Pharmacodynamics

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

Pharmacokinetics

Systemic Bioavailability



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



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



The effects of food on the bioavailability of the sertraline tablet and oral solution were studied in subjects administered a single dose with and without food. For the tablet, AUC was slightly increased when drug was administered with food but the Cmax was 25% greater, while the time to reach peak plasma concentration (Tmax) decreased from 8 hours post-dosing to 5.5 hours. For the oral solution, Tmax was slightly prolonged from 5.9 hours to 7 hours with food.



Metabolism



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



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



Protein Binding



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



Pediatric Pharmacokinetics



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



Age



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



Liver Disease



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



Renal Disease 



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

Clinical Trials

Major Depressive Disorder



The efficacy of sertraline hydrochloride as a treatment for major depressive disorder was established in two placebo-controlled studies in adult outpatients meeting DSM-III criteria for major depressive disorder. Study 1 was an 8-week study with flexible dosing of sertraline hydrochloride in a range of 50 to 200 mg/day; the mean dose for completers was 145 mg/day. Study 2 was a 6-week fixed-dose study, including sertraline hydrochloride doses of 50, 100, and 200 mg/day. Overall, these studies demonstrated sertraline hydrochloride to be superior to placebo on the Hamilton Depression Rating Scale and the Clinical Global Impression Severity and Improvement scales. Study 2 was not readily interpretable regarding a dose response relationship for effectiveness.



Study 3 involved depressed outpatients who had responded by the end of an initial 8-week open treatment phase on sertraline hydrochloride 50 to 200 mg/day. These patients (N=295) were randomized to continuation for 44 weeks on double-blind sertraline hydrochloride 50 to 200 mg/day or placebo. A statistically significantly lower relapse rate was observed for patients taking sertraline hydrochloride compared to those on placebo. The mean dose for completers was 70 mg/day.



Analyses for gender effects on outcome did not suggest any differential responsiveness on the basis of sex.



Obsessive-Compulsive Disorder (OCD)



The effectiveness of sertraline hydrochloride in the treatment of OCD was demonstrated in three multicenter placebo-controlled studies of adult outpatients (Studies 1 to 3). Patients in all studies had moderate to severe OCD (DSM-III or DSM-III-R) with mean baseline ratings on the Yale–Brown Obsessive-Compulsive Scale (YBOCS) total score ranging from 23 to 25.



Study 1 was an 8-week study with flexible dosing of sertraline hydrochloride in a range of 50 to 200 mg/day; the mean dose for completers was 186 mg/day. Patients receiving sertraline hydrochloride experienced a mean reduction of approximately 4 points on the YBOCS total score which was significantly greater than the mean reduction of 2 points in placebo-treated patients.



Study 2 was a 12-week fixed-dose study, including sertraline hydrochloride doses of 50, 100, and 200 mg/day. Patients receiving sertraline hydrochloride doses of 50 and 200 mg/day experienced mean reductions of approximately 6 points on the YBOCS total score which were significantly greater than the approximately 3 point reduction in placebo-treated patients.



Study 3 was a 12-week study with flexible dosing of sertraline hydrochloride in a range of 50 to 200 mg/day; the mean dose for completers was 185 mg/day. Patients receiving sertraline hydrochloride experienced a mean reduction of approximately 7 points on the YBOCS total score which was significantly greater than the mean reduction of approximately 4 points in placebo-treated patients. 



Analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex.



The effectiveness of sertraline hydrochloride for the treatment of OCD was also demonstrated in a 12-week, multicenter, placebo-controlled, parallel group study in a pediatric outpatient population (children and adolescents, ages 6 to 17). Patients receiving sertraline hydrochloride in this study were initiated at doses of either 25 mg/day (children, ages 6 to 12) or 50 mg/day (adolescents, ages 13 to 17), and then titrated over the next four weeks to a maximum dose of 200 mg/day, as tolerated. The mean dose for completers was 178 mg/day. Dosing was once a day in the morning or evening. Patients in this study had moderate to severe OCD (DSM-III-R) with mean baseline ratings on the Children’s Yale-Brown Obsessive-Compulsive Scale (CYBOCS) total score of 22. Patients receiving sertraline experienced a mean reduction of approximately 7 units on the CYBOCS total score which was significantly greater than the 3 unit reduction for placebo patients. Analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex.



In a longer-term study, patients meeting DSM-III-R criteria for OCD who had responded during a 52-week single-blind trial on sertraline hydrochloride 50 to 200 mg/day (N=224) were randomized to continuation of sertraline hydrochloride or to substitution of placebo for up to 28 weeks of observation for discontinuation due to relapse or insufficient clinical response. Response during the single-blind phase was defined as a decrease in the YBOCS score of ≥ 25% compared to baseline and a CGI-­I of 1 (very much improved), 2 (much improved) or 3 (minimally improved). Relapse during the double-blind phase was defined as the following conditions being met (on three consecutive visits for 1 and 2, and for visit 3 for condition 3): (1) YBOCS score increased by ≥ 5 points, to a minimum of 20, relative to baseline; (2) CGI-I increased by ≥ one point; and (3) worsening of the patient’s condition in the investigator’s judgment, to justify alternative treatment. Insufficient clinical response indicated a worsening of the patient’s condition that resulted in study discontinuation, as assessed by the investigator. Patients receiving continued sertraline hydrochloride treatment experienced a significantly lower rate of discontinuation due to relapse or insufficient clinical response over the subsequent 28 weeks compared to those receiving placebo. This pattern was demonstrated in male and female subjects.



Panic Disorder



The effectiveness of sertraline hydrochloride in the treatment of panic disorder was demonstrated in three double-blind, placebo-controlled studies (Studies 1 to 3) of adult outpatients who had a primary diagnosis of panic disorder (DSM-III-R), with or without agoraphobia.



Studies 1 and 2 were 10-week flexible dose studies. Sertraline hydrochloride was initiated at 25 mg/day for the first week, and then patients were dosed in a range of 50 to 200 mg/day on the basis of clinical response and toleration. The mean sertraline hydrochloride  doses for completers to 10 weeks were 131 mg/day and 144 mg/day, respectively, for Studies 1 and 2. In these studies, sertraline hydrochloride was shown to be significantly more effective than placebo on change from baseline in panic attack frequency and on the Clinical Global Impression Severity of Illness and Global Improvement scores. The difference between sertraline hydrochloride and placebo in reduction from baseline in the number of full panic attacks was approximately 2 panic attacks per week in both studies.



Study 3 was a 12-week fixed-dose study, including sertraline hydrochloride doses of 50, 100, and 200 mg/day. Patients receiving sertraline hydrochloride experienced a significantly greater reduction in panic attack frequency than patients receiving placebo. Study 3 was not readily interpretable regarding a dose response relationship for effectiveness.



Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age, race, or gender. 



In a longer-term study, patients meeting DSM-III-R criteria for Panic Disorder who had responded during a 52-week open trial on sertraline hydrochloride 50 to 200 mg/day (N=183) were randomized to continuation of sertraline hydrochloride or to substitution of placebo for up to 28 weeks of observation for discontinuation due to relapse or insufficient clinical response. Response during the open phase was defined as a CGI-I score of 1(very much improved) or 2 (much improved). Relapse during the double-blind phase was defined as the following conditions being met on three consecutive visits: (1) CGI-I ≥ 3; (2) meets DSM-III-R criteria for Panic Disorder; (3) number of panic attacks greater than at baseline. Insufficient clinical response indicated a worsening of the patient’s condition that resulted in study discontinuation, as assessed by the investigator. Patients receiving continued sertraline hydrochloride treatment experienced a significantly lower rate of discontinuation due to relapse or insufficient clinical response over the subsequent 28 weeks compared to those receiving placebo. This pattern was demonstrated in male and female subjects. 



Posttraumatic Stress Disorder (PTSD)



The effectiveness of sertraline hydrochloride in the treatment of PTSD was established in two multicenter placebo-controlled studies (Studies 1 to 2) of adult outpatients who met DSM-III-R criteria for PTSD. The mean duration of PTSD for these patients was 12 years (Studies 1 and 2 combined) and 44% of patients (169 of the 385 patients treated) had secondary depressive disorder.



Studies 1 and 2 were 12-week flexible dose studies. Sertraline hydrochloride was initiated at 25 mg/day for the first week, and patients were then dosed in the range of 50 to 200 mg/day on the basis of clinical response and toleration. The mean sertraline hydrochloride dose for completers was 146 mg/day and 151 mg/day, respectively for Studies 1 and 2. Study outcome was assessed by the Clinician-Administered PTSD Scale Part 2 (CAPS) which is a multi-item instrument that measures the three PTSD diagnostic symptom clusters of reexperiencing/intrusion, avoidance/numbing, and hyperarousal as well as the patient-rated Impact of Event Scale (IES) which measures intrusion and avoidance symptoms. Sertraline hydrochloride was shown to be significantly more effective than placebo on change from baseline to endpoint on the CAPS, IES and on the Clinical Global Impressions (CGI) Severity of Illness and Global Improvement scores. In two additional placebo-controlled PTSD trials, the difference in response to treatment between patients receiving sertraline hydrochloride and patients receiving placebo was not statistically significant. One of these additional studies was conducted in patients similar to those recruited for Studies 1 and 2, while the second additional study was conducted in predominantly male veterans.



As PTSD is a more common disorder in women than men, the majority (76%) of patients in these trials were women (152 and 139 women on sertraline and placebo versus 39 and 55 men on sertraline and placebo; Studies 1 and 2 combined). Post hoc exploratory analyses revealed a significant difference between sertraline hydrochloride and placebo on the CAPS, IES and CGI in women, regardless of baseline diagnosis of comorbid major depressive disorder, but essentially no effect in the relatively smaller number of men in these studies. The clinical significance of this apparent gender interaction is unknown at this time. There was insufficient information to determine the effect of race or age on outcome.



In a longer-term study, patients meeting DSM-III-R criteria for PTSD who had responded during a 24-week open trial on sertraline hydrochloride 50 to 200 mg/day (N=96) were randomized to continuation of sertraline hydrochloride or to substitution of placebo for up to 28 weeks of observation for relapse. Response during the open phase was defined as a CGI-I of 1 (very much improved) or 2 (much improved), and a decrease in the CAPS-2 score of > 30% compared to baseline. Relapse during the double-blind phase was defined as the following conditions being met on two consecutive visits: (1) CGI-I ≥ 3; (2) CAPS-2 score increased by ≥ 30% and by ≥ 15 points relative to baseline; and (3) worsening of the patient's condition in the investigator's judgment. Patients receiving continued sertraline hydrochloride treatment experienced significantly lower relapse rates over the subsequent 28 weeks compared to those receiving placebo. This pattern was demonstrated in male and female subjects. 



Premenstrual Dysphoric Disorder (PMDD)



The effectiveness of sertraline hydrochloride for the treatment of PMDD was established in two double-blind, parallel group, placebo-controlled flexible dose trials (Studies 1 and 2) conducted over 3 menstrual cycles. Patients in Study 1 met DSM-III-R criteria for Late Luteal Phase Dysphoric Disorder (LLPDD), the clinical entity now referred to as Premenstrual Dysphoric Disorder (PMDD) in DSM-IV. Patients in Study 2 met DSM-IV criteria for PMDD. Study 1 utilized daily dosing throughout the study, while Study 2 utilized luteal phase dosing for the 2 weeks prior to the onset of menses. The mean duration of PMDD symptoms for these patients was approximately 10.5 years in both studies. Patients on oral contraceptives were excluded from these trials; therefore, the efficacy of sertraline in combination with oral contraceptives for the treatment of PMDD is unknown. 



Efficacy was assessed with the Daily Record of Severity of Problems (DRSP), a patient-rated instrument that mirrors the diagnostic criteria for PMDD as identified in the DSM-IV, and includes assessments for mood, physical symptoms, and other symptoms. Other efficacy assessments included the Hamilton Depression Rating Scale (HAMD-17), and the Clinical Global Impression Severity of Illness (CGI-S) and Improvement (CGI-I) scores.



In Study 1, involving N=251 randomized patients; sertraline hydrochloride treatment was initiated at 50 mg/day and administered daily throughout the menstrual cycle.  In subsequent cycles, patients were dosed in the range of 50 to 150 mg/day on the basis of clinical response and toleration. The mean dose for completers was 102 mg/day. Sertraline hydrochloride administered daily throughout the menstrual cycle was significantly more effective than placebo on change from baseline to endpoint on the DRSP total score, the HAMD-17 total score, and the CGI-S score, as well as the CGI-I score at endpoint. 



In Study 2, involving N=281 randomized patients, sertraline hydrochloride treatment was initiated at 50 mg/day in the late luteal phase (last 2 weeks) of each menstrual cycle and then discontinued at the onset of menses. In subsequent cycles, patients were dosed in the range of 50 to 100 mg/day in the luteal phase of each cycle, on the basis of clinical response and toleration. Patients who were titrated to 100 mg/day received 50 mg/day for the first 3 days of the cycle, then 100 mg/day for the remainder of the cycle. The mean sertraline hydrochloride dose for completers was 74 mg/day. Sertraline hydrochloride administered in the late luteal phase of the menstrual cycle was significantly more effective than placebo on change from baseline to endpoint on the DRSP total score and the CGI-S score, as well as the CGI-I score at endpoint. 



There was insufficient information to determine the effect of race or age on outcome in these studies. 



Social Anxiety Disorder



The effectiveness of sertraline hydrochloride in the treatment of social anxiety disorder (also known as social phobia) was established in two multicenter placebo-controlled studies (Study 1 and 2) of adult outpatients who met DSM-IV criteria for social anxiety disorder.



Study 1 was a 12-week, multicenter, flexible dose study comparing sertraline hydrochloride (50 to 200 mg/day) to placebo, in which sertraline hydrochloride was initiated at 25 mg/day for the first week. Study outcome was assessed by (a) the Liebowitz Social Anxiety Scale (LSAS), a 24-item clinician administered instrument that measures fear, anxiety and avoidance of social and performance situations, and by (b) the proportion of responders as defined by the Clinical Global Impression of Improvement (CGI-I) criterion of CGI-I ≤ 2 (very much or much improved). Sertraline hydrochloride was statistically significantly more effective than placebo as measured by the LSAS and the percentage of responders. 



Study 2 was a 20-week, multicenter, flexible dose study that compared sertraline hydrochloride (50 to 200 mg/day) to placebo. Study outcome was assessed by the (a) Duke Brief Social Phobia Scale (BSPS), a multi-item clinician-rated instrument that measures fear, avoidance and physiologic response to social or performance situations, (b) the Marks Fear Questionnaire Social Phobia Subscale (FQ-SPS), a 5-item patient-rated instrument that measures change in the severity of phobic avoidance and distress, and (c) the CGI-I responder criterion of ≤ 2. Sertraline hydrochloride was shown to be statistically significantly more effective than placebo as measured by the BSPS total score and fear, avoidance and physiologic factor scores, as well as the FQ-SPS total score, and to have significantly more responders than placebo as defined by the CGI-I.



Subgroup analyses did not suggest differences in treatment outcome on the basis of gender. There was insufficient information to determine the effect of race or age on outcome.  



In a longer-term study, patients meeting DSM-IV criteria for social anxiety disorder who had responded while assigned to sertraline hydrochloride (CGI-I of 1 or 2) during a 20-week placebo-controlled trial on sertraline hydrochloride 50 to 200 mg/day were randomized to continuation of sertraline hydrochloride or to substitution of placebo for up to 24 weeks of observation for relapse. Relapse was defined as ≥ 2 point increase in the Clinical Global Impression – Severity of Illness (CGI-S) score compared to baseline or study discontinuation due to lack of efficacy. Patients receiving sertraline hydrochloride continuation treatment experienced a statistically significantly lower relapse rate over this 24­-week study than patients randomized to placebo substitution.

Clinical Worsening and Suicide Risk

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



The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied.

There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.

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



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



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



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



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



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



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

Screening Patients for Bipolar Disorder

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

Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including sertraline hydrochloride, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).



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 gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.



The concomitant use of sertraline hydrochloride with MAOIs intended to treat psychiatric disorders is contraindicated. Sertraline hydrochloride should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking sertraline hydrochloride. Sertraline hydrochloride should be discontinued before initiating treatment with the MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION).



If concomitant use of sertraline hydrochloride with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.



Treatment with sertraline hydrochloride and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.



Angle-Closure Glaucoma



The pupillary dilation that occurs following use of many antidepressant drugs including sertraline hydrochloride may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

General

Activation of Mania/Hypomania



During premarketing testing, hypomania or mania occurred in approximately 0.4% of sertraline hydrochloride treated patients. 



Weight Loss



Significant weight loss may be an undesirable result of treatment with sertraline for some patients, but on average, patients in controlled trials had minimal, 1 to 2 pound weight loss, versus smaller changes on placebo. Only rarely have sertraline patients been discontinued for weight loss.



Seizure



Sertraline hydrochloride has not been evaluated in patients with a seizure disorder. These patients were excluded from clinical studies during the product’s premarket testing. No seizures were observed among approximately 3000 patients treated with sertraline hydrochloride in the development program for major depressive disorder. However, 4 patients out of approximately 1800 (220<18 years of age) exposed during the development program for obsessive-compulsive disorder experienced seizures, representing a crude incidence of 0.2%. Three of these patients were adolescents, two with a seizure disorder and one with a family history of seizure disorder, none of whom were receiving anticonvulsant medication. Accordingly, sertraline hydrochloride should be introduced with care in patients with a seizure disorder.



Discontinuation of Treatment with Sertraline Hydrochloride



During marketing of sertraline hydrochloride and other SSRIs and SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.



Patients should be monitored for these symptoms when discontinuing treatment with sertraline hydrochloride. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND ADMINISTRATION).



Abnormal Bleeding



SSRIs and SNRIs, including sertraline hydrochloride, may increase the risk of bleeding events ranging from ecchymoses, hematomas, epistaxis, petechiae, and gastrointestinal hemorrhage to life-threatening hemorrhage. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants or other drugs known to affect platelet function may add to this risk. 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.



Patients should be cautioned about the risk of bleeding associated with the concomitant use of sertraline hydrochloride and NSAIDs, aspirin, or other drugs that affect coagulation.



Weak Uricosuric Effect



Sertraline hydrochloride is associated with a mean decrease in serum uric acid of approximately 7%. The clinical significance of this weak uricosuric effect is unknown.



Use in Patients with Concomitant Illness



Clinical experience with sertraline hydrochloride in patients with certain concomitant systemic illness is limited. Caution is advisable in using sertraline hydrochloride in patients with diseases or conditions that could affect metabolism or hemodynamic responses.



Patients with a recent history of myocardial infarction or unstable heart disease were excluded from clinical studies during the product’s premarket testing. However, the electrocardiograms of 774 patients who received sertraline hydrochloride in double-blind trials were evaluated and the data indicate that sertraline hydrochloride is not associated with the development of significant ECG abnormalities.



Sertraline hydrochloride administered in a flexible dose range of 50 to 200 mg/day (mean dose of 89 mg/day) was evaluated in a post-marketing, placebo-controlled trial of 372 randomized subjects with a DSM-IV diagnosis of major depressive disorder and recent history of myocardial infarction or unstable angina requiring hospitalization.  Exclusions from this trial included, among others, patients with uncontrolled hypertension, need for cardiac surgery, history of CABG within 3 months of index event, severe or symptomatic bradycardia, non-atherosclerotic cause of angina, clinically significant renal impairment (creatinine > 2.5 mg/dL), and clinically significant hepatic dysfunction. Sertraline hydrochloride treatment initiated during the acute phase of recovery (within 30 days post-MI or post-hospitalization for unstable angina) was indistinguishable from placebo in this study on the following week 16 treatment endpoints:  left ventricular ejection fraction, total cardiovascular events (angina, chest pain, edema, palpitations, syncope, postural dizziness, CHF, MI, tachycardia, bradycardia, and changes in BP), and major cardiovascular events involving death or requiring hospitalization (for MI, CHF, stroke, or angina).



Sertraline hydrochloride is extensively metabolized by the liver. In patients with chronic mild liver impairment, sertraline clearance was reduced, resulting in increased AUC, Cmax and elimination half-life. The effects of sertraline in patients with moderate and severe hepatic impairment have not been studied. The use of sertraline in patients with liver disease must be approached with caution. If sertraline is administered to patients with liver impairment, a lower or less frequent dose should be used (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).



Since sertraline hydrochloride is extensively metabolized, excretion of unchanged drug in urine is a minor route of elimination. A clinical study comparing sertraline pharmacokinetics in healthy volunteers to that in patients with renal impairment ranging from mild to severe (requiring dialysis) indicated that the pharmacokinetics and protein binding are unaffected by renal disease. Based on the pharmacokinetic results, there is no need for dosage adjustment in patients with renal impairment (see CLINICAL PHARMACOLOGY).



Interference with Cognitive and Motor Performance 



In controlled studies, sertraline hydrochloride did not cause sedation and did not interfere with psychomotor performance (See Information for Patients).

Information for Patients

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with sertraline hydrochloride and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for sertraline hydrochloride. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.



Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking sertraline hydrochloride.



Clinical Worsening and Suicide Risk



Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.



Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of SNRIs and SSRIs, including sertraline hydrochloride, and triptans, tramadol, or other serotonergic agents.



Patients should be advised that taking sertraline hydrochloride can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.



Patients should be told that although sertraline hydrochloride has not been shown to impair the ability of normal subjects to perform tasks requiring complex motor and mental skills in laboratory experiments, drugs that act upon the central nervous system may affect some individuals adversely. Therefore, patients should be told that until they learn how they respond to sertraline hydrochloride they should be careful doing activities when they need to be alert, such as driving a car or operating machinery.



Patients should be cautioned about the concomitant use of sertraline hydrochloride and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding.



Patients should be told that although sertraline hydrochloride has not been shown in experiments with normal subjects to increase the mental and motor skill impairments caused by alcohol, the concomitant use of sertraline hydrochloride and alcohol is not advised.



Patients should be told that while no adverse interaction of sertraline hydrochloride with over-the-counter (OTC) drug products is known to occur, the potential for interaction exists. Thus, the use of any OTC product should be initiated cautiously according to the directions of use given for the OTC product.



Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.



Patients should be advised to notify their physician if they are breast feeding an infant.

Laboratory Tests

False-positive urine immunoassay screening tests for benzodiazepines have been reported in patients taking sertraline. This is due to lack of specificity of the screening tests. False-positive test results may be expected for several days following discontinuation of sertraline therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish sertraline from benzodiazepines.

Drug Interactions

Potential Effects of Coadministration of Drugs Highly Bound to Plasma Proteins



Because sertraline is tightly bound to plasma protein, the administration of sertraline hydrochloride to a patient taking another drug which is tightly bound to protein (e.g., warfarin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect. Conversely, adverse effects may result from displacement of protein bound sertraline hydrochloride by other tightly bound drugs.



In a study comparing prothrombin time AUC (0 to 120 hr) following dosing with warfarin (0.75 mg/kg) before and after 21 days of dosing with either sertraline hydrochloride (50 to 200 mg/day) or placebo, there was a mean increase in prothrombin time of 8% relative to baseline for sertraline hydrochloride compared to a 1% decrease for placebo (p<0.02). The normalization of prothrombin time for the sertraline hydrochloride tablets group was delayed compared to the placebo group. The clinical significance of this change is unknown. Accordingly, prothrombin time should be carefully monitored when sertraline hydrochloride therapy is initiated or stopped.



Cimetidine



In a study assessing disposition of sertraline hydrochloride (100 mg) on the second of 8 days of cimetidine administration (800 mg daily), there were significant increases in sertraline hydrochloride mean AUC (50%), Cmax (24%) and half-life (26%) compared to the placebo group. The clinical significance of these changes is unknown.



CNS Active Drugs 



In a study comparing the disposition of intravenously administered diazepam before and after 21 days of dosing with either sertraline hydrochloride (50 to 200 mg/day escalating dose) or placebo, there was a 32% decrease relative to baseline in diazepam clearance for the sertraline hydrochloride group compared to a 19% decrease relative to baseline for the placebo group (p<0.03). There was a 23% increase in Tmax for desmethyldiazepam in the sertraline hydrochloride group compared to a 20% decrease in the placebo group (p<0.03). The clinical significance of these changes is unknown.



In a placebo-controlled trial in normal volunteers, the administration of two doses of sertraline hydrochloride did not significantly alter steady-state lithium levels or the renal clearance of lithium.



Nonetheless, at this time, it is recommended that plasma lithium levels be monitored following initiation of sertraline hydrochloride therapy with appropriate adjustments to the lithium dose.



In a controlled study of a single dose (2 mg) of pimozide, 200 mg sertraline (q.d.) co-administration to steady state was associated with a mean increase in pimozide AUC and Cmax of about 40%, but was not associated with any changes in EKG. Since the highest recommended pimozide dose (10 mg) has not been evaluated in combination with sertraline, the effect on QT interval and PK parameters at doses higher than 2 mg at this time are not known. While the mechanism of this interaction is unknown, due to the narrow therapeutic index of pimozide and due to the interaction noted at a low dose of pimozide, concomitant administration of sertraline hydrochloride and pimozide should be contraindicated (see CONTRAINDICATIONS).



Results of a placebo-controlled trial in normal volunteers suggest that chronic administration of sertraline 200 mg/day does not produce clinically important inhibition of phenytoin metabolism. Nonetheless, at this time, it is recommended that plasma phenytoin concentrations be monitored following initiation of sertraline hydrochloride therapy with appropriate adjustments to the phenytoin dose, particularly in patients with multiple underlying medical conditions and/or those receiving multiple concomitant medications.



The effect of sertraline hydrochloride on valproate levels has not been evaluated in clinical trials.  In the absence of such data, it is recommended that plasma valproate levels be monitored following initiation of sertraline hydrochloride therapy with appropriate adjustments to the valproate dose. 



The risk of using sertraline hydrochloride in combination with other CNS active drugs has not been systematically evaluated. Consequently, caution is advised if the concomitant administration of sertraline hydrochloride and such drugs is required.



There is limited controlled experience regarding the optimal timing of switching from other drugs effective in the treatment of major depressive disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, premenstrual dysphoric disorder and social anxiety disorder to sertraline hydrochloride. Care and prudent medical judgment should be exercised when switching, particularly from long-acting agents. The duration of an appropriate washout period which should intervene before switching from one selective serotonin reuptake inhibitor (SSRI) to another has not been established.



Monoamine Oxidase Inhibitors



See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION.



Drugs Metabolized by P450 3A4 



In three separate in vivo interaction studies, sertraline was co-administered with cytochrome P450 3A4 substrates, terfenadine, carbamazepine, or cisapride under steady-state conditions. The results of these studies indicated that sertraline did not increase plasma concentrations of terfenadine, carbamazepine, or cisapride. These data indicate that sertraline’s extent of inhibition of P450 3A4 activity is not likely to be of clinical significance. Results of the interaction study with cisapride indicate that sertraline 200 mg (q.d.) induces the metabolism of cisapride (cisapride AUC and Cmax were reduced by about 35%).

Pregnancy

Teratogenic Effects

Pregnancy Category C



Reproduction studies have been performed in rats and rabbits at doses up to 80 mg/kg/day and 40 mg/kg/day, respectively. These doses correspond to approximately 4 times the maximum recommended human dose (MRHD) on a mg/m2 basis. There was no evidence of teratogenicity at any dose level. When pregnant rats and rabbits were given sertraline during the period of organogenesis, delayed ossification was observed in fetuses at doses of 10 mg/kg (0.5 times the MRHD on a mg/m2 basis) in rats and 40 mg/kg (4 times the MRHD on a mg/m2 basis) in rabbits. When female rats received sertraline during the last third of gestation and throughout lactation, there was an increase in the number of stillborn pups and in the number of pups dying during the first 4 days after birth. Pup body weights were also decreased during the first four days after birth. These effects occurred at a dose of 20 mg/kg (1 times the MRHD on a mg/m2 basis). The no effect dose for rat pup mortality was 10 mg/kg (0.5 times the MRHD on a mg/m2 basis). The decrease in pup survival was shown to be due to in utero exposure to sertraline. The clinical significance of these effects is unknown. There are no adequate and well-controlled studies in pregnant women. Sertraline hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and Delivery

The effect of sertraline hydrochloride on labor and delivery in humans is unknown.

Nursing Mothers

It is not known whether, and if so in what amount, sertraline or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when sertraline hydrochloride is administered to a nursing woman.

Pediatric Use

The efficacy of sertraline hydrochloride for the treatment of obsessive-compulsive disorder was demonstrated in a 12-week, multicenter, placebo-controlled study with 187 outpatients ages 6 to 17 (see Clinical Trials under CLINICAL PHARMACOLOGY). Safety and effectiveness in the pediatric population other than pediatric patients with OCD have not been established (see BOX WARNING and WARNINGS-Clinical Worsening and Suicide Risk). Two placebo controlled trials (N=373) in pediatric patients with MDD have been conducted with sertraline hydrochloride, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of sertraline hydrochloride in a child or adolescent must balance the potential risks with the clinical need.



The safety of sertraline hydrochloride use in children and adolescents with OCD, ages 6 to 18, was evaluated in a 12-week, multicenter, placebo-controlled study with 187 outpatients, ages 6 to 17, and in a flexible dose, 52 week open extension study of 137 patients, ages 6 to 18, who had completed the initial 12­-week, double-blind, placebo-controlled study. Sertraline hydrochloride was administered at doses of either 25 mg/day (children, ages 6 to 12) or 50 mg/day (adolescents, ages 13 to 18) and then titrated in weekly 25 mg/day or 50 mg/day increments, respectively, to a maximum dose of 200 mg/day based upon clinical response. The mean dose for completers was 157 mg/day. In the acute 12-week pediatric study and in the 52-week study, sertraline hydrochloride had an adverse event profile generally similar to that observed in adults.



Sertraline pharmacokinetics were evaluated in 61 pediatric patients between 6 and 17 years of age with major depressive disorder or OCD and revealed similar drug exposures to those of adults when plasma concentration was adjusted for weight (see Pharmacokineticsunder CLINICAL PHARMACOLOGY).



Approximately 600 patients with major depressive disorder or OCD between 6 and 17 years of age have received sertraline hydrochloride in clinical trials, both controlled and uncontrolled. The adverse event profile observed in these patients was generally similar to that observed in adult studies with sertraline hydrochloride (see ADVERSE REACTIONS). As with other SSRIs, decreased appetite and weight loss have been observed in association with the use of sertraline hydrochloride. In a pooled analysis of two 10-week, double-blind, placebo-controlled, flexible dose (50 to 200 mg) outpatient trials for major depressive disorder (N=373), there was a difference in weight change between sertraline and placebo of roughly 1 kilogram, for both children (ages 6 to 11) and adolescents (ages 12 to 17), in both cases representing a slight weight loss for sertraline compared to a slight gain for placebo. At baseline the mean weight for children was 39 kg for sertraline and 38.5 kg for placebo.  At baseline the mean weight for adolescents was 61.4 kg for sertraline and 62.5 kg for placebo. There was a bigger difference between sertraline and placebo in the proportion of outliers for clinically important weight loss in children than in adolescents. For children, about 7% had a weight loss > 7% of body weight compared to none of the placebo patients;  for adolescents, about 2% had a weight loss > 7% of body weight compared to about 1% of the placebo patients. A subset of these patients who completed the randomized controlled trials (sertraline N=99, placebo N=122) were continued into a 24-week, flexible-dose, open-label, extension study. A mean weight loss of approximately 0.5 kg was seen during the first eight weeks of treatment for subjects with first exposure to sertraline during the open-label extension study, similar to mean weight loss observed among sertraline treated subjects during the first eight weeks of the randomized controlled trials. The subjects continuing in the open label study began gaining weight compared to baseline by week 12 of sertraline treatment. Those subjects who completed 34 weeks of sertraline treatment (10 weeks in a placebo controlled trial + 24 weeks open label, N=68) had weight gain that was similar to that expected using data from age-adjusted peers. Regular monitoring of weight and growth is recommended if treatment of a pediatric patient with an SSRI is to be continued long term. Safety and effectiveness in pediatric patients below the age of 6 have not been established.



The risks, if any, that may be associated with sertraline hydrochloride’s use beyond 1 year in children and adolescents with OCD or major depressive disorder have not been systematically assessed. The prescriber should be mindful that the evidence relied upon to conclude that sertraline is safe for use in children and adolescents derives from clinical studies that were 10 to 52 weeks in duration and from the extrapolation of experience gained with adult patients. In particular, there are no studies that directly evaluate the effects of long-term sertraline use on the growth, development, and maturation of children and adolescents. Although there is no affirmative finding to suggest that sertraline possesses a capacity to adversely affect growth, development or maturation, the absence of such findings is not compelling evidence of the absence of the potential of sertraline to have adverse effects in chronic use (see WARNINGS – Clinical Worsening and Suicide Risk).

Geriatric Use

U.S. geriatric clinical studies of sertraline hydrochloride in major depressive disorder included 663 sertraline hydrochloride-treated subjects ≥ 65 years of age, of those, 180 were ≥ 75 years of age. No overall differences in the pattern of adverse reactions were observed in the geriatric clinical trial subjects relative to those reported in younger subjects (see ADVERSE REACTIONS), and other reported experience has not identified differences in safety patterns between the elderly and younger subjects. As with all medications, greater sensitivity of some older individuals cannot be ruled out. There were 947 subjects in placebo-controlled geriatric clinical studies of sertraline hydrochloride in major depressive disorder. No overall differences in the pattern of efficacy were observed in the geriatric clinical trial subjects relative to those reported in younger subjects.



Other Adverse Events in Geriatric Patients. In 354 geriatric subjects treated with sertraline hydrochloride in placebo-controlled trials, the overall profile of adverse events was generally similar to that shown in Tables 2 and 3. Urinary tract infection was the only adverse event not appearing in Tables 2 and 3 and reported at an incidence of at least 2% and at a rate greater than placebo in placebo-controlled trials.



SSRIs and SNRIs, including sertraline hydrochloride, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see PRECAUTIONS, Hyponatremia).

Controlled Substance Class

Sertraline hydrochloride is not a controlled substance.

Physical and Psychological Dependence

In a placebo-controlled, double-blind, randomized study of the comparative abuse liability of sertraline hydrochloride, alprazolam, and d-amphetamine in humans, sertraline hydrochloride did not produce the positive subjective effects indicative of abuse potential, such as euphoria or drug liking, that were observed with the other two drugs. Premarketing clinical experience with sertraline hydrochloride did not reveal any tendency for a withdrawal syndrome or any drug-seeking behavior. In animal studies sertraline hydrochloride does not demonstrate stimulant or barbiturate-like (depressant) abuse potential. As with any CNS active drug, however, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of sertraline hydrochloride misuse or abuse (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).

Discontinuation of Treatment with Sertraline Hydrochloride Tablets

Symptoms associated with discontinuation of sertraline hydrochloride tablets and other SSRIs and SNRIs, have been reported (see PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.