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 50-200 mg/day. These patients (N=295) were randomized to continuation for 44 weeks on double-blind sertraline hydrochloride 50-200 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.
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 50-150 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 50-100 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.
INDICATIONS AND USAGE
Major Depressive Disorder – Sertraline hydrochloride is indicated for the treatment of major depressive disorder in adults.
The efficacy of sertraline hydrochloride in the treatment of a major depressive episode was established in six to eight week controlled trials of adult outpatients whose diagnoses corresponded most closely to the DSM-III category of major depressive disorder (see Clinical Trials under CLINICAL PHARMACOLOGY).
A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation.
The antidepressant action of sertraline hydrochloride in hospitalized depressed patients has not been adequately studied.
The efficacy of sertraline hydrochloride in maintaining an antidepressant response for up to 44 weeks following 8 weeks of open-label acute treatment (52 weeks total) was demonstrated in a placebo-controlled trial. The usefulness of the drug in patients receiving sertraline hydrochloride for extended periods should be reevaluated periodically (see Clinical Trials under CLINICAL PHARMACOLOGY).
Premenstrual Dysphoric Disorder (PMDD) – Sertraline hydrochloride is indicated for the treatment of premenstrual dysphoric disorder (PMDD) in adults.
The efficacy of sertraline hydrochloride 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-IIIR/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 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 for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
All Dosage Forms of Sertraline hydrochloride:
Sertraline hydrochloride is contraindicated in patients with a hypersensitivity to sertraline or any of the inactive ingredients in sertraline hydrochloride tablets.
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. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.
|Age Range||Drug-Placebo Difference inNumber of Cases of Suicidalityper 1000 Patients Treated|
|Increases Compared to placebo|
|<18||14 additional cases|
|18-24||5 additional cases|
|Decreases Compared to placebo|
|25-64||1 fewer case|
|>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 ADMINISTRATION—Discontinuation of Treatment with sertraline hydrochloride, 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 .)
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