Sertraline, a selective serotonin-reuptake inhibitor (SSRI), is an antidepressant agent.1, 611
Sertraline hydrochloride is used in the treatment of major depressive disorder in adults.1, 10, 11, 33, 148, 149, 150, 151, 152, 159, 339, 341, 611 Sertraline also has been used for the treatment of major depressive disorder in pediatric patients ≥10 years of age† .639
The efficacy of sertraline for the acute treatment of major depressive disorder in adults was established in 2 placebo-controlled studies in adult outpatients who met Diagnostic and Statistical Manual of Mental Disorders (DSM)-III criteria for major depression.1, 11, 151, 611 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.1, 11, 611 In the second study of 6 weeks' duration, sertraline was administered in fixed doses of 50, 100, and 200 mg daily.1, 151 These 2 studies demonstrated that sertraline was superior to placebo in improving scores on the Hamilton Depression Rating Scale and the Clinical Global Impression (CGI) Severity and Improvement Scales.1, 11, 151, 611
In a third study, outpatients with major depressive disorder 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 receive placebo for 44 weeks in a double-blind manner.1 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.1, 611
An analysis of these 3 controlled studies for possible gender-related effects on treatment outcome did not suggest any difference in efficacy based on gender.1, 611
Most clinical studies have shown that the antidepressant effect of usual dosages of sertraline in patients with depression is greater than placebo1, 11, 151, 152 and comparable to usual dosages of tricyclic antidepressants (TCAs; e.g., amitriptyline),10, 11, 152 other selective serotonin reuptake inhibitors (SSRIs; e.g., fluoxetine),148, 150 and other antidepressants (e.g., nefazodone).149 In geriatric patients with major depression, sertraline appears to be as effective as amitriptyline.10, 11 The onset of action of sertraline appears to be comparable to that of TCAs.10, 11, 152
Treatment options for major depressive disorder include pharmacologic and nonpharmacologic (e.g., psychotherapy) approaches.613, 614, 615, 616 Several classes of antidepressant drugs are available for treatment of major depressive disorder.613, 614, 615, 616 In general, these drugs have shown similar effectiveness; therefore, treatment is guided by specific patient- and drug-related factors.613, 615, 616
A legacy practice guideline from the American Psychiatric Association (APA) states that the effectiveness of antidepressants for major depressive disorder is comparable between and within classes, including SSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs), TCAs, monoamine oxidase inhibitors (MAOIs), and other antidepressants (e.g., bupropion, mirtazapine, trazodone).613 Therefore, initial selection of an antidepressant can be based on: patient preference; prior response to medication; safety, tolerability, and anticipated adverse effects; concurrent psychiatric and medical conditions; specific properties of the medication (e.g., half-life, actions on cytochrome P-450 [CYP] isoenzymes, other drug interactions); and cost.613
The Department of Veterans Affairs and Department of Defense have developed guidelines for the management of major depressive disorder in adults.614 Treatment of uncomplicated major depressive disorder can be initiated with either psychotherapy (e.g., cognitive behavioral therapy) or pharmacotherapy, depending on patient preference; for patients with severe, persistent, or recurrent major depressive disorder, a combination of pharmacotherapy and psychotherapy is suggested.614 When pharmacotherapy is used as initial therapy, either bupropion, mirtazapine, an SSRI, SNRI, trazodone, vilazodone, or vortioxetine is suggested.614 There is no evidence to suggest superiority of one agent over another.614 The guidelines recommend against using esketamine, ketamine, MAOIs, nefazodone, or TCAs as initial therapy.614 For patients not responding to initial therapy, recommendations include switching to another antidepressant (including MAOIs or TCAs), switching to or augmenting with psychotherapy, or augmenting with a second-generation antipsychotic.614
The American Academy of Pediatrics (AAP) and the American Academy of Child & Adolescent Psychiatry (AACAP) have developed guidelines for the management of adolescent depression in primary care, providing recommendations for pediatric and young adult patients.639, 640 The AAP guidelines focus on adolescent patients 10-21 years of age and state that for moderate and/or severe depression, primary care clinicians should recommend scientifically tested and proven treatments including psychotherapies and/or antidepressant treatment.639 When antidepressant treatment is indicated by clinical presentation and patient and family preference, an SSRI should be used.639 The AACAP guidelines suggest cognitive-behavioral therapy and interpersonal therapy could be offered to children and adolescents with major depressive disorder or persistent depressive disorder.640 An SSRI other than paroxetine (preferably fluoxetine) could be offered to children and adolescents with major depressive disorder.640 The specific SSRI to be used (e.g., citalopram, escitalopram, fluoxetine, or sertraline) should be based on safety and efficacy data, as well as potential drug interactions, favorable experiences of a family member, cost, and availability of the medication.639, 640
Sertraline hydrochloride is used in the treatment of obsessive-compulsive disorder (OCD) in adults and pediatric patients ≥6 years of age.1, 611
The efficacy of sertraline for the management of OCD has been established in several multicenter, placebo-controlled studies, including one study of 8 weeks' duration in adults, 2 studies of 12 weeks' duration in adults and one study of 80 weeks' duration in adults and one study of 12 weeks' duration in children and adolescents 6-17 years of age.1, 156, 611, 612, 617 Patients in these studies had moderate to severe OCD with mean baseline Yale-Brown Obsessive-Compulsive Scale (YBOCS) scores of 23-25 in adults and 22 in children and adolescents (measured in the Children's Yale-Brown Obsessive-Compulsive Scale [CY-BOCS]).1, 156, 611, 617 In the 8-week study with flexible dosing, adult patients received sertraline ranging from 50-200 mg daily; the mean dosage for those completing the study was 186 mg daily.1, 156 Total scores on the YBOCS decreased by an average of approximately 4 points in sertraline-treated patients, which was substantial as compared to the 2-point decreases in patients receiving placebo.1, 156
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 YBOCS score than those receiving placebo (approximately 6 to approximately 3 points, respectively).1, 156 In a 12-week study with flexible dosing ranging from 50-200 mg daily, the mean sertraline dosage in adult patients completing the study was 185 mg daily.1 YBOCS scores in 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 placebo-treated patients.1
In an 80-week study involving sertraline dosages of 50-200 mg daily, adults 18-79 years of age who had responded during a 52-week placebo-controlled trial were randomized to continue sertraline or matching placebo for up to an additional 28 weeks.1, 611, 612 Response was defined as a decrease in YBOCS score of ≥25% compared to baseline and CGI Severity and Improvement Scale score of 1 (very much improved), 2 (much improved), or 3 (minimally improved).1, 611, 612 Efficacy at the end of the 80-week period was assessed based on risk reduction of OCD relapse.1, 611, 612 Relapse was defined as an increase in YBOCS score by ≥5 points from baseline (to a minimum of 20 points relative to baseline) on 3 consecutive visits, an increase in CGI Severity and Improvement Scale score by ≥1 point on 3 consecutive visits, and observed worsening of the patient's condition that, in the investigator's judgement, justified an alternative treatment on the third visit.1, 611, 612 Among the 109 patients randomized to sertraline, there was a substantially lower rate of discontinuation due to relapse or insufficient clinical response at the end of the 80-week trial compared to the 114 patients randomized to placebo.1, 611, 612
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.1, 611, 617 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.1, 611, 617 The drug produced substantially greater reductions in scores in the CY-BOCS, the National Institute of Mental Health Global Obsessive-Compulsive Scale (NIMH-OC), and the CGI Severity and Improvement Scale score; total scores on the CY-BOCS decreased by an average of approximately 7 points in sertraline-treated patients and 3 points in patients receiving placebo.1, 611, 617 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 age or gender of the patient.1, 611
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 than SSRIs (as determined by measures on the YBOCS), although all drugs were superior to placebo.227 Like clomipramine, SSRIs reduce but do not completely eliminate obsessions and compulsions.1
Legacy practice guidelines from the APA include cognitive-behavioral therapy and pharmacotherapy as safe and effective first-line treatments for OCD.619 For pharmacotherapy, SSRIs (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) are first-line.619 All SSRIs appear to be equally effective, but individual patient response is variable; when selecting an SSRI, clinicians should consider the safety and acceptability of particular side effects for the patient, potential drug interactions, past treatment response, and the presence of comorbid medical conditions.619 If a patient does not respond to one SSRI, they may switch to a different SSRI, switch to clomipramine, augment their current SSRI with a second-generation antipsychotic, switch to venlafaxine, or switch to mirtazapine.619 Updated guidelines from international experts state that escitalopram, fluvoxamine, fluoxetine, paroxetine, and sertraline are first-line treatments for OCD.618
A practice parameter from AACAP provides recommendations for the treatment of OCD in children and adolescents.644 Cognitive-behavioral therapy (CBT) is recommended when possible as first-line treatment for mild to moderate cases of OCD; drug therapy is indicated in addition to CBT in cases of moderate to severe OCD.644 SSRIs (e.g., sertraline, fluvoxamine, fluoxetine, paroxetine) are the first-line medications recommended by AACAP.644 Guidelines from international experts state fluvoxamine, fluoxetine, and sertraline are first-line drugs for OCD in children and adolescents.618
Sertraline hydrochloride is used for panic disorder with or without agoraphobia in adults.1 Sertraline hydrochloride has also been used for panic disorder in pediatric patients ≥6 years of age† .641
The efficacy of sertraline for panic disorder was established in 3 double-blind, placebo-controlled studies in adult patients who met DSM-III-R criteria for panic disorder with or without agoraphobia.1, 630, 631, 632 The first 2 studies were of 10 weeks' duration and used a flexible dosing schedule.1, 630, 631 Sertraline therapy was initiated at 25 mg daily for the first week and then escalated to 50-200 mg daily depending on clinical response and tolerability.1, 630, 631 The mean sertraline dosages for those completing the study were 131 and 144 mg daily for the first 2 studies.1 Overall, these 2 studies demonstrated sertraline was superior to placebo in decreasing the frequency of panic attacks and improving scores on the CGI Severity of Illness and Global Improvement Scales.1, 630, 631 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.1
The third study was a fixed-dose study of 12 weeks' duration.1, 632 Sertraline was given in dosages of 50, 100, and 200 mg daily.1, 632 Patients receiving sertraline demonstrated substantially greater reduction in panic attack frequency than patients receiving placebo.1, 632 However, results of this study were not readily interpretable regarding a dose-response relationship for efficacy in this condition.1
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.1
Efficacy of sertraline for panic disorder has also been assessed in an 80-week study consisting of a 52-week open-label period and a 28-week double-blind period.1, 633 Adult patients who responded to treatment with sertraline 50-200 mg daily during the open-label period were randomized to continue sertraline or matching placebo for the double-blind period.1, 633 Response was defined as a CGI Severity and Improvement Scale score of 1 (very much improved) or 2 (much improved).1, 633 Efficacy at the end of the double-blind period was measured by panic disorder relapse, defined as a CGI Severity and Improvement Scale score ≥3, meeting the DSM-III-R criteria for panic disorder, and a greater number of panic attacks than at baseline for 3 consecutive visits.1, 633 Among the 183 patients randomized to sertraline or placebo at week 52, there was a substantially lower rate of discontinuation due to relapse or insufficient clinical response for patients receiving sertraline versus placebo at the end of the study.1, 633
Legacy guidelines from the APA state SSRIs, SNRIs, TCAs, benzodiazepines, and cognitive behavioral therapy have all demonstrated efficacy for the initial treatment of panic disorder.620 Evidence is insufficient to recommend any of these pharmacological or psychosocial interventions over others; choice of initial therapy should be based on patient preference, past treatment history, presence of comorbid medical or psychiatric conditions, potential adverse effects, potential drug interactions, cost, and treatment availability.620 For patients who prefer to initiate pharmacological treatment, SSRIs and SNRIs are typically recommended first line.620 TCAs and benzodiazepines have similar efficacy to SSRIs and SNRIs, but are less favorable as initial therapy due to their adverse effect profiles and warnings for use.620 Updated guidelines from international experts state that first-line medications for panic disorder include citalopram, escitalopram, fluvoxamine, fluoxetine, paroxetine, sertraline, and venlafaxine.621
The AACAP guideline for the assessment and treatment of children and adolescents with anxiety disorders provides recommendations for pediatric patients with panic disorder.641 Cognitive-behavioral therapy is recommended for patients 6-18 years of age with panic disorder.641 AACAP also recommends an SSRI be offered to patients in this age group.641 The specific SSRI used (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, or vilazodone) should be based on pharmacokinetics, pharmacodynamics, tolerability, cost, and unique risks, warnings, or precautions associated with the medication.641
Sertraline hydrochloride is used for posttraumatic stress disorder (PTSD).1, 270
The efficacy of sertraline for PTSD has been established in 2 placebo-controlled studies of 12 weeks' duration in adult patients (76% women) who met DSM-III-R criteria for chronic PTSD (duration of symptoms 3 months or longer).1, 270, 634 The mean duration of PTSD for these patients was approximately 12 years and 44% of patients had secondary depressive disorders.1 Sertraline was initiated at 25 mg daily for the first week and then escalated (using a flexible dosage schedule) to 50-200 mg daily based on clinical response and tolerability.1, 270 The mean sertraline dosage for patients who completed studies 1 and 2 was 146 mg and 151 mg daily, respectively.1, 270, 634 Overall, these 2 studies showed that sertraline was superior to placebo in improving scores on the Clinician-Administered PTSD Scale Part 2 (CAPS) 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 CGI Severity of Illness and Global Improvement Scales.1, 270, 634
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.1 One of these studies was conducted primarily in male veterans while the other had a similar patient population of the prior 2 placebo-controlled studies.1
Since PTSD is a more common disorder in women than men, the majority (76%) of patients in reported studies were women.1, 270 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, CGI Scale) in women (regardless of a baseline diagnosis of comorbid depression), but essentially no effect in the limited number of men studied.1 The clinical importance of this apparent gender effect is unknown.1 There are insufficient data to determine whether race or age has any effect on the efficacy of sertraline for PTSD.1
Efficacy of sertraline for PTSD has been assessed in a 28-week, double-blind, placebo-controlled, relapse prevention study.1, 635 Adult patients who responded to sertraline during a 24-week trial were randomized to continue sertraline 50-200 mg daily or placebo.1, 635 Response was defined as a CGI Improvement score of ≥3; a CAPS-2 score increased by ≥30% and by ≥15 points relative to baseline; and worsening of the patient's condition in the investigator's judgment.1, 635 Of the 96 patients randomized, there was substantially lower relapse rate in patients receiving sertraline compared to placebo at the end of the 28-week double-blind period.1, 635
A Cochrane review of pharmacological treatments for PTSD found beneficial effects in treatment response with SSRIs collectively compared to placebo.636 Treatment response was defined by a CGI Improvement Scale score of either 1 (very much improved) or 2 (much improved).636 Benefit was also noted for treatment response with the SSRIs paroxetine and sertraline when evaluated individually.636
Legacy guidelines from the APA state that treatment for PTSD involves 3 different approaches, used alone or in combination: psychopharmacology, psychotherapy, and education/supportive measures.622 The selection of a specific treatment strategy depends on patient-specific factors, such as age, gender, history, comorbid medical and psychiatric conditions, and propensity for aggression or self-harm.622 SSRIs are considered the first-line treatment for patients with PTSD because they have been shown to improve all major symptoms of PTSD (reexperiencing, avoidance/numbing, and hyperarousal), are effective treatments for common comorbidities of PTSD (e.g., depression, panic disorder, social anxiety disorder, OCD), may reduce clinical symptoms that often complicate PTSD (e.g., suicidal, impulsive, and aggressive behaviors), and have relatively few side effects.622 SSRIs with evidence for efficacy in PTSD include fluoxetine, sertraline, and paroxetine.622
The Department of Veterans Affairs and Department of Defense have developed guidelines for the treatment of PTSD.623 These guidelines recommend specific types of psychotherapy (e.g., cognitive processing therapy, eye movement desensitization and reprocessing, prolonged exposure therapy) over pharmacologic interventions for PTSD.623 If pharmacologic therapy is used, the guidelines recommend paroxetine, sertraline, or venlafaxine; there is insufficient evidence to recommend for or against other medications (including other SSRIs).623
Premenstrual Dysphoric Disorder
Sertraline hydrochloride is used for premenstrual dysphoric disorder (PMDD) in adults.1, 140, 160, 637
The efficacy of sertraline for 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.1 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 CGI of Severity of Illness and Improvement, and/or the Hamilton Depression Rating Scales (HAMD-17).1, 637 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.1
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 (e.g., depressive symptoms, physical symptoms, anger/irritability) and functional impairment associated with this disorder.140 The beneficial effect of the drug was apparent by the first treatment cycle.140 In an open study comparing sertraline and desipramine in the treatment of PMDD, sertraline and possibly desipramine were found to be effective; however, sertraline was better tolerated than desipramine.160 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.140, 160 In addition, efficacy of sertraline used in conjunction with oral contraceptives for PMDD has not been determined since patients receiving oral contraceptives were excluded from most clinical studies.1, 140
The American College of Obstetricians and Gynecologists (ACOG) has published a clinical practice guideline on the management of premenstrual disorders, including PMDD.624 Treatment options for premenstrual disorders range from lifestyle and behavioral interventions to medical management with SSRIs or hormonal agents.624 Many patients may benefit from a multimodal approach to management.624 In this guideline, ACOG recommends SSRIs for affective premenstrual symptoms; SSRIs with evidence to support their use in PMDD include sertraline, paroxetine, and fluoxetine.624 SSRIs may be administered continuously or intermittently (i.e., during the luteal phase).624
Sertraline hydrochloride is used for social anxiety disorder in adults.1 Sertraline hydrochloride has also been used for social anxiety disorder in pediatric patients ≥6 years of age.†.641
The efficacy of sertraline for social anxiety disorder has been established in 2 multicenter, placebo-controlled studies in adult outpatients who met DSM-IV criteria for social anxiety disorder.1 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 CGI Global Improvement Scale) compared with 26% receiving placebo (intent-to-treat analysis).638 Sertraline 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 situations, 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.1, 638 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).281 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 responded to placebo in the initial study and continued to receive placebo in the subsequent study.282 Based on an intent-to-treat analysis, 4% of patients who continued treatment with sertraline, 36% of patients randomized to 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.282
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.1 There was insufficient information to determine the effect of race or age on treatment outcome.1
Guidelines from international experts state that escitalopram, fluvoxamine, paroxetine, sertraline, and venlafaxine are recommended first-line agents for the pharmacological treatment of social anxiety disorder.621
The AACAP guideline for the assessment and treatment of children and adolescents with anxiety disorders provides recommendations for pediatric patients with social anxiety disorder.641 Cognitive-behavioral therapy is recommended for patients 6-18 years of age with social anxiety disorder.641 AACAP also recommends that an SSRI be offered to patients in this age group.641 The specific SSRI used (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, or vilazodone) should be based on pharmacokinetics, pharmacodynamics, tolerability, cost, and unique risks, warnings, or precautions associated with the medication.641
Like some other SSRIs, sertraline has been used with some success for premature ejaculation†.67, 217, 218, 219 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.218 The drug was well tolerated in most patients.218 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.217
Guidelines from the American Urological Association and the Sexual Medicine Society of North America strongly recommend daily SSRIs, on-demand clomipramine, and topical penile anesthetics as first-line agents for premature ejaculation.628 Daily treatment with paroxetine, sertraline, fluoxetine, citalopram, or clomipramine has been found to be effective in delaying ejaculation; on-demand administration of clomipramine, paroxetine, sertraline, or fluoxetine 3-6 hours prior to intercourse is modestly efficacious, but with substantially less ejaculatory delay than daily treatment.628
Sertraline hydrochloride has been used for generalized anxiety disorder in adults and pediatric patients ≥6 years of age†. 621 641
Guidelines from international experts state the SSRIs escitalopram, paroxetine, and sertraline, as well as the SNRIs venlafaxine and duloxetine, are first-line treatments for adults with generalized anxiety disorder.621
The AACAP guideline for assessment and treatment of children and adolescents with anxiety disorders provides recommendations for pediatric patients with generalized anxiety disorder.641 Cognitive-behavioral therapy is recommended for patients 6-18 years of age with generalized anxiety disorder.641 AACAP also recommends that an SSRI be offered to patients in this age group.641 The specific SSRI to be used (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, or vilazodone) should be based on pharmacokinetics, pharmacodynamics, tolerability, cost, and unique risks, warnings, or precautions associated with the medication.641 Guidelines from international experts state fluvoxamine and sertraline are effective in treating generalized anxiety disorders and mixed anxiety disorders in children and adolescents.621
Sertraline hydrochloride has been used for bulimia nervosa† and binge-eating disorder† in adults.642, 643 Guidelines from the APA state adults with bulimia nervosa should be treated with eating-disorder specific cognitive-behavioral therapy and an SSRI (e.g., fluoxetine).642 For adults with binge-eating disorder who prefer medication or have not responded to psychotherapy alone, the APA suggests treatment with either an antidepressant medication or lisdexamfetamine.642 The specific role for sertraline is not discussed in the APA guideline.642 Guidelines from international experts for pharmacological treatment of eating disorders list SSRIs, including sertraline, as options for bulimia nervosa and binge-eating disorder.643 The use of sertraline for bulimia nervosa is based on data from a single 12-week placebo-controlled trial in 20 female patients.643 The use of sertraline for binge-eating disorder is based on data from 2 randomized, placebo-controlled trials and an open-label study.643
Dispensing and Administration Precautions
Sertraline is administered orally as tablets, capsules, or oral solution.1, 611 The drug usually is administered once daily in the morning or evening, with or without food.1, 3, 4, 5, 611
Commercially available sertraline hydrochloride concentrate for oral solution is a clear, colorless solution with a menthol scent containing 20 mg of sertraline per mL and 12% alcohol.1 When the oral solution is used, measure the dose carefully using the calibrated dropper provided by the manufacturer.1 The dropper has 25 mg and 50 mg graduation marks only.1 Dilute the appropriate dose in 4 ounces (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade, or orange juice before administration.1 Mix the diluted solution and administer immediately.1 A slight haze may occasionally appear in the diluted oral solution, but the manufacturer states that this is normal.1 Sertraline hydrochloride oral solution should be diluted only in the liquids specified by the manufacturer, and should be used immediately after dilution.1
Swallow sertraline capsules whole; do not open, crush, or chew the capsules.611
Store sertraline tablets, capsules, and concentrate for oral solution at 20-25°C (excursions permitted between 15-30°C).1, 611
Dosage of sertraline hydrochloride is expressed in terms of sertraline.1 The capsule formulation is only approved for use in the treatment of major depressive disorder in adults and obsessive-compulsive disorder in adults and pediatric patients ≥6 years of age.611
The initial dosage of sertraline is 50 mg orally once daily.1 In patients with an inadequate response, increase the dosage in increments of 25-50 mg per day at intervals of at least 1 week, depending on tolerability, to a maximum dosage of 200 mg daily.1
Do not initiate treatment with sertraline capsules since the only available dose strengths are 150 mg and 200 mg.611 Use sertraline tablets or oral solution for initial dosage, titration, and dosages below 150 mg once daily.611 Sertraline capsules can be administered in patients receiving 100 mg or 125 mg of sertraline for at least 1 week.611 The recommended dosage of sertraline capsules is 150 mg or 200 mg once daily; the maximum recommended dosage is 200 mg once daily.611
The starting dosage is 50 mg orally once daily.1 In patients with an inadequate response, increase dosage in increments of 25-50 mg per day at intervals of at least 1 week, depending on tolerability, to a maximum dosage of 200 mg daily.1
Do not initiate treatment with sertraline capsules since the only available dose strengths are 150 mg and 200 mg.611 Use sertraline tablets or oral solution for initial dosage, titration, and dosages below 150 mg once daily.611 Sertraline capsules can be administered in patients receiving 100 mg or 125 mg of sertraline for at least 1 week.611 The recommended dosage of sertraline capsules is 150 mg or 200 mg once daily; the maximum recommended dosage is 200 mg once daily.611
The starting dosage is 25 mg orally once daily.1 In patients with an inadequate response, increase dosage in increments of 25-50 mg per day at intervals of at least 1 week, depending on tolerability, to a maximum dosage of 200 mg daily.1
The starting dosage is 25 mg orally once daily.1 In patients with an inadequate response, increase dosage in increments of 25-50 mg per day at intervals of at least 1 week, depending on tolerability, to a maximum dosage of 200 mg daily.1
Premenstrual Dysphoric Disorder
The starting dosage is 50 mg orally once daily.1 The dosage can be administered continuously (daily throughout the menstrual cycle) or intermittently (only during the luteal phase of the menstrual cycle, i.e., starting the daily dosage 14 days prior to the anticipated onset of menstruation and continuing through the onset of menses).1 Intermittent dosing is repeated with each new cycle.1
For patients with an inadequate response with continuous dosing, increase dosage in increments of 50 mg per menstrual cycle up to 150 mg per day.1
For patients with an inadequate response with intermittent dosing, administer 50 mg per day during the first 3 days of dosing followed by 100 mg per day during the remaining days in the dosing cycle.1 Continue with 100 mg per day in subsequent cycles.1
The starting dosage is 25 mg orally once daily.1 In patients with an inadequate response, increase dosage in increments of 25-50 mg per day at intervals of at least 1 week, depending on tolerability, to a maximum dosage of 200 mg daily.1
For OCD in pediatric patients 6-12 years of age, the starting dosage is 25 mg orally once daily.1
For OCD in pediatric patients 13-17 years of age, the starting dosage is 50 mg orally once daily.1
In patients with an inadequate response, increase dosage in increments of 25-50 mg per day at intervals of at least 1 week, depending on tolerability, to a maximum dosage of 200 mg daily.1
Do not initiate treatment with sertraline capsules since the only available dose strengths are 150 mg and 200 mg.611 Use sertraline tablets or oral solution for initial dosage, titration, and dosages below 150 mg once daily.611 Sertraline capsules can be administered in patients receiving 100 mg or 125 mg of sertraline for at least 1 week.611 The recommended dosage of sertraline capsules is 150 mg or 200 mg once daily; the maximum recommended dosage is 200 mg once daily.611
For patients with mild hepatic impairment (Child Pugh score 5-6), half the recommended daily dosage should be used.1
Use in moderate (Child Pugh score 7-9) or severe hepatic impairment (Child Pugh score 10-15) is not recommended.1
Sertraline capsules are not recommended in patients with any level of hepatic impairment as they have not been studied in these patients.611 Dosage adjustments are not possible with the available strengths of sertraline capsules.611
The manufacturer states that no dosage adjustment is necessary in patients with mild to severe renal impairment.1, 611
Dosage selection for elderly patients should be conservative, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy.1, 611
Pharmacogenomic Considerations in Dosing
Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines provide dosing recommendations for sertraline based on CYP2C19 and CYP2B6 phenotypes.700 For patients identified as CYP2C19 or CYP2B6 ultrarapid, rapid, or normal metabolizers, initiate therapy with the recommended starting dosage.700 For CYP2C19 or CYP2B6 intermediate metabolizers, initiate therapy with the recommended starting dosage and consider a slower titration schedule and a lower maintenance dosage than CYP2C19 or CYP2B6 normal metabolizers.700 For CYP2C19 poor metabolizers, consider a lower starting dosage, slower titration schedule, and a 50% reduction of the standard maintenance dosage or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2C19.700 For CYP2B6 poor metabolizers, consider a lower starting dosage, slower titration schedule, and a 25% reduction of the standard maintenance dosage or select a clinically appropriate alternative antidepressant not predominantly metabolized by CYP2B6.700 No recommendations are given for patients with indeterminate CYP2C19 or CYP2B6 phenotypes.700
For patients identified as having variants in both CYP2C19 and CYP2B6 phenotypes, see Table 1 for CPIC recommendations.700
Phenotype by metabolizer type | CYP2B6 ultrarapid or rapid | CYP2B6 normal | CYP2B6 intermediate | CYP2B6 poor | CYP2B6 intermediate |
|---|---|---|---|---|---|
CYP2C19 ultrarapid or rapid | Initiate with recommended starting dosage. If no response, consider titrating to higher maintenance dosage or switching to an alternate agent not predominantly metabolized by CYP2C19 or CYP2B6 | Initiate with recommended starting dosage | Initiate with recommended starting dosage | Initiate with recommended starting dosage | Initiate with recommended starting dosage |
CYP2C19 normal | Initiate with recommended starting dosage | Initiate with recommended starting dosage | Initiate with recommended starting dosa consider a slower titration and lower maintenance dosage | Consider a lower starting dosage, slower titration, and a 25% reduction of the standard maintenance dosage as compared with CYP2B6 normal metabolizer. Or select an appropriate alternate antidepressant not predominantly metabolized by CYP2B6 | Initiate with recommended starting dosage |
CYP2C19 intermediate | Initiate with recommended starting dosage | Initiate with recommended starting dosa consider a slower titration and lower maintenance dosage | Initiate with recommended starting dosage. Consider a slower titration and lower maintenance dosage than normal metabolizers. | Consider a lower starting dosage, slower titration, and a 50% reduction of the standard maintenance dosage as compared with CYP2B6 normal metabolizers. | Initiate with recommended starting dosa consider a slower titration and lower maintenance dosage |
CYP2C19 poor | Consider a lower starting dosage, slower titration, and a 50% reduction of the standard maintenance dosage as compared with CYP2C19 normal metabolizers. Or select an appropriate alternate antidepressant not predominantly metabolized by CYP2C19. | Consider a lower starting dosage, slower titration, and a 50% reduction of the standard maintenance dosage as compared with CYP2C19 normal metabolizers. Or select an appropriate alternate antidepressant not predominantly metabolized by CYP2C19. | Consider a lower starting dosage, slower titration, and a 50% reduction of the standard maintenance dosage as compared with CYP2C19 normal metabolizers. Or select an appropriate alternate antidepressant not predominantly metabolized by CYP2C19. | Select an alternate antidepressant not primarily metabolized by CYP2C19 or CYP2B6. | Consider a lower starting dosage, slower titration, and a 50% reduction of the standard maintenance dosage as compared with CYP2C19 normal metabolizers. Or select an appropriate alternate antidepressant not predominantly metabolized by CYP2C19 |
CYP2C19 indeterminate | Initiate with recommended starting dosage | Initiate with recommended starting dosage | Initiate with recommended starting dosage. Consider a slower titration and lower maintenance dosage. | Consider a lower starting dosage, slower titration, and a 25% reduction of the standard maintenance dosage as compared with CYP2B6 normal metabolizer. Or select an appropriate alternate antidepressant not predominantly metabolized by CYP2B6 | No recommendation |
Increased Risk of Suicidal Thoughts and Behaviors in Children and Young Adults
A boxed warning about the increased risk of suicidal thoughts and behaviors in pediatric and young adult patients is included in the prescribing information for sertraline.1, 611 In pooled analyses of placebo-controlled trials of antidepressant drugs (including selective serotonin-reuptake inhibitors [SSRIs]) that included approximately 77,000 adult patients and over 4,400 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients ≤24 years of age was greater than in placebo-treated patients.1, 611 For patients <18 years of age, 14 additional cases of increased suicidal thoughts/behaviors per 1000 patients treated were observed compared to placebo; 5 additional cases per 1000 patients treated were observed in those between 18 and 24 years of age.1, 611 It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extend to longer-term use, i.e., beyond 4 months.1, 611 However, there is substantial evidence from studies in adults with major depressive disorder that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors.1, 611
Monitor all antidepressant-treated patients for any indication of clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of therapy, and at times of dosage changes.1, 611 Counsel family members or caregivers to monitor for changes and to alert the healthcare provider.1, 611 Consider changing the therapeutic regimen, including discontinuation of sertraline, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.1, 611
Other Warnings and Precautions
SSRIs, including sertraline, can precipitate serotonin syndrome, a potentially life-threatening condition.1, 611 The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines, and St. John's Wort) and with drugs that impair metabolism of serotonin (i.e., MAOIs).1, 611
Serotonin syndrome can also occur when these drugs are used alone.1, 611 Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or GI symptoms (e.g., nausea, vomiting, diarrhea).1, 611
The concomitant use of sertraline with MAOIs is contraindicated.1, 611 Do not initiate sertraline in a patient being treated with MAOIs such as linezolid or IV methylene blue.1, 611 If it is necessary to initiate treatment with an MAOI such as linezolid or IV methylene blue in a patient receiving sertraline, discontinue sertraline before initiating treatment with the MAOI.1, 611
Monitor all patients for the emergence of serotonin syndrome.1, 611 Discontinue treatment with sertraline and any concomitant serotonergic agents immediately if the above symptoms occur and initiate supportive symptomatic treatment.1, 611 If concomitant use with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.1, 611
Drugs that interfere with serotonin reuptake inhibition, including sertraline, increase the risk of bleeding events.1, 611 Concomitant use of aspirin, nonsteroidal anti-inflammatory agents (NSAIAs), other antiplatelet drugs, warfarin, and other anticoagulants may add to this risk.1, 611 Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding.1, 611 Based on data from the published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage.1, 611 Bleeding events related to drugs that interfere with serotonin reuptake have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.1, 611
Inform patients about the increased risk of bleeding associated with concomitant use of sertraline and antiplatelet agents or anticoagulants.1, 611 For patients taking warfarin, carefully monitor the INR.1, 611
Activation of Mania or Hypomania
In patients with bipolar disorder, treating a depressive episode with sertraline or another antidepressant may precipitate a mixed/manic episode.1, 611 During controlled clinical trials, patients with bipolar disorder were generally excluded; however, symptoms of mania or hypomania were reported in 0.4% of patients treated with sertraline.1, 611 Prior to initiating treatment, screen patients for any personal or family history of bipolar disorder, mania, or hypomania.1, 611
Adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt discontinuation, may include nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures.1, 611 Reduce sertraline dosage gradually rather than discontinuing abruptly.1, 611
Patients with a history of seizures were excluded from clinical studies evaluating the efficacy and safety of sertraline.1, 611 Use with caution in patients with a seizure disorder.1, 611
The pupillary dilation that occurs following use of many antidepressant drugs (including sertraline) may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.1, 611 Avoid use of antidepressants, including sertraline, in patients with untreated anatomically narrow angles.1, 611
Hyponatremia may occur as a result of treatment with SSRIs, including sertraline.1, 611 Cases with serum sodium lower than 110 mmol/L have been reported.1, 611 Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls.1, 611 Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.1, 611 In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).1, 611
In patients with symptomatic hyponatremia, discontinue sertraline and institute appropriate medical intervention.1, 611 Elderly patients, patients taking diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia with SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs).1, 611
False Positive Effects on Screening Tests for Benzodiazepines
False-positive urine immunoassay screening tests for benzodiazepines have been reported in patients taking sertraline.1, 611 This finding is due to lack of specificity of the screening test.1, 611 False-positive test results may be expected for several days following discontinuation of sertraline.1, 611 Confirmatory tests, such as gas chromatography/mass spectrometry, will help distinguish sertraline from benzodiazepines.1, 611
Post-marketing cases of QTc prolongation and torsades de pointes with sertraline have been reported.1, 611 Most reports were confounded by other risk factors.1, 611 In a thorough QTc study of 54 healthy adult subjects, there was a positive relationship between the length of the rate-adjusted QTc interval and serum sertraline concentration.1, 611 Use sertraline with caution in patients with risk factors for QTc prolongation.1, 611
Use of SSRIs, including sertraline, may cause symptoms of sexual dysfunction.1, 611 In male patients, SSRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction.1, 611 In female patients, SSRI use may result in decreased libido and delayed or absent orgasm.1, 611
It is important for prescribers to inquire about sexual function prior to initiation and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported.1, 611 When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder.1, 611 Discuss potential management strategies to support patients in making informed decisions about treatment.1, 611
Allergic Reactions to FD&C Yellow No. 5 (Tartrazine)
Sertraline capsules contain FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons.611 Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.611
The dropper dispenser for sertraline concentrate for oral solution contains dry natural rubber, a consideration for patients with latex sensitivity.1
Overall, available published epidemiologic studies of pregnant females exposed to sertraline in the first trimester suggest no difference in major birth defect risk compared to the background rate for major birth defects in comparator populations.1, 611 Studies that have reported specific major birth defects are inconclusive.1, 611
Animal studies have not demonstrated teratogenicity; however, delayed fetal ossification was observed when sertraline was administered during the period of organogenesis at doses less than the maximum recommended human dose (MRHD) in rats and doses 3.1 times the MRHD in rabbits on a mg/m2 basis in adolescents.1, 611 When sertraline was administered to female rats during the last third of gestation, there was an increase in the number of stillborn pups and pup deaths during the first 4 days after birth at the MRHD.1, 611
Data from observational studies report exposure to SSRIs, particularly in the month before delivery, is associated with a less than a 2-fold increase in the risk of postpartum hemorrhage.1, 611 Exposure to SSRIs and SNRIs, including sertraline, in late pregnancy may lead to increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding, and/or persistent pulmonary hypertension of the newborn (PPHN).1, 611 When treating a pregnant female with sertraline during the third trimester, carefully consider both the potential risks and benefits of treatment.1, 611 Monitor neonates exposed to sertraline in the third trimester of pregnancy for PPHN and drug discontinuation syndrome.1, 611
Females who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than females who continue antidepressants.1, 611 Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum.1, 611
There is a pregnancy exposure registry that monitors pregnancy outcomes in females exposed to antidepressants during pregnancy.1, 611 Advise patients to register by calling the National Pregnancy Registry for Antidepressants at 1-866-961-2388 or visiting online at [Web].1, 611
Sertraline oral solution contains 12% alcohol and is not recommended during pregnancy because there is no known safe level of alcohol exposure during pregnancy.1
Available data demonstrate low sertraline levels in human milk (average of 2% of maternal sertraline serum levels; range of 0-15% of maternal sertraline serum levels) with no adverse reactions observed in infants in a pooled analysis of 53 mother-infant pairs.1, 611 There are no data on the effects of sertraline on milk production.1, 611 Consider developmental and health benefits of breastfeeding along with the mother's clinical need for sertraline and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.1, 611
Safety and efficacy of sertraline in children with obsessive-compulsive disorder (OCD) younger than 6 years of age have not been established.1 Safety and efficacy of sertraline in pediatric patients with other disorders (e.g., major depressive disorder, panic disorder, posttraumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), social anxiety disorder) have not been established.1, 611 The overall adverse effect profile of sertraline in 281 pediatric patients who received sertraline in placebo-controlled clinical trials was generally similar to that seen in the adult clinical studies.1 As with other SSRIs, decreased appetite and weight loss have been observed in association with sertraline therapy.1
Monitor all patients being treated with antidepressants for clinical worsening, suicidal thoughts, and unusual changes in behavior, especially during the initial few months of treatment, or at times of dosage increases or decreases.1, 611 Monitor weight and growth in pediatric patients.1, 611
The oral sertraline solution contains 12% alcohol.1
The effect of age on the elimination of sertraline has not been fully elucidated.1, 83 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).1, 611 Based on these results, the manufacturers state that steady-state should be achieved in about 2-3 weeks in older individuals.1, 611 In addition, decreased clearance of the sertraline metabolite, N-desmethylsertraline, was noted in older males but not in older females.1, 611
Of the total number of patients in clinical studies of sertraline for major depressive disorder, OCD, panic disorder, PTSD, social anxiety disorder, and PMDD, 797 (17%) were ≥65 years of age and 197 (4%) were ≥75 years of age.1, 611
No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients.1, 611 In general, dosage selection for an elderly patient should be conservative, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.1, 611
In 354 geriatric patients treated with sertraline for major depressive disorder in placebo-controlled trials, the overall profile of adverse effects was generally similar to younger patients, except for tinnitus and arthralgia with an incidence of at least 2% and at a rate greater than placebo in geriatric patients.1, 611
SSRIs, including sertraline, and SNRIs have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction.1, 611
Because sertraline is extensively metabolized by the liver, hepatic impairment can affect the elimination of the drug.1, 83, 137 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 approximately 2-3 times greater exposure to the drug and its metabolite (desmethylsertraline) than that reported for age-matched individuals without hepatic impairment.1 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.137 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.137
The recommended dosage in patients with mild hepatic impairment (Child-Pugh score 5-6) is half the recommended dosage due to increased exposure in this patient population.1 Sertraline use is not recommended in patients with moderate (Child-Pugh score 7-10) or severe hepatic impairment (Child-Pugh score 10-15) because sertraline is extensively metabolized, and the effects in patients with moderate and severe hepatic impairment have not been studied.1
The use of sertraline capsules is not recommended in patients with hepatic impairment.611
Clinically important decreases in sertraline clearance are not anticipated if the drug is used in patients with renal impairment.1, 611 Results of a multiple-dose study indicate that the pharmacokinetics of sertraline are not affected by renal impairment.1, 611 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.1, 611 No dosage adjustment is needed in patients with mild to severe renal impairment.1, 611
Limited data indicate sertraline is not appreciably removed by hemodialysis.185 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.1, 83, 185
The most common adverse reactions in pooled placebo-controlled clinical trials (incidence of ≥5% and twice that observed in the placebo group) were nausea, diarrhea/loose stool, tremor, dyspepsia, decreased appetite, hyperhidrosis, ejaculation failure, and decreased libido.1, 611
Sertraline is a cytochrome P-450 (CYP) 2D6 inhibitor with less inhibitory effects at lower dosages.1, 611 In vivo and preclinical drug interaction studies demonstrate sertraline does not inhibit CYP3A4 activity; however, it may have some CYP3A4 and hepatic microsomal inducer activity.1, 611
Drugs Metabolized by Hepatic Microsomal Enzymes
Animal studies have demonstrated that sertraline induces hepatic microsomal enzymes.1 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.1, 83, 611 The manufacturer states that this small change in antipyrine half-life reflects a clinically unimportant change in hepatic metabolism.1, 83, 611 Nonetheless, caution should be exercised when sertraline is given to patients receiving drugs that are hepatically metabolized and that have a low therapeutic index, such as warfarin.83
CYP2D6 Substrates
Sertraline, like many other antidepressants (e.g., other selective serotonin-reuptake inhibitors [SSRIs], many tricyclic antidepressants [TCAs]), inhibits the activity of CYP2D6 and potentially may increase plasma concentrations of concomitantly administered drugs that also are metabolized by this isoenzyme.1, 100, 611 Although similar interactions are possible with other SSRIs, there is considerable variability among the drugs in the extent to which they inhibit CYP2D6.1, 100, 611 At lower doses, sertraline has demonstrated a less prominent inhibitory effect on CYP2D6 than some other SSRIs.1, 100, 611 Nevertheless, even sertraline has the potential for clinically important CYP2D6 inhibition.1, 611 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 TCAs, class IC antiarrhythmics (e.g., propafenone, flecainide, encainide), and some phenothiazines (e.g., thioridazine).1, 100, 611
Caution should be used whenever concurrent therapy with sertraline and other drugs metabolized by CYP2D6 is considered.1, 611 Examples of drugs metabolized by CYP2D6 include propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thioridazine, tolterodine, and venlafaxine.1, 611 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.1, 611 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.1, 611
CYP3A4 Substrates
Results of in vitro and in vivo studies of concomitant administration of sertraline with the CYP3A4 substrates terfenadine, carbamazepine, and cisapride did not increase plasma concentrations of these drugs.1, 611 These data indicate sertraline's inhibition of CYP3A4 activity is not likely to be of clinical significance.1, 611
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 AUC of cisapride were decreased by about 35% in the study.1, 611 However, the manufacturers of sertraline state that the extent of sertraline's inhibition of CYP3A4 activity is unlikely to be of clinical importance.1, 611
Use of SSRIs such as sertraline concurrently with other drugs that affect serotonergic neurotransmission increases the risk of serotonin syndrome.1, 611 Examples of serotonergic drugs include other SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), triptans, TCAs, opioids, lithium, tryptophan, buspirone, amphetamines, and St. John's Wort.1, 611
Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases.1, 611 If serotonin syndrome occurs, consider discontinuation of sertraline and/or concomitant serotonergic drugs.1, 611
Drugs Highly Bound to Plasma Protein
Sertraline is highly protein bound.1, 611 The concomitant use of sertraline with another drug that is highly bound to plasma protein (e.g., warfarin) may increase free concentrations of sertraline or other tightly-bound drugs in plasma.1, 611
Monitor for adverse reactions and reduce dosage of sertraline or other protein-bound drugs as warranted.1, 611
Drugs that Interfere with Hemostasis
Concurrent use of sertraline with an antiplatelet agent or anticoagulant such as aspirin, clopidogrel, heparin, or warfarin can potentiate the risk of bleeding.1, 611 Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline and antiplatelet or anticoagulant agents.1, 611 For patients taking warfarin, closely monitor the INR.1, 611
Use of SSRIs such as sertraline concurrently with monoamine oxidase inhibitors (MAOIs), including selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, and methylene blue, increases the risk of serotonin syndrome.1, 611 Concomitant use of sertraline with MAOIs is contraindicated; at least 14 days should elapse after discontinuing an MAOI before starting therapy with sertraline.1, 611 If it is necessary to initiate treatment with an MAOI such as linezolid or IV methylene blue in a patient taking sertraline, discontinue sertraline before initiating treatment with the MAOI.1, 611
Drugs that Prolong the QTc Interval
The risk of QTc prolongation and/or ventricular arrhythmias (e.g., torsades de pointes) is increased with concomitant use of other drugs that prolong QTc interval.1, 611 Examples include specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol); specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol, or tacrolimus).1, 611
Avoid concomitant use of drugs known to prolong the QTc interval.1, 611 Pimozide is contraindicated for use with sertraline.1, 611
Sertraline administration did not potentiate the cognitive and psychomotor effects induced by alcohol in healthy individuals.1, 3, 19, 34, 35, 83, 146, 611
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.1, 83, 84, 611 No dosage adjustment of atenolol is required.1, 611
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.1, 611 No dosage adjustment of sertraline is required.1, 611
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.1, 136, 611 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.1,r611 136, No dosage adjustment of diazepam is required.1, 611
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.1, 83, 172, 611 No dosage adjustment of digoxin is required.1, 611
Due to the alcohol content of the solution, the concomitant use of the sertraline oral solution with disulfiram is contraindicated.1
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.1, 335, 611 No dosage adjustment of lithium is required.1, 611 In addition, because of the potential risk of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution is advised during concurrent sertraline and lithium use.1, 611
Since sertraline can increase phenytoin concentrations and phenytoin is a narrow therapeutic index drug, monitor phenytoin levels when initiating or titrating sertraline.1, 611 Reduce phenytoin dosage if needed.1, 611
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.1, 611 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 unknown.1, 611 Concomitant use of sertraline and pimozide is contraindicated because of the low therapeutic index of pimozide and the reported interaction between the 2 drugs occurred at a low dose of pimozide.1, 611
Sertraline is a selective serotonin-reuptake inhibitor (SSRI).1 Sertraline potentiates serotonergic activity in the central nervous system through inhibition of neuronal reuptake of serotonin.1 Studies at clinically relevant doses have demonstrated that sertraline blocks the uptake of serotonin into human platelets.1, 611 In vitro studies in animals also suggest that sertraline is a potent and selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal reuptake.1, 611 In vitro studies have shown that sertraline has no significant affinity for adrenergic, cholinergic, gamma-aminobutyric acid (GABA), dopaminergic, histaminergic, serotonergic (5-HT1A, 5-HT1B, 5-HT2), or benzodiazepine receptors.1, 611 The chronic administration of sertraline was found in animals to down regulate brain norepinephrine receptors.1, 611 Sertraline does not inhibit monoamine oxidase.1, 611 Although the mechanism of antidepressant action of antidepressant agents may involve inhibition of the reuptake of various neurotransmitters (i.e., serotonin, norepinephrine) at the presynaptic neuronal membrane,3, 76 it has been suggested that postsynaptic receptor modification is mainly responsible for the antidepressant action observed during long-term administration of antidepressant agents.3, 76, 91
Data from in vitro studies suggest that sertraline is more potent than fluvoxamine, fluoxetine, or clomipramine as a serotonin-reuptake inhibitor.3, 76, 88 Serotonergic mechanisms also appear to be involved at least in part in a number of other pharmacologic effects associated with SSRIs, including sertraline, such as decreased food intake and altered food selection76, 85, 90, 92, 93 as well as decreased alcohol intake.86, 87
Sertraline appears to be slowly but well absorbed from the GI tract following oral administration.3, 83, 100, 222 The oral bioavailability of sertraline in humans has not been fully elucidated because a preparation for IV administration is not available.1, 4 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.1, 4 In animals, the oral bioavailability of sertraline ranges from 22 to 36%.4, 95 The manufacturer states that bioavailability of a single dose of sertraline hydrochloride tablets is approximately equal to that of an equivalent dose of sertraline hydrochloride oral solution.1
The effect of food on absorption of sertraline hydrochloride given as tablets or oral solution has been studied in single-dose studies.1, 3 Administration of a sertraline hydrochloride tablet with food slightly increased the 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.1, 3 Administration of sertraline capsules with food causes a small increase in maximum serum concentration and AUC.611
Peak plasma sertraline concentrations usually occur within 4.5 to 8.4 hours following oral administration of 50 to 200 mg once daily for 14 days.1, 3, 4, 5, 83, 222, 611 Peak plasma sertraline concentrations following administration of single oral doses of 50 to 200 mg are proportional and linearly related to dose.1, 3, 83, 222 Peak plasma concentrations and bioavailability are increased in geriatric individuals.3
Following multiple dosing, steady-state plasma sertraline concentrations should be achieved after approximately 1 week of once-daily dosing.1, 83 When compared with a single dose, there is an approximate 2-fold accumulation of sertraline after multiple daily dosing in dosages ranging from 50 to 200 mg daily.1 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 days 1 and 14.1
Distribution of sertraline and its metabolites into human body tissues and fluids has not been fully characterized.4 However, limited pharmacokinetic data suggest the drug and some of its metabolites are widely distributed in body tissues.4, 83 The drug crosses the blood-brain barrier in humans and animals.3 At i n vitro plasma concentrations ranging from 20 to 500 ng/mL, sertraline is approximately 98% bound to plasma proteins, principally to albumin and α1-acid glycoprotein.1, 3, 4, 5, 95 Protein binding is independent of plasma concentrations from 20 to 2000 mcg/mL.4 However, sertraline and N-desmethylsertraline did not alter the plasma protein binding of two other highly protein bound drugs, warfarin or propranolol, at concentrations of 300 and 200 ng/mL, respectively.1, 83
Like some other SSRIs, sertraline undergoes metabolism via N-demethylation to form N-desmethylsertraline, the principal metabolite.1, 100 Data from in vivo and in vitro studies have shown that N-desmethylsertraline is approximately 5 to 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.1, 76, 100
The elimination half-life of sertraline averages approximately 25 to 26 hours and that of desmethylsertraline averages about 62 to 104 hours.1, 3, 5 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.3, 83 Following oral administration, sertraline and its metabolites are excreted in both urine and feces.1, 5
Following oral administration of a single, radiolabeled dose in 2 healthy males, unchanged sertraline accounted for less than 5% of plasma radioactivity.1 Approximately 40 to 45% of the radiolabeled dose was excreted in urine within 9 days.1 Unchanged sertraline was not detectable in urine.1 During the same period, approximately 40 to 45% of the radiolabeled drug was eliminated in feces, including 12 to 14% of unchanged sertraline.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | For solution, concentrate | 20 mg (of sertraline) per mL* | ||
Zoloft® (with calibrated dropper dispenser containing latex rubber) | Viatris Specialty | |||
Tablets, film-coated | 25 mg (of sertraline)* | |||
Zoloft® | Viatris Specialty | |||
50 mg (of sertraline)* | Sertraline Hydrochloride Tablets | |||
Zoloft® | Viatris Specialty | |||
100 mg (of sertraline)* | Sertraline Hydrochloride Tablets | |||
Zoloft® | Viatris Specialty | |||
Capsules | 150 mg (of sertraline)* | Sertraline Hydrochloride Capsules | ||
200 mg (of sertraline)* | Sertraline Hydrochloride Capsules |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
1. Viatris Specialty LLC. Zoloft® (sertraline hydrochloride) tablets and oral solution prescribing information. Morgantown, WV; 2023 Aug.
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