Sertraline

INDICATIONS AND USAGE Major Depressive Disorder – Sertraline hydrochloride is indicated for the treatment of major depressive disorder in adults. The efficacy of Sertraline hydrochloride in the treatment of a major depressive episode was established in six to eight week controlled trials of adult outpatients whose diagnoses corresponded most closely to the DSM-III category of major depressive disorder (see Clinical Trials under CLINICAL PHARMACOLOGY ). A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation. The antidepressant action of sertraline hydrochloride in hospitalized depressed patients has not been adequately studied. The efficacy of sertraline hydrochloride in maintaining an antidepressant response for up to 44 weeks following 8 weeks of open-label acute treatment (52 weeks total) was demonstrated in a placebo-controlled trial. The usefulness of the drug in patients receiving sertraline hydrochloride for extended periods should be reevaluated periodically (see Clinical Trials under CLINICAL PHARMACOLOGY ). Obsessive-Compulsive Disorder – Sertraline hydrochloride is indicated for the treatment of obsessions and compulsions in patients with obsessive-compulsive disorder (OCD), as defined in the DSM-III-R; i.e., the obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning. The efficacy of Sertraline hydrochloride was established in 12-week trials with obsessive-compulsive outpatients having diagnoses of obsessive-com

DOSAGE AND ADMINISTRATION Initial Treatment Dosage for Adults Major Depressive Disorder –Sertraline hydrochloride treatment should be administered at a dose of 50 mg once daily. While a relationship between dose and effect has not been established for major depressive disorder, OCD, panic disorder, PTSD or social anxiety disorder, patients were dosed in a range of 50-200 mg/day in the clinical trials demonstrating the effectiveness of Sertraline hydrochloride for the treatment of this indication. Consequently, a dose of 50 mg, administered once daily, is recommended as the initial therapeutic dose. Patients not responding to a 50 mg dose may benefit from dose increases up to a maximum of 200 mg/day. Given the 24 hour elimination half-life of sertraline hydrochloride, dose changes should not occur at intervals of less than 1 week. Premenstrual Dysphoric Disorder – Sertraline hydrochloride treatment should be initiated with a dose of 50 mg/day, either daily throughout the menstrual cycle or limited to the luteal phase of the menstrual cycle, depending on physician assessment. While a relationship between dose and effect has not been established for PMDD, patients were dosed in the range of 50-150 mg/day with dose increases at the onset of each new menstrual cycle (see Clinical Trials under CLINICAL PHARMACOLOGY ). Patients not responding to a 50 mg/day dose may benefit from dose increases (at 50 mg increments/ menstrual cycle) up to 150 mg/day when dosing daily throughout the menstrual cycle, or 100 mg/day when dosing during the luteal phase of the menstrual cycle. If a 100 mg/day dose has been established with luteal phase dosing, a 50 mg/day titration step for three days should be utilized at the beginning of each luteal phase dosing period. Sertraline hydrochloride should be administered once daily, either in the morning or evening. Dosage for Pediatric Population (Children and Adolescents) Obsessive-Compulsive Disorder – Sertraline hydrochloride treatment should be initiated with a dose of 25 mg once daily in children (ages 6-12) and at a dose of 50 mg once daily in adolescents (ages 13-17). While a relationship between dose and effect has not been established for OCD, patients were dosed in a range of 25-200 mg/day in the clinical trials demonstrating the effectiveness of Sertraline hydrochloride for pediatric patients (6-17 years) with OCD. Patients not responding to an initial dose of 25 or 50 mg/day may benefit from dose increases up to a maximum of 200 mg/day. For children with OCD, their generally lower body weights compared to adults should be taken into consideration in advancing the dose, in order to avoid excess dosing. Given the 24 hour elimination half-life of Sertraline hydrochloride, dose changes should not occur at intervals of less than 1 week. Sertraline hydrochloride should be administered once daily, either in the morning or evening. Maintenance/Continuation/Extended Treatment Major Depressive Disorder –It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy beyond response to the acute episode. Systematic evaluation of sertraline hydrochloride has demonstrated that its antidepressant efficacy is maintained for periods of up to 44 weeks following 8 weeks of initial treatment at a dose of 50-200 mg/day (mean dose of 70 mg/day) (see Clinical Trials under CLINICAL PHARMACOLOGY ). It is not known whether the dose of sertraline hydrochloride needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment. Posttraumatic Stress Disorder –It is generally agreed that PTSD requires several months or longer of sustained pharmacological therapy beyond response to initial treatment. Systematic evaluation of Sertraline hydrochloride has demonstrated that its efficacy in PTSD is maintained for periods of up to 28 weeks following 24 weeks of treatment at a dose of 50-200 mg/day (see Clinical Trials under CLINICAL PHARMACOLOGY ). It is not known whether the dose of Sertraline hydrochloride needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment. Social Anxiety Disorder –Social anxiety disorder is a chronic condition that may require several months or longer of sustained pharmacological therapy beyond response to initial treatment. Systematic evaluation of Sertraline hydrochloride has demonstrated that its efficacy in social anxiety disorder is maintained for periods of up to 24 weeks following 20 weeks of treatment at a dose of 50-200 mg/day (see Clinical Trials under CLINICAL PHARMACOLOGY ). Dosage adjustments should be made to maintain patients on the lowest effective dose and patients should be periodically reassessed to determine the need for long-term treatment. Ob

ADVERSE REACTIONS During its premarketing assessment, multiple doses of sertraline hydrochloride were administered to over 4000 adult subjects as of February 18, 2000. The conditions and duration of exposure to sertraline hydrochloride varied greatly, and included (in overlapping categories) clinical pharmacology studies, open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, fixed-dose and titration studies, and studies for multiple indications, including major depressive disorder and PMDD. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. In the tabulations that follow, a World Health Organization dictionary of terminology has been used to classify reported adverse events. The frequencies presented, therefore, represent the proportion of the over 4000 adult individuals exposed to multiple doses of sertraline hydrochloride who experienced a treatment-emergent adverse event of the type cited on at least one occasion while receiving sertraline hydrochloride. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. It is important to emphasize that events reported during therapy were not necessarily caused by it. The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied. Incidence in Placebo-Controlled Trials – Table 2 enumerates the most common treatment-emergent adverse events associated with the use of Sertraline hydrochloride (incidence of at least 5% for Sertraline hydrochloride and at least twice that for placebo within at least one of the indications) for the treatment of adult patients with major depressive disorder/other*, OCD, panic disorder, PTSD, PMDD and social anxiety disorder in placebo-controlled clinical trials. Most patients in major depressive disorder/other*, OCD, panic disorder, PTSD and social anxiety disorder studies received doses of 50 to 200 mg/day. Patients in the PMDD study with daily dosing throughout the menstrual cycle received doses of 50 to 150 mg/day, and in the PMDD study with dosing during the luteal phase of the menstrual cycle received doses of 50 to 100 mg/day. Table 3 enumerates treatment-emergent adverse events that occurred in 2% or more of adult patients treated with Sertraline hydrochloride and with incidence greater than placebo who participated in controlled clinical trials comparing Sertraline hydrochloride with placebo in the treatment of major depressive disorder/other*, OCD, panic disorder, PTSD, PMDD and social anxiety disorder. Table 3 provides combined data for the pool of studies that are provided separately by indication in Table 2. TABLE 2 MOST COMMON TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN PLACEBO-CONTROLLED CLINICAL TRIALS *Major depressive disorder and other premarketing controlled trials. (1) Primarily ejaculatory delay. Denominator used was for male patients only (N=271 sertraline hydrochloride major depressive disorder/other*; N=271 placebo major depressive disorder/other*; N=296 sertraline hydrochloride OCD; N=219 placebo OCD; N=216 sertraline hydrochloride panic disorder; N=134 placebo panic disorder; N=130 sertraline hydrochloride PTSD; N=149 placebo PTSD; No male patients in PMDD studies; N=205 sertraline hydrochloride social anxiety disorder; N=153 placebo social anxiety disorder). (2) The luteal phase and daily dosing PMDD trials were not designed for making direct comparisons between the two dosing regimens. Therefore, a comparison between the two dosing regimens of the PMDD trials of incidence rates shown in Table 2 should be avoided. Percentage of Patients Reporting Event Major Depressive Disorder/Other* OCD Panic Disorder PTSD Body System/Adverse Event Sertraline (N=861) Placebo (N=853) Sertraline (N=533) Placebo (N=373) Sertraline (N=430) Placebo (N=275) Sertraline (N=374) Placebo (N=376) Autonomic Nervous System Disorders Ejaculation Failure (1) 7 <1 17 2 19 1 11 1 Mouth Dry 16 9 14 9 15 10 11 6 Sweating Increased 8 3 6 1 5 1 4 2 Center. & Peripheral. Nervous. System Disorders Somnolence 13 6 15 8 15 9

Drug Interactions Potential Effects of Coadministration of Drugs Highly Bound to Plasma Proteins –Because sertraline is tightly bound to plasma protein, the administration of sertraline hydrochloride to a patient taking another drug which is tightly bound to protein (e.g., warfarin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect. Conversely, adverse effects may result from displacement of protein bound sertraline hydrochloride by other tightly bound drugs. In a study comparing prothrombin time AUC (0-120 hr) following dosing with warfarin (0.75 mg/kg) before and after 21 days of dosing with either sertraline hydrochloride (50-200 mg/day) or placebo, there was a mean increase in prothrombin time of 8% relative to baseline for sertraline hydrochloride compared to a 1% decrease for placebo (p<0.02). The normalization of prothrombin time for the sertraline hydrochloride group was delayed compared to the placebo group. The clinical significance of this change is unknown. Accordingly, prothrombin time should be carefully monitored when sertraline hydrochloride therapy is initiated or stopped. Cimetidine –In a study assessing disposition of sertraline hydrochloride (100 mg) on the second of 8 days of cimetidine administration (800 mg daily), there were significant increases in sertraline hydrochloride mean AUC (50%), C max (24%) and half-life (26%) compared to the placebo group. The clinical significance of these changes is unknown. CNS Active Drugs –In a study comparing the disposition of intravenously administered diazepam before and after 21 days of dosing with either sertraline hydrochloride (50 to 200 mg/day escalating dose) or placebo, there was a 32% decrease relative to baseline in diazepam clearance for the sertraline hydrochloride group compared to a 19% decrease relative to baseline for the placebo group (p<0.03). There was a 23% increase in T max for desmethyldiazepam in the sertraline hydrochloride group compared to a 20% decrease in the placebo group (p<0.03). The clinical significance of these changes is unknown. In a placebo-controlled trial in normal volunteers, the administration of two doses of Sertraline hydrochloride did not significantly alter steady-state lithium levels or the renal clearance of lithium. Nonetheless, at this time, it is recommended that plasma lithium levels be monitored following initiation of Sertraline hydrochloride therapy with appropriate adjustments to the lithium dose. In a controlled study of a single dose (2 mg) of pimozide, 200 mg sertraline (q.d.) co-administration to steady state was associated with a mean increase in pimozide AUC and C max of about 40%, but was not associated with any changes in EKG. Since the highest recommended pimozide dose (10 mg) has not been evaluated in combination with sertraline, the effect on QT interval and PK parameters at doses higher than 2 mg at this time are not known. While the mechanism of this interaction is unknown, due to the narrow therapeutic index of pimozide and due to the interaction noted at a low dose of pimozide, concomitant administration of Sertraline hydrochloride and pimozide should be contraindicated (see CONTRAINDICATIONS ). Results of a placebo-controlled trail in normal volunteers suggest that chronic administration of sertraline 200 mg/day does not produce clinically important inhibition of phenytoin metabolism. Nonetheless, at this time, it is recommended that plasma phenytoin concentrations be monitored following initiation of Sertraline Hydrochloride therapy with appropriate adjustments to the phenytoin dose, particularly in patients with multiple underlying medical conditions and/or those receiving multiple concomitant medications. The effect of Sertraline hydrochloride on valproate levels has not been evaluated in clinical trials. In the absence of such data, it is recommended that plasma valproate levels be monitored following initiation of Sertraline hydrochloride therapy with appropriate adjustments to the valproate dose. The risk of using sertraline hydrochloride in combination with other CNS active drugs has not been systematically evaluated. Consequently, caution is advised if the concomitant administration of sertraline hydrochloride and such drugs is required. There is limited controlled experience regarding the optimal timing of switching from other drugs effective in the treatment of major depressive disorder, premenstrual dysphoric disorder to sertraline hydrochloride. Care and prudent medical judgment should be exercised when switching, particularly from long-acting agents. The duration of an appropriate washout period which should intervene before switching from one selective serotonin reuptake inhibitor (SSRI) to another has not been established. Monoamine Oxidase Inhibitors –See CONTRAINDICATIONS , WARNINGS and DOSAGE AND ADMINISTRATION . Drugs Metabolized by P450 3A4 –In three separate in vivo interaction studies, sertraline was co-admini