Sertraline - Pharmacology Sertraline Hydrochloride

Sertraline is a selective serotonin reuptake inhibitor (SSRI) for oral administration. It has a molecular weight of 342.7. Sertraline hydrochloride, USP has the following chemical name: (1S-cis)-4-(3,4-dichlorophenyl)-1 ,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride. The empirical formula C₁₇H₁₇NCl₂HCl is represented by the following structural formula:

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

Sertraline tablets, USP are supplied for oral administration as scored tablets containing sertraline hydrochloride equivalent to 25 mg, 50 mg and 100 mg of sertraline and the following inactive ingredients: dibasic calcium phosphate dihydrate, hydroxypropyl cellulose, microcrystalline cellulose, magnesium stearate, opadry green (titanium dioxide, hypromellose 3cP, hypromellose 6cP, Macrogol/Peg 400, polysorbate 80, D&C Yellow #10 Aluminum Lake, and FD&C Blue # 2/Indigo Carmine Aluminum Lake for 25 mg tablet), opadry light blue (hypromellose 3cP, hypromellose 6cP, titanium dioxide, Macrogol/Peg 400, FD&C Blue # 2/Indigo Carmine Aluminum Lake and polysorbate 80 for 50 mg tablet), opadry yellow (hypromellose 3cP, hypromellose 6cP, titanium dioxide, Macrogol/Peg 400, polysorbate 80, Iron Oxide Yellow, Iron Oxide Red for 100 mg tablet) and sodium starch glycolate.

The mechanism of action of sertraline is presumed to be linked to 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. ln vitro studies have shown that sertraline has no significant affinity for adrenergic (alpha₁, alpha₂,beta), cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5HT_1A, 5HT_1B, 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.

Systemic Bioavailability

In man, following oral once-daily dosing over the range of 50 to 200 mg for 14 days, mean peak plasma concentrations (C_max) 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 C_max 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 C_max 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 C_max 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 C_max was 25% greater, while the time to reach peak plasma concentration (T_max) decreased from 8 hours post-dosing to 5.5 hours. For the oral concentrate, T_max was slightly prolonged from 5.9 hours to 7.0 hours with food.

Metabolism

Sertraline undergoes extensive first pass metabolism. The principal initial pathway of metabolism for sertraline is N-demethylation. N-desmethylsertraline has a plasma terminal elimination half-life of 62 to 104 hours. Both in vitro biochemical and in vivo pharmacological testing have shown N-desmethylsertraline to be substantially less active than sertraline. Both sertraline and N-desmethylsertraline undergo oxidative deamination and subsequent reduction, hydroxylation, and glucuronide conjugation. In a study of radiolabeled sertraline involving two healthy male subjects, sertraline accounted for less than 5% of the plasma radioactivity. About 40 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 _{(0-24 hour),} C_max and C_min, with about a 5 fold 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 to12 years, 32 aged 13 to17 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 to12 year old group exhibited a mean sertraline AUC _{(0-24 hr)} of 3107 ng-hr/mL, mean C_max of 165 ng/mL, and mean half-life of 26.2 hr. The 13 to 17 year old group exhibited a mean sertraline AUC _{(0-24 hr)} of 2296 ng-hr/mL, mean C_max 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 _{(0-24 hr)} of 2570 ng-hr/mL, mean C_max 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 _{(0-24 hr)} and C_max 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 year 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 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 desmethyl-sertraline 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).

Major Depressive Disorder

The 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 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 doses of 50 mg, 100 mg, 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  50 to 200 mg/day. These patients (N=295) were randomized to continuation for 44 weeks on double-blind sertraline 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 mg, 100 mg, 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 Disorder

The 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 2 panic attacks per week in both studies.

Study 3 was a 12-week fixed-dose study, including sertraline doses of 50 mg, 100 mg, 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 versus 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 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 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 50-100 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 Disorder

The 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.