FDA label 406597c0-b09a-227f-e054-00144ff88e88

BOXED WARNING 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 Tablets 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 Tablets are not approved for the treatment of major depressive disorder in pediatric patients. (See Warnings: Clinical Worsening and Suicide Risk , Precautions: Information for Patients , and Precautions: Pediatric Use )

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 18-24) 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. The risk differences (drug-placebo differences in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. Table 1 AgeDrug-Placebo Difference in Number of Cases of SuicidalityRangeper 1000 Patients Treated Increases Compared to Placebo<1814 additional cases18245 additional casesDecreases Compared to Placebo25641 fewer case6 fewer casesNo 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 Tablets). 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 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, sertralineshould 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 sertralinebefore starting an MAOI. The concomitant use of sertraline hydrochloride with MAOIs intended to treat depression is contraindicated (see CONTRAINDICATIONS and WARNINGSPotential 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 sertraline hydrochloride treatment, but particularly with concomitant use of serotonergic drugs (including triptans) and 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 sertraline hydrochloride with MAOIs intended to treat depression is contraindicated. If concomitant treatment of SNRIs and SSRIs, including sertraline hydrochloride, 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 SNRIs and SSRIs, including serteraline hydrochloride, with serotonin precursors (such as tryptophan) is not recommended. Treatment with sertraline hydrochloride 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.

ADVERSE REACTIONS During its premarketing assessment, multiple doses of sertraline hydrochloride were administered to over 4000 adult subjects as of February 18, 2000. The conditions and duration of exposure to sertraline hydrochloride varied greatly, and included (in overlapping categories) clinical pharmacology studies, open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, fixed-dose and titration studies, and studies for multiple indications, including major depressive disorder and PMDD. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. In the tabulations that follow, a World Health Organization dictionary of terminology has been used to classify reported adverse events. The frequencies presented, therefore, represent the proportion of the over 4000 adult individuals exposed to multiple doses of sertraline hydrochloride who experienced a treatment-emergent adverse event of the type cited on at least one occasion while receiving sertraline hydrochloride. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. It is important to emphasize that events reported during therapy were not necessarily caused by it. The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and 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 hydrochloride and at least twice that for placebo) for the treatment of adult patients with major depressive disorder/other* in placebo-controlled clinical trials. Most patients in major depressive disorder/other* and PMDD 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 2 MOST COMMON TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN PLACEBO-CONTROLLED CLINICAL TRIALS Percentage of Patients Reporting EventMajor DepressivePMDDPMDD Luteal PhaseDisorder/Other*Daily DosingDosing (2)Body System/SertralinePlaceboSertralinePlaceboSertralinePlaceboAdverse EventHCl(N=853)HCl(N=122)HCl(N=127)(N=861)(N=121)(N=136)Autonomic Nervous System Disorders Ejaculation Failure(1)7<1N/AN/AN/AN/AMouth Dry16963103Sweating Increased836<130 Center. & Periph. Nerv. System Disorders Somnolence1367<120Tremor11320<1<1Dizziness1276375 General Fatigue11816710<1Pain126<132Malaise<119575 Gastrointestinal Disorders Abdominal Pain227<133Anorexia323250Constipation862312Diarrhea/Loose Stools189133137Dyspepsia637273Nausea2612239133 Psychiatric Disorders Agitation642<110Insomnia16917111210Libido Decreased1<111242 *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. Associated with Discontinuation in Placebo-Controlled Clinical Trials Table 3 lists the adverse events associated with discontinuation of sertraline treatment (incidence at least twice that for placebo and at least 1% for sertraline in clinical trials) in major depressive disorder/other*and PMDD. TABLE 3 MOST COMMON ADVERSE EVENTS ASSOCIATED WITH DISCONTINUATION IN PLACEBO-CONTROLLED CLINICAL TRIALS AdverseMajor DepressivePMDDPMDD LutealEventDisorder/Other*Daily DosingPhase Dosing(N=861)(N=121)(N=136) Abdominal PainAgitation1%AnxietyDiarrhea/2%2%Loose StoolsDizzinessDry Mouth1%DyspepsiaEjaculation1%N/AN/AFailure (1)FatigueHeadache2%Hot Flushes1%Insomnia1%1%Nausea4%2%1%Nervousness2%Palpitation1%Somnolence1%Tremor2%(1)Primarily ejaculatory delay. Denominator used was for male patients only *Major depressive disorder and other premarketing controlled trials. 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 4 below displays the incidence of sexual side effects reported by at least 2% of patients taking sertraline hydrochloride in placebo-controlled trials. TABLE 4 Adverse EventSertralinePlacebo 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, 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): 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, 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 Body as a WholeGeneral DisordersRare: allergic reaction, allergy. Cardiovascular Central and Peripheral Nervous System Disorders Disorders of Skin and Appendages Endocrine DisordersRare: exophthalmos, gynecomastia. Gastrointestinal Disorders General Hearing and Vestibular DisordersRare: hyperacusis, labyrinthine disorder. Hematopoietic and LymphaticRare: anemia, anterior chamber eye hemorrhage. Liver and Biliary System DisordersRare: abnormal hepatic function. Metabolic and Nutritional Disorders Musculoskeletal System Disorders Psychiatric Disorders Reproductive Respiratory System Disorders Special Senses Urinary System Disorders 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 treatment in patients with major depressive disorder, and PMDD is similar. Other Events Observed During the Post marketing 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.