BOXED WARNING SECTION.


Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of sertraline hydrochloride or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Sertraline hydrochloride is not approved for use in pediatric patients except for patients with obsessive compulsive disorder (OCD). (See Warnings: Clinical Worsening and Suicide Risk, Precautions: Information for Patients, and Precautions: Pediatric Use.)

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 25 mg(100's Bottle) NDC 13107-011-01 Sertraline hydrochloride Tablets 25 mg* PHARMACIST: PLEASE DISPENSE WITH MEDICATION GUIDE PROVIDED SEPARATELY Rx only 100 Tablets AUROBINDO

ADVERSE REACTIONS SECTION.


ADVERSE REACTIONS During its premarketing assessment, multiple doses of sertraline hydrochloridewere administered to over 4000 adult subjects as of February 18, 2000. The conditions and duration of exposure to sertraline hydrochloridevaried 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, OCD, panic disorder, PTSD, PMDD and social anxiety disorder. 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 hydrochloridewho 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 non-drug 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 hydrochlorideand 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 hydrochlorideand with incidence greater than placebo who participated in controlled clinical trials comparing sertraline hydrochloridewith 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 Percentage of Patients Reporting Event Major Depressive Disorder/Other* OCD Panic Disorder PTSD Body System/Adverse Event Sertraline Hydrochloride (N=861) Placebo (N=853) Sertraline Hydrochloride (N=533) Placebo (N=373) Sertraline Hydrochloride (N=430) Placebo (N=275) Sertraline Hydrochloride (N=374) Placebo (N=376) (1) Primarily ejaculatory delay. Denominator used was for male patients only (N=271 sertraline hydrochloridemajor depressive disorder/other*; N=271 placebo major depressive disorder/other*; N=296 sertraline hydrochlorideOCD; N=219 placebo OCD; N=216 sertraline hydrochloridepanic disorder; N=134 placebo panic disorder; N=130 sertraline hydrochloridePTSD; N=149 placebo PTSD; No male patients in PMDD studies; N=205 sertraline hydrochloridesocial anxiety disorder; N=153 placebo social anxiety disorder). * Major depressive disorder and other premarketing controlled trials. (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. 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. & Periph. Nerv. System Disorders Somnolence 13 6 15 8 15 9 13 9 Tremor 11 3 8 1 5 1 5 1 Dizziness 12 7 17 9 10 10 8 5 General Fatigue 11 8 14 10 11 6 10 5 Pain 1 2 3 1 3 3 4 6 Malaise <1 1 1 1 7 14 10 10 Gastrointestinal Disorders Abdominal Pain 2 2 5 5 6 7 6 5 Anorexia 3 2 11 2 7 2 8 2 Constipation 8 6 6 4 7 3 3 3 Diarrhea/Loose Stools 18 9 24 10 20 9 24 15 Dyspepsia 6 3 10 4 10 8 6 6 Nausea 26 12 30 11 29 18 21 11 Psychiatric Disorders Agitation 6 4 6 3 6 2 5 5 Insomnia 16 9 28 12 25 18 20 11 Libido Decreased 1 <1 11 2 7 1 7 2 PMDD Daily Dosing PMDD Luteal Phase Dosing(2) Social Anxiety Disorder Body System/Adverse Event Sertraline Hydrochloride (N=121) Placebo (N=122) Sertraline Hydrochloride (N=136) Placebo (N=127) Sertraline Hydrochloride (N=344) Placebo (N=268) Autonomic Nervous System Disorders Ejaculation Failure(1) N/A N/A N/A N/A 14 - Mouth Dry 6 3 10 3 12 4 Sweating Increased 6 <1 3 0 11 2 Center. & Periph. Nerv. System Disorders Somnolence 7 <1 2 0 9 6 Tremor 2 0 <1 <1 9 3 Dizziness 6 3 7 5 14 6 General Fatigue 16 7 10 <1 12 6 Pain 6 <1 3 2 1 3 Malaise 9 5 7 5 8 3 Gastrointestinal Disorders Abdominal Pain 7 <1 3 3 5 5 Anorexia 3 2 5 0 6 3 Constipation 2 3 1 2 5 3 Diarrhea/Loose Stools 13 3 13 7 21 8 Dyspepsia 7 2 7 3 13 5 Nausea 23 9 13 3 22 8 Psychiatric Disorders Agitation 2 <1 1 0 4 2 Insomnia 17 11 12 10 25 10 Libido Decreased 11 2 4 2 9 3 TABLE 3 TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN PLACEBO-CONTROLLED CLINICAL TRIALS Percentage of Patients Reporting Event Major Depressive Disorder/Other*, OCD, Panic Disorder, PTSD, PMDD and Social Anxiety Disorder combined Body System/Adverse Event** Sertraline Hydrochloride (N=2799) Placebo (N=2394) (1) Primarily ejaculatory delay. Denominator used was for male patients only (N=1118 sertraline hydrochloride; N=926 placebo). * Major depressive disorder and other premarketing controlled trials. ** Included are events reported by at least 2% of patients taking sertraline hydrochlorideexcept the following events, which had an incidence on placebo greater than or equal to sertraline hydrochloride: abdominal pain, back pain, flatulence, malaise, pain, pharyngitis, respiratory disorder, upper respiratory tract infection. Autonomic Nervous System Disorders Ejaculation Failure(1) 14 1 Mouth Dry 14 8 Sweating Increased 7 2 Center. & Periph. Nerv. System Disorders Somnolence 13 7 Dizziness 12 7 Headache 25 23 Paresthesia 2 1 Tremor 8 2 Disorders of Skin and Appendages Rash 3 2 Gastrointestinal Disorders Anorexia 6 2 Constipation 6 4 Diarrhea/Loose Stools 20 10 Dyspepsia 8 4 Nausea 25 11 Vomiting 4 2 General Fatigue 12 7 Psychiatric Disorders Agitation 5 3 Anxiety 4 3 Insomnia 21 11 Libido Decreased 6 2 Nervousness 5 4 Special Senses Vision Abnormal 3 2 Associated with Discontinuation in Placebo-Controlled Clinical Trials Table 4 lists the adverse events associated with discontinuation of sertraline hydrochloride treatment (incidence at least twice that for placebo and at least 1% for sertraline hydrochloride in clinical trials) in major depressive disorder/other*, OCD, panic disorder, PTSD, PMDD and social anxiety disorder. TABLE 4 MOST COMMON ADVERSE EVENTS ASSOCIATED WITH DISCONTINUATION IN PLACEBO-CONTROLLED CLINICAL TRIALS Adverse Event Major Depressive Disorder/Other*, OCD, Panic Disorder, PTSD, PMDD and Social Anxiety Disorder Combined (N=2799) Major Depressive Disorder/ Other* (N=861) OCD (N=533) Panic Disorder (N=430) PTSD (N=374) PMDD Daily Dosing (N=121) PMDD Luteal Phase Dosing (N=136) Social Anxiety Disorder (N=344) (1) Primarily ejaculatory delay. Denominator used was for male patients only (N=271 major depressive disorder/other*; N=296 OCD; N=216 panic disorder; N=130 PTSD; No male patients in PMDD studies; N=205 social anxiety disorder). * Major depressive disorder and other premarketing controlled trials. Abdominal Pain 1% Agitation 1% 2% Anxiety 2% Diarrhea/ Loose Stools 2% 2% 2% 1% 2% Dizziness 1% Dry Mouth 1% Dyspepsia 1% Ejaculation Failure(1) 1% 1% 1% 2% N/A N/A 2% Fatigue 2% Headache 1% 2% 1% 2% Hot Flushes 1% Insomnia 2% 1% 3% 2% 1% 3% Nausea 3% 4% 3% 3% 2% 2% 1% 2% Nervousness 2% Palpitation 1% Somnolence 1% 1% 2% 2% Tremor 2% Male and Female Sexual Dysfunction with SSRIs Although changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that selective serotonin reuptake inhibitors (SSRIs) can cause such untoward sexual experiences. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling, are likely to underestimate their actual incidence. Table 5 below displays the incidence of sexual side effects reported by at least 2% of patients taking sertraline hydrochloridein placebo-controlled trials. TABLE 5 Adverse Event Sertraline Hydrochloride Placebo * Denominator used was for male patients only (N=1118 sertraline hydrochloride; N=926 placebo) ** Denominator used was for male and female patients (N=2799 sertraline hydrochloride; N=2394 placebo) Ejaculation failure* (primarily delayed ejaculation) 14% 1% Decreased libido** 6% 1% There are no adequate and well-controlled studies examining sexual dysfunction with sertraline treatment. Priapism has been reported with all SSRIs. While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects. Other Adverse Events in Pediatric Patients In over 600 pediatric patients treated with sertraline hydrochloride, the overall profile of adverse events was generally similar to that seen in adult studies. However, the following adverse events, from controlled trials, not appearing in Tables 2 and 3, were reported at an incidence of at least 2% and occurred at a rate of at least twice the placebo rate (N=281 patients treated with sertraline hydrochloride): fever, hyperkinesia, urinary incontinence, aggressive reaction, sinusitis, epistaxis and purpura. Other Events Observed During the Premarketing Evaluation of Sertraline Hydrochloride Following is a list of treatment-emergent adverse events reported during premarketing assessment of sertraline hydrochloride in clinical trials (over 4000 adult subjects) except those already listed in the previous tables or elsewhere in labeling. 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 an event of the type cited on at least one occasion while receiving sertraline hydrochloride. All events are included except those already listed in the previous tables or elsewhere in labeling and those reported in terms so general as to be uninformative and those for which a causal relationship to sertraline hydrochloride treatment seemed remote. It is important to emphasize that although the events reported occurred during treatment with sertraline hydrochloride, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Events of major clinical importance are also described in the PRECAUTIONS section. Autonomic Nervous System Disorders Frequent: impotence; Infrequent: flushing, increased saliva, cold clammy skin, mydriasis; Rare: pallor, glaucoma, priapism, vasodilation. Body as a Whole General Disorders Rare: allergic reaction, allergy. Cardiovascular Frequent: palpitations, chest pain; Infrequent: hypertension, tachycardia, postural dizziness, postural hypotension, periorbital edema, peripheral edema, hypotension, peripheral ischemia, syncope, edema, dependent edema; Rare: precordial chest pain, substernal chest pain, aggravated hypertension, myocardial infarction, cerebrovascular disorder. Central and Peripheral Nervous System Disorders Frequent: hypertonia, hypoesthesia; Infrequent: twitching, confusion, hyperkinesia, vertigo, ataxia, migraine, abnormal coordination, hyperesthesia, leg cramps, abnormal gait, nystagmus, hypokinesia; Rare: dysphonia, coma, dyskinesia, hypotonia, ptosis, choreoathetosis, hyporeflexia. Disorders of Skin and Appendages lnfrequent: pruritus, acne, urticaria, alopecia, dry skin, erythematous rash, photosensitivity reaction, maculopapular rash; Rare: follicular rash, eczema, dermatitis, contact dermatitis, bullous eruption, hypertrichosis, skin discoloration, pustular rash. Endocrine Disorders Rare: exophthalmos, gynecomastia. Gastrointestinal Disorders Frequent: appetite increased; Infrequent: dysphagia, tooth caries aggravated, eructation, esophagitis, gastroenteritis; Rare: melena, glossitis, gum hyperplasia, hiccup, stomatitis, tenesmus, colitis, diverticulitis, fecal incontinence, gastritis, rectum hemorrhage, hemorrhagic peptic ulcer, proctitis, ulcerative stomatitis, tongue edema, tongue ulceration. General Frequent: back pain, asthenia, malaise, weight increase; Infrequent: fever, rigors, generalized edema; Rare: face edema, aphthous stomatitis. Hearing and Vestibular Disorders Rare: hyperacusis, labyrinthine disorder. Hematopoietic and Lymphatic Rare: anemia, anterior chamber eye hemorrhage. Liver and Biliary System Disorders Rare: abnormal hepatic function. Metabolic and Nutritional Disorders Infrequent: thirst; Rare: hypoglycemia, hypoglycemia reaction. Musculoskeletal System Disorders Frequent: myalgia; Infrequent: arthralgia, dystonia, arthrosis, muscle cramps, muscle weakness. Psychiatric Disorders Frequent: yawning, other male sexual dysfunction, other female sexual dysfunction; Infrequent: depression, amnesia, paroniria, teeth-grinding, emotional lability, apathy, abnormal dreams, euphoria, paranoid reaction, hallucination, aggressive reaction, aggravated depression, delusions; Rare: withdrawal syndrome, suicide ideation, libido increased, somnambulism, illusion. Reproductive Infrequent: menstrual disorder, dysmenorrhea, intermenstrual bleeding, vaginal hemorrhage, amenorrhea, leukorrhea; Rare : female breast pain, menorrhagia, balanoposthitis, breast enlargement, atrophic vaginitis, acute female mastitis. Respiratory System Disorders Frequent: rhinitis; Infrequent: coughing, dyspnea, upper respiratory tract infection, epistaxis, bronchospasm, sinusitis; Rare: hyperventilation, bradypnea, stridor, apnea, bronchitis, hemoptysis, hypoventilation, laryngismus, laryngitis. Special Senses Frequent: tinnitus; Infrequent: conjunctivitis, earache, eye pain, abnormal accommodation; Rare : xerophthalmia, photophobia, diplopia, abnormal lacrimation, scotoma, visual field defect. Urinary System Disorders Infrequent: micturition frequency, polyuria, urinary retention, dysuria, nocturia, urinary incontinence; Rare : cystitis, oliguria, pyelonephritis, hematuria, renal pain, strangury. Laboratory Tests In man, asymptomatic elevations in serum transaminases (SGOT [or AST] and SGPT [or ALT]) have been reported infrequently (approximately 0.8%) in association with sertraline hydrochloride administration. These hepatic enzyme elevations usually occurred within the first 1 to 9 weeks of drug treatment and promptly diminished upon drug discontinuation. Sertraline hydrochloride therapy was associated with small mean increases in total cholesterol (approximately 3%) and triglycerides (approximately 5%), and a small mean decrease in serum uric acid (approximately 7%) of no apparent clinical importance. The safety profile observed with sertraline hydrochloride treatment in patients with major depressive disorder, OCD, panic disorder, PTSD, PMDD and social anxiety disorder is similar. Other Events Observed During the Postmarketing Evaluation of Sertraline Hydrochloride Reports of adverse events temporally associated with sertraline hydrochloride that have been received since market introduction, that are not listed above and that may have no causal relationship with the drug, include the following: acute renal failure, anaphylactoid reaction, angioedema, blindness, optic neuritis, cataract, increased coagulation times, bradycardia, AV block, atrial arrhythmias, QT-interval prolongation, ventricular tachycardia (including torsade de pointes-type arrhythmias), hypothyroidism, agranulocytosis, aplastic anemia and pancytopenia, leukopenia, thrombocytopenia, lupus-like syndrome, serum sickness, hyperglycemia, galactorrhea, hyperprolactinemia, extrapyramidal symptoms, oculogyric crisis, serotonin syndrome, psychosis, pulmonary hypertension, severe skin reactions, which potentially can be fatal, such as Stevens-Johnson syndrome, vasculitis, photosensitivity and other severe cutaneous disorders, rare reports of pancreatitis, and liver eventsclinical features (which in the majority of cases appeared to be reversible with discontinuation of sertraline hydrochloride) occurring in one or more patients include: elevated enzymes, increased bilirubin, hepatomegaly, hepatitis, jaundice, abdominal pain, vomiting, liver failure and death.

INDICATIONS & USAGE SECTION.


INDICATIONS & USAGE Major Depressive Disorder Sertraline hydrochloride tablets are indicated for the treatment of major depressive disorder in adults. The efficacy of sertraline hydrochloride tablets 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 tablets in hospitalized depressed patients has not been adequately studied. The efficacy of sertraline hydrochloride tablets 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 tablets for extended periods should be reevaluated periodically (see Clinical Trials under CLINICAL PHARMACOLOGY ). Obsessive-Compulsive Disorder Sertraline hydrochloride tablets are indicated for the treatment of obsessions and compulsions in patients with obsessive-compulsive disorder (OCD), as defined in the DSM-III-R; i.e., the obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning. The efficacy of sertraline hydrochloride tablets were established in 12-week trials with obsessive-compulsive outpatients having diagnoses of obsessive-compulsive disorder as defined according to DSM-III or DSM-III-R criteria (see Clinical Trials under CLINICAL PHARMACOLOGY ). Obsessive-compulsive disorder is characterized by recurrent and persistent ideas, thoughts, impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable. The efficacy of sertraline hydrochloride tablets in maintaining a response, in patients with OCD who responded during a 52-week treatment phase while taking sertraline hydrochloride tablets and were then observed for relapse during a period of up to 28 weeks, was demonstrated in a placebo-controlled trial (see Clinical Trials under CLINICAL PHARMACOLOGY ). Nevertheless, the physician who elects to use sertraline hydrochloride tablets for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION ). Panic Disorder Sertraline hydrochloride tablets are indicated for the treatment of panic disorder in adults, with or without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks. The efficacy of sertraline hydrochloride tablets were established in three 10 to 12 week trials in adult panic disorder patients whose diagnoses corresponded to the DSM-III-R category of panic disorder (see Clinical Trials under CLINICAL PHARMACOLOGY ). Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes. The efficacy of sertraline hydrochloride tablets in maintaining a response, in adult patients with panic disorder who responded during a 52-week treatment phase while taking sertraline hydrochloride tablets and were then observed for relapse during a period of up to 28 weeks, was demonstrated in a placebo-controlled trial (see Clinical Trials under CLINICAL PHARMACOLOGY ). Nevertheless, the physician who elects to use sertraline hydrochloride tablets for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION ). Posttraumatic Stress Disorder (PTSD) Sertraline hydrochloride tablets are indicated for the treatment of posttraumatic stress disorder in adults. The efficacy of sertraline hydrochloride tablets in the treatment of PTSD was established in two 12-week placebo-controlled trials of adult outpatients whose diagnosis met criteria for the DSM-III-R category of PTSD (see Clinical Trials under CLINICAL PHARMACOLOGY ). PTSD, as defined by DSM-III-R/IV, requires exposure to a traumatic event that involved actual or threatened death or serious injury, or threat to the physical integrity of self or others, and a response which involves intense fear, helplessness, or horror. Symptoms that occur as a result of exposure to the traumatic event include reexperiencing of the event in the form of intrusive thoughts, flashbacks or dreams, and intense psychological distress and physiological reactivity on exposure to cues to the event; avoidance of situations reminiscent of the traumatic event, inability to recall details of the event, and/or numbing of general responsiveness manifested as diminished interest in significant activities, estrangement from others, restricted range of affect, or sense of foreshortened future; and symptoms of autonomic arousal including hypervigilance, exaggerated startle response, sleep disturbance, impaired concentration, and irritability or outbursts of anger. A PTSD diagnosis requires that the symptoms are present for at least a month and that they cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. The efficacy of sertraline hydrochloride tablets in maintaining a response in adult patients with PTSD for up to 28 weeks following 24 weeks of open-label treatment was demonstrated in a placebo-controlled trial. Nevertheless, the physician who elects to use sertraline hydrochloride tablets for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION ). Premenstrual Dysphoric Disorder (PMDD) Sertraline hydrochloride tablets are indicated for the treatment of premenstrual dysphoric disorder (PMDD) in adults. The efficacy of sertraline hydrochloride tablets in the treatment of PMDD was established in 2 placebo-controlled trials of female adult outpatients treated for 3 menstrual cycles who met criteria for the DSM-III-R/IV category of PMDD (see Clinical Trials under CLINICAL PHARMACOLOGY ). The essential features of PMDD include markedly depressed mood, anxiety or tension, affective lability, and persistent anger or irritability. Other features include decreased interest in activities, difficulty concentrating, lack of energy, change in appetite or sleep, and feeling out of control. Physical symptoms associated with PMDD include breast tenderness, headache, joint and muscle pain, bloating and weight gain. These symptoms occur regularly during the luteal phase and remit within a few days following onset of menses; the disturbance markedly interferes with work or school or with usual social activities and relationships with others. In making the diagnosis, care should be taken to rule out other cyclical mood disorders that may be exacerbated by treatment with an antidepressant. The effectiveness of sertraline hydrochloride tablets in long-term use, that is, for more than 3 menstrual cycles, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use sertraline hydrochloride tablets for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION ). Social Anxiety Disorder Sertraline hydrochloride tablets are indicated for the treatment of social anxiety disorder, also known as social phobia in adults. The efficacy of sertraline hydrochloride tablets in the treatment of social anxiety disorder was established in two placebo-controlled trials of adult outpatients with a diagnosis of social anxiety disorder as defined by DSM-IV criteria (see Clinical Trials under CLINICAL PHARMACOLOGY ). Social anxiety disorder, as defined by DSM-IV, is characterized by marked and persistent fear of social or performance situations involving exposure to unfamiliar people or possible scrutiny by others and by fears of acting in a humiliating or embarrassing way. Exposure to the feared social situation almost always provokes anxiety and feared social or performance situations are avoided or else are endured with intense anxiety or distress. In addition, patients recognize that the fear is excessive or unreasonable and the avoidance and anticipatory anxiety of the feared situation is associated with functional impairment or marked distress. The efficacy of sertraline hydrochloride tablets in maintaining a response in adult patients with social anxiety disorder for up to 24 weeks following 20 weeks of sertraline hydrochloride tablets treatment was demonstrated in a placebo-controlled trial. Physicians who prescribe sertraline hydrochloride tablets for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see Clinical Trials under CLINICAL PHARMACOLOGY ).

DRUG ABUSE AND DEPENDENCE SECTION.


DRUG ABUSE AND DEPENDENCE CONTROLLED SUBSTANCE CLASS Sertraline hydrochloride is not a controlled substance. PHYSICAL AND PSYCHOLOGICAL DEPENDENCE In a placebo-controlled, double-blind, randomized study of the comparative abuse liability of sertraline hydrochloride, alprazolam, and d-amphetamine in humans, sertraline hydrochloride did not produce the positive subjective effects indicative of abuse potential, such as euphoria or drug liking, that were observed with the other two drugs. Premarketing clinical experience with sertraline hydrochloride did not reveal any tendency for a withdrawal syndrome or any drug-seeking behavior. In animal studies sertraline hydrochloride does not demonstrate stimulant or barbiturate-like (depressant) abuse potential. As with any CNS active drug, however, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of sertraline hydrochloride misuse or abuse (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).

DOSAGE & ADMINISTRATION SECTION.


DOSAGE & ADMINISTRATION Initial Treatment Dosage for Adults Major Depressive Disorder and Obsessive-Compulsive Disorder Sertraline hydrochloride tablets treatment should be administered at a dose of 50 mg once daily. Panic Disorder, Posttraumatic Stress Disorder and Social Anxiety Disorder Sertraline hydrochloride tablets treatment should be initiated with a dose of 25 mg once daily. After one week, the dose should be increased to 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 to 200 mg/day in the clinical trials demonstrating the effectiveness of sertraline hydrochloride tablets for the treatment of these indications. 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 tablets 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 to 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 tablets should be administered once daily, either in the morning or evening. Dosage for Pediatric Population (Children and Adolescents) Obsessive-Compulsive Disorder Sertraline hydrochloride tablets treatment should be initiated with a dose of 25 mg once daily in children (ages 6 to 12) and at a dose of 50 mg once daily in adolescents (ages 13 to 17). While a relationship between dose and effect has not been established for OCD, patients were dosed in a range of 25 to 200 mg/day in the clinical trials demonstrating the effectiveness of sertraline hydrochloride tablets for pediatric patients (6 to 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 tablets 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 tablets have 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 to 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 tablets 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 tablets 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 to 200 mg/day (see Clinical Trials under CLINICAL PHARMACOLOGY ). It is not known whether the dose of sertraline hydrochloride tablets 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 tablets 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 to 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. Obsessive-Compulsive Disorder and Panic Disorder It is generally agreed that OCD and Panic Disorder require several months or longer of sustained pharmacological therapy beyond response to initial treatment. Systematic evaluation of continuing sertraline hydrochloride tablets for periods of up to 28 weeks in patients with OCD and Panic Disorder who have responded while taking sertraline hydrochloride tablets during initial treatment phases of 24 to 52 weeks of treatment at a dose range of 50 to 200 mg/day has demonstrated a benefit of such maintenance treatment (see Clinical Trials under CLINICAL PHARMACOLOGY ). It is not known whether the dose of sertraline hydrochloride tablets needed for maintenance treatment is identical to the dose needed to achieve an initial response. Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment. Premenstrual Dysphoric Disorder The effectiveness of sertraline hydrochloride tablets in long-term use, that is, for more than 3 menstrual cycles, has not been systematically evaluated in controlled trials. However, as women commonly report that symptoms worsen with age until relieved by the onset of menopause, it is reasonable to consider continuation of a responding patient. Dosage adjustments, which may include changes between dosage regimens (e.g., daily throughout the menstrual cycle versus during the luteal phase of the menstrual cycle), may be needed to maintain the patient on the lowest effective dosage and patients should be periodically reassessed to determine the need for continued treatment. Switching Patients to or from a Monoamine Oxidase Inhibitor At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with sertraline hydrochloride tablets. In addition, at least 14 days should be allowed after stopping sertraline hydrochloride tablets before starting an MAOI (see CONTRAINDICATIONS and WARNINGS ). Special Populations Dosage for Hepatically Impaired Patients The use of sertraline in patients with liver disease should be approached with caution. The effects of sertraline in patients with moderate and severe hepatic impairment have not been studied. If sertraline is administered to patients with liver impairment, a lower or less frequent dose should be used (see CLINICAL PHARMACOLOGY and PRECAUTIONS ). Treatment of Pregnant Women During the Third Trimester Neonates exposed to sertraline hydrochloride tablets and other SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS ). When treating pregnant women with sertraline hydrochloride tablets during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering sertraline hydrochloride tablets in the third trimester. Discontinuation of Treatment with Sertraline Hydrochloride Tablets Symptoms associated with discontinuation of sertraline hydrochloride tablets and other SSRIs and SNRIs, have been reported (see PRECAUTIONS ). Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.

HOW SUPPLIED SECTION.


HOW SUPPLIED Sertraline hydrochloride tablets, contains sertraline hydrochloride equivalent to 25 mg, 50 mg and 100 mg of sertraline. Sertraline hydrochloride tablets are supplied as: 25 mg Tablets: Green colored, biconvex, capsule shaped film coated tablets debossed with A on one side and with a score line in between 1 and 6 on the other side. NDC 13107-011-30 Bottles of 30 NDC 13107-011-50 Bottles of 50 NDC 13107-011-60 Bottles of 60 NDC 13107-011-90 Bottles of 90 NDC 13107-011-01 Bottles of 100 NDC 13107-011-05 Bottles of 500 NDC 13107-011-51 Bottles of 5000 50 mg Tablets: Blue colored, biconvex, capsule shaped film coated tablets debossed with A on one side and with a score line in between 1 and 7 on the other side. NDC 13107-012-30 Bottles of 30 NDC 13107-012-50 Bottles of 50 NDC 13107-012-60 Bottles of 60 NDC 13107-012-90 Bottles of 90 NDC 13107-012-01 Bottles of 100 NDC 13107-012-05 Bottles of 500 NDC 13107-012-51 Bottles of 5000 100 mg Tablets: Yellow colored, biconvex, capsule shaped film coated tablets debossed with A on one side and with a score line in between 1 and 8 on the other side. NDC 13107-013-30 Bottles of 30 NDC 13107-013-50 Bottles of 50 NDC 13107-013-60 Bottles of 60 NDC 13107-013-90 Bottles of 90 NDC 13107-013-01 Bottles of 100 NDC 13107-013-05 Bottles of 500 NDC 13107-013-25 Bottles of 2500 Store at 20 to 25 C (68 to 77F); excursions permitted to 15 to 30C (59 to 86F) [see USP Controlled Room Temperature]. Manufactured by:Aurolife Pharma LLCDayton, NJ08810 Manufactured for: Aurobindo Pharma USA, Inc. Dayton, NJ08810 Revised: 02/2011

SPL UNCLASSIFIED SECTION.


PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 100 mg(100's Bottle) NDC 13107-013-01 SERTRALINE HYDROCHLORIDE TABLETS 100 mg* PHARMACIST: PLEASE DISPENSE WITH MEDICATION GUIDE PROVIDED SEPARATELY Rx only 100 Tablets AUROBINDO

DESCRIPTION SECTION.


DESCRIPTION Sertraline hydrochloride tablets are a selective serotonin reuptake inhibitor (SSRI) for oral administration. It has a molecular weight of 342.7. Sertraline hydrochloride has the following chemical name: (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride. The molecular formula C17H17NCl2HCl is represented by the following structural formula: Sertraline hydrochloride is a white crystalline powder that is slightly soluble in water and isopropyl alcohol, and sparingly soluble in ethanol. Sertraline hydrochloride tablets are supplied for oral administration as scored tablets containing sertraline hydrochloride equivalent to 25 mg, 50 mg, and 100 mg of sertraline and the following inactive ingredients: microcrystalline cellulose, sodium starch glycolate, hydroxypropyl cellulose, dibasic calcium phosphate dihydrate, magnesium stearate, hypromellose, titanium dioxide, polyethylene glycol, and polysorbate 80. Besides, 25 mg contains D&C yellow #10 aluminum lake, FD&C blue #1 aluminum lake, FD&C red #40 aluminum lake; 50 mg contains FD&C blue #2 aluminum lake; and 100 mg contains iron oxide yellow.

OVERDOSAGE SECTION.


OVERDOSAGE Human Experience Of 1,027 cases of overdose involving sertraline hydrochloride worldwide, alone or with other drugs, there were 72 deaths (circa 1999). Among 634 overdoses in which sertraline hydrochloride was the only drug ingested, 8 resulted in fatal outcome, 75 completely recovered, and 27 patients experienced sequelae after overdosage to include alopecia, decreased libido, diarrhea, ejaculation disorder, fatigue, insomnia, somnolence and serotonin syndrome. The remaining 524 cases had an unknown outcome. The most common signs and symptoms associated with non-fatal sertraline hydrochloride overdosage were somnolence, vomiting, tachycardia, nausea, dizziness, agitation and tremor. The largest known ingestion was 13.5 grams in a patient who took sertraline hydrochloride alone and subsequently recovered. However, another patient who took 2.5 grams of sertraline hydrochloride alone experienced a fatal outcome. Other important adverse events reported with sertraline hydrochloride overdose (single or multiple drugs) include bradycardia, bundle branch block, coma, convulsions, delirium, hallucinations, hypertension, hypotension, manic reaction, pancreatitis, QT-interval prolongation, serotonin syndrome, stupor and syncope. Overdose Management Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. Ensure an adequate airway, oxygenation and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients. Activated charcoal should be administered. Due to large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for sertraline are known.In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians Desk Reference (PDR).

PRECAUTIONS SECTION.


PRECAUTIONS General Activation of Mania/Hypomania During premarketing testing, hypomania or mania occurred in approximately 0.4% of sertraline hydrochloride treated patients. Weight Loss Significant weight loss may be an undesirable result of treatment with sertraline for some patients, but on average, patients in controlled trials had minimal, 1 to 2 pound weight loss, versus smaller changes on placebo. Only rarely have sertraline patients been discontinued for weight loss. Seizure Sertraline hydrochloride has not been evaluated in patients with a seizure disorder. These patients were excluded from clinical studies during the products premarket testing. No seizures were observed among approximately 3000 patients treated with sertraline hydrochloride in the development program for major depressive disorder. However, 4 patients out of approximately 1800 (220 2.5 mg/dL), and clinically significant hepatic dysfunction. Sertraline hydrochloride treatment initiated during the acute phase of recovery (within 30 days post-MI or post-hospitalization for unstable angina) was indistinguishable from placebo in this study on the following week 16 treatment endpoints: left ventricular ejection fraction, total cardiovascular events (angina, chest pain, edema, palpitations, syncope, postural dizziness, CHF, MI, tachycardia, bradycardia, and changes in BP), and major cardiovascular events involving death or requiring hospitalization (for MI, CHF, stroke, or angina). Sertraline hydrochloride is extensively metabolized by the liver. In patients with chronic mild liver impairment, sertraline clearance was reduced, resulting in increased AUC, Cmax and elimination half-life. The effects of sertraline in patients with moderate and severe hepatic impairment have not been studied. The use of sertraline in patients with liver disease must be approached with caution. If sertraline is administered to patients with liver impairment, a lower or less frequent dose should be used (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION ). Since sertraline hydrochloride is extensively metabolized, excretion of unchanged drug in urine is a minor route of elimination. A clinical study comparing sertraline pharmacokinetics in healthy volunteers to that in patients with renal impairment ranging from mild to severe (requiring dialysis) indicated that the pharmacokinetics and protein binding are unaffected by renal disease. Based on the pharmacokinetic results, there is no need for dosage adjustment in patients with renal impairment (see CLINICAL PHARMACOLOGY ). Interference with Cognitive and Motor Performance In controlled studies, sertraline hydrochloride did not cause sedation and did not interfere with psychomotor performance. (See Information for Patients .) Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including sertraline hydrochloride. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk (see GeriatricUse) Discontinuation of sertraline hydrochloride should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. Platelet Function There have been rare reports of altered platelet function and/or abnormal results from laboratory studies in patients taking sertraline hydrochloride. While there have been reports of abnormal bleeding or purpura in several patients taking sertraline hydrochloride, it is unclear whether sertraline hydrochloride had a causative role. Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with sertraline hydrochloride and should counsel them in its appropriate use. A patient Medication Guide about Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions is available for sertraline hydrochloride. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking sertraline hydrochloride. Clinical Worsening and Suicide Risk Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of SNRIs and SSRIs, including sertraline hydrochloride, and triptans, tramadol, or other serotonergic agents. Patients should be told that although sertraline hydrochloride has not been shown to impair the ability of normal subjects to perform tasks requiring complex motor and mental skills in laboratory experiments, drugs that act upon the central nervous system may affect some individuals adversely. Therefore, patients should be told that until they learn how they respond to sertraline hydrochloride they should be careful doing activities when they need to be alert, such as driving a car or operating machinery. Patients should be cautioned about the concomitant use of sertraline hydrochloride and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding. Patients should be told that although sertraline hydrochloride has not been shown in experiments with normal subjects to increase the mental and motor skill impairments caused by alcohol, the concomitant use of sertraline hydrochloride and alcohol is not advised. Patients should be told that while no adverse interaction of sertraline hydrochloride with over-the-counter (OTC) drug products is known to occur, the potential for interaction exists. Thus, the use of any OTC product should be initiated cautiously according to the directions of use given for the OTC product. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Patients should be advised to notify their physician if they are breast feeding an infant. Laboratory Tests None. 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 to 120 hr) following dosing with warfarin (0.75 mg/kg) before and after 21 days of dosing with either sertraline hydrochloride (50 to 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 7% of body weight compared to none of the placebo patients; for adolescents, about 2% had a weight loss > 7% of body weight compared to about 1% of placebo patients. A subset of these patients who completed the randomized controlled trials (sertraline N=99, placebo N=122) were continued into a 24-week, flexible-dose, open-label, extension study. A mean weight loss of approximately 0.5 kg was seen during the first eight weeks of treatment for subjects with first exposure to sertraline during the open-label extension study, similar to mean weight loss observed among sertraline treated subjects during the first eight weeks of the randomized controlled trials. The subjects continuing in the open label study began gaining weight compared to baseline by week 12 of sertraline treatment. Those subjects who completed 34 weeks of sertraline 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. Regular monitoring of weight and growth is recommended if treatment of a pediatric patient with an SSRI is to be continued long term. Safety and effectiveness in pediatric patients below the age of 6 have not been established.The risks, if any, that may be associated with sertraline hydrochlorides use beyond 1 year in children and adolescents with OCD or major depressive disorder have not been systematically assessed. The prescriber should be mindful that the evidence relied upon to conclude that sertraline is safe for use in children and adolescents derives from clinical studies that were 10 to 52 weeks in duration and from the extrapolation of experience gained with adult patients. In particular, there are no studies that directly evaluate the effects of long-term sertraline use on the growth, development, and maturation of children and adolescents. Although there is no affirmative finding to suggest that sertraline possesses a capacity to adversely affect growth, development or maturation, the absence of such findings is not compelling evidence of the absence of the potential of sertraline to have adverse effects in chronic use (see WARNINGS Clinical Worsening and Suicide Risk ). Geriatric Use U.S. geriatric clinical studies of sertraline hydrochloride in major depressive disorder included 663 sertraline hydrochloride-treated subjects 65 years of age, of those, 180 were 75 years of age. No overall differences in the pattern of adverse reactions were observed in the geriatric clinical trial subjects relative to those reported in younger subjects (see ADVERSE REACTIONS ), and other reported experience has not identified differences in safety patterns between the elderly and younger subjects. As with all medications, greater sensitivity of some older individuals cannot be ruled out. There were 947 subjects in placebo-controlled geriatric clinical studies of sertraline hydrochloride in major depressive disorder. No overall differences in the pattern of efficacy were observed in the geriatric clinical trial subjects relative to those reported in younger subjects. Other Adverse Events in Geriatric Patients.In 354 geriatric subjects treated with sertraline hydrochloride in placebo-controlled trials, the overall profile of adverse events was generally similar to that shown in Tables 2 and 3. Urinary tract infection was the only adverse event not appearing inTables 2 and 3 and reported at an incidence of at least 2% and at a rate greater than placebo in placebo-controlled trials. SSRIs and SNRIs, including sertraline hydrochloride, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see PRECAUTIONS, Hyponatremia ).

SPL MEDGUIDE SECTION.


MEDICATION GUIDE Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or ActionsRead the Medication Guide that comes with you or your family members antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family members healthcare provider about: all risks and benefits of treatment with antidepressant medicines all treatment choices for depression or other serious mental illness What is the most important information I should know about antidepressant medicines, depression, and other serious mental illnesses, and suicidal thoughts or actions? 1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. 2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. 3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. Call a healthcare provider right away if you or your family member has any of the following symptoms especially if they are new, worse, or worry you: thoughts about suicide or dying attempts to commit suicide new or worse depression new or worse anxiety feeling very agitated or restless panic attacks trouble sleeping (insomnia) new or worse irritability acting aggressive, being angry, or violent acting on dangerous impulses an extreme increase in activity and talking (mania) other unusual changes in behavior or mood Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. What else do I need to know about antidepressant medicines? Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms. Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants. Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member. Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider. Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk with your childs healthcare provider for more information. This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants. Manufactured by:Aurolife Pharma LLCDayton, NJ08810 Manufactured for: Aurobindo Pharma USA, Inc. Dayton, NJ08810 Revised: 02/2011

CLINICAL PHARMACOLOGY SECTION.


CLINICAL PHARMACOLOGY Pharmacodynamics The mechanism of action of sertraline is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin (5HT). Studies at clinically relevant doses in man have demonstrated that sertraline blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that sertraline is a potent and selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro studies have shown that sertraline has no significant affinity for adrenergic (alpha1, alpha2, beta), cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5HT1A, 5HT1B, 5HT2), or benzodiazepine receptors; antagonism of such receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects for other psychotropic drugs. The chronic administration of sertraline was found in animals to down regulate brain norepinephrine receptors, as has been observed with other drugs effective in the treatment of major depressive disorder. Sertraline does not inhibit monoamine oxidase. Pharmacokinetics Systemic Bioavailability In man, following oral once-daily 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. Based on this pharmacokinetic parameter, steady-state sertraline plasma levels should be achieved after approximately one week of once-daily dosing. Linear dose-proportional pharmacokinetics were demonstrated in a single dose study in which the Cmax and area under the plasma concentration time curve (AUC) of sertraline were proportional to dose over a range of 50 to 200 mg. Consistent with the terminal elimination half-life, there is an approximately two-fold accumulation, compared to a single dose, of sertraline with repeated dosing over a 50 to 200 mg dose range. The single dose bioavailability of sertraline tablets is approximately equal to an equivalent dose of solution. In a relative bioavailability study comparing the pharmacokinetics of 100 mg sertraline as the oral solution to a 100 mg sertraline tablet in 16 healthy adults, the solution to tablet ratio of geometric mean AUC and Cmax values were 114.8% and 120.6%, respectively. 90% confidence intervals (CI) were within the range of 80 to 125% with the exception of the upper 90% CI limit for Cmax which was 126.5%. The effects of food on the bioavailability of the sertraline tablet was studied in subjects administered a single dose with and without food. For the tablet, AUC was slightly increased when drug was administered with food but the Cmaxwas 25% greater, while the time to reach peak plasma concentration (Tmax) decreased from 8 hours post-dosing to 5.5 hours. Metabolism Sertraline undergoes extensive first pass metabolism. The principal initial pathway of metabolism for sertraline is N-demethylation. N-desmethylsertraline has a plasma terminal elimination half-life of 62 to 104 hours. Both in vitro biochemical and in vivo pharmacological testing have shown N-desmethylsertraline to be substantially less active than sertraline. Both sertraline and N-desmethylsertraline undergo oxidative deamination and subsequent reduction, hydroxylation, and glucuronide conjugation. In a study of radiolabeled sertraline involving two healthy male subjects, sertraline accounted for less than 5% of the plasma radioactivity. About 40 to 45% of the administered radioactivity was recovered in urine in 9 days. Unchanged sertraline was not detectable in the urine. For the same period, about 40 to 45% of the administered radioactivity was accounted for in feces, including 12 to 14% unchanged sertraline. Desmethylsertraline exhibits time-related, dose dependent increases in AUC (0 to 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, viz., warfarin and propranolol (see PRECAUTIONS ). Pediatric Pharmacokinetics Sertraline pharmacokinetics were evaluated in a group of 61 pediatric patients (29 aged 6 to 12 years, 32 aged 13 to 17 years) with a DSM-III-R diagnosis of major depressive disorder or obsessive-compulsive disorder. Patients included both males (N=28) and females (N=33). During 42 days of chronic sertraline dosing, sertraline was titrated up to 200 mg/day and maintained at that dose for a minimum of 11 days. On the final day of sertraline 200 mg/day, the 6 to 12 year old group exhibited a mean sertraline AUC (0 to 24 hr) of 3107 ng-hr/mL, mean Cmax of 165 ng/mL, and mean half-life of 26.2 hr. The 13 to 17 year old group exhibited a mean sertraline AUC (0 to 24 hr) of 2296 ng-hr/mL, mean Cmax of 123 ng/mL, and mean half-life of 27.8 hr. Higher plasma levels in the 6 to 12 year old group were largely attributable to patients with lower body weights. No gender associated differences were observed. By comparison, a group of 22 separately studied adults between 18 and 45 years of age (11 male, 11 female) received 30 days of 200 mg/day sertraline and exhibited a mean sertraline AUC (0 to 24 hr) of 2570 ng-hr/mL, mean Cmax of 142 ng/mL, and mean half-life of 27.2 hr. Relative to the adults, both the 6 to 12 year olds and the 13 to 17 year olds showed about 22% lower AUC (0 to 24 hr) and Cmax values when plasma concentration was adjusted for weight. These data suggest that pediatric patients metabolize sertraline with slightly greater efficiency than adults. Nevertheless, lower doses may be advisable for pediatric patients given their lower body weights, especially in very young patients, in order to avoid excessive plasma levels (see DOSAGE AND ADMINISTRATION ). Age Sertraline plasma clearance in a group of 16 (8 male, 8 female) elderly patients treated for 14 days at a dose of 100 mg/day was approximately 40% lower than in a similarly studied group of younger (25 to 32 y.o.) individuals. Steady-state, therefore, should be achieved after 2 to 3 weeks in older patients. The same study showed a decreased clearance of desmethylsertraline in older males, but not in older females. Liver Disease As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of sertraline. In patients with chronic mild liver impairment (N=10, 8 patients with Child-Pugh scores of 5 to 6 and 2 patients with Child-Pugh scores of 7 to 8) who received 50 mg sertraline per day maintained for 21 days, sertraline clearance was reduced, resulting in approximately 3-fold greater exposure compared to age-matched volunteers with no hepatic impairment (N=10). The exposure to desmethylsertraline was approximately 2-fold greater compared to age-matched volunteers with no hepatic impairment. There were no significant differences in plasma protein binding observed between the two groups. The effects of sertraline in patients with moderate and severe hepatic impairment have not been studied. The results suggest that the use of sertraline in patients with liver disease must be approached with caution. If sertraline is administered to patients with liver impairment, a lower or less frequent dose should be used (see PRECAUTIONS and DOSAGE AND ADMINISTRATION ). Renal Disease Sertraline is extensively metabolized and excretion of unchanged drug in urine is a minor route of elimination. In volunteers with mild to moderate (CLcr=30 to 60 mL/min), moderate to severe (CLcr=10 to 29 mL/min) or severe (receiving hemodialysis) renal impairment (N=10 each group), the pharmacokinetics and protein binding of 200 mg sertraline per day maintained for 21 days were not altered compared to age-matched volunteers (N=12) with no renal impairment. Thus sertraline multiple dose pharmacokinetics appear to be unaffected by renal impairment (see PRECAUTIONS ). Clinical Trials Major Depressive Disorder The efficacy of sertraline hydrochloride as a treatment for major depressive disorder was established in two placebo-controlled studies in adult outpatients meeting DSM-III criteria for major depressive disorder. Study 1 was an 8-week study with flexible dosing of sertraline hydrochloride in a range of 50 to 200 mg/day; the mean dose for completers was 145 mg/day. Study 2 was a 6-week fixed-dose study, including sertraline hydrochloride doses of 50, 100, and 200 mg/day. Overall, these studies demonstrated sertraline hydrochloride to be superior to placebo on the Hamilton Depression Rating Scale and the Clinical Global Impression Severity and Improvement scales. Study 2 was not readily interpretable regarding a dose response relationship for effectiveness. Study 3 involved depressed outpatients who had responded by the end of an initial 8-week open treatment phase on sertraline hydrochloride 50 to 200 mg/day. These patients (N=295) were randomized to continuation for 44 weeks on double-blind sertraline hydrochloride 50 to 200 mg/day or placebo. A statistically significantly lower relapse rate was observed for patients taking sertraline hydrochloride compared to those on placebo. The mean dose for completers was 70 mg/day. Analyses for gender effects on outcome did not suggest any differential responsiveness on the basis of sex. Obsessive-Compulsive Disorder (OCD) The effectiveness of sertraline hydrochloride in the treatment of OCD was demonstrated in three multicenter placebo-controlled studies of adult outpatients (Studies 1 to 3). Patients in all studies had moderate to severe OCD (DSM-III or DSM-III-R) with mean baseline ratings on the YaleBrown Obsessive-Compulsive Scale (YBOCS) total score ranging from 23 to 25. Study 1 was an 8-week study with flexible dosing of sertraline hydrochloride in a range of 50 to 200 mg/day; the mean dose for completers was 186 mg/day. Patients receiving sertraline hydrochloride experienced a mean reduction of approximately 4 points on the YBOCS total score which was significantly greater than the mean reduction of 2 points in placebo-treated patients. Study 2 was a 12-week fixed-dose study, including sertraline hydrochloride doses of 50, 100, and 200 mg/day. Patients receiving sertraline hydrochloride doses of 50 and 200 mg/day experienced mean reductions of approximately 6 points on the YBOCS total score which were significantly greater than the approximately 3 point reduction in placebo-treated patients. Study 3 was a 12-week study with flexible dosing of sertraline hydrochloride in a range of 50 to 200 mg/day; the mean dose for completers was 185 mg/day. Patients receiving sertraline hydrochloride experienced a mean reduction of approximately 7 points on the YBOCS total score which was significantly greater than the mean reduction of approximately 4 points in placebo-treated patients. Analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex. The effectiveness of sertraline hydrochloride for the treatment of OCD was also demonstrated in a 12-week, multicenter, placebo-controlled, parallel group study in a pediatric outpatient population (children and adolescents, ages 6 to 17). Patients receiving sertraline hydrochloride in this study were initiated at doses of either 25 mg/day (children, ages 6 to 12) or 50 mg/day (adolescents, ages 13 to 17), and then titrated over the next four weeks to a maximum dose of 200 mg/day, as tolerated. The mean dose for completers was 178 mg/day. Dosing was once a day in the morning or evening. Patients in this study had moderate to severe OCD (DSM-III-R) with mean baseline ratings on the Childrens Yale-Brown Obsessive-Compulsive Scale (CYBOCS) total score of 22. Patients receiving sertraline experienced a mean reduction of approximately 7 units on the CYBOCS total score which was significantly greater than the 3 unit reduction for placebo patients. Analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex. In a longer-term study, patients meeting DSM-III-R criteria for OCD who had responded during a 52-week single-blind trial on sertraline hydrochloride 50 to 200 mg/day (N=224) were randomized to continuation of sertraline hydrochloride or to substitution of placebo for up to 28 weeks of observation for discontinuation due to relapse or insufficient clinical response. Response during the single-blind phase was defined as a decrease in the YBOCS score of 25% compared to baseline and a CGI-I of 1 (very much improved), 2 (much improved) or 3 (minimally improved). Relapse during the double-blind phase was defined as the following conditions being met (on three consecutive visits for 1 and 2, and for visit 3 for condition 3): (1) YBOCS score increased by 5 points, to a minimum of 20, relative to baseline; (2) CGI-I increased by one point; and (3) worsening of the patients condition in the investigators judgment, to justify alternative treatment. Insufficient clinical response indicated a worsening of the patients condition that resulted in study discontinuation, as assessed by the investigator. Patients receiving continued sertraline hydrochloride treatment experienced a significantly lower rate of discontinuation due to relapse or insufficient clinical response over the subsequent 28 weeks compared to those receiving placebo. This pattern was demonstrated in male and female subjects. Panic Disorder The effectiveness of sertraline hydrochloride in the treatment of panic disorder was demonstrated in three double-blind, placebo-controlled studies (Studies 1 to 3) of adult outpatients who had a primary diagnosis of panic disorder (DSM-III-R), with or without agoraphobia. Studies 1 and 2 were 10-week flexible dose studies. Sertraline hydrochloride was initiated at 25 mg/day for the first week, and then patients were dosed in a range of 50 to 200 mg/day on the basis of clinical response and toleration. The mean sertraline hydrochloride doses for completers to 10 weeks were 131 mg/day and 144 mg/day, respectively, for Studies 1 and 2. In these studies, sertraline hydrochloride was shown to be significantly more effective than placebo on change from baseline in panic attack frequency and on the Clinical Global Impression Severity of Illness and Global Improvement scores. The difference between sertraline hydrochloride and placebo in reduction from baseline in the number of full panic attacks was approximately 2 panic attacks per week in both studies. Study 3 was a 12-week fixed-dose study, including sertraline hydrochloride doses of 50, 100, and 200 mg/day. Patients receiving sertraline hydrochloride experienced a significantly greater reduction in panic attack frequency than patients receiving placebo. Study 3 was not readily interpretable regarding a dose response relationship for effectiveness. Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age, race, or gender. In a longer-term study, patients meeting DSM-III-R criteria for Panic Disorder who had responded during a 52-week open trial on sertraline hydrochloride 50 to 200 mg/day (N=183) were randomized to continuation of sertraline hydrochloride or to substitution of placebo for up to 28 weeks of observation for discontinuation due to relapse or insufficient clinical response. Response during the open phase was defined as a CGI-I score of 1(very much improved) or 2 (much improved). Relapse during the double-blind phase was defined as the following conditions being met on three consecutive visits: (1) CGI-I 3; (2) meets DSM-III-R criteria for Panic Disorder; (3) number of panic attacks greater than at baseline. Insufficient clinical response indicated a worsening of the patients condition that resulted in study discontinuation, as assessed by the investigator. Patients receiving continued sertraline hydrochloride treatment experienced a significantly lower rate of discontinuation due to relapse or insufficient clinical response over the subsequent 28 weeks compared to those receiving placebo. This pattern was demonstrated in male and female subjects. Posttraumatic Stress Disorder (PTSD) The effectiveness of sertraline hydrochloride in the treatment of PTSD was established in two multicenter placebo-controlled studies (Studies 1 to 2) of adult outpatients who met DSM-III-R criteria for PTSD. The mean duration of PTSD for these patients was 12 years (Studies 1 and 2 combined) and 44% of patients (169 of the 385 patients treated) had secondary depressive disorder. Studies 1 and 2 were 12-week flexible dose studies. Sertraline hydrochloride was initiated at 25 mg/day for the first week, and patients were then dosed in the range of 50 to 200 mg/day on the basis of clinical response and toleration. The mean sertraline hydrochloride dose for completers was 146 mg/day and 151 mg/day, respectively for Studies 1 and 2. Study outcome was assessed by the Clinician-Administered PTSD Scale Part 2 (CAPS) which is a multi-item instrument that measures the three PTSD diagnostic symptom clusters of reexperiencing/intrusion, avoidance/numbing, and hyperarousal as well as the patient-rated Impact of Event Scale (IES) which measures intrusion and avoidance symptoms. Sertraline hydrochloride was shown to be significantly more effective than placebo on change from baseline to endpoint on the CAPS, IES and on the Clinical Global Impressions (CGI) Severity of Illness and Global Improvement scores. In two additional placebo-controlled PTSD trials, the difference in response to treatment between patients receiving sertraline hydrochloride and patients receiving placebo was not statistically significant. One of these additional studies was conducted in patients similar to those recruited for Studies 1 and 2, while the second additional study was conducted in predominantly male veterans. As PTSD is a more common disorder in women than men, the majority (76%) of patients in these trials were women (152 and 139 women on sertraline and placebo versus 39 and 55 men on sertraline and placebo; Studies 1 and 2 combined). Post hoc exploratory analyses revealed a significant difference between sertraline hydrochloride and placebo on the CAPS, IES and CGI in women, regardless of baseline diagnosis of comorbid major depressive disorder, but essentially no effect in the relatively smaller number of men in these studies. The clinical significance of this apparent gender interaction is unknown at this time. There was insufficient information to determine the effect of race or age on outcome. In a longer-term study, patients meeting DSM-III-R criteria for PTSD who had responded during a 24-week open trial on sertraline hydrochloride 50 to 200 mg/day (N=96) were randomized to continuation of sertraline hydrochloride or to substitution of placebo for up to 28 weeks of observation for relapse. Response during the open phase was defined as a CGI-I of 1 (very much improved) or 2 (much improved), and a decrease in the CAPS-2 score of > 30% compared to baseline. Relapse during the double-blind phase was defined as the following conditions being met on two consecutive visits: (1) CGI-I 3; (2) CAPS-2 score increased by 30% and by 15 points relative to baseline; and (3) worsening of the patient's condition in the investigator's judgment. Patients receiving continued sertraline hydrochloride treatment experienced significantly lower relapse rates over the subsequent 28 weeks compared to those receiving placebo. This pattern was demonstrated in male and female subjects. Premenstrual Dysphoric Disorder (PMDD) The effectiveness of sertraline hydrochloride for the treatment of PMDD was established in two double-blind, parallel group, placebo-controlled flexible dose trials (Studies 1 and 2) conducted over 3 menstrual cycles. Patients in Study 1 met DSM-III-R criteria for Late Luteal Phase Dysphoric Disorder (LLPDD), the clinical entity now referred to as Premenstrual Dysphoric Disorder (PMDD) in DSM-IV. Patients in Study 2 met DSM-IV criteria for PMDD. Study 1 utilized daily dosing throughout the study, while Study 2 utilized luteal phase dosing for the 2 weeks prior to the onset of menses. The mean duration of PMDD symptoms for these patients was approximately 10.5 years in both studies. Patients on oral contraceptives were excluded from these trials; therefore, the efficacy of sertraline in combination with oral contraceptives for the treatment of PMDD is unknown. Efficacy was assessed with the Daily Record of Severity of Problems (DRSP), a patient-rated instrument that mirrors the diagnostic criteria for PMDD as identified in the DSM-IV, and includes assessments for mood, physical symptoms, and other symptoms. Other efficacy assessments included the Hamilton Depression Rating Scale (HAMD-17), and the Clinical Global Impression Severity of Illness (CGI-S) and Improvement (CGI-I) scores. In Study 1, involving N=251 randomized patients, sertraline hydrochloride treatment was initiated at 50 mg/day and administered daily throughout the menstrual cycle. In subsequent cycles, patients were dosed in the range of 50 to 150 mg/day on the basis of clinical response and toleration. The mean dose for completers was 102 mg/day. Sertraline hydrochloride administered daily throughout the menstrual cycle was significantly more effective than placebo on change from baseline to endpoint on the DRSP total score, the HAMD-17 total score, and the CGI-S score, as well as the CGI-I score at endpoint. In Study 2, involving N=281 randomized patients, sertraline hydrochloride treatment was initiated at 50 mg/day in the late luteal phase (last 2 weeks) of each menstrual cycle and then discontinued at the onset of menses. In subsequent cycles, patients were dosed in the range of 50 to 100 mg/day in the luteal phase of each cycle, on the basis of clinical response and toleration. Patients who were titrated to 100 mg/day received 50 mg/day for the first 3 days of the cycle, then 100 mg/day for the remainder of the cycle. The mean sertraline hydrochloride dose for completers was 74 mg/day. Sertraline hydrochloride administered in the late luteal phase of the menstrual cycle was significantly more effective than placebo on change from baseline to endpoint on the DRSP total score and the CGI-S score, as well as the CGI-I score at endpoint. There was insufficient information to determine the effect of race or age on outcome in these studies. Social Anxiety Disorder The effectiveness of sertraline hydrochloride in the treatment of social anxiety disorder (also known as social phobia) was established in two multicenter placebo-controlled studies (Study 1 and 2) of adult outpatients who met DSM-IV criteria for social anxiety disorder. Study 1 was a 12-week, multicenter, flexible dose study comparing sertraline hydrochloride (50 to 200 mg/day) to placebo, in which sertraline hydrochloride was initiated at 25 mg/day for the first week. Study outcome was assessed by (a) the Liebowitz Social Anxiety Scale (LSAS), a 24-item clinician administered instrument that measures fear, anxiety and avoidance of social and performance situations, and by (b) the proportion of responders as defined by the Clinical Global Impression of Improvement (CGI-I) criterion of CGI-I 2 (very much or much improved). Sertraline hydrochloride was statistically significantly more effective than placebo as measured by the LSAS and the percentage of responders. Study 2 was a 20-week, multicenter, flexible dose study that compared sertraline hydrochloride (50 to 200 mg/day) to placebo. Study outcome was assessed by the (a) Duke Brief Social Phobia Scale (BSPS), a multi-item clinician-rated instrument that measures fear, avoidance and physiologic response to social or performance situations, (b) the Marks Fear Questionnaire Social Phobia Subscale (FQ-SPS), a 5-item patient-rated instrument that measures change in the severity of phobic avoidance and distress, and (c) the CGI-I responder criterion of 2. Sertraline hydrochloride was shown to be statistically significantly more effective than placebo as measured by the BSPS total score and fear, avoidance and physiologic factor scores, as well as the FQ-SPS total score, and to have significantly more responders than placebo as defined by the CGI-I. Subgroup analyses did not suggest differences in treatment outcome on the basis of gender. There was insufficient information to determine the effect of race or age on outcome. In a longer-term study, patients meeting DSM-IV criteria for social anxiety disorder who had responded while assigned to sertraline hydrochloride (CGI-I of 1 or 2) during a 20-week placebo-controlled trial on sertraline hydrochloride 50 to 200 mg/day were randomized to continuation of sertraline hydrochloride or to substitution of placebo for up to 24 weeks of observation for relapse. Relapse was defined as 2 point increase in the Clinical Global Impression Severity of Illness (CGI-S) score compared to baseline or study discontinuation due to lack of efficacy. Patients receiving sertraline hydrochloride continuation treatment experienced a statistically significantly lower relapse rate over this 24-week study than patients randomized to placebo substitution.

CONTRAINDICATIONS SECTION.


CONTRAINDICATIONS Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated (see WARNINGS ). Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS ).Sertraline hydrochloride tablets are contraindicated in patients with a hypersensitivity to sertraline or any of the inactive ingredients in sertraline hydrochloride tablets.

WARNINGS SECTION.


WARNINGS Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied.There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo 65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATIONDiscontinuation of Treatment with Sertraline Hydrochloride Tablets , for a description of the risks of discontinuation of sertraline hydrochloride). Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for sertraline hydrochloride should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that sertraline hydrochloride is not approved for use in treating bipolar depression. Cases of serious sometimes fatal reactions have been reported in patients receiving sertraline hydrochloride, a selective serotonin reuptake inhibitor (SSRI), in combination with a monoamine oxidase inhibitor (MAOI). Symptoms of a drug interaction between an SSRI and an MAOI include: hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes that include confusion, irritability, and extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued an SSRI and have been started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore, sertraline hydrochloride should not be used in combination with an MAOI, or within 14 days of discontinuing treatment with an MAOI. Similarly, at least 14 days should be allowed after stopping sertraline hydrochloride before starting an MAOI. The concomitant use of sertraline hydrochloride with MAOIs intended to treat depression is contraindicated (see CONTRAINDICATIONS and WARNINGS - Potential for Interaction with Monoamine Oxidase Inhibitors ). Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions The development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including sertralinehydrochloride treatment, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs which impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms. The concomitant use of sertralinehydrochloride with MAOIs intended to treat depression is contraindicated. If concomitant treatment of sertralinehydrochloride with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of sertralinehydrochloride with serotonin precursors (such as tryptophan) is not recommended. Treatment with sertralinehydrochloride and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.