.1% of sertraline-treated patients. Fatigue, severe abdominal cramping, memory impairment, and influenza-like symptoms were reported 2 days following abrupt discontinuance of sertraline in one patient; when sertraline was restarted, the symptoms remitted. Electric shock-like sensations occurred in another patient 1 day after the last administered dose of sertraline; these sensations became less intense and eventually disappeared 13 weeks after sertraline therapy was discontinued.(See Chronic Toxicity.)

Suicidality

Suicidal ideation has been reported in less than 0.1% of adults receiving sertraline. The US Food and Drug Administration (FDA) has determined that antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (18-24 years of age) with major depressive disorder and other psychiatric disorders. Patients, therefore, should be appropriately monitored and closely observed for clinical worsening, suicidality, and unusual changes in behavior, particularly during initiation of sertraline therapy (i.e., the first few months) and during periods of dosage adjustments.(See Cautions: Precautions and Contraindications and see Cautions: Pediatric Precautions.)

GI Effects

Like other selective serotonin-reuptake inhibitors (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine), sertraline therapy is associated with a relatively high incidence of GI disturbances, principally nausea, dry mouth, and diarrhea/loose stools. The most frequent adverse effect associated with sertraline therapy is nausea, which occurred in about 28% of patients receiving the drug in controlled clinical trials. In clinical trials, nausea required discontinuance of sertraline in about 4% of patients. In general, the incidence of nausea associated with selective serotonin-reuptake inhibitors appears to be higher when therapy is initiated with high doses but decreases as therapy with these drugs is continued. While the mechanism(s) of sertraline-induced GI effects has not been fully elucidated, they appear to arise at least in part because of increased serotonergic activity in the GI tract (which may result in stimulation of small intestine motility and inhibition of gastric and large intestine motility) and possibly because of the drug's effect on central serotonergic type 3 (5-HT3) receptors.

Diarrhea or loose stools occurred in about 20%, dry mouth in about 15%, constipation in about 7%, dyspepsia in about 8%, or anorexia in about 6% of patients receiving sertraline in controlled clinical trials. Other adverse GI effects associated with sertraline therapy include vomiting which occurred in about 4% and flatulence which occurred in about 3% of patients receiving the drug in controlled clinical trials. Abdominal pain was reported in approximately 2% and taste perversion in about 1% of patients receiving sertraline. In clinical trials, diarrhea or loose stools required discontinuance of sertraline in about 3% of patients and dry mouth required discontinuance of therapy in about 1% of patients.

Epidemiologic case-control and cohort design studies have suggested that selective serotonin-reuptake inhibitors may increase the risk of upper GI bleeding. Although the precise mechanism for this increased risk remains to be clearly established, serotonin release by platelets is known to play an important role in hemostasis, and selective serotonin-reuptake inhibitors decrease serotonin uptake from the blood by platelets thereby decreasing the amount of serotonin in platelets. In addition, concurrent use of aspirin or other nonsteroidal anti-inflammatory drugs was found to substantially increase the risk of GI bleeding in patients receiving selective serotonin-reuptake inhibitors in 2 of these studies. Although these studies focused on upper GI bleeding, there is some evidence suggesting that bleeding at other sites may be similarly potentiated. Further clinical studies are needed to determine the clinical importance of these findings.(See Cautions: Hematologic Effects and also see Drug Interactions: Drugs Affecting Hemostasis.)

Although a causal relationship to sertraline has not been established, dysphagia, esophagitis, aggravation of dental caries, gastroenteritis, eructation, and increased salivation have been reported in 0.1-1% of patients receiving the drug. Aphthous stomatitis, ulcerative stomatitis, stomatitis, tongue ulceration or edema, glossitis, diverticulitis, gastritis, hemorrhagic peptic ulcer, rectal hemorrhage, colitis, proctitis, fecal incontinence, melena, or tenesmus has been reported in less than 0.1% of patients receiving sertraline; however, these adverse effects have not been definitely attributed to the drug. Pancreatitis also has been reported rarely in association with sertraline; however, a causal relationship to the drug has not been clearly established.

Although a causal relationship has not been established, nocturnal bruxism (clenching and/or grinding of the teeth during sleep) has developed within 2-4 weeks following initiation of sertraline or fluoxetine therapy in several patients. The bruxism remitted upon reduction in dosage of the serotonin-reuptake inhibitor and/or the addition of buspirone therapy.

Speech blockage also has been reported in at least one sertraline-treated patient.

Dermatologic and Sensitivity Reactions

Sweating occurred in about 7% of patients receiving sertraline in controlled clinical trials.

Rash, which may be erythematous, follicular, maculopapular, or pustular, has been reported in about 3% of patients receiving sertraline in controlled clinical trials. Adverse dermatologic effects reported in 0.1-1% of patients receiving sertraline in controlled clinical trials include acne, alopecia, dry skin, urticaria, pruritus, and photosensitivity reaction (which may be severe); however, these adverse effects have not been definitely attributed to sertraline. Bullous eruption, eczema, contact dermatitis, skin discoloration, and hypertrichosis have been reported in less than 0.1% of patients receiving the drug, although a causal relationship to sertraline has not been established. Allergy, allergic reaction, and angioedema also have been reported rarely.

Other dermatologic and sensitivity events, which can be severe and potentially may be fatal, reported during the postmarketing surveillance of sertraline have included anaphylactoid reaction, angioedema, Stevens-Johnson syndrome, erythema multiforme, and vasculitis.

Metabolic Effects

Thirst has been reported in 0.1-1% of patients receiving sertraline in controlled clinical trials.

Weight loss occurred in 0.1-1% of patients receiving sertraline. In controlled clinical trials, patients lost an average of about 0.45-0.9 kg while receiving sertraline. Rarely, weight loss has required discontinuance of therapy. Like fluoxetine, sertraline exhibits anorexigenic activity and can cause anorexia, which may be more pronounced in overweight patients and those with carbohydrate craving. Anorexia occurred in about 3% of patients receiving sertraline in controlled clinical trials and required discontinuance in at least 1% of patients. Increased appetite and weight gain have been reported in at least 1% of patients receiving sertraline in controlled clinical trials, although a causal relationship to the drug has not been established.(See Cautions: Pediatric Precautions.)

Sertraline use has been associated with small mean decreases (approximately 7%) in serum uric acid concentration as a result of a weak uricosuric effect; the clinical importance is not known and there have been no cases of acute renal failure associated with the drug. Small mean increases in serum total cholesterol (about 3%) and triglyceride (about 5%) concentrations also have been reported in patients receiving sertraline. Hypercholesterolemia has been reported in less than 0.1% of patients. Other adverse effects reported in less than 0.1% of patients receiving the drug include dehydration and hypoglycemia. These adverse effects have not been definitely attributed to sertraline.

Ocular and Otic Effects

Abnormal vision (including blurred vision) occurred in about 4% of patients receiving sertraline in controlled clinical trials. Adverse ocular effects reported in 0.1-1% of patients receiving sertraline include abnormality of accommodation, conjunctivitis, and ocular pain. Although a causal relationship to sertraline has not been established, anisocoria, abnormal lacrimation, xerophthalmia, diplopia, scotoma, visual field defect, exophthalmos, hemorrhage of the anterior chamber of the eye, or photophobia has been reported in less than 0.1% of patients receiving the drug. Other adverse ocular effects reported during postmarketing surveillance of sertraline have included blindness, optic neuritis, and cataract; however, a causal relationship to the drug has not been established.

SSRIs, including sertraline, may have an effect on pupil size resulting in mydriasis. This mydriatic effect potentially can narrow the eye angle resulting in increased intraocular pressure and angle-closure glaucoma, particularly in predisposed patients. Mydriasis has been reported in 0.1-1% of patients receiving sertraline and glaucoma has been reported in less than 0.1% of patients receiving the drug. (See Cautions: Precautions and Contraindications.)

Tinnitus occurred in at least 1% of patients receiving sertraline in controlled clinical trials. Earache has been reported in 0.1-1% of patients, and hyperacusis and labyrinthine disorder have been reported in less than 0.1% of patients.

Cardiovascular Effects

Sertraline does not exhibit clinically important anticholinergic activity, and current evidence suggests that sertraline is less cardiotoxic than many antidepressant agents (e.g., tricyclic antidepressants, monoamine oxidase inhibitors).(See Cardiovascular Considerations in Uses: Major Depressive Disorder and also see Pharmacology: Cardiovascular Effects.) However, bradycardia, AV block, atrial arrhythmias, QT-interval prolongation, and ventricular tachycardia (including torsades de pointes-type arrhythmias) have been reported during postmarketing surveillance evaluations of the drug.

Hot flushes occurred in about 2% of patients receiving sertraline in controlled clinical trials. Palpitation and chest pain have been reported in at least 1% of patients receiving sertraline in controlled clinical trials. In one patient with underlying coronary artery disease, chest pain developed suddenly and was relieved with sublingual nitroglycerin but was not associated with ECG changes; the mechanism of this effect, particularly regarding any potential cardiovascular effect, is unclear and alternative mechanisms (e.g., GI) for the chest pain have been proposed.

Unlike tricyclic antidepressants, sertraline has been associated with hypotension (e.g., orthostatic) infrequently; in controlled clinical trials, postural effects (e.g., dizziness, hypotension [which can also be nonpostural]) occurred in 0.1-1% of patients receiving sertraline. Syncope also occurred in at least 0.1% of patients.

Hypertension, peripheral ischemia, and tachycardia have been reported in 0.1-1% of patients receiving the drug, although a definite causal relationship to sertraline has not been established. Precordial or substernal chest pain, aggravated hypertension, myocardial infarction, pallor, vasodilation, and cerebrovascular disorder have been reported in less than 0.1% of patients receiving sertraline; these adverse effects have not been definitely attributed to the drug. Cerebrovascular spasm (including reversible cerebral vasoconstriction syndrome and Call-Fleming Syndrome) also has been reported during postmarketing experience with sertraline.

Generalized, dependent, periorbital, or peripheral edema has been reported in at least 0.1% of patients receiving sertraline, and facial edema has been reported rarely. However, a causal relationship to the drug has not been established.

Musculoskeletal Effects

Myalgia or back pain occurred in at least 1% of patients receiving sertraline in controlled clinical trials. Arthralgia, arthrosis, leg or other muscle cramps, or muscle weakness has been reported in 0.1-1% of patients receiving sertraline; these adverse effects have not been definitely attributed to the drug.

Hematologic Effects

Purpura, aplastic anemia, pancytopenia, leukopenia, thrombocytopenia, and abnormal bleeding have been reported occasionally in patients receiving sertraline; however, these adverse effects have not been definitely attributed to the drug.

Altered platelet function and/or abnormal platelet laboratory results have been reported rarely, but a causal relationship to sertraline remains to be established. In addition, in at least one patient with idiopathic thrombocytopenic purpura, sertraline therapy was associated with an increase in platelet counts. Anemia has been reported in less than 0.1% of patients receiving sertraline, although a causal relationship to the drug has not been established. Neutropenia also has been reported rarely with sertraline use and has been a reason for drug discontinuance. Agranulocytosis and septic shock developed in a geriatric woman who had been receiving sertraline for about 1 month in addition to atenolol, bendroflumethiazide, and thioridazine; the patient responded to anti-infective and granulocyte colony-stimulating factor therapy and made a full recovery within 10 days.

Bleeding complications (e.g., ecchymosis, purpura, menorrhagia, rectal bleeding) have been reported infrequently in patients receiving selective serotonin-reuptake inhibitors. Although the precise mechanism for these reactions has not been established, it has been suggested that impaired platelet aggregation and prolonged bleeding time may be due at least in part to inhibition of serotonin reuptake into platelets and/or that increased capillary fragility and vascular tone may contribute to these cases.(See Cautions: GI Effects and also see Drug Interactions: Drugs Affecting Hemostasis.)

Respiratory Effects

Rhinitis or yawning has been reported in at least 1% of patients receiving sertraline in controlled clinical trials. Adverse respiratory effects reported in 0.1-1% of patients receiving the drug include bronchospasm, dyspnea, epistaxis, upper respiratory tract infection, sinusitis, and coughing; however, a definite causal relationship to sertraline has not been established. Adverse respiratory effects reported in less than 0.1% of patients receiving sertraline include bradypnea, hypoventilation, hyperventilation, apnea, stridor, hiccups, hemoptysis, bronchitis, laryngismus, and laryngitis. Pulmonary hypertension also has been reported during postmarketing surveillance evaluations of the drug. However, these adverse effects have not been definitely attributed to the drug.

Renal, Electrolyte, and Genitourinary Effects

Sexual Dysfunction

Like other selective serotonin-reuptake inhibitors, adverse effects on sexual function have been reported in both men and women receiving sertraline. Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they also may occur as the result of pharmacologic therapy. It is difficult to determine the true incidence and severity of adverse effects on sexual function during sertraline therapy, in part because patients and clinicians may be reluctant to discuss these effects. Therefore, incidence data reported in product labeling and earlier studies are most likely underestimates of the true incidence of adverse sexual effects. Recent reports indicate that up to 50% of patients receiving selective serotonin-reuptake inhibitors describe some form of sexual dysfunction during treatment and the actual incidence may be even higher.

Sexual dysfunction (principally ejaculatory delay) is the most common adverse urogenital effect of sertraline in males, occurring in about 14% of male patients receiving the drug in controlled clinical trials. In some cases, this effect has been used for therapeutic benefit in the treatment of premature ejaculation.(See Uses: Premature Ejaculation.) Impotence has occurred in at least 1% of male patients receiving sertraline in controlled trials, and priapism has been reported rarely. Female sexual dysfunction (e.g., anorgasmia) has been reported in at least 1% of female patients receiving the drug in controlled clinical trials. Decreased libido has been reported in males and females, occurring in 6% of patients in controlled clinical studies. Sexual dysfunction (principally ejaculatory delay) required discontinuance of therapy in at least 1% of patients in controlled clinical trials. Increased libido has been reported in less than 1% of patients receiving the drug.

Results of some (but not all) studies in men and women suggest that paroxetine may be associated with a higher incidence of sexual dysfunction than some other currently available selective serotonin-reuptake inhibitors, including sertraline and citalopram. Since it is difficult to know the precise risk of sexual dysfunction associated with serotonin-reuptake inhibitors, clinicians should routinely inquire about such possible adverse effects in patients receiving these drugs.

The long-term effects of selective serotonin-reuptake inhibitors on sexual function have not been fully determined to date. In a double-blind study evaluating 6 months of sertraline or citalopram therapy in depressed patients, sexual desire and overall sexual functioning (as measured on the UKU Side Effect Scale) substantially improved in women and sexual desire improved in men. In men, no change in orgasmic dysfunction, erectile dysfunction, or overall sexual functioning was reported after 6 months of therapy with sertraline or citalopram, although there was a trend toward worsening of ejaculatory dysfunction. However, in the subgroups of women and men reporting no sexual problems at baseline, approximately 12% of women reported decreased sexual desire and 14% reported orgasmic dysfunction after 6 months of citalopram therapy; the corresponding figures in the same subgroup of men were approximately 17 and 19%, respectively, and as many as 25% experienced ejaculatory dysfunction after 6 months. No substantial differences between sertraline and citalopram were reported in this study.

Management of sexual dysfunction caused by selective serotonin-reuptake inhibitor therapy includes waiting for tolerance to develop; using a lower dosage of the drug; using drug holidays; delaying administration of the drug until after coitus; or changing to another antidepressant. Although further study is needed, there is some evidence that adverse sexual effects of the selective serotonin-reuptake inhibitors may be reversed by concomitant use of certain drugs, including buspirone, 5-hydroxytryptamine-2 (5-HT2) receptor antagonists (e.g., nefazodone), 5-HT3 receptor inhibitors (e.g., granisetron), or α2-adrenergic receptor antagonists (e.g., yohimbine), selective phosphodiesterase (PDE) inhibitors (e.g., sildenafil), or dopamine receptor agonists (e.g., amantadine, dextroamphetamine, pemoline [no longer commercially available in the US], methylphenidate). In most patients, sexual dysfunction is fully reversed 1-3 days after discontinuance of the antidepressant.

Other Renal, Electrolyte, and Genitourinary Effects

Although a definite causal relationship to sertraline has not been established, menstrual disorders, dysmenorrhea, intermenstrual bleeding, amenorrhea, vaginal hemorrhage, and leukorrhea have been reported in 0.1-1% of patients receiving sertraline. In addition, menorrhagia, breast enlargement, female breast pain or tenderness, acute mastitis in females, gynecomastia, and atrophic vaginitis have been reported in less than 0.1% of patients receiving sertraline; however, a causal relationship to the drug has not been clearly established.

Treatment with SSRIs, including sertraline, and selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs) may result in hyponatremia. In many cases, this hyponatremia appears to be due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and was reversible when the SSRI or SNRI was discontinued. Cases with serum sodium concentrations lower than 110 mEq/L have been reported. Hyponatremia and SIADH in patients receiving SSRIs usually develop an average of 2 weeks after initiating therapy (range: 3-120 days). Geriatric individuals and patients receiving diuretics or who are otherwise volume depleted may be at greater risk of developing hyponatremia during therapy with SSRIs or SNRIs. Discontinuance of sertraline should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Because geriatric patients may be at increased risk for hyponatremia associated with these drugs, clinicians prescribing sertraline in such patients should be aware of the possibility that such reactions may occur. In addition, periodic monitoring of serum sodium concentrations (particularly during the first several months) in geriatric patients receiving SSRIs has been recommended by some clinicians.

A variety of urinary disorders, including urinary frequency, polyuria, urinary hesitancy and/or retention, dysuria, nocturia, and urinary incontinence, has been reported in 0.1-1% of patients receiving sertraline; however, these effects have not been definitely attributed to the drug. In addition, cystitis, oliguria, pyelonephritis, hematuria, renal pain, strangury, and balanoposthitis have been reported in less than 0.1% of patients receiving sertraline, although a causal relationship to the drug has not been clearly established.

Hepatic Effects

Impaired hepatic function has been reported in less than 1% of patients receiving sertraline in controlled clinical trials; in most cases, such reactions appeared to be reversible upon discontinuance of sertraline therapy. Asymptomatic elevations in serum AST (SGOT) and ALT (SGPT) concentrations have been reported in approximately 0.8% of patients receiving the drug and occasionally have been a reason for drug discontinuance. Elevations in aminotransferase concentrations usually occurred within the first 1-9 weeks of sertraline therapy and were rapidly reversible following discontinuance of the drug. In addition, in at least 2 patients, elevated liver enzymes returned to normal levels with continued therapy.

Increased serum alkaline phosphatase and bilirubin concentrations occurred rarely in patients receiving sertraline in clinical trials and required discontinuance of therapy in some cases. Other clinical features associated with adverse hepatic reactions that have been reported in at least one patient include hepatitis, hepatomegaly, jaundice, abdominal pain, vomiting, hepatic failure, and death. However, these effects have not been definitely attributed to the drug.

Endocrine Effects

Low levels of total thyroxine developed in a depressed adolescent who had been receiving sertraline therapy; however, it appears that sertraline only displaced the bound fraction of total thyroxine but was not associated with true hypothyroidism. In a limited number of hypothyroid patients receiving thyroxine therapy, elevated serum thyrotropin and reduced serum thyroxine concentrations have been observed following the initiation of sertraline therapy. Hypothyroidism also has been reported.(See Cautions: Precautions and Contraindications.)

Diabetes mellitus, hyperglycemia, hyperprolactinemia, and galactorrhea have been reported rarely in sertraline-treated patients; however, a causal relationship to the drug has not been established.

Other Adverse Effects

Cold clammy skin, flushing, fever, or rigors has been reported in 0.1-1% of patients receiving the drug, although a causal relationship to sertraline has not been established. In addition, lupus-like syndrome and serum sickness have been reported during postmarketing surveillance evaluations of the drug; however, a causal relationship has not been definitively established.

Precautions and Contraindications

Worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior may occur in both adult and pediatric (see Cautions: Pediatric Precautions) patients with major depressive disorder or other psychiatric disorders, whether or not they are taking antidepressants. This risk may persist until clinically important remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. However, there has been a long-standing concern 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 studies of antidepressants (i.e., selective serotonin-reuptake inhibitors [SSRIs] and other antidepressants) have shown an increased risk of suicidality in children, adolescents, and young adults (18-24 years of age) with major depressive disorder and other psychiatric disorders. An increased suicidality risk was not demonstrated with antidepressants compared to placebo in adults older than 24 years of age and a reduced risk was observed in adults 65 years of age or older. It currently 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 major depressive disorder that antidepressants can delay the recurrence of depression.

The US Food and Drug Administration (FDA) recommends that all patients being treated with antidepressants for any indication be appropriately monitored and closely observed for clinical worsening, suicidality, and unusual changes in behavior, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, also should be advised to monitor patients on a daily basis for the emergence of agitation, irritability, or unusual changes in behavior as well as the emergence of suicidality, and to report such symptoms immediately to a health-care provider.

Although a causal relationship between the emergence of symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania 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. Consequently, consideration should be given to changing the therapeutic regimen or discontinuing therapy in patients whose depression is persistently worse or in patients experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if such manifestations are severe, abrupt in onset, or were not part of the patient's presenting symptoms. If a decision is made to discontinue therapy, sertraline dosage should be tapered as rapidly as is feasible but with recognition of the risks of abrupt discontinuance.(See Dosage and Administration: Dosage.) FDA also recommends that the drugs be prescribed in the smallest quantity consistent with good patient management, in order to reduce the risk of overdosage.

It is generally believed (though not established in controlled trials) that treating a major depressive episode with an antidepressant alone may increase the likelihood of precipitating a mixed or manic episode in patients at risk for bipolar disorder. Therefore, patients should be adequately screened for bipolar disorder prior to initiating treatment with an antidepressant; such screening should include a detailed psychiatric history (e.g., family history of suicide, bipolar disorder, and depression).

Potentially life-threatening serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions have been reported with SSRIs, including sertraline, and selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs) alone, but particularly with concurrent administration of other serotonergic drugs (including serotonin [5-hydroxytryptamine; 5-HT] type 1 receptor agonists [''triptans'']), drugs that impair the metabolism of serotonin (e.g., monoamine oxidase [MAO] inhibitors), or antipsychotic agents or other dopamine antagonists. Symptoms of serotonin syndrome 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 GI symptoms (e.g., nausea, vomiting, diarrhea). In its most severe form, serotonin syndrome may resemble NMS, which is characterized by hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation in vital signs, and mental status changes. Patients receiving sertraline should be monitored for the development of serotonin syndrome or NMS-like signs and symptoms.

Concurrent or recent (i.e., within 2 weeks) therapy with MAO inhibitors used for treatment of depression is contraindicated in patients receiving sertraline and vice versa. If concurrent therapy with sertraline and a 5-HT1 receptor agonist (triptan) is clinically warranted, the patient should be observed carefully, particularly during initiation of therapy, when dosage is increased, or when another serotonergic agent is initiated. Concomitant use of sertraline and serotonin precursors (e.g., tryptophan) is not recommended. If signs and symptoms of serotonin syndrome or NMS develop during sertraline therapy, treatment with sertraline and any concurrently administered serotonergic or antidopaminergic agents, including antipsychotic agents, should be discontinued immediately and supportive and symptomatic treatment should be initiated.(See Drug Interactions: Serotonergic Drugs.)

The dropper dispenser provided with Zoloft oral solution contains natural latex proteins in the form of dry natural rubber which may cause sensitivity reactions in susceptible individuals.

Because clinical experience with sertraline in patients with certain concurrent systemic disease, including cardiovascular disease and renal impairment, is limited, caution should be exercised when sertraline is administered to patients with any systemic disease or condition that may alter metabolism of the drug or adversely affect hemodynamic function.(See Dosage and Administration: Dosage.)

Sertraline should be used with caution in patients with hepatic impairment, since prolonged elimination of the drug has been reported to occur in patients with liver cirrhosis.(See Pharmacokinetics: Elimination and see Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

The manufacturers recommend that patients receiving sertraline be advised to notify their clinician if they are taking or plan to take nonprescription (over-the-counter) or prescription medications or alcohol-containing beverages or preparations. Although no interactions with nonprescription medications have been reported to date, the potential for such adverse drug interactions exists. Therefore, the use of any nonprescription medication should be initiated cautiously according to the directions of use provided on the nonprescription medication. Although sertraline has not been shown to potentiate the impairment of mental and motor skills caused by alcohol, the manufacturers recommend that patients be advised to avoid alcohol while receiving the drug.

Sertraline generally is less sedating than most other currently available antidepressants and does not appear to produce substantial impairment of cognitive or psychomotor function. However, patients should be cautioned that sertraline may impair their ability to perform activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle) and to avoid such activities until they experience how the drug affects them. Because the risk of using sertraline concomitantly with other CNS active drugs has not been evaluated systematically to date, the manufacturers recommend that such therapy be employed cautiously.

Seizures have been reported in patients receiving therapeutic dosages of sertraline. Because of limited experience with sertraline in patients with a history of seizures, the drug should be used with caution in such patients.

Activation of mania and hypomania has occurred in patients receiving therapeutic dosages of sertraline. The drug should be used with caution in patients with a history of mania or hypomania.

Treatment with SSRIs, including sertraline, and selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs) may result in hyponatremia. In many cases, this hyponatremia appears to be due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and was reversible when sertraline was discontinued. Cases with serum sodium concentrations lower than 110 mEq/L have been reported. Geriatric individuals and patients receiving diuretics or who are otherwise volume depleted may be at greater risk of developing hyponatremia during therapy with SSRIs or SNRIs. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls; more severe and/or acute cases have been associated with hallucinations, syncope, seizures, coma, respiratory arrest, and death. Discontinuance of sertraline should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.(See Cautions: Renal, Electrolyte, and Genitourinary Effects and also see Cautions: Geriatric Precautions.)

Altered platelet function has been reported rarely in patients receiving sertraline. In addition, use of the drug has been associated with several reports of abnormal bleeding or purpura. While a causal relationship to sertraline remains to be established, pending such establishment, the drug should be used with caution in patients with an underlying coagulation defect since the possible effects on hemostasis may be exaggerated in such patients.(See Cautions: Hematologic Effects.)

SSRIs, including sertraline, may have an effect on pupil size resulting in mydriasis. This mydriatic effect potentially can narrow the eye angle resulting in increased intraocular pressure and angle-closure glaucoma, particularly in predisposed patients. Sertraline should therefore by used with caution in patients with angle-closure glaucoma or a history of glaucoma.

Sertraline has a weak uricosuric effect.(See Cautions: Metabolic Effects.) Pending further elucidation of the clinical importance, if any, of this effect, the drug should be used with caution in patients who may be adversely affected (e.g., those at risk for acute renal failure).

Because sertraline therapy has been associated with anorexia and weight loss (see Cautions: Metabolic Effects), the drug should be used with caution in patients who may be adversely affected by these effects (e.g., underweight patients).

Like many other antidepressant drugs, sertraline has been associated with hypothyroidism, elevated serum thyrotropin, and/or reduced serum thyroxine concentrations in a limited number of patients. Because of reports with other antidepressant agents and the complex interrelationship between the hypothalamic-pituitary-thyroid axis and affective (mood) disorders, at least one manufacturer recommends that thyroid function be reassessed periodically in patients with thyroid disease who are receiving sertraline.

Commercially available sertraline hydrochloride oral solution (Zoloft) contains alcohol. Therefore, concomitant use of sertraline hydrochloride oral solution and disulfiram is contraindicated.

Sertraline is contraindicated in patients concurrently receiving pimozide.(See Drug Interactions: Pimozide.)

Sertraline also is contraindicated in patients who are hypersensitive to the drug or any ingredient in the formulation.

Pediatric Precautions

Safety and efficacy of sertraline in children with obsessive-compulsive disorder (OCD) younger than 6 years of age have not been established. Safety and efficacy of sertraline in pediatric patients with other disorders (e.g., major depressive disorder, panic disorder, posttraumatic stress disorder, premenstrual dysphoric disorder, social phobia) have not been established. The overall adverse effect profile of sertraline in over 600 pediatric patients who received sertraline in controlled and uncontrolled clinical trials was generally similar to that seen in the adult clinical studies. As with other SSRIs, decreased appetite and weight loss have been observed in association with sertraline therapy.

Efficacy of sertraline in pediatric patients with major depressive disorder was evaluated in 2 randomized, 10-week, double-blind, placebo-controlled, flexible-dose (50-200 mg daily) trials in 373 children and adolescents with major depressive disorder, but data from these studies were not sufficient to establish efficacy in pediatric patients. In a safety analysis of the pooled data from these 2 studies, a difference in weight change between the sertraline and placebo groups was noted of approximately 1 kg for both pediatric patients (6-11 years of age) and adolescents (12-17 years of age) representing a slight weight loss for those receiving sertraline and a slight weight gain for those receiving placebo. In addition, a larger difference was noted in children than in adolescents between the sertraline and placebo groups in the proportion of outliers for clinically important weight loss; about 7% of the children and about 2% of the adolescents receiving sertraline in these studies experienced a weight loss of more than 7% of their body weight compared with none of those receiving placebo.

A subset of patients who completed these controlled trials was continued into a 24-week, flexible-dose, open-label, extension study. A mean weight loss of approximately 0.5 kg was observed during the initial 8 weeks of treatment for those pediatric patients first exposed to sertraline during the extension study, which was similar to the weight loss observed among sertraline-treated patients during the first 8 weeks of the randomized controlled trials. The patients continuing in the extension study began gaining weight relative to their baseline weight by week 12 of sertraline therapy, and patients who completed the entire 34 weeks of therapy with the drug had a weight gain that was similar to that expected using data from age-adjusted peers. The manufacturers state that periodic monitoring of weight and growth is recommended in pediatric patients receiving long-term therapy with sertraline or other selective serotonin-reuptake inhibitors (SSRIs).

FDA warns that antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder and other psychiatric disorders. The risk of suicidality for these drugs was identified in a pooled analysis of data from a total of 24 short-term (4-16 weeks), placebo-controlled studies of 9 antidepressants (i.e., sertraline, bupropion, citalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, venlafaxine) in over 4400 children and adolescents with major depressive disorder, OCD, or other psychiatric disorders. The analysis revealed a greater risk of adverse events representing suicidal behavior or thinking (suicidality) during the first few months of treatment in pediatric patients receiving antidepressants than in those receiving placebo. However, a more recent meta-analysis of 27 placebo-controlled trials of 9 antidepressants (SSRIs and others) in patients younger than 19 years of age with major depressive disorder, OCD, or non-OCD anxiety disorders suggests that the benefits of antidepressant therapy in treating these conditions may outweigh the risks of suicidal behavior or suicidal ideation. No suicides occurred in these pediatric trials.

The risk of suicidality in FDA's pooled analysis differed across the different psychiatric indications, with the highest incidence observed in the major depressive disorder studies. In addition, although there was considerable variation in risk among the antidepressants, a tendency toward an increase in suicidality risk in younger patients was found for almost all drugs studied. It is currently unknown whether the suicidality risk in pediatric patients extends to longer-term use (i.e., beyond several months).

As a result of this analysis and public discussion of the issue, FDA has directed manufacturers of all antidepressants to add a boxed warning to the labeling of their products to alert clinicians of this suicidality risk in children and adolescents and to recommend appropriate monitoring and close observation of patients receiving these agents.(See Cautions: Precautions and Contraindications.) The drugs that are the focus of the revised labeling are all drugs included in the general class of antidepressants, including those that have not been studied in controlled clinical trials in pediatric patients, since the available data are not adequate to exclude any single antidepressant from an increased risk. In addition to the boxed warning and other information in professional labeling on antidepressants, FDA currently recommends that a patient medication guide explaining the risks associated with the drugs be provided to the patient each time the drugs are dispensed. Caregivers of pediatric patients whose depression is persistently worse or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality during antidepressant therapy should consult their clinician regarding the best course of action (e.g., whether the therapeutic regimen should be changed or the drugs discontinued).Patients should not discontinue use of selective serotonin-reuptake inhibitors without first consulting their clinician; it is very important that the drugs not be abruptly discontinued (see Dosage and Administration: Dosage), as withdrawal effects may occur.

Anyone considering the use of sertraline in a child or adolescent for any clinical use must balance the potential risk of therapy with the clinical need.

Geriatric Precautions

In clinical studies in geriatric patients, 660 patients receiving sertraline for the treatment of depression were 65 years of age or older, and 180 were 75 years of age or older. No overall differences in efficacy or adverse effects were observed for geriatric patients in these studies relative to younger patients, and other clinical experience has revealed no evidence of age-related differences in safety. In addition, no adverse effects on psychomotor performance were observed in geriatric individuals who received the drug in one controlled study. However, the possibility that older patients may exhibit increased sensitivity to the drug cannot be excluded.(See Dosage in Geriatric Patients under Dosage and Administration.)

Limited evidence suggests that geriatric patients may be more likely than younger patients to develop sertraline-induced hyponatremia and transient syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Therefore, clinicians prescribing sertraline in geriatric patients should be aware of the possibility that such reactions may occur. Periodic monitoring (especially during the first several months) of serum sodium concentrations in geriatric patients receiving the drug has been recommended by some clinicians.(See Cautions: Precautions and Contraindications.)

As with other psychotropic drugs, geriatric patients receiving antidepressants appear to have an increased risk of hip fracture. Despite the fewer cardiovascular and anticholinergic effects associated with selective serotonin-reuptake inhibitors (SSRIs), these drugs did not show any advantage over tricyclic antidepressants with regard to hip fracture in a case-control study. In addition, there was little difference in the rates of falls between nursing home residents receiving SSRIs and those receiving tricyclic antidepressants in a retrospective study. Therefore, all geriatric individuals receiving either type of antidepressant should be considered to be at increased risk of falls and appropriate measures should be taken.

In pooled data analyses, a reduced risk of suicidality was observed in adults 65 years of age or older with antidepressant therapy compared with placebo.(See Cautions: Precautions and Contraindications.)

Plasma clearance of sertraline may be decreased in geriatric patients; plasma clearance of the less active metabolite, N-desmethylsertraline, also may be decreased in older males.

Mutagenicity and Carcinogenicity

Sertraline was not mutagenic, with or without metabolic activation, in several in vitro tests including the bacterial mutation assay and the mouse lymphoma mutation assay. Sertraline also was not mutagenic in tests for cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes.

Lifetime studies to determine the carcinogenic potential of sertraline were performed in CD-1 mice and Long-Evans rats receiving dosages up to 40 mg/kg daily. This dosage corresponded to 1 and 2 times the maximum recommended human dose on a mg/m basis in mice and rats, respectively. There was a dose-related increase in the incidence of hepatic adenomas in male mice receiving sertraline dosages of 10-40 mg/kg (0.25-1 times the maximum recommended human dose on a mg/m basis). No increase was seen in female mice or in rats of either gender receiving the same dosages, nor was there an increase in hepatocellular carcinomas. Hepatic adenomas have a variable rate of spontaneous occurrence in this strain of mice, and the relevance of this finding to humans is not known. There was an increase in follicular adenomas of the thyroid, not accompanied by thyroid hyperplasia, in female rats receiving a sertraline dosage of 40 mg/kg (2 times the maximum recommended human dose on a mg/m basis). There also was an increase in uterine adenocarcinomas in rats receiving sertraline dosages of 10-40 mg/kg (0.5-2 times the maximum recommended human dose on a mg/m basis); however, this effect could not be directly attributed to the drug.

Pregnancy, Fertility, and Lactation

Pregnancy

Some neonates exposed to sertraline and other SSRIs or SNRIs late in the third trimester of pregnancy have developed complications that have sometimes been severe and required prolonged hospitalization, respiratory support, enteral nutrition, and other forms of supportive care in special-care nurseries. Such complications can arise immediately upon delivery and usually last several days or up to 2-4 weeks. Clinical findings reported in the neonates have included respiratory distress, cyanosis, apnea, seizures, temperature instability or fever, feeding difficulty, dehydration, excessive weight loss, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, lethargy, reduced or lack of reaction to pain stimuli, and constant crying. These clinical features appear to be consistent with either a direct toxic effect of the SSRI or SNRI or, possibly, a drug withdrawal syndrome. It should be noted that in some cases the clinical picture was consistent with serotonin syndrome (see Drug Interactions: Serotonergic Drugs).

Infants exposed to SSRIs in late pregnancy may have an increased risk of persistent pulmonary hypertension of the newborn (PPHN). PPHN is a rare heart and lung condition occurring in an estimated 1-2 infants per 1000 live births in the general population; it occurs when a neonate does not adapt to breathing outside the womb. Some experts have suggested that respiratory distress in neonates exposed to SSRIs may occur along a spectrum of seriousness in association with maternal use of SSRIs, with PPHN among the most serious consequences. Neonates with PPHN may require intensive care support, including mechanical ventilation; in severe cases, multiple organ damage, including brain damage, and even death may occur. Although several epidemiologic studies have suggested an increased risk of PPHN with SSRI use during pregnancy, other studies did not demonstrate a statistically significant association. Thus, the FDA states that it is currently unclear whether use of SSRIs, including sertraline, during pregnancy can cause PPHN and recommends that clinicians not alter their current clinical practice of treating depression during pregnancy.

When treating a pregnant woman with sertraline during the third trimester of pregnancy, the clinician should carefully consider the potential risks and benefits of such therapy. Clinicians should consider that in a prospective longitudinal study of 201 women with a history of recurrent major depression who were euthymic in the context of antidepressant therapy at the beginning of pregnancy, women who discontinued their antidepressant medication (SSRIs, tricyclic antidepressants, or others) during pregnancy were found to be substantially more likely to have a relapse of depression than were women who continued to receive their antidepressant therapy while pregnant. Consideration may be given to cautiously tapering sertraline therapy in the third trimester prior to delivery if the drug is administered during pregnancy.(See Treatment of Pregnant Women during the Third Trimester under Dosage and Administration: Dosage.)

For additional information on the management of depression in women prior to conception and during pregnancy, including treatment algorithms, the FDA advises clinicians to consult the joint American Psychiatric Association and American College of Obstetricians and Gynecologists guidelines (at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3103063/pdf/nihms293836.pdf).

Most epidemiologic studies of pregnancy outcome following first-trimester exposure to SSRIs, including sertraline, conducted to date have not revealed evidence of an increased risk of major congenital malformations. In a prospective, controlled, multicenter study, maternal use of several SSRIs (sertraline, fluvoxamine, paroxetine) in a limited number of pregnant women did not appear to increase the risk of congenital malformation, miscarriage, stillbirth, or premature delivery when used during pregnancy at recommended dosages. Birth weight and gestational age in neonates exposed to the drugs were similar to those in the control group. In another small study based on medical records review, the incidence of congenital anomalies reported in infants born to women who were treated with sertraline and other SSRIs during pregnancy was comparable to that observed in the general population. However, the results of epidemiologic studies indicate that exposure to paroxetine during the first trimester of pregnancy may increase the risk for congenital malformations, particularly cardiovascular malformations. Additional epidemiologic studies are needed to more thoroughly evaluate the relative safety of sertraline and other SSRIs during pregnancy, including their potential teratogenic risks and possible effects on neurobehavioral development.

The manufacturers state that there are no adequate and controlled studies to date using sertraline in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the potential risks to the fetus. Women should be advised to notify their clinician if they become pregnant or plan to become pregnant during therapy with the drug. FDA states that women who are pregnant or thinking about becoming pregnant should not discontinue any antidepressant, including sertraline, without first consulting their clinician. The decision whether or not to continue antidepressant therapy should be made only after careful consideration of the potential benefits and risks of antidepressant therapy for each individual pregnant patient. If a decision is made to discontinue treatment with sertraline or other SSRIs before or during pregnancy, discontinuance of therapy should be done in consultation with the clinician in accordance with the prescribing information for the antidepressant and the patient should be closely monitored for possible relapse of depression.

Reproduction studies in rats using sertraline dosages up to 80 mg/kg daily and in rabbits using dosages up to 40 mg/kg daily have not revealed evidence of teratogenicity; these dosages correspond to approximately 4 times the maximum recommended human dosage on a mg/m basis. No evidence of teratogenicity was observed at any dosage studied. When pregnant rats and rabbits were given sertraline during the period of or

Drug Interactions

Serotonergic Drugs

Use of selective serotonin-reuptake-inhibitors (SSRIs) such as sertraline concurrently or in close succession with other drugs that affect serotonergic neurotransmission may result in serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions. Symptoms of serotonin syndrome 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 GI symptoms (e.g., nausea, vomiting, diarrhea). Although the syndrome appears to be relatively uncommon and usually mild in severity, serious and potentially life-threatening complications, including seizures, disseminated intravascular coagulation, respiratory failure, and severe hyperthermia as well as death occasionally have been reported. In its most severe form, serotonin syndrome may resemble NMS, which is characterized by hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation in vital signs, and mental status changes. The precise mechanism of these reactions is not fully understood; however, they appear to result from excessive serotonergic activity in the CNS, probably mediated by activation of serotonin 5-HT1A receptors. The possible involvement of dopamine and 5-HT2 receptors also has been suggested, although their roles remain unclear.

Serotonin syndrome most commonly occurs when 2 or more drugs that affect serotonergic neurotransmission are administered either concurrently or in close succession. Serotonergic agents include those that increase serotonin synthesis (e.g., the serotonin precursor tryptophan), stimulate synaptic serotonin release (e.g., some amphetamines, dexfenfluramine [no longer commercially available in the US], fenfluramine [no longer commercially available in the US]), inhibit the reuptake of serotonin after release (e.g., SSRIs, selective serotonin- and norepinephrine-reuptake inhibitors [SNRIs], tricyclic antidepressants, trazodone, dextromethorphan, meperidine, tramadol), decrease the metabolism of serotonin (e.g., MAO inhibitors), have direct serotonin postsynaptic receptor activity (e.g., buspirone), or nonspecifically induce increases in serotonergic neuronal activity (e.g., lithium salts). Selective agonists of serotonin (5-hydroxytryptamine; 5-HT) type 1 receptors (''triptans'') and dihydroergotamine, agents with serotonergic activity used in the management of migraine headache, and St. John's wort (Hypericum perforatum) also have been implicated in serotonin syndrome.

The combination of SSRIs and MAO inhibitors may result in serotonin syndrome or NMS-like reactions. Such reactions have also been reported in patients receiving SSRIs concomitantly with tryptophan, lithium, dextromethorphan, sumatriptan, dihydroergotamine, or antipsychotics or other dopamine antagonists. In rare cases, serotonin syndrome reportedly has occurred in patients receiving the recommended dosage of a single serotonergic agent (e.g., clomipramine) or during accidental overdosage (e.g., sertraline intoxication in a child). Some other drugs that have been implicated in precipitating symptoms suggestive of serotonin syndrome or NMS-like reactions include buspirone, bromocriptine, dextropropoxyphene, linezolid, methylene blue, methylenedioxymethamphetamine (MDMA; ''ecstasy''), selegiline (a selective MAO-B inhibitor), and sibutramine (an SNRI used for the management of obesity [no longer commercially available in the US]). Other drugs that have been associated with the syndrome but for which less convincing data are available include carbamazepine, fentanyl, and pentazocine.

Clinicians should be aware of the potential for serious, possibly fatal reactions associated with serotonin syndrome or NMS-like reactions in patients receiving 2 or more drugs that affect serotonergic neurotransmission, even if no such interactions with the specific drugs have been reported to date in the medical literature. Pending further accumulation of data, serotonergic drugs should be used cautiously in combination and such combinations avoided whenever clinically possible. Serotonin syndrome may be more likely to occur when initiating therapy, increasing the dosage, or following the addition of another serotonergic drug. Some clinicians state that patients who have experienced serotonin syndrome may be at higher risk for recurrence of the syndrome upon reinitiation of serotonergic drugs. Pending further experience in such cases, some clinicians recommend that therapy with serotonergic agents be limited following recovery. In cases in which the potential benefit of the drug is thought to outweigh the risk of serotonin syndrome, lower potency agents and reduced dosages should be used, combination serotonergic therapy should be avoided, and patients should be monitored carefully for manifestations of serotonin syndrome. If signs and symptoms of serotonin syndrome or NMS develop during therapy, treatment with sertraline and any concurrently administered serotonergic or antidopaminergic agents, including antipsychotic agents, should be discontinued immediately and supportive and symptomatic treatment should be initiated.

For further information on serotonin syndrome, including manifestations and treatment, see Drug Interactions: Serotonergic Drugs, in Fluoxetine Hydrochloride 28:16.04.20.

Monoamine Oxidase Inhibitors

Potentially serious, sometimes fatal serotonin syndrome or NMS-like reactions have been reported in patients receiving SSRIs, including sertraline, in combination with an MAO inhibitor. Severe serotonin syndrome reaction developed several hours after initiating sertraline in a woman already receiving phenelzine, lithium, thioridazine, and doxepin. Such reactions also have been reported in patients who recently have discontinued an SSRI and have been started on an MAO inhibitor.

Because of the potential risk of serotonin syndrome or NMS-like reactions, concomitant use of sertraline and MAO inhibitors is contraindicated. At least 2 weeks should elapse between discontinuance of MAO inhibitor therapy and initiation of sertraline therapy and vice versa.

Linezolid

Linezolid, an anti-infective agent that is a nonselective and reversible MAO inhibitor, has been associated with drug interactions resulting in serotonin syndrome, including some associated with SSRIs, and potentially may also cause NMS-like reactions. Because of the risk of serotonin syndrome, linezolid generally should not be used in patients receiving sertraline. The US Food and Drug Administration (FDA) states that certain life-threatening or urgent situations may necessitate immediate linezolid treatment in a patient receiving a serotonergic drug, including SSRIs. In such emergency situations, the availability of alternative anti-infectives should be considered and the benefits of linezolid should be weighed against the risk of serotonin syndrome. If linezolid is indicated in such emergency situations, sertraline must be immediately discontinued and the patient monitored for symptoms of CNS toxicity (e.g., mental changes, muscle twitching, excessive sweating, shivering/shaking, diarrhea, loss of coordination, fever) for 2 weeks or until 24 hours after the last linezolid dose, whichever comes first. Treatment with sertraline may be resumed 24 hours after the last linezolid dose.

If nonemergency use of linezolid is being planned for a patient receiving sertraline, sertraline should be withheld for at least 2 weeks prior to initiating linezolid.

Treatment with sertraline should not be initiated in a patient receiving linezolid; when necessary, sertraline may be started 24 hours after the last linezolid dose. (See )

Methylene Blue

There have been case reports of serotonin syndrome in patients who received methylene blue, which is a potent and selective inhibitor of MAO-A, while receiving serotonergic drugs, including SSRIs (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline). Therefore, methylene blue generally should not be used in patients receiving sertraline. The FDA states that certain emergency situations (e.g., methemoglobinemia, ifosfamide-induced encephalopathy) may necessitate immediate use of methylene blue in a patient receiving sertraline. In such emergency situations, the availability of alternative interventions should be considered and the benefits of methylene blue should be weighed against the risk of serotonin syndrome. If methylene blue is indicated in such emergency situations, sertraline must be immediately discontinued and the patient monitored for symptoms of CNS toxicity (e.g., mental changes, muscle twitching, excessive sweating, shivering/shaking, diarrhea, loss of coordination, fever) for 2 weeks or until 24 hours after the last methylene blue dose, whichever come first. Treatment with sertraline may be resumed 24 hours after the last methylene blue dose.

If nonemergency use of methylene blue is being planned for a patient receiving sertraline, sertraline should be withheld for at least 2 weeks prior to initiating methylene blue.

Treatment with sertraline should not be initiated in a patient receiving methylene blue; when necessary, sertraline may be started 24 hours after the last methylene blue dose.

Moclobemide

Moclobemide (not commercially available in the US), a selective and reversible MAO-A inhibitor, has been associated with serotonin syndrome, and such reactions have been fatal in several cases in which the drug was given in combination with the SSRI citalopram or with clomipramine. Pending further experience with such combinations, some clinicians recommend that concurrent therapy with moclobemide and SSRIs be used only with extreme caution and that SSRIs should have been discontinued for some time (depending on the elimination half-lives of the drug and its active metabolites) before initiating moclobemide therapy.

Selegiline

Selegiline, a selective MAO-B inhibitor used in the management of parkinsonian syndrome, has been reported to cause serotonin syndrome when given concurrently with SSRIs (e.g., fluoxetine, paroxetine, sertraline). Although selegiline is a selective MAO-B inhibitor at therapeutic dosages, the drug appears to lose its selectivity for the MAO-B enzyme at higher dosages (e.g., those exceeding 10 mg/kg), thereby increasing the risk of serotonin syndrome in patients receiving higher dosages of the drug either alone or in combination with other serotonergic agents. The manufacturer of selegiline recommends avoiding concurrent selegiline and SSRI therapy. In addition, the manufacturer of selegiline recommends that at least 2 weeks elapse between discontinuance of selegiline and initiation of SSRI therapy.

Isoniazid

Isoniazid, an antituberculosis agent, appears to have some MAO-inhibiting activity. In addition, iproniazid (not commercially available in the US), another antituberculosis agent structurally related to isoniazid that also possesses MAO-inhibiting activity, reportedly has resulted in serotonin syndrome in at least 2 patients when given in combination with meperidine. Pending further experience, clinicians should be aware of the potential for serotonin syndrome when isoniazid is given in combination with SSRI therapy (such as sertraline) or other serotonergic agents.

Tryptophan and Other Serotonin Precursors

Because of the potential risk of serotonin syndrome or NMS-like reactions, concurrent use of tryptophan or other serotonin precursors should be avoided in patients receiving sertraline.

5-HT1 Receptor Agonists (''Triptans'')

Weakness, hyperreflexia, and incoordination have been reported rarely during postmarketing surveillance in patients receiving sumatriptan concomitantly with an SSRI (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline); these reactions resembled serotonin syndrome. Oral or subcutaneous sumatriptan and SSRIs were used concomitantly in some clinical studies without unusual adverse effects. However, an increase in the frequency of migraine attacks and a decrease in the effectiveness of sumatriptan in relieving migraine headache have been reported in a patient receiving subcutaneous injections of sumatriptan intermittently while undergoing fluoxetine therapy.

Clinicians prescribing 5-HT1 receptor agonists, SSRIs, and SNRIs should consider that 5-HT1 receptor agonists often are used intermittently and that either the 5-HT1 receptor agonist, SSRI, or SNRI may be prescribed by a different clinician. Clinicians also should weigh the potential risk of serotonin syndrome or NMS-like reactions with the expected benefit of using a 5-HT1 receptor agonist concurrently with SSRI or SNRI therapy. If concomitant treatment with sumatriptan or another 5-HT1 receptor agonist and sertraline is clinically warranted, the patient should be observed carefully, particularly during treatment initiation, dosage increases, and following the addition of other serotonergic agents. Patients receiving concomitant 5-HT1 receptor agonist and SSRI or SNRI therapy should be informed of the possibility of serotonin syndrome or NMS-like reactions and advised to immediately seek medical attention if they experience signs or symptoms of these syndromes.

Sibutramine

Because of the possibility of developing potentially serious, sometimes fatal serotonin syndrome or NMS-like reactions, sibutramine (no longer commercially available in the US) should be used with caution in patients receiving sertraline.

Other Selective Serotonin-reuptake Inhibitors and Selective Serotonin- and Norepinephrine-reuptake Inhibitors

Concomitant administration of sertraline with other SSRIs or SNRIs potentially may result in serotonin syndrome or NMS-like reactions and is therefore not recommended.(See Dosage and Administration: Dosage.)

Antipsychotic Agents and Other Dopamine Antagonists

Concomitant use of antipsychotic agents and other dopamine antagonists with sertraline rarely may result in potentially serious, sometimes fatal serotonin syndrome or NMS-like reactions. If signs and symptoms of serotonin syndrome or NMS occur, treatment with sertraline and any concurrently administered antidopaminergic or serotonergic agents should be immediately discontinued and supportive and symptomatic treatment initiated.(See Drug Interactions: Clozapine and also see Drug Interactions: Pimozide.)

Tramadol and Other Serotonergic Drugs

Because of the potential risk of serotonin syndrome or NMS-like reactions, caution is advised whenever SSRIs, including sertraline, and SNRIs are concurrently administered with other drugs that may affect serotonergic neurotransmitter systems, including tramadol and St. John's wort (Hypericum perforatum).

Drugs Undergoing Hepatic Metabolism or Affecting Hepatic Microsomal Enzymes

Animal studies have demonstrated that sertraline induces hepatic microsomal enzymes. In humans, microsomal enzyme induction by sertraline was minimal as determined by a small (5%) but statistically significant decrease in antipyrine half-life following sertraline administration (200 mg daily) for 21 days. The manufacturers state that this small change in antipyrine half-life reflects a clinically unimportant change in hepatic metabolism. Nonetheless, caution should be exercised when sertraline is given to patients receiving drugs that are hepatically metabolized and that have a low therapeutic ratio, such as warfarin.(See Drug Interactions: Protein-bound Drugs and also see Anticoagulants under Drug Interactions: Drugs Affecting Hemostasis.)

Drugs Metabolized by Cytochrome P-450 (CYP) 2D6

Sertraline, like many other antidepressants (e.g., other SSRIs, many tricyclic antidepressants) is metabolized by the drug-metabolizing cytochrome P-450 (CYP) 2D6 isoenzyme (debrisoquine hydroxylase). In addition, like many other drugs metabolized by CYP2D6, sertraline inhibits the activity of CYP2D6 and potentially may increase plasma concentrations of concomitantly administered drugs that also are metabolized by this isoenzyme. Although similar interactions are possible with other SSRIs, there is considerable variability among the drugs in the extent to which they inhibit CYP2D6. At lower doses, sertraline has demonstrated a less prominent inhibitory effect on CYP2D6 than some other SSRIs. Nevertheless, even sertraline has the potential for clinically important CYP2D6 inhibition.

Concomitant use of sertraline with other drugs metabolized by CYP2D6 has not been systematically studied. The extent to which this potential interaction may become clinically important depends on the extent of inhibition of CYP2D6 by the antidepressant and the therapeutic index of the concomitantly administered drug. The drugs for which this potential interaction is of greatest concern are those that are metabolized principally by CYP2D6 and have a narrow therapeutic index, such as tricyclic antidepressants, class IC antiarrhythmics (e.g., propafenone, flecainide, encainide), and some phenothiazines (e.g., thioridazine).

Caution should be used whenever concurrent therapy with sertraline and other drugs metabolized by CYP2D6 is considered. Because concomitant use of sertraline and thioridazine may result in increased plasma concentrations of the phenothiazine and increase the risk of serious, potentially fatal, adverse cardiac effects (e.g., cardiac arrhythmias), the manufacturer of thioridazine states that the drug should not be used concomitantly with any drug that inhibits the CYP2D6 isoenzyme. The manufacturers of sertraline state that concurrent use of a drug metabolized by CYP2D6 may necessitate the administration of dosages of the other drug that are lower than those usually prescribed. Furthermore, whenever sertraline therapy is discontinued (and plasma concentrations of sertraline are decreased) during concurrent therapy with another drug metabolized by CYP2D6, an increased dosage of the concurrently administered drug may be necessary.

Drugs Metabolized by Cytochrome P-450 (CYP) 3A4

Although sertraline can inhibit the cytochrome P-450 (CYP) 3A4 isoenzyme, results of in vitro and in vivo studies indicate that the drug is a much less potent inhibitor of this enzyme than many other drugs. In an in vivo drug interaction study, concomitant use of sertraline and the CYP3A4 substrate, carbamazepine, under steady-state conditions had no effect on plasma concentrations of carbamazepine. The manufacturers of sertraline state that these data suggest that the extent of sertraline's inhibition of CYP3A4 activity is unlikely to be of clinical importance. However, a marked increase in plasma concentrations (ranging from 80-250%) and bone marrow suppression developed within 1-2 months of initiating sertraline in a patient previously stabilized on carbamazepine and flecainide therapy. Although the precise mechanism for this possible interaction and the role of the cytochrome P-450 enzyme system are unclear, some clinicians recommend that carbamazepine concentrations be monitored during concomitant sertraline therapy.

Results of an in vivo drug interaction study with cisapride indicate that concomitant use of sertraline (200 mg daily) induces the metabolism of cisapride; peak plasma concentrations and area under the plasma concentration-time curve (AUC) of cisapride were decreased by about 35% in the study. However, the manufacturers of sertraline state that the extent of sertraline's inhibition of CYP3A4 activity is unlikely to be of clinical importance.

Results of another drug interaction study in which sertraline was used concomitantly with terfenadine (no longer commercially available in the US), a drug metabolized principally by the cytochrome P-450 microsomal enzyme system (mainly by the CYP3A4 isoenzyme), indicate that concurrent use of sertraline did not increase plasma concentrations of terfenadine and, therefore, the manufacturers state that these data suggest that the extent of sertraline's inhibition of CYP3A4 activity is unlikely to be of clinical importance. However, the manufacturer of astemizole (no longer commercially available in the US) and some clinicians state that until the clinical importance of these findings is established, concomitant use of sertraline with astemizole or terfenadine is not recommended since substantially increased plasma concentrations of unchanged astemizole or terfenadine could occur resulting in an increased risk of serious adverse cardiac effects.

Tricyclic and Other Antidepressants

The extent to which SSRI interactions with tricyclic antidepressants may pose clinical problems depends on the degree of inhibition and the pharmacokinetics of the serotonin-reuptake inhibitor involved. In healthy individuals, sertraline has been shown to substantially reduce the clearance of two tricyclic antidepressants, desipramine and imipramine. This interaction appears to result from sertraline-induced inhibition of CYP2D6. Thus, the manufacturers and some clinicians recommend that caution be exercised during concurrent use of tricyclics with sertraline since sertraline may inhibit the metabolism of the tricyclic antidepressant. In addition, plasma tricyclic concentrations may need to be monitored and the dosage of the tricyclic reduced during concomitant administration.(See Dosage and Administration: Dosage and also see Drugs Metabolized by Cytochrome P-450 [CYP] 2D6 under Drug Interactions: Drugs Undergoing Hepatic Metabolism or Affecting Hepatic Microsomal Enzymes.)

Clinical experience regarding the optimal timing of switching from other antidepressants to sertraline therapy is limited. Therefore, the manufacturers recommend that care and prudent medical judgment be exercised when switching from other antidepressants to sertraline, particularly from long-acting agents (e.g., fluoxetine). Pending further experience in patients being transferred from therapy with another antidepressant to sertraline and as the clinical situation permits, it generally is recommended that the previous antidepressant be discontinued according to the recommended guidelines for the specific antidepressant prior to initiation of sertraline therapy.(See Drug Interactions: Serotonergic Drugs.)

Protein-bound Drugs

Because sertraline is highly protein bound, the drug theoretically could be displaced from binding sites by, or it could displace from binding sites, other protein-bound drugs such as oral anticoagulants or digitoxin. In vitro studies to date have shown that sertraline has no effect on the protein binding of 2 other highly protein-bound drugs, propranolol or warfarin; these findings also have been confirmed in clinical studies. However, pending further accumulation of data, patients receiving sertraline concomitantly with any highly protein-bound drug should be observed for potential adverse effects associated with combined therapy.(See Anticoagulants under Drug Interactions: Drugs Affecting Hemostasis.)

Drugs Affecting Hemostasis

Anticoagulants

In a study comparing prothrombin time AUC (0-120 hour) following a dose of warfarin (0.75 mg/kg) or placebo prior to and after 21 days of either sertraline (50-200 mg daily) or placebo, prothrombin time increased by an average of 8% compared with baseline in the sertraline group and decreased by an average of 1% in those receiving placebo. In addition, the normalization of prothrombin time was slightly delayed in those receiving sertraline when compared with those receiving placebo. Because the clinical importance of these findings is not known, prothrombin time should be monitored carefully whenever sertraline therapy is initiated or discontinued in patients receiving anticoagulants.(See Drug Interactions: Protein-bound Drugs.)

Other Drugs That Interfere with Hemostasis

Epidemiologic case-control and cohort design studies that have demonstrated an association between selective serotonin-reuptake inhibitor therapy and an increased risk of upper GI bleeding also have shown that concurrent use of aspirin or other nonsteroidal anti-inflammatory agents substantially increases the risk of GI bleeding. Although these studies focused on upper GI bleeding, there is some evidence suggesting that bleeding at other sites may be similarly potentiated. The precise mechanism for this increased risk remains to be clearly established; however, serotonin release by platelets is known to play an important role in hemostasis, and selective serotonin-reuptake inhibitors decrease serotonin uptake from the blood by platelets, thereby decreasing the amount of serotonin in platelets. Patients receiving sertraline should be cautioned about the concomitant use of drugs that interfere with hemostasis, including aspirin and other nonsteroidal anti-inflammatory agents.

Alcohol

Sertraline administration did not potentiate the cognitive and psychomotor effects induced by alcohol in healthy individuals. In addition, no apparent additive CNS depressant effects were observed in geriatric patients receiving sertraline together with moderate amounts of alcohol. Nonetheless, the manufacturers state that concurrent use of sertraline and alcohol is not recommended.

Electroconvulsive Therapy

The effects of sertraline in conjunction with electroconvulsive therapy (ECT) have not been evaluated to date in clinical studies.

Cimetidine

In a study evaluating the effect of the addition of a single dose of sertraline (100 mg) on the second of 8 days of cimetidine administration (800 mg daily), the mean AUC, peak concentration, and elimination half-life of sertraline increased substantially (by 50, 24, and 26%, respectively) compared with the placebo group. The clinical importance of these changes is unknown.

Benzodiazepines

In a study comparing the disposition of diazepam administered IV before and after 21 days of sertraline therapy (dosage titrated from 50-200 mg daily) or placebo, there was a 32% decrease in diazepam clearance in the sertraline recipients and a 19% decrease in those receiving placebo when compared with baseline. There was a 23% increase in the time to maximal plasma concentration for desmethyldiazepam in the sertraline group compared with a 20% decrease in the placebo group. The clinical importance of these findings is unknown; however, they suggest that sertraline and N-desmethylsertraline are not likely to substantially inhibit the CYP2C19 and CYP3A3/4 hepatic isoenzymes involved in the metabolism of diazepam.

Clozapine

Concomitant use of SSRIs such as sertraline in patients receiving clozapine can increase plasma concentrations of the antipsychotic agent. In a study in schizophrenic patients receiving clozapine under steady-state conditions, initiation of paroxetine therapy resulted in only minor changes in plasma concentrations of clozapine and its metabolites; however, initiation of fluvoxamine therapy resulted in increases that were threefold compared with baseline. In other published reports, concomitant use of clozapine and SSRIs (fluvoxamine, paroxetine, sertraline) resulted in modest increases (less than twofold) in clozapine and metabolite concentrations. The manufacturer of clozapine states that caution should be exercised and patients closely monitored if clozapine is used in patients receiving SSRIs, and a reduction in clozapine dosage should be considered. (See Antipsychotic Agents and Other Dopamine Antagonists under Drug Interactions: Serotonergic Drugs.)

Lithium

In a placebo-controlled trial, the administration of 2 doses of sertraline did not substantially alter steady-state plasma lithium concentrations or the renal clearance of lithium. Pending further accumulation of data, however, the manufacturers recommend that plasma lithium concentrations be monitored following initiation of sertraline in patients receiving lithium and that lithium dosage be adjusted accordingly. In addition, because of the potential risk of serotonin syndrome or NMS-like reactions, caution is advised during concurrent sertraline and lithium use.(See Drug Interactions: Serotonergic Drugs.)

Hypoglycemic Drugs

In a placebo-controlled study in healthy male volunteers, sertraline administration for 22 days (including 200 mg daily for the final 13 days) caused a small but statistically significant decrease (16%) in the clearance of a 1-g IV dose of tolbutamide compared with baseline values and an increase in the terminal elimination half-life (from 6.9 to 8.6 hours). The decrease in clearance was not accompanied by any substantial changes in the plasma protein binding or the apparent volume of distribution of tolbutamide, which suggests that the change in tolbutamide clearance may be caused by a slight inhibition of the cytochrome P-450 isoenzyme CYP2C9/10 when sertraline is given in the maximum recommended dosage. The clinical importance of these findings remains to be determined.

Digoxin

In a placebo-controlled trial in healthy volunteers, sertraline administration for 17 days (including 200 mg daily for the final 10 days) did not alter serum digoxin concentrations or renal clearance of digoxin. The results of this study suggest that dosage adjustment of digoxin may not be necessary in patients receiving concomitant sertraline.

Atenolol

In a double-blind, placebo-controlled, randomized, crossover study, a single, 100-mg dose of sertraline had no effect on the β-adrenergic blocking activity of atenolol when administered to a limited number of healthy males.

Amiodarone

A decrease in the plasma concentrations of amiodarone and its active metabolite, desmethylamiodarone, to 82 and 85% of the baseline values, respectively, occurred in one patient following the discontinuance of sertraline and carbamazepine therapy, suggesting that sertraline may have been inhibiting the metabolism of amiodarone by CYP3A4.

Phenytoin

In a randomized, double-blind, placebo-controlled trial, chronic administration of high dosages of sertraline (200 mg daily) did not substantially affect the pharmacokinetics or pharmacodynamics of phenytoin when the 2 drugs were given concurrently in healthy volunteers. However, substantial reductions in plasma sertraline concentrations have been observed in sertraline-treated patients concurrently receiving phenytoin; it was suggested that induction of the cytochrome P-450 isoenzymes may be responsible. In addition, concurrent administration of sertraline and phenytoin reportedly resulted in elevated phenytoin concentrations in 2 geriatric patients. Pending further accumulation of data, the manufacturers and some clinicians recommend that plasma phenytoin concentrations be monitored following initiation of sertraline therapy and that phenytoin dosage should be adjusted as necessary, particularly in patients with multiple underlying medical conditions and/or those receiving multiple concomitant drugs.

Pimozide

Concomitant use of sertraline and pimozide has resulted in substantial increases in peak plasma concentrations and area under the plasma concentration-time curve (AUC) of pimozide. In one controlled study, administration of a single 2-mg dose of pimozide in individuals receiving sertraline 200 mg daily resulted in a mean increase in pimozide AUC and peak plasma concentrations of about 40%, but was not associated with changes in ECG parameters. The effects on QT interval and pharmacokinetic parameters of pimozide administered in higher doses (i.e., doses exceeding 2 mg) in combination with sertraline are as yet unknown. Concomitant use of sertraline and pimozide is contraindicated because of the low therapeutic index of pimozide and because the reported interaction between the 2 drugs occurred at a low dose of pimozide. The mechanism of this interaction is as yet unknown. (See Antipsychotic Agents and Other Dopamine Antagonists under Drug Interactions: Serotonergic Drugs.)

Valproic Acid

The effect of sertraline on plasma valproic acid concentrations remains to be evaluated in clinical studies. In the absence of such data, the manufacturers recommend monitoring plasma valproic acid concentrations following initiation of sertraline therapy and adjusting the dosage of valproic acid as necessary.

Pharmacokinetics

In all human studies described in the Pharmacokinetics section, sertraline was administered as the hydrochloride salt; dosages and concentrations are expressed in terms of sertraline.

Absorption

Sertraline appears to be slowly but well absorbed from the GI tract following oral administration. The oral bioavailability of sertraline in humans has not been fully elucidated to date because a preparation for IV administration is not available. However, the relative proportion of an oral dose that reaches systemic circulation unchanged appears to be relatively small because sertraline undergoes extensive first-pass metabolism. In animals, the oral bioavailability of sertraline ranges from 22-36%. The manufacturers state that the bioavailability of a single dose of sertraline hydrochloride tablets is approximately equal to that of an equivalent dose of sertraline hydrochloride oral solution. In a study in healthy adults who received a single 100-mg dose of sertraline as a tablet or oral solution, the solution to tablet ratios of the mean geometric AUC and peak plasma concentration were 114.8 and 120.6%, respectively.

The effect of food on the absorption of sertraline hydrochloride given as tablets or the oral solution has been studied in single-dose studies. Administration of a sertraline hydrochloride tablet with food slightly increased the area under the concentration-time curve (AUC) of sertraline, increased peak plasma concentrations by approximately 25%, and decreased the time to achieve peak plasma concentrations from about 8 to 5.5 hours. Administration of sertraline hydrochloride oral solution with food increased the time to achieve peak plasma concentrations from 5.9 to 7.0 hours.

Peak plasma sertraline concentrations usually occur within 4.5-8.4 hours following oral administration of 50-200 mg once daily for 14 days. Peak plasma sertraline concentrations following administration of single oral doses of 50-200 mg are proportional and linearly related to dose. Peak plasma concentrations and bioavailability are increased in geriatric individuals.

Following multiple dosing, steady-state plasma sertraline concentrations should be achieved after approximately 1 week of once-daily dosing. When compared with a single dose, there is an approximate twofold accumulation of sertraline after multiple daily dosing in dosages ranging from 50-200 mg daily.N-Desmethylsertraline, sertraline's principal metabolite, exhibits time-related, dose-dependent increases in AUC (0-24 hour), peak plasma concentrations, and trough plasma concentrations with about a 5- to 9-fold increase in these parameters between day 1 and 14.

As with other serotonin-reuptake inhibitors, the relationship between plasma sertraline and N-desmethylsertraline concentrations and the therapeutic and/or toxic effects of the drug has not been clearly established.

Distribution

Distribution of sertraline and its metabolites into human body tissues and fluids has not been fully characterized. However, limited pharmacokinetic data suggest that the drug and some of its metabolites are widely distributed in body tissues. Although the apparent volume of distribution of sertraline has not been determined in humans, values exceeding 20 L/kg have been reported in rats and dogs. The drug crosses the blood-brain barrier in humans and animals.

At in vitro plasma concentrations ranging from 20-500 ng/mL, sertraline is approximately 98% bound to plasma proteins, principally to albumin and α1-acid glycoprotein. Protein binding is independent of plasma concentrations from 20-2000 mcg/mL. However, sertraline and N-desmethylsertraline did not alter the plasma protein binding of 2 other highly protein bound drugs, warfarin or propranolol, at concentrations of 300 and 200 ng/mL, respectively.

Sertraline and N-desmethylsertraline are distributed into milk. In a study involving 12 lactating women who received oral dosages of sertraline ranging from 25-200 mg daily, both sertraline and N-desmethylsertraline were present in all breast milk samples, with the highest concentrations observed in hind milk 7-10 hours after the maternal dose. Detectable concentrations of sertraline were found in 3 and N-desmethylsertraline in 6, respectively, out of 11 nursing infants.

Elimination

The elimination half-life of sertraline averages approximately 25-26 hours and that of desmethylsertraline averages about 62-104 hours. In geriatric adults elimination half-life may be increased (e.g., to about 36 hours); however, such prolongation does not appear clinically important and does not warrant dosing alterations.

The exact metabolic fate of sertraline has not been fully elucidated. Sertraline appears to be extensively metabolized, probably in the liver, to N-desmethylsertraline and several other metabolites. Like some other serotonin-reuptake inhibitors, sertraline undergoes metabolism via N-demethylation to form N-desmethylsertraline, the principal metabolite. Unlike some other serotonin-reuptake inhibitors, the drug metabolizing isoenzyme CYP2D6 (a cytochrome P-450 isoenzyme implicated in the sparteine/debrisoquine polymorphism) does not appear to have a major role in the conversion of sertraline to N-desmethylsertraline. Nonetheless, sertraline has the potential for clinically important inhibition of this enzyme.(See Drug Interactions: Drugs Undergoing Hepatic Metabolism or Affecting Hepatic Microsomal Enzymes.) In vitro, the conversion of sertraline to N-desmethylsertraline correlates more with CYP3A3/4 activity than with CYP2D6 activity. Data from in vivo and in vitro studies have shown that N-desmethylsertraline is approximately 5-10 times less potent as an inhibitor of serotonin reuptake than sertraline; however, the metabolite retains selectivity for serotonin reuptake compared with either norepinephrine or dopamine reuptake. Both sertraline and desmethylsertraline undergo oxidative deamination and subsequent reduction, hydroxylation, and glucuronide conjugation. Desmethylsertraline has an elimination half-life approximately 2.5 times that of sertraline.

Following oral administration, sertraline and its metabolites are excreted in both urine and feces. Following oral administration of a single, radiolabeled dose in 2 healthy males, unchanged sertraline accounted for less than 5% of plasma radioactivity. Approximately 40-45% of the radiolabeled dose was excreted in urine within 9 days. Unchanged sertraline was not detectable in urine. During the same period, approximately 40-45% of the radiolabeled drug was eliminated in feces, including 12-14% of unchanged sertraline.

The effect of age on the elimination of sertraline has not been fully elucidated. Plasma clearance of sertraline was approximately 40% lower in a group of 16 geriatric patients (8 males and 8 females) who received 100 mg of the drug for 14 days than that reported in a similar study involving younger individuals (from 25-32 years of age). Based on these results, the manufacturers state that steady-state should be achieved in about 2-3 weeks in older individuals. In addition, decreased clearance of N-desmethylsertraline was noted in older males but not in older females.(See Dosage and Administration: Dosage in Geriatric Patients.)

Because sertraline is extensively metabolized by the liver, hepatic impairment can affect the elimination of the drug. In one study in patients with chronic mild hepatic impairment (Child-Pugh scores of 5-8) who received 50 mg of sertraline daily for 21 days, sertraline clearance was reduced resulting in a 2-3 times greater exposure to the drug and its metabolite (desmethylsertraline) than that reported for age-matched individuals without hepatic impairment. In a single-dose study in patients with mild, stable cirrhosis, the elimination half-life of sertraline was prolonged to a mean of 52 hours compared with 22 hours in individuals without hepatic disease. In addition, peak plasma concentrations and AUC values for sertraline were 1.7- and 4.4-fold higher, respectively, in patients with hepatic impairment when compared with healthy individuals without liver disease, reflecting decreased clearance of the drug. The pharmacokinetics of sertraline have not been studied to date in patients with moderate and severe hepatic impairment; therefore, the manufacturers recommend that sertraline be administered with caution and in reduced dosage or less frequently in patients with hepatic impairment.(See Cautions: Precautions and Contraindications and see Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Because sertraline is extensively metabolized in the liver and renal clearance of the drug is negligible, the manufacturers state that clinically important decreases in sertraline clearance are not anticipated if the drug is used in patients with renal impairment. Results of a multiple-dose study indicate that the pharmacokinetics of sertraline are not affected by renal impairment. In this study, individuals with mild to moderate renal impairment (creatinine clearance: 30-60 mL/minute), moderate to severe renal impairment (creatinine clearance: 10-29 mL/minute), or severe renal impairment (undergoing hemodialysis) received 200 mg of sertraline daily for 21 days; the pharmacokinetics and protein binding of the drug in these patients were similar to those reported for age-matched individuals without renal impairment.(See Cautions: Precautions and Contraindications and see Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Limited data indicate that sertraline is not appreciably removed by hemodialysis. Because of the large volume of distribution of sertraline and its principal metabolite, peritoneal dialysis, forced diuresis, hemoperfusion, and/or exchange transfusion also are likely to be ineffective in removing substantial amounts of sertraline and N-desmethylsertraline from the body.

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