Zoloft - Pharmacology sertraline hydrochloride

Pharmacology refers to the chemical makeup and behavior of ZOLOFT (sertraline hydrochloride solution, concentrate).

Description

ZOLOFT contains sertraline hydrochloride, an SSRI. Sertraline hydrochloride has a molecular weight of 342.7 and has the following chemical name: (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride. The empirical formula C17H17NCl2∙HCl is represented by the following structural formula:

zoloft 01.jpg

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

ZOLOFT tablets for oral administration contain 28.0 mg, 56.0 mg and 111.9 mg sertraline hydrochloride equivalent to 25, 50 and 100 mg of sertraline and the following inactive ingredients: dibasic calcium phosphate dihydrate, D & C Yellow #10 aluminum lake (in 25 mg tablet), FD & C Blue #1 aluminum lake (in 25 mg tablet), FD & C Red #40 aluminum lake (in 25 mg tablet), FD & C Blue #2 aluminum lake (in 50 mg tablet), hydroxypropyl cellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, synthetic yellow iron oxide (in 100 mg tablet), and titanium dioxide.

ZOLOFT oral solution is available in a multidose 60 mL bottle. Each mL of solution contains 22.4 mg sertraline hydrochloride equivalent to 20 mg of sertraline. The solution contains the following inactive ingredients: glycerin, alcohol (12%), menthol, butylated hydroxytoluene (BHT). The oral solution must be diluted prior to administration [See Dosage and Administration (2.7)]. The dispenser contains dry natural rubber.

Clinical Pharmacology

mechanism of action

Sertraline potentiates serotonergic activity in the central nervous system through inhibition of neuronal reuptake of serotonin (5-HT).

pharmacodynamics

Studies at clinically relevant doses 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. The chronic administration of sertraline was found in animals to down regulate brain norepinephrine receptors. Sertraline does not inhibit monoamine oxidase.

Alcohol

In healthy subjects, the acute cognitive and psychomotor effects of alcohol were not potentiated by ZOLOFT.

Cardiac Electrophysiology

The effect of sertraline on the QTc interval was evaluated in a randomized, double-blind, placebo- and positive-controlled three-period crossover thorough QTc study in 54 healthy adult subjects. At 2-fold the maximum recommended daily dose (~3-fold the steady-state exposure for sertraline and N-desmethylsertraline), the largest mean ΔΔQTc was 10 ms with upper bound of two-sided 90% confidence interval of 12 ms. The length of the QTc interval was also positively correlated with serum concentrations of sertraline and N- desmethylsertraline concentrations. These concentration-based analyses, however, indicated a lesser effect on QTc at maximally observed concentration than in the primary analysis [See Warnings and Precautions (5), Adverse Reactions (6), Drug Interactions (7), Overdosage (10)].

pharmacokinetics

Absorption

Following oral once-daily ZOLOFT 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. Consistent with the terminal elimination half-life, there is an approximately two-fold accumulation up to steady-state concentrations, which are achieved after 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. The single dose bioavailability of ZOLOFT tablets is approximately equal to an equivalent dose of ZOLOFT oral solution. Administration with food causes a small increase in Cmax and AUC.

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 40–45% of the administered radioactivity was recovered in urine in 9 days. Unchanged sertraline was not detectable in the urine. For the same period, about 40–45% of the administered radioactivity was accounted for in feces, including 12–14% unchanged sertraline.

Desmethylsertraline exhibits time-related, dose dependent increases in AUC (0–24-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, warfarin and propranolol.

Studies in Specific Populations

Pediatric Patients

Sertraline pharmacokinetics were evaluated in a group of 61 pediatric patients (29 aged 6–12 years, 32 aged 13–17 years) including both males (N=28) and females (N=33). Relative to the adults, pediatric patients aged 6–12 years and 13–17 years showed about 22% lower AUC (0–24 hr) and Cmax values when plasma concentration was adjusted for weight. The half-life was similar to that in adults, and no gender-associated differences were observed [See Dosage and Administration (2.1), Use in Specific Populations (8.4)].

Geriatric Patients

Sertraline plasma clearance in a group of 16 (8 male, 8 female) elderly patients treated with 100 mg/day of ZOLOFT for 14 days was approximately 40% lower than in a similarly studied group of younger (25 to 32 year old) individuals. Steady-state, therefore, was 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 [See Use in Specific Populations (8.5)].

Hepatic Impairment

In patients with chronic mild liver impairment (N=10: 8 patients with Child-Pugh scores of 5–6; and 2 patients with Child-Pugh scores of 7–8) who received 50 mg of ZOLOFT per day for 21 days, sertraline clearance was reduced, resulting in approximately 3-fold greater exposure compared to age-matched volunteers with normal hepatic function (N=10). The exposure to desmethylsertraline was approximately 2-fold greater in patients with mild hepatic impairment compared to age-matched volunteers with normal hepatic function. There were no significant differences in plasma protein binding observed between the two groups. The effects of ZOLOFT in patients with moderate and severe hepatic impairment have not been studied [See Dosage and Administration (2.4), Use in Specific Populations (8.6)].

Renal Impairment

Sertraline is extensively metabolized and excretion of unchanged drug in urine is a minor route of elimination. In volunteers with mild to moderate (CLcr=30–60 mL/min), moderate to severe (CLcr=10–29 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 Use in Specific Populations (8.7)].

Drug Interaction Studies

Pimozide

In a controlled study of a single dose (2 mg) of pimozide, 200 mg ZOLOFT (once daily) 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 ECG. The highest recommended pimozide dose (10 mg) has not been evaluated in combination with ZOLOFT. The effect on QTc interval and PK parameters at doses higher than 2 mg of pimozide are not known [See Drug Interactions (7.1)].

Drugs Metabolized by CYP2D6

Many antidepressant drugs (e.g., SSRIs, including ZOLOFT, and most tricyclic antidepressant drugs) inhibit the biochemical activity of the drug metabolizing isozyme CYP2D6 (debrisoquin hydroxylase), and, thus, may increase the plasma concentrations of co-administered drugs that are metabolized by CYP2D6. The drugs for which this potential interaction is of greatest concern are those metabolized primarily by CYP2D6 and that have a narrow therapeutic index (e.g., tricyclic antidepressant drugs and the Type 1C antiarrhythmics propafenone and flecainide). The extent to which this interaction is an important clinical problem depends on the extent of the inhibition of CYP2D6 by the antidepressant and the therapeutic index of the co-administered drug. There is variability among the drugs effective in the treatment of MDD in the extent of clinically important 2D6 inhibition, and in fact ZOLOFT at lower doses has a less prominent inhibitory effect on 2D6 than some others in the class. Nevertheless, even ZOLOFT has the potential for clinically important 2D6 inhibition [See Drug Interactions (7.1)].

Phenytoin

Clinical trial data suggested that ZOLOFT may increase phenytoin concentrations [See Drug Interactions (7.1)].

Cimetidine

In a study assessing disposition of ZOLOFT (100 mg) on the second of 8 days of cimetidine administration (800 mg daily), there were increases in ZOLOFT mean AUC (50%), Cmax (24%) and half-life (26%) compared to the placebo group [See Drug Interactions (7.2)].

Diazepam

In a study comparing the disposition of intravenously administered diazepam before and after 21 days of dosing with either ZOLOFT (50 to 200 mg/day escalating dose) or placebo, there was a 32% decrease relative to baseline in diazepam clearance for the ZOLOFT 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 ZOLOFT group compared to a 20% decrease in the placebo group (p<0.03) [See Drug Interactions (7.2)].

Lithium

In a placebo-controlled trial in normal volunteers, the administration of two doses of ZOLOFT did not significantly alter steady-state lithium levels or the renal clearance of lithium [See Drug Interactions (7.2)].

Tolbutamide

In a placebo-controlled trial in normal volunteers, administration of ZOLOFT for 22 days (including 200 mg/day for the final 13 days) caused a statistically significant 16% decrease from baseline in the clearance of tolbutamide following an intravenous 1000 mg dose. ZOLOFT administration did not noticeably change either the plasma protein binding or the apparent volume of distribution of tolbutamide, suggesting that the decreased clearance was due to a change in the metabolism of the drug [See Drug Interactions (7.2)].

Atenolol

ZOLOFT (100 mg) when administered to 10 healthy male subjects had no effect on the beta-adrenergic blocking ability of atenolol [See Drug Interactions (7.2)].

Digoxin

In a placebo-controlled trial in normal volunteers, administration of ZOLOFT for 17 days (including 200 mg/day for the last 10 days) did not change serum digoxin levels or digoxin renal clearance [See Drug Interactions (7.2)].

Drugs Metabolized by CYP3A4

In three separate in vivo interaction studies, ZOLOFT was co-administered with CYP3A4 substrates, terfenadine, carbamazepine, or cisapride under steady-state conditions. The results of these studies indicated that ZOLOFT did not increase plasma concentrations of terfenadine, carbamazepine, or cisapride. These data indicate that ZOLOFT's extent of inhibition of CYP3A4 activity is not likely to be of clinical significance. Results of the interaction study with cisapride indicate that ZOLOFT 200 mg (once daily) induces the metabolism of cisapride (cisapride AUC and Cmax were reduced by about 35%) [See Drug Interactions (7.2)].

Microsomal Enzyme Induction

Preclinical studies have shown ZOLOFT to induce hepatic microsomal enzymes. In clinical studies, ZOLOFT was shown to induce hepatic enzymes minimally as determined by a small (5%) but statistically significant decrease in antipyrine half-life following administration of 200 mg of ZOLOFT per day for 21 days. This small change in antipyrine half-life reflects a clinically insignificant change in hepatic metabolism.

Nonclinicaltoxicology

carcinogenesis, mutagenesis, impairment of fertility

Carcinogenesis

Lifetime carcinogenicity studies were carried out in CD-1 mice and Long-Evans rats at doses up to 40 mg/kg/day. These doses correspond to 1 times (mice) and 2 times (rats) the maximum recommended human dose (MRHD) of 200 mg/day on a mg/m2 basis. There was a dose-related increase of liver adenomas in male mice receiving sertraline at 10–40 mg/kg (0.25–1.0 times the MRHD on a mg/m2 basis). No increase was seen in female mice or in rats of either sex receiving the same treatments, nor was there an increase in hepatocellular carcinomas. Liver adenomas have a variable rate of spontaneous occurrence in the CD-1 mouse and are of unknown significance to humans. There was an increase in follicular adenomas of the thyroid in female rats receiving sertraline at 40 mg/kg (2 times the MRHD on a mg/m2 basis); this was not accompanied by thyroid hyperplasia. While there was an increase in uterine adenocarcinomas in rats receiving sertraline at 10–40 mg/kg (0.5–2.0 times the MRHD on a mg/m2 basis) compared to placebo controls, this effect was not clearly drug related.

Mutagenesis

Sertraline had no genotoxic effects, with or without metabolic activation, based on the following assays: bacterial mutation assay; mouse lymphoma mutation assay; and tests for cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes.

Impairment of Fertility

A decrease in fertility was seen in one of two rat studies at a dose of 80 mg/kg (3.1 times the maximum recommended human dose on a mg/m2 basis in adolescents).

Clinical Studies

Efficacy of ZOLOFT was established in the following trials:

major depressive disorder

The efficacy of ZOLOFT as a treatment for MDD was established in two randomized, double-blind, placebo-controlled studies and one double-blind, randomized-withdrawal study following an open label study in adult (ages 18 to 65) outpatients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-III) criteria for MDD (studies MDD-1 and MDD-2).

  • Study MDD-1 was an 8-week, 3-arm study with flexible dosing of ZOLOFT, amitriptyline, and placebo. Adult patients received ZOLOFT (N=126, in a daily dose titrated weekly to 50 mg, 100 mg, or 200 mg), amitriptyline (N=123, in a daily dose titrated weekly to 50 mg, 100 mg, or 150 mg), or placebo (N= 130).
  • Study MDD-2 was a 6-week, multicenter parallel study of three fixed doses of ZOLOFT administered once daily at 50 mg (N=82), 100 mg (N=75), and 200 mg (N=56) doses and placebo (N=76) in the treatment of adult outpatients with MDD.

Overall, these studies demonstrated ZOLOFT to be superior to placebo on the Hamilton Rating Scale for Depression (HAMD-17) and the Clinical Global Impression Severity (CGI-S) of Illness and Global Improvement (CGI-I) scores. Study MDD-2 was not readily interpretable regarding a dose response relationship for effectiveness.

A third study (Study MDD-3) involved adult outpatients meeting the DSM-III criteria for MDD who had responded by the end of an initial 8-week open treatment phase on ZOLOFT 50–200 mg/day. These patients (n=295) were randomized to continuation on double-blind ZOLOFT 50–200 mg/day or placebo for 44 weeks. A statistically significantly lower relapse rate was observed for patients taking ZOLOFT compared to those on placebo: ZOLOFT [n=11 (8%)] and placebo [n=31 (39%)]. The mean ZOLOFT 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

Adults with OCD

The effectiveness of ZOLOFT in the treatment of OCD was demonstrated in three multicenter placebo-controlled studies of adult (age 18–65) non-depressed outpatients (Studies OCD-1, OCD-2, and OCD-3). Patients in all three studies had moderate to severe OCD (DSM-III or DSM-III-R) with mean baseline ratings on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) total score ranging from 23 to 25.

  • Study OCD-1 was an 8-week randomized, placebo-controlled study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day, titrated in 50 mg increments every 4 days to a maximally tolerated dose; the mean dose for completers was 186 mg/day. Patients receiving ZOLOFT (N=43) experienced a mean reduction of approximately 4 points on the Y-BOCS total score which was statistically significantly greater than the mean reduction of 2 points in placebo-treated patients (N=44). The mean change in Y-BOCS from baseline to last visit (the primary efficacy endpoint) was -3.79 (ZOLOFT) and -1.48 (placebo).
  • Study OCD-2 was a 12-week randomized, placebo-controlled fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day. ZOLOFT (N=240) was titrated to the assigned dose over two weeks in 50 mg increments every 4 days. Patients receiving ZOLOFT doses of 50 and 200 mg/day experienced mean reductions of approximately 6 points on the Y-BOCS total score, which were statistically significantly greater than the approximately 3 point reduction in placebo-treated patients (N=84). The mean change in Y-BOCS from baseline to last visit (the primary efficacy endpoint) was -5.7 (pooled results from ZOLOFT 50 mg, 100 mg, and 150 mg) and -2.85 (placebo).
  • Study OCD-3 was a 12-week randomized, placebo controlled study with flexible dosing of ZOLOFT in a range of 50 to 200 mg/day; the mean dose for completers was 185 mg/day. ZOLOFT (N=241) was titrated to the assigned dose over two weeks in 50 mg increments every 4 days. Patients receiving ZOLOFT experienced a mean reduction of approximately 7 points on the Y-BOCS total score which was statistically significantly greater than the mean reduction of approximately 4 points in placebo-treated patients (N=84). The mean change in Y-BOCS from baseline to last visit (the primary efficacy endpoint) was - 6.5 (ZOLOFT) and -3.6 (placebo).

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

The effectiveness of ZOLOFT was studied in the risk reduction of OCD relapse. In Study OCD-4, patients ranging in age from 18–79 meeting DSM-III-R criteria for OCD who had responded during a 52-week single-blind trial on ZOLOFT 50–200 mg/day (n=224) were randomized to continuation of ZOLOFT or to substitution of placebo for up to 28 weeks of observation for analysis of discontinuation due to relapse or insufficient clinical response. Response during the single-blind phase was defined as a decrease in the Y-BOCS score of ≥ 25% compared to baseline and a CGI-I of 1 (very much improved), 2 (much improved) or 3 (minimally improved). Insufficient clinical response during the double-blind phase indicated a worsening of the patient's condition that resulted in study discontinuation, as assessed by the investigator. Relapse during the double-blind phase was defined as the following conditions being met (on three consecutive visits for 1 and 2, and condition 3 being met at visit 3):

  • Condition 1: Y-BOCS score increased by ≥ 5 points, to a minimum of 20, relative to baseline;
  • Condition 2: CGI-I increased by ≥ one point; and
  • Condition 3: Worsening of the patient's condition in the investigator's judgment, to justify alternative treatment.

Patients receiving continued ZOLOFT treatment experienced a statistically 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.

Pediatric Patients with OCD

The effectiveness of ZOLOFT for the treatment of OCD was demonstrated in a 12-week, multicenter, placebo-controlled, parallel group study in a pediatric outpatient population (ages 6–17) (Study OCD-5). ZOLOFT (N=92) was initiated at doses of either 25 mg/day (pediatric patients ages 6–12) or 50 mg/day (adolescents, ages 13–17), and then titrated at 3 and 4 day intervals (25 mg incremental dose for pediatric patients ages 6–12) or 1 week intervals (50 mg incremental dose adolescents ages 13–17) 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 (CY-BOCS) total score of 22. Patients receiving ZOLOFT experienced a mean reduction of approximately 7 units on the CY-BOCS total score which was statistically significantly greater than the 3 unit reduction for placebo patients (n=95). Analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex.

panic disorder

The effectiveness of ZOLOFT in the treatment of PD was demonstrated in three double-blind, placebo-controlled studies (Studies PD-1, PD-2, and PD-3) of adult outpatients who had a primary diagnosis of PD (DSM-III-R), with or without agoraphobia.

  • Studies PD-1 and PD-2 were 10-week flexible dose studies of ZOLOFT (N=80 study PD-1 and N=88 study PD-2) compared to placebo (N=176 study PD-1 and PD-2). In both studies, ZOLOFT was initiated at 25 mg/day for the first week, then titrated in weekly increments of 50 mg per day to a maximum dose of 200 mg/day on the basis of clinical response and toleration. The mean ZOLOFT doses for completers to 10 weeks were 131 mg/day and 144 mg/day, respectively, for Studies PD-1 and PD-2. In these studies, ZOLOFT was shown to be statistically significantly more effective than placebo on change from baseline in panic attack frequency and on the Clinical Global Impression Severity (CGI-S) of Illness and Global Improvement (CGI-I) scores. The difference between ZOLOFT and placebo in reduction from baseline in the number of full panic attacks was approximately 2 panic attacks per week in both studies.
  • Study PD-3 was a 12-week randomized, double-blind fixed-dose study, including ZOLOFT doses of 50, 100, and 200 mg/day. Patients receiving ZOLOFT (50 mg N=43, 100 mg N=44, 200 mg N=45) experienced a statistically significantly greater reduction in panic attack frequency than patients receiving placebo (N=45). Study PD-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 Study PD-4, patients meeting DSM-III-R criteria for PD who had responded during a 52-week open trial on ZOLOFT 50–200 mg/day (n=183) were randomized to continuation of ZOLOFT 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). Insufficient clinical response in the double-blind phase indicated a worsening of the patient's condition that resulted in study discontinuation, as assessed by the investigator. 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 PD;
  • (3)number of panic attacks greater than at baseline.

Patients receiving continued ZOLOFT treatment experienced a statistically 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

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

Studies PSTD-1 and PSTD-2 were 12-week flexible dose studies. ZOLOFT was initiated at 25 mg/day for the first week, and titrated in weekly increments of 50 mg per day to a maximum dose of 200 mg/day on the basis of clinical response and tolerability. The mean ZOLOFT dose for completers was 146 mg/day and 151 mg/day, respectively, for Studies PSTD-1 and PSTD-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. Patients receiving ZOLOFT (N=99 and N=94, respectively) showed statistically significant improvement compared to placebo (N=83 and N=92) on change from baseline to endpoint on the CAPS, IES, and on the Clinical Global Impressions (CGI-S) Severity of Illness and Global Improvement (CGI-I) scores.

In two additional placebo-controlled PTSD trials (Studies PSTD-3 and PSTD-4), the difference in response to treatment between patients receiving ZOLOFT and patients receiving placebo was not statistically significant. One of these additional studies was conducted in patients similar to those recruited for Studies PSTD-1 and PSTD-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 Studies PSTD-1 and PSTD-2 described above were women. Post hoc exploratory analyses revealed a statistically significant difference between ZOLOFT 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 effect is unknown at this time. There was insufficient information to determine the effect of race or age on outcome.

In Study PSTD-5, patients meeting DSM-III-R criteria for PTSD who had responded during a 24-week open trial on ZOLOFT 50–200 mg/day (n=96) were randomized to continuation of ZOLOFT 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 ZOLOFT treatment experienced statistically significantly lower relapse rates over the subsequent 28 weeks compared to those receiving placebo. This pattern was demonstrated in male and female subjects.

social anxiety disorder

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

Study SAD-1 was a 12-week, flexible dose study comparing ZOLOFT (50–200 mg/day), n=211, to placebo, n=204, in which ZOLOFT was initiated at 25 mg/day for the first week, then titrated to the maximum tolerated dose in 50 mg increments biweekly. Study outcomes were assessed by the:

  • (1)Liebowitz Social Anxiety Scale (LSAS), a 24-item clinician administered instrument that measures fear, anxiety, and avoidance of social and performance situations, and
  • (2)Proportion of responders as defined by the Clinical Global Impression of Improvement (CGI-I) criterion of CGI-I ≤ 2 (very much or much improved).

ZOLOFT was statistically significantly more effective than placebo as measured by the LSAS and the percentage of responders.

Study SAD-2 was a 20-week, flexible dose study that compared ZOLOFT (50–200 mg/day), n=135, to placebo, n=69. ZOLOFT was titrated to the maximum tolerated dose in 50 mg increments every 3 weeks. Study outcome was assessed by the:

  • (1)Duke Brief Social Phobia Scale (BSPS), a multi-item clinician-rated instrument that measures fear, avoidance and physiologic response to social or performance situations,
  • (2)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
  • (3)CGI-I responder criterion of ≤ 2.

ZOLOFT 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 statistically 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 Study SAD-3, patients meeting DSM-IV criteria for SAD who had responded while assigned to ZOLOFT (CGI-I of 1 or 2) during a 20-week placebo-controlled trial on ZOLOFT 50–200 mg/day were randomized to continuation of ZOLOFT 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 ZOLOFT continuation treatment experienced a statistically significantly lower relapse rate during this 24-week period than patients randomized to placebo substitution.

premenstrual dysphoric disorder

The effectiveness of ZOLOFT for the treatment of PMDD was established in two double-blind, parallel group, placebo-controlled flexible dose trials (Studies PMDD-1 and PMDD-2) conducted over 3 menstrual cycles in adult female patients. The effectiveness of ZOLOFT for PMDD for more than 3 menstrual cycles has not been systematically evaluated in controlled trials.

Patients in Study PMDD-1 met DSM-III-R criteria for Late Luteal Phase Dysphoric Disorder (LLPDD), the clinical entity referred to as PMDD in DSM-IV. Patients in Study PMDD-2 met DSM-IV criteria for PMDD. Study PMDD-1 utilized continuous daily dosing throughout the study, while Study PMDD-2 utilized luteal phase dosing (intermittent dosing) for the 2 weeks prior to the onset of menses. The mean duration of PMDD symptoms was approximately 10.5 years in both studies. Patients taking oral contraceptives were excluded from these trials; therefore, the efficacy of ZOLOFT 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 Rating Scale for Depression (HAMD-17), and the Clinical Global Impression Severity of Illness (CGI-S) and Improvement (CGI-I) scores.

  • In Study PMDD-1, involving 251 randomized patients, (n=125 on ZOLOFT and n=126 on placebo), ZOLOFT treatment was initiated at 50 mg/day and administered daily throughout the menstrual cycle. In subsequent cycles, ZOLOFT was titrated in 50 mg increments at the beginning of each menstrual cycle up to a maximum of 150 mg/day on the basis of clinical response and tolerability. The mean dose for completers was 102 mg/day. ZOLOFT administered daily throughout the menstrual cycle was statistically 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 PMDD-2, involving 281 randomized patients, (n=142 on ZOLOFT and n=139 on placebo), ZOLOFT 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 (intermittent dosing). 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 tolerability. Patients who received 100 mg/day started with 50 mg/day for the first 3 days of the cycle, then 100 mg/day for the remainder of the cycle. The mean ZOLOFT dose for completers was 74 mg/day. ZOLOFT administered in the late luteal phase of the menstrual cycle was statistically 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 (Week 12).

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

This drug label information is as submitted to the Food and Drug Administration (FDA) and is intended for informational purposes only. If you think you may have a medical emergency, immediately call your doctor or dial 911. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
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