Zoloft Prescribing Information
In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and over 4,400 pediatric patients, the incidence of suicidal thoughts and behaviors in pediatric and young adult patients was greater in antidepressant-treated patients than in placebo-treated patients. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 2.
No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about antidepressant drug effect on suicide.
Age Range (years) | Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1000 Patients Treated |
Increases Compared to Placebo | |
<18 | 14 additional patients |
18-24 | 5 additional patients |
Decreases Compared to Placebo | |
25-64 | 1 fewer patient |
≥65 | 6 fewer patients |
It is unknown whether the risk of suicidal thoughts and behaviors in pediatric and young adult patients extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression.
Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing ZOLOFT, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.
ZOLOFT is indicated for the treatment of the following
Efficacy of ZOLOFT was established in the following trials:
• MDD: two short-term trials and one maintenance trials in adults[See Clinical Studies (14.1)].• OCD: three short-term trials in adults and one short-term trial in pediatric patients[See Clinical Studies (14.2)].• PD: three short-term trials and one maintenance trial in adults[See Clinical Studies (14.3)].• PTSD: two short-term trials and one maintenance trial in adults[See Clinical Studies (14.4)].• SAD: two short-term trials and one maintenance trial in adults[See Clinical Studies (14.5)].• PMDD: two short-term trials in adult female patients[See Clinical Studies (14.6)].
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.
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.
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.
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.
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.
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.
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.
• Major depressive disorder (MDD)• Obsessive-compulsive disorder (OCD)• Panic disorder (PD)• Posttraumatic stress disorder (PTSD)• Social anxiety disorder (SAD)• Premenstrual dysphoric disorder (PMDD)
Indication | Starting Dosage | Maximum Dosage | |||||||||||||||||||||
MDD ( The recommended initial dosage and maximum ZOLOFT dosage in patients with MDD, OCD, PD, PTSD, and SAD are displayed in Table 1 below. A dosage of 25 mg or 50 mg per day is the initial therapeutic dosage. For adults and pediatric patients, subsequent dosages may be increased in case of an inadequate response in 25 to 50 mg per day increments once a week, depending on tolerability, up to a maximum of 200 mg per day. Given the 24-hour elimination half-life of ZOLOFT, the recommended interval between dose changes is one week.
| 50 mg per day | 200 mg per day | |||||||||||||||||||||
OCD ( The recommended initial dosage and maximum ZOLOFT dosage in patients with MDD, OCD, PD, PTSD, and SAD are displayed in Table 1 below. A dosage of 25 mg or 50 mg per day is the initial therapeutic dosage. For adults and pediatric patients, subsequent dosages may be increased in case of an inadequate response in 25 to 50 mg per day increments once a week, depending on tolerability, up to a maximum of 200 mg per day. Given the 24-hour elimination half-life of ZOLOFT, the recommended interval between dose changes is one week.
| 25 mg per day (ages 6-12) 50 mg per day (ages ≥ 13) | 200 mg per day | |||||||||||||||||||||
PD, PTSD, SAD ( The recommended initial dosage and maximum ZOLOFT dosage in patients with MDD, OCD, PD, PTSD, and SAD are displayed in Table 1 below. A dosage of 25 mg or 50 mg per day is the initial therapeutic dosage. For adults and pediatric patients, subsequent dosages may be increased in case of an inadequate response in 25 to 50 mg per day increments once a week, depending on tolerability, up to a maximum of 200 mg per day. Given the 24-hour elimination half-life of ZOLOFT, the recommended interval between dose changes is one week.
| 25 mg per day | 200 mg per day | |||||||||||||||||||||
PMDD ( The recommended starting ZOLOFT dosage in adult women with PMDD is 50 mg per day. ZOLOFT may be administered either continuously (every day throughout the menstrual cycle) or intermittently (only during the luteal phase of the menstrual cycle, i.e., starting the daily dosage 14 days prior to the anticipated onset of menstruation and continuing through the onset of menses). Intermittent dosing would be repeated with each new cycle.
| 50 mg per day | 150 mg per day | |||||||||||||||||||||
PMDD ( The recommended starting ZOLOFT dosage in adult women with PMDD is 50 mg per day. ZOLOFT may be administered either continuously (every day throughout the menstrual cycle) or intermittently (only during the luteal phase of the menstrual cycle, i.e., starting the daily dosage 14 days prior to the anticipated onset of menstruation and continuing through the onset of menses). Intermittent dosing would be repeated with each new cycle.
| 50 mg per day during luteal phase only | 100 mg per day during luteal phase only | |||||||||||||||||||||
• If inadequate response to starting dosage, titrate in 25-50 mg per day increments once weekly in MDD, OCD, PD, PTSD, and SAD ()2.1 Dosage in Patients with MDD, OCD, PD, PTSD, and SADThe recommended initial dosage and maximum ZOLOFT dosage in patients with MDD, OCD, PD, PTSD, and SAD are displayed in Table 1 below. A dosage of 25 mg or 50 mg per day is the initial therapeutic dosage.
For adults and pediatric patients, subsequent dosages may be increased in case of an inadequate response in 25 to 50 mg per day increments once a week, depending on tolerability, up to a maximum of 200 mg per day. Given the 24-hour elimination half-life of ZOLOFT, the recommended interval between dose changes is one week.
Table 1: Recommended Daily Dosage of ZOLOFT in Patients with MDD, OCD, PD, PTSD, and SAD IndicationStarting DoseTherapeutic RangeAdultsMDD
50 mg
50-200 mg
OCD
50 mg
PD, PTSD, SAD
25 mg
Pediatric PatientsOCD (ages 6-12 years old)
25 mg
50-200 mg
OCD (ages 13-17 years old)
50 mg
• See Full Prescribing Information for titration in PMDD ()2.2 Dosage in Patients with PMDDThe recommended starting ZOLOFT dosage in adult women with PMDD is 50 mg per day. ZOLOFT may be administered either continuously (every day throughout the menstrual cycle) or intermittently (only during the luteal phase of the menstrual cycle, i.e., starting the daily dosage 14 days prior to the anticipated onset of menstruation and continuing through the onset of menses). Intermittent dosing would be repeated with each new cycle.
• When dosingcontinuously, patients not responding to a 50 mg dosage may benefit from dosage increases at 50 mg increments per menstrual cycle up to 150 mg per day.• When dosingintermittently, patients not responding to a 50 mg dosage may benefit from increasing the dosage up to a maximum of 100 mg per day during the next menstrual cycle (and subsequent cycles) as follows: 50 mg per day during the first 3 days of dosing followed by 100 mg per day during the remaining days in the dosing cycle.
• Hepatic impairment:o Mild: Recommended starting and maximum dosage is half recommended dosage ()2.4 Dosage Modifications in Patients with Hepatic ImpairmentBoth the recommended starting dosage and therapeutic range in patients with mild hepatic impairment (Child Pugh scores 5 or 6) are half the recommended daily dosage
[See Dosage and Administration (2.1, 2.2)]. The use of ZOLOFT in patients with moderate (Child Pugh scores 7 to 9) or severe hepatic impairment (Child Pugh scores 10-15) is not recommended[See Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].o Moderate or severe: Not recommended ()2.4 Dosage Modifications in Patients with Hepatic ImpairmentBoth the recommended starting dosage and therapeutic range in patients with mild hepatic impairment (Child Pugh scores 5 or 6) are half the recommended daily dosage
[See Dosage and Administration (2.1, 2.2)]. The use of ZOLOFT in patients with moderate (Child Pugh scores 7 to 9) or severe hepatic impairment (Child Pugh scores 10-15) is not recommended[See Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].• When discontinuing ZOLOFT, reduce dose gradually (,2.6 Discontinuation of Treatment with ZOLOFTAdverse reactions may occur upon discontinuation of ZOLOFT
[See Warnings and Precautions (5.5)]. Gradually reduce the dosage rather than stopping ZOLOFT abruptly whenever possible.)5.4 Activation of Mania or HypomaniaIn patients with bipolar disorder, treating a depressive episode with ZOLOFT or another antidepressant may precipitate a mixed/manic episode. In controlled clinical trials, patients with bipolar disorder were generally excluded; however, symptoms of mania or hypomania were reported in 0.4% of patients treated with ZOLOFT. Prior to initiating treatment with ZOLOFT, screen patients for any personal or family history of bipolar disorder, mania, or hypomania.
• Oral solution: Must be diluted before administration ()2.7 Preparation of ZOLOFT Oral SolutionZOLOFT oral solution must be diluted before use.
• Use the supplied calibrated dropper to measure the amount of ZOLOFT oral solution needed• Note: The supplied calibrated dropper has 25 mg and 50 mg graduation marks only• Mix with 4 ounces (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or orange juice ONLY. After mixing, a slight haze may appear, which is normal.
Instruct patients or caregivers to immediately take the dose after mixing.
• Pregnancy: Third trimester use may increase risk for persistent pulmonary hypertension and withdrawal in the neonate. ()8.1 PregnancyRisk SummaryOverall, available published epidemiologic studies of pregnant women exposed to sertraline in the first trimester suggest no difference in major birth defect risk compared to the background rate for major birth defects in comparator populations. Some studies have reported increases for specific major birth defects; however, these study results are inconclusive
[See Data]. There are clinical considerations regarding neonates exposed to SSRIs and SNRIs, including ZOLOFT, during the third trimester of pregnancy[See Clinical Considerations].Although no teratogenicity was observed in animal reproduction studies, delayed fetal ossification was observed when sertraline was administered during the period of organogenesis at doses less than the maximum recommended human dose (MRHD) in rats and doses 3.1 times the MRHD in rabbits on a mg/m2basis in adolescents. When sertraline was administered to female rats during the last third of gestation, there was an increase in the number of stillborn pups and pup deaths during the first four days after birth at the MRHD
[See Data].The background risk of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Advise a pregnant woman of possible risks to the fetus when prescribing ZOLOFT.
ZOLOFT oral solution contains 12% alcohol and is not recommended during pregnancy because there is no known safe level of alcohol exposure during pregnancy.
Clinical ConsiderationsDisease-associated maternal and/or embryo/fetal riskA prospective longitudinal study followed 201 pregnant women with a history of major depression who were euthymic taking antidepressants at the beginning of pregnancy. The women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants. Consider the risks of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum.
Fetal/Neonatal adverse reactionsExposure to SSRIs and SNRIs, including ZOLOFT in late pregnancy may lead to an increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding, and/or persistent pulmonary hypertension of the newborn (PPHN).
When treating a pregnant woman with ZOLOFT during the third trimester, carefully consider both the potential risks and benefits of treatment. Monitor neonates who were exposed to ZOLOFT in the third trimester of pregnancy for PPHN and drug discontinuation syndrome
[See Data].DataHuman DataThird Trimester ExposureNeonates exposed to ZOLOFT and other SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. These findings are based on post-marketing reports. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. In some cases, the clinical picture was consistent with serotonin syndrome
[See Warnings and Precautions (5.2)].Exposure during late pregnancy to SSRIs may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1-2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20thweek of gestation compared to infants who had not been exposed to antidepressants during pregnancy. A study of 831,324 infants born in Sweden in 1997-2005 found a PPHN risk ratio of 2.4 (95% CI 1.2-4.3) associated with patient-reported maternal use of SSRIs “in early pregnancy” and a PPHN risk ratio of 3.6 (95% CI 1.2-8.3) associated with a combination of patient-reported maternal use of SSRIs “in early pregnancy” and an antenatal SSRI prescription “in later pregnancy”.
First Trimester ExposureThe weight of evidence from epidemiologic studies of pregnant women exposed to sertraline in the first trimester suggest no difference in major birth defect risk compared to the background rate for major birth defects in pregnant women who were not exposed to sertraline. A meta-analysis of studies suggest no increase in the risk of total malformations (summary odds ratio=1.01, 95% CI=0.88-1.17) or cardiac malformations (summary odds ratio=0.93, 95% CI=0.70-1.23) among offspring of women with first trimester exposure to sertraline. An increased risk of congenital cardiac defects, specifically septal defects, the most common type of congenital heart defect, was observed in some published epidemiologic studies with first trimester sertraline exposure; however, most of these studies were limited by the use of comparison populations that did not allow for the control of confounders such as the underlying depression and associated conditions and behaviors, which may be factors associated with increased risk of these malformations.
Animal DataReproduction studies have been performed in rats and rabbits at doses up to 80 mg/kg/day and 40 mg/kg/day, respectively. These doses correspond to approximately 3.1 times the maximum recommended human dose (MRHD) of 200 mg/day on a mg/m2basis in adolescents. There was no evidence of teratogenicity at any dose level. When pregnant rats and rabbits were given sertraline during the period of organogenesis, delayed ossification was observed in fetuses at doses of 10 mg/kg (0.4 times the MRHD on a mg/m2 basis) in rats and 40 mg/kg (3.1 times the MRHD on a mg/m2basis) in rabbits. When female rats received sertraline during the last third of gestation and throughout lactation, there was an increase in stillborn pups and pup deaths during the first 4 days after birth. Pup body weights were also decreased during the first four days after birth. These effects occurred at a dose of 20 mg/kg (0.8 times the MRHD on a mg/m2basis). The no effect dose for rat pup mortality was 10 mg/kg (0.4 times the MRHD on a mg/m2basis). The decrease in pup survival was shown to be due to
in uteroexposure to sertraline. The clinical significance of these effects is unknown.• Pediatric use: Safety and effectiveness of ZOLOFT in pediatric patients other than those with OCD have not been established. ()8.4 Pediatric UseThe safety and efficacy of ZOLOFT have been established in the treatment of OCD in pediatric patients aged 6 to 17
[See Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2)]. Safety and effectiveness in pediatric patients in patients with OCD below the age of 6 have not been established. Safety and effectiveness have not been established in pediatric patients for indications other than OCD. Two placebo-controlled trials were conducted in pediatric patients with MDD, but the data were not sufficient to support an indication for use in pediatric patients.Monitoring Pediatric Patients Treated with ZOLOFTMonitor all patients being treated with antidepressants for clinical worsening, suicidal thoughts, and unusual changes in behavior, especially during the initial few months of treatment, or at times of dose increases or decreases
[See Boxed Warning, Warnings and Precautions (5.1)]. Decreased appetite and weight loss have been observed with the use of SSRIs. Monitor weight and growth in pediatric patients treated with an SSRI such as ZOLOFT.Weight Loss in Studies in Pediatric Patients with MDDIn a pooled analysis of two 10-week, double-blind, placebo-controlled, flexible dose (50-200 mg) outpatient trials for MDD (n=373), there was a difference in weight change between ZOLOFT and placebo of roughly 1 kg, for both children (ages 6-11) and adolescents (ages 12-17), in both age groups representing a slight weight loss for the ZOLOFT group compared to a slight gain for the placebo group. For children, about 7% of the ZOLOFT-treated patients had a weight loss greater than 7% of body weight compared to 0% of the placebo-treated patients; for adolescents, about 2% of ZOLOFT-treated patients had a weight loss > 7% of body weight compared to about 1% of placebo-treated patients.
A subset of patients who completed the randomized controlled trials in patients with MDD (ZOLOFT n=99, placebo n=122) were continued into a 24-week, flexible-dose, open-label, extension study. Those subjects who completed 34 weeks of ZOLOFT treatment (10 weeks in a placebo-controlled trial + 24 weeks open-label, n=68) had weight gain that was similar to that expected using data from age-adjusted peers. However, there are no studies that directly evaluate the long-term effects of ZOLOFT on the growth, development, and maturation in pediatric patients.
Alcohol Content in ZOLOFT Oral SolutionZOLOFT oral solution contains 12% alcohol.
Juvenile Animal DataA study conducted in juvenile rats at clinically relevant doses showed delay in sexual maturation, but there was no effect on fertility in either males or females.
In this study in which juvenile rats were treated with oral doses of sertraline at 0, 10, 40 or 80 mg/kg/day from postnatal day 21 to 56, a delay in sexual maturation was observed in males treated with 80 mg/kg/day and females treated with doses ≥10 mg/kg/day. There was no effect on male and female reproductive endpoints or neurobehavioral development up to the highest dose tested (80 mg/kg/day), except a decrease in auditory startle response in females at 40 and 80 mg/kg/day at the end of treatment but not at the end of the drug-free period. The highest dose of 80 mg/kg/day produced plasma levels (AUC) of sertraline 5 times those seen in pediatric patients (6-17 years of age) receiving the maximum recommended dose of sertraline (200 mg/day).
ZOLOFT is contraindicated in patients:
• Taking, or within 14 days of stopping, MAOIs, (including the MAOIs linezolid and intravenous methylene blue) because of an increased risk of serotonin syndrome[See.,5.2 Serotonin SyndromeSerotonin-norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs), including ZOLOFT, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs
[See Contraindications (4), Drug Interactions (7.1)]. Serotonin syndrome can also occur when these drugs are used alone.Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
The concomitant use of ZOLOFT with MAOIs is contraindicated. In addition, do not initiate ZOLOFT in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking ZOLOFT, discontinue ZOLOFT before initiating treatment with the MAOI
[See Contraindications (4), Drug Interactions (7.1)].Monitor all patients taking ZOLOFT for the emergence of serotonin syndrome. Discontinue treatment with ZOLOFT and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of ZOLOFT with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.
]7.1 Clinically Significant Drug InteractionsTable 5 includes clinically significant drug interactions with ZOLOFT
[See Clinical Pharmacology (12.3)].Table 5. Clinically-Significant Drug Interactions with ZOLOFT Monoamine Oxidase Inhibitors (MAOIs)Clinical Impact:The concomitant use of SSRIs including ZOLOFT and MAOIs increases the risk of serotonin syndrome.
Intervention:ZOLOFT is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue
[See Dosage and Administration (2.5), Contraindications (4), Warnings and Precautions (5.2)].Examples:selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
PimozideClinical Impact:Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QTc prolongation and ventricular arrhythmias.
Intervention:Concomitant use of pimozide and ZOLOFT is contraindicated
[See Contraindications (4)].Other Serotonergic DrugsClinical Impact:The concomitant use of serotonergic drugs with ZOLOFT increases the risk of serotonin syndrome.
Intervention:Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of ZOLOFT and/or concomitant serotonergic drugs
[See Warnings and Precautions (5.2)].Examples:other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort
Drugs that Interfere with Hemostasis (antiplatelet agents and anticoagulants)Clinical Impact:The concurrent use of an antiplatelet agent or anticoagulant with ZOLOFT may potentiate the risk of bleeding.
Intervention:Inform patients of the increased risk of bleeding associated with the concomitant use of ZOLOFT and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio
[See Warnings and Precautions (5.3)].Examples:aspirin, clopidogrel, heparin, warfarin
Drugs Highly Bound to Plasma ProteinClinical Impact:ZOLOFT is highly bound to plasma protein. The concomitant use of ZOLOFT with another drug that is highly bound to plasma protein may increase free concentrations of ZOLOFT or other tightly-bound drugs in plasma
[See Clinical Pharmacology (12.3)].Intervention:Monitor for adverse reactions and reduce dosage of ZOLOFT or other protein-bound drugs as warranted.
Examples:warfarin
Drugs Metabolized by CYP2D6Clinical Impact:ZOLOFT is a CYP2D6 inhibitor
[See Clinical Pharmacology (12.3)]. The concomitant use of ZOLOFT with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate.Intervention:Decrease the dosage of a CYP2D6 substrate if needed with concomitant ZOLOFT use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if ZOLOFT is discontinued.
Examples:propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thioridazine, tolterodine, venlafaxine
PhenytoinClinical Impact:Phenytoin is a narrow therapeutic index drug. ZOLOFT may increase phenytoin concentrations.
Intervention:Monitor phenytoin levels when initiating or titrating ZOLOFT. Reduce phenytoin dosage if needed.
Examples:phenytoin, fosphenytoin
Drugs that Prolong the QTc IntervalClinical Impact:The risk of QTc prolongation and/or ventricular arrhythmias (e.g., TdP) is increased with concomitant use of other drugs which prolong the QTc interval
[See Warnings and Precautions (5.10), Clinical Pharmacology (12.2)].Intervention:Pimozide is contraindicated for use with sertraline. Avoid the concomitant use of drugs known to prolong the QTc interval.
Examples:Specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol); specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus).
• Taking pimozide[See.]7.1 Clinically Significant Drug InteractionsTable 5 includes clinically significant drug interactions with ZOLOFT
[See Clinical Pharmacology (12.3)].Table 5. Clinically-Significant Drug Interactions with ZOLOFT Monoamine Oxidase Inhibitors (MAOIs)Clinical Impact:The concomitant use of SSRIs including ZOLOFT and MAOIs increases the risk of serotonin syndrome.
Intervention:ZOLOFT is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue
[See Dosage and Administration (2.5), Contraindications (4), Warnings and Precautions (5.2)].Examples:selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
PimozideClinical Impact:Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QTc prolongation and ventricular arrhythmias.
Intervention:Concomitant use of pimozide and ZOLOFT is contraindicated
[See Contraindications (4)].Other Serotonergic DrugsClinical Impact:The concomitant use of serotonergic drugs with ZOLOFT increases the risk of serotonin syndrome.
Intervention:Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of ZOLOFT and/or concomitant serotonergic drugs
[See Warnings and Precautions (5.2)].Examples:other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort
Drugs that Interfere with Hemostasis (antiplatelet agents and anticoagulants)Clinical Impact:The concurrent use of an antiplatelet agent or anticoagulant with ZOLOFT may potentiate the risk of bleeding.
Intervention:Inform patients of the increased risk of bleeding associated with the concomitant use of ZOLOFT and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio
[See Warnings and Precautions (5.3)].Examples:aspirin, clopidogrel, heparin, warfarin
Drugs Highly Bound to Plasma ProteinClinical Impact:ZOLOFT is highly bound to plasma protein. The concomitant use of ZOLOFT with another drug that is highly bound to plasma protein may increase free concentrations of ZOLOFT or other tightly-bound drugs in plasma
[See Clinical Pharmacology (12.3)].Intervention:Monitor for adverse reactions and reduce dosage of ZOLOFT or other protein-bound drugs as warranted.
Examples:warfarin
Drugs Metabolized by CYP2D6Clinical Impact:ZOLOFT is a CYP2D6 inhibitor
[See Clinical Pharmacology (12.3)]. The concomitant use of ZOLOFT with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate.Intervention:Decrease the dosage of a CYP2D6 substrate if needed with concomitant ZOLOFT use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if ZOLOFT is discontinued.
Examples:propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thioridazine, tolterodine, venlafaxine
PhenytoinClinical Impact:Phenytoin is a narrow therapeutic index drug. ZOLOFT may increase phenytoin concentrations.
Intervention:Monitor phenytoin levels when initiating or titrating ZOLOFT. Reduce phenytoin dosage if needed.
Examples:phenytoin, fosphenytoin
Drugs that Prolong the QTc IntervalClinical Impact:The risk of QTc prolongation and/or ventricular arrhythmias (e.g., TdP) is increased with concomitant use of other drugs which prolong the QTc interval
[See Warnings and Precautions (5.10), Clinical Pharmacology (12.2)].Intervention:Pimozide is contraindicated for use with sertraline. Avoid the concomitant use of drugs known to prolong the QTc interval.
Examples:Specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol); specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus).
• With known hypersensitivity to sertraline (e.g., anaphylaxis, angioedema)[See.,6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described below are from randomized, double-blind, placebo-controlled trials of ZOLOFT (mostly 50 mg to 200 mg per day) in 3066 adults diagnosed with MDD, OCD, PD, PTSD, SAD, and PMDD. These 3066 patients exposed to ZOLOFT for 8 to12 weeks represent 568 patient-years of exposure. The mean age was 40 years; 57% were females and 43% were males.
The most common adverse reactions (≥5% and twice placebo) in all pooled placebo-controlled clinical trials of all ZOLOFT-treated patients with MDD, OCD, PD, PTSD, SAD and PMDD were nausea, diarrhea/loose stool, tremor, dyspepsia, decreased appetite, hyperhidrosis, ejaculation failure, and decreased libido (see Table 3). The following are the most common adverse reactions in trials of ZOLOFT (≥5% and twice placebo) by indication that were not mentioned previously.
• MDD: somnolence;• OCD: insomnia, agitation;• PD: constipation, agitation;• PTSD: fatigue;• PMDD: somnolence, dry mouth, dizziness, fatigue, and abdominal pain;• SAD: insomnia, dizziness, fatigue, dry mouth, malaise.
Table 3: Common Adverse Reactions in Pooled Placebo-Controlled Trials in Adults with MDD, OCD, PD, PTSD, SAD, and PMDDAdverse reactions that occurred greater than 2% in ZOLOFT-treated patients and at least 2% greater in ZOLOFT-treated patients than placebo-treated patients. ZOLOFT(N=3066)Placebo(N=2293)Cardiac disordersPalpitations
4%
2%
Eye disordersVisual impairment
4%
2%
Gastrointestinal disordersNausea
26%
12%
Diarrhea/Loose stools
20%
10%
Dry mouth
14%
9%
Dyspepsia
8%
4%
Constipation
6%
4%
Vomiting
4%
1%
General disorders and administration site conditionsFatigue
12%
8%
Metabolism and nutrition disordersDecreased appetite
7%
2%
Nervous system disordersDizziness
12%
8%
Somnolence
11%
6%
Tremor
9%
2%
Psychiatric DisordersInsomnia
20%
13%
Agitation
8%
5%
Libido decreased
6%
2%
Reproductive system and breast disordersEjaculation failureDenominator used was for male patients only (n=1316 ZOLOFT; n=973 placebo).
8%
1%
Erectile dysfunction
4%
1%
Ejaculation disorder
3%
0%
Male sexual dysfunction
2%
0%
Skin and subcutaneous tissue disordersHyperhidrosis
7%
3%
Adverse Reactions Leading to Discontinuation in Placebo-Controlled Clinical TrialsIn all placebo-controlled studies in patients with MDD, OCD, PD, PTSD, SAD and PMDD, 368 (12%) of the 3066 patients who received ZOLOFT discontinued treatment due to an adverse reaction, compared with 93 (4%) of the 2293 placebo-treated patients. In placebo-controlled studies, the following were the common adverse reactions leading to discontinuation in ZOLOFT-treated patients:
• MDD, OCD, PD, PTSD, SAD and PMDD: nausea (3%), diarrhea (2%), agitation (2%), and insomnia (2%).• MDD (>2% and twice placebo): decreased appetite, dizziness, fatigue, headache, somnolence, tremor, and vomiting.• OCD: somnolence.• PD: nervousness and somnolence.
Male and Female Sexual DysfunctionAlthough changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of SSRI treatment. However, reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance and satisfaction are difficult to obtain, in part because patients and healthcare providers may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in labeling may underestimate their actual incidence.
Table 4 below displays the incidence of sexual adverse reactions reported by at least 2% of ZOLOFT-treated patients and twice placebo from pooled placebo-controlled trials. For men and all indications, the most common adverse reactions (>2% and twice placebo) included: ejaculation failure, decreased libido, erectile dysfunction, ejaculation disorder, and male sexual dysfunction. For women, the most common adverse reaction (≥2% and twice placebo) was decreased libido.
Table 4: Most Common Sexual Adverse Reactions (≥2% and twice placebo) in Men or Women from ZOLOFT Pooled Controlled Trials in Adults with MDD, OCD, PD, PTSD, SAD, and PMDD ZOLOFTPlaceboMen only(N=1316)(N=973)Ejaculation failure
8%
1%
Libido decreased
7%
2%
Erectile dysfunction
4%
1%
Ejaculation disorder
3%
0%
Male sexual dysfunction
2%
0%
Women only(N=1750)(N=1320)Libido decreased
4%
2%
Adverse Reactions in Pediatric PatientsIn 281 pediatric patients treated with ZOLOFT in placebo-controlled studies, the overall profile of adverse reactions was generally similar to that seen in adult studies. Adverse reactions that do not appear in Table 3 (most common adverse reactions in adults) yet were reported in at least 2% of pediatric patients and at a rate of at least twice the placebo rate include fever, hyperkinesia, urinary incontinence, aggression, epistaxis, purpura, arthralgia, decreased weight, muscle twitching, and anxiety.
Other Adverse Reactions Observed During the Premarketing Evaluation of ZOLOFTOther infrequent adverse reactions, not described elsewhere in the prescribing information, occurring at an incidence of < 2% in patients treated with ZOLOFT were:
Cardiac disorders- tachycardiaEar and labyrinth disorders- tinnitusEndocrine disorders- hypothyroidismEye disorders- mydriasis, blurred visionGastrointestinal disorders- hematochezia, melena, rectal hemorrhageGeneral disorders and administration site conditions- edema, gait disturbance, irritability, pyrexiaHepatobiliary disorders- elevated liver enzymesImmune system disorders- anaphylaxisMetabolism and nutrition disorders- diabetes mellitus, hypercholesterolemia, hypoglycemia, increased appetiteMusculoskeletal and connective tissue disorders- arthralgia, muscle spasms, tightness, or twitchingNervous system disorders- ataxia, coma, convulsion, decreased alertness, hypoesthesia, lethargy, psychomotor hyperactivity, syncopePsychiatric disorders- aggression, bruxism, confusional state, euphoric mood, hallucinationRenal and urinary disorders- hematuriaReproductive system and breast disorders- galactorrhea, priapism, vaginal hemorrhageRespiratory, thoracic and mediastinal disorders- bronchospasm, epistaxis, yawningSkin and subcutaneous tissue disorders- alopecia; cold sweat; dermatitis; dermatitis bullous; pruritus; purpura; erythematous, follicular, or maculopapular rash; urticariaVascular disorders- hemorrhage, hypertension, vasodilation]6.2 Post-marketing ExperienceThe following adverse reactions have been identified during postapproval use of ZOLOFT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Bleeding or clotting disorders- increased coagulation times (altered platelet function)Cardiac disorders- AV block, bradycardia, atrial arrhythmias, QTc-interval prolongation, ventricular tachycardia (including Torsade de Pointes)[See Clinical Pharmacology (12.2)]Endocrine disorders- gynecomastia, hyperprolactinemia, menstrual irregularities, SIADHEye disorders- blindness, optic neuritis, cataractHepatobiliary disorders- severe liver events (including hepatitis, jaundice, liver failure with some fatal outcomes), pancreatitisHemic and lymphatic disorders- agranulocytosis, aplastic anemia and pancytopenia, leukopenia, thrombocytopenia, lupus-like syndrome, serum sicknessImmune system disorders- angioedemaMetabolism and nutrition disorders- hyponatremia, hyperglycemiaMusculoskeletal and connective tissue disorders- rhabdomyolysis, trismusNervous system disorders- serotonin syndrome, extrapyramidal symptoms (including akathisia and dystonia), oculogyric crisisPsychiatric disorders- psychosis, enuresis, paroniriaRenal and urinary disorders- acute renal failureRespiratory, thoracic and mediastinal disorders- pulmonary hypertension, eosinophilic pneumoniaSkin and subcutaneous tissue disorders- photosensitivity skin reaction and other severe cutaneous reactions, which potentially can be fatal, such as Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN)Vascular disorders- cerebrovascular spasm (including reversible cerebral vasoconstriction syndrome and Call‑Fleming syndrome), vasculitis
In addition to the contraindications for all ZOLOFT formulations listed above, ZOLOFT oral solution is contraindicated in patients:
• Taking disulfiram. ZOLOFT oral solution contains alcohol, and concomitant use of ZOLOFT and disulfiram may result in a disulfiram-alcohol reaction.