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 BioavailabilityIn man, following oral once daily dosing over the range of 50 mg 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 mg to 200 mg. Consistent with the terminal elimination half-life, there is an approximately 2-fold accumulation, compared to a single-dose, of Sertraline with repeated dosing over a 50 mg 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. Ninety percent 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 concentrate were studied in subjects administered a single-dose with and without food. For the tablet, AUC was slightly increased when drug was administered with food but the Cmax was 25% greater, while the time to reach peak plasma concentration (Tmax) decreased from 8 hours post-dosing to 5.5 hours. For the oral concentrate, Tmax was slightly prolonged from 5.9 hours to 7 hours with food.
MetabolismSertraline 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-fold to 9-fold increase in these pharmacokinetic parameters between day 1 and day 14.
Protein BindingIn 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 PharmacokineticsSertraline 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).
AgeSertraline plasma clearance in a group of 16 (eight male, eight 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 years old) 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 DiseaseAs 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, eight patients with Child-Pugh scores of 5 to 6 and two 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 DiseaseSertraline 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 DisorderThe efficacy of Sertraline 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 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 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 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 in a range of 50 to 200 mg/day; the mean dose for completers was 186 mg/day. Patients receiving Sertraline 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 doses of 50, 100, and 200 mg/day. Patients receiving Sertraline 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 in a range of 50 to 200 mg/day; the mean dose for completers was 185 mg/day. Patients receiving Sertraline 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 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 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 50 to 200 mg/day (n = 224) were randomized to continuation of Sertraline 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 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 DisorderThe effectiveness of Sertraline 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 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 doses for completers to 10 weeks were 131 mg/day and 144 mg/day, respectively, for Studies 1 and 2. In these studies, Sertraline 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 and placebo in reduction from baseline in the number of full panic attacks was approximately two panic attacks per week in both studies.
Study 3 was a 12-week fixed-dose study, including Sertraline doses of 50, 100 and 200 mg/day. Patients receiving Sertraline 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 50 to 200 mg/day (n = 183) were randomized to continuation of Sertraline 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 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 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 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 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 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 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 vs. 39 and 55 men on Sertraline and placebo; Studies 1 and 2 combined). Post hoc exploratory analyses revealed a significant difference between Sertraline 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 50 to 200 mg/day (n = 96) were randomized to continuation of Sertraline 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 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 for the treatment of PMDD was established in two double-blind, parallel group, placebo-controlled flexible dose trials (Studies 1 and 2) conducted over three 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 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 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 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 dose for completers was 74 mg/day. Sertraline 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 DisorderThe effectiveness of Sertraline 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 (50 to 200 mg/day) to placebo, in which Sertraline 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 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 (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 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 (CGI-I of 1 or 2) during a 20-week placebo-controlled trial on Sertraline 50 to 200 mg/day were randomized to continuation of Sertraline 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 continuation treatment experienced a statistically significantly lower relapse rate over this 24-week study than patients randomized to placebo substitution.
Indications and Usage for Sertraline
Major Depressive Disorder
Sertraline tablets are indicated for the treatment of major depressive disorder in adults.
The efficacy of Sertraline hydrochloride in the treatment of a major depressive episode was established in 6-week to 8-week controlled trials of adult outpatients whose diagnoses corresponded most closely to the DSM-III category of major depressive disorder (see CLINICAL PHARMACOLOGY: Clinical Trials).
A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least four of the following eight symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation.
The antidepressant action of Sertraline tablets in hospitalized depressed patients has not been adequately studied.
The efficacy of Sertraline hydrochloride in maintaining an antidepressant response for up to 44 weeks following 8 weeks of open-label acute treatment (52 weeks total) was demonstrated in a placebo-controlled trial. The usefulness of the drug in patients receiving Sertraline tablets for extended periods should be reevaluated periodically (see CLINICAL PHARMACOLOGY: Clinical Trials).
Obsessive-Compulsive Disorder
Sertraline tablets are indicated for the treatment of obsessions and compulsions in patients with obsessive-compulsive disorder (OCD), as defined in the DSM-III-R; i.e., the obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning.
The efficacy of Sertraline was established in 12-week trials with obsessive-compulsive outpatients having diagnoses of obsessive-compulsive disorder as defined according to DSM-III or DSM-III-R criteria (see CLINICAL PHARMACOLOGY: Clinical Trials).
Obsessive-compulsive disorder is characterized by recurrent and persistent ideas, thoughts, impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable.
The efficacy of Sertraline in maintaining a response, in patients with OCD who responded during a 52-week treatment phase while taking Sertraline tablets and were then observed for relapse during a period of up to 28 weeks, was demonstrated in a placebo-controlled trial (see CLINICAL PHARMACOLOGY: Clinical Trials). Nevertheless, the physician who elects to use Sertraline tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Panic Disorder
Sertraline tablets are indicated for the treatment of panic disorder in adults, with or without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks.
The efficacy of Sertraline was established in three 10 to 12 week trials in adult panic disorder patients whose diagnoses corresponded to the DSM-III-R category of panic disorder (see CLINICAL PHARMACOLOGY: Clinical Trials).
Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.
The efficacy of Sertraline in maintaining a response, in adult patients with panic disorder who responded during a 52-week treatment phase while taking Sertraline tablets and were then observed for relapse during a period of up to 28 weeks, was demonstrated in a placebo-controlled trial (see CLINICAL PHARMACOLOGY: Clinical Trials). Nevertheless, the physician who elects to use Sertraline tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Posttraumatic Stress Disorder (PTSD)
Sertraline tablets are indicated for the treatment of posttraumatic stress disorder in adults.
The efficacy of Sertraline in the treatment of PTSD was established in two 12-week placebo-controlled trials of adult outpatients whose diagnosis met criteria for the DSM-III-R category of PTSD (see CLINICAL PHARMACOLOGY: Clinical Trials).
PTSD, as defined by DSM-III-R/IV, requires exposure to a traumatic event that involved actual or threatened death or serious injury, or threat to the physical integrity of self or others, and a response which involves intense fear, helplessness, or horror. Symptoms that occur as a result of exposure to the traumatic event include reexperiencing of the event in the form of intrusive thoughts, flashbacks or dreams, and intense psychological distress and physiological reactivity on exposure to cues to the event; avoidance of situations reminiscent of the traumatic event, inability to recall details of the event, and/or numbing of general responsiveness manifested as diminished interest in significant activities, estrangement from others, restricted range of affect, or sense of foreshortened future; and symptoms of autonomic arousal including hypervigilance, exaggerated startle response, sleep disturbance, impaired concentration, and irritability or outbursts of anger. A PTSD diagnosis requires that the symptoms are present for at least a month and that they cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
The efficacy of Sertraline in maintaining a response in adult patients with PTSD for up to 28 weeks following 24 weeks of open-label treatment was demonstrated in a placebo-controlled trial. Nevertheless, the physician who elects to use Sertraline tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Premenstrual Dysphoric Disorder (PMDD)
Sertraline tablets are indicated for the treatment of premenstrual dysphoric disorder (PMDD) in adults.
The efficacy of Sertraline in the treatment of PMDD was established in two placebo-controlled trials of female adult outpatients treated for three menstrual cycles who met criteria for the DSM-III-R/IV category of PMDD (see CLINICAL PHARMACOLOGY: Clinical Trials).
The essential features of PMDD include markedly depressed mood, anxiety or tension, affective lability, and persistent anger or irritability. Other features include decreased interest in activities, difficulty concentrating, lack of energy, change in appetite or sleep, and feeling out of control. Physical symptoms associated with PMDD include breast tenderness, headache, joint and muscle pain, bloating and weight gain. These symptoms occur regularly during the luteal phase and remit within a few days following onset of menses; the disturbance markedly interferes with work or school or with usual social activities and relationships with others. In making the diagnosis, care should be taken to rule out other cyclical mood disorders that may be exacerbated by treatment with an antidepressant.
The effectiveness of Sertraline in long-term use, that is, for more than three menstrual cycles, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use Sertraline for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Social Anxiety Disorder
Sertraline tablets are indicated for the treatment of social anxiety disorder, also known as social phobia in adults.
The efficacy of Sertraline in the treatment of social anxiety disorder was established in two placebo-controlled trials of adult outpatients with a diagnosis of social anxiety disorder as defined by DSM-IV criteria (see CLINICAL PHARMACOLOGY: Clinical Trials).
Social anxiety disorder, as defined by DSM-IV, is characterized by marked and persistent fear of social or performance situations involving exposure to unfamiliar people or possible scrutiny by others and by fears of acting in a humiliating or embarrassing way. Exposure to the feared social situation almost always provokes anxiety and feared social or performance situations are avoided or else are endured with intense anxiety or distress. In addition, patients recognize that the fear is excessive or unreasonable and the avoidance and anticipatory anxiety of the feared situation is associated with functional impairment or marked distress.
The efficacy of Sertraline in maintaining a response in adult patients with social anxiety disorder for up to 24 weeks following 20 weeks of Sertraline tablet treatment was demonstrated in a placebo-controlled trial. Physicians who prescribe Sertraline tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient (see CLINICAL PHARMACOLOGY: Clinical Trials).
Contraindications
Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated (see WARNINGS). Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS).
Sertraline tablets are contraindicated in patients with a hypersensitivity to Sertraline or any of the inactive ingredients in Sertraline tablets.
Warnings
Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents and young adults (ages 18 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 nine antidepressant drugs in over 4,400 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 1,000 patients treated) are provided in Table 1.
Table 1
| Age Range |
Drug-Placebo Difference in
Number of Cases of Suicidality
Per 1,000 Patients Treated |
| Increases Compared to Placebo |
| < 18 |
14 additional cases |
| 18 to 24 |
5 additional cases |
| Decreases Compared to Placebo |
| 25 to 64 |
1 fewer case |
| ≥ 65 |
6 fewer cases |
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 Tablets, for a description of the risks of discontinuation of Sertraline).
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 healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Sertraline 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 tablets are not approved for use in treating bipolar depression.
Cases of serious sometimes fatal reactions have been reported in patients receiving Sertraline hydrochloride, a selective serotonin reuptake inhibitor (SSRI), in combination with a monoamine oxidase inhibitor (MAOI). Symptoms of a drug interaction between an SSRI and an MAOI include: hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes that include confusion, irritability and extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have rec
