5 WARNINGS AND PRECAUTIONS

5.1 Suicidal Thoughts and Behaviors in Adolescent and Young Adults

In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and over 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1,000 patients treated are provided in Table 1.

It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors.

Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing Sertraline HCl Capsules, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

5.2 Serotonin Syndrome

SSRIs, including Sertraline HCl Capsules, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications (4), Drug Interactions (7.1)]. Serotonin syndrome can also occur when these drugs are used alone.

Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

The concomitant use of Sertraline HCl Capsules with MAOIs is contraindicated. In addition, do not initiate Sertraline HCl Capsules in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral ingestion or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Sertraline HCl Capsules, discontinue Sertraline HCl Capsules before initiating treatment with the MAOI [see Contraindications (4), Drug Interactions (7.1)].

Monitor all patients taking Sertraline HCl Capsules for the emergence of serotonin syndrome. Discontinue treatment with Sertraline HCl Capsules and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of Sertraline HCl Capsules with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

5.3 Increased Risk of Bleeding

Drugs that interfere with serotonin reuptake inhibition, including Sertraline HCl Capsules, increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), other antiplatelet drugs, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Based on data from the published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Use in Specific Populations (8.1)]. Bleeding events related to drugs that interfere with serotonin reuptake have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.

Inform patients about the increased risk of bleeding associated with the concomitant use of Sertraline HCl Capsules and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio.

5.4 Activation of Mania or Hypomania

In patients with bipolar disorder, treating a depressive episode with Sertraline HCl Capsules or another antidepressant may precipitate a mixed/manic episode. In controlled clinical trials with another sertraline HCl product, patients with bipolar disorder were generally excluded; however, symptoms of mania or hypomania were reported in 0.4% of patients treated with sertraline. Prior to initiating treatment with Sertraline HCl Capsules, screen patients for any personal or family history of bipolar disorder, mania, or hypomania [see Dosage and Administration (2.3)].

5.5 Discontinuation Syndrome

Adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt discontinuation, include: nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible [see Dosage and Administration (2.5)].

5.6 Seizures

Sertraline HCl has not been systematically evaluated in patients with seizure disorders. Patients with a history of seizures were excluded from clinical studies. Sertraline HCl Capsules should be prescribed with caution in patients with a seizure disorder.

5.7 Angle-Closure Glaucoma

The pupillary dilation that occurs following use of many antidepressant drugs, including sertraline HCl, may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Avoid use of antidepressants, including Sertraline HCl Capsules, in patients with untreated anatomically narrow angles.

5.8 Hyponatremia

Hyponatremia may occur as a result of treatment with SSRIs, including Sertraline HCl Capsules. Cases with serum sodium lower than 110 mmol/L have been reported with another sertraline HCl product. 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 or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).

In patients with symptomatic hyponatremia, discontinue Sertraline HCl Capsules and institute appropriate medical intervention. Elderly patients, patients taking diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia with SSRIs [see Use in Specific Populations (8.5)].

5.9 False-Positive Effects on Screening Tests for Benzodiazepines

False-positive urine immunoassay screening tests for benzodiazepines have been reported in patients taking another sertraline HCl product. This finding is due to lack of specificity of the screening tests. False-positive test results may be expected for several days following discontinuation of Sertraline HCl Capsules. Confirmatory tests, such as gas chromatography/mass spectrometry, will help distinguish Sertraline HCl Capsules from benzodiazepines [see Drug Interactions (7.3)].

5.10 QTc Prolongation

During post-marketing use of sertraline, cases of QTc prolongation and Torsade de Pointes (TdP) have been reported. Most reports were confounded by other risk factors. In a randomized, double-blind, placebo- and positive-controlled three-period crossover thorough QTc study in 54 healthy adult subjects, there was a positive relationship between the length of the rate-adjusted QTc interval and serum sertraline concentration. Therefore, Sertraline HCl Capsules should be used with caution in patients with risk factors for QTc prolongation [see Drug Interactions (7.1), Clinical Pharmacology (12.2)].

5.11 Allergic Reactions to FD&C Yellow No. 5 (Tartrazine)

Sertraline HCl Capsules contain FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

5.12 Sexual Dysfunction

Use of SSRIs, including Sertraline HCl Capsules, may cause symptoms of sexual dysfunction [see Adverse Reactions (6.1)]. In male patients, SSRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SSRI use may result in decreased libido and delayed or absent orgasm.

It is important for prescribers to inquire about sexual function prior to initiation of Sertraline HCl Capsules and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.

2 DOSAGE AND ADMINISTRATION

2.1 Dosage in Patients with MDD and OCD

Do not initiate treatment with Sertraline HCl Capsules because the only available dose strengths are 150 mg and 200 mg. Use another sertraline HCl product for initial dosage, titration, and dosages below 150 mg once daily. Refer to Prescribing Information of the other sertraline HCl products for the recommended dosage for those products.

Sertraline HCl Capsules can be initiated in patients receiving 100 mg or 125 mg of sertraline HCl for at least one week. The recommended dosage of Sertraline HCl Capsules is 150 mg or 200 mg once daily. The maximum recommended dosage is 200 mg once daily.

2.2 Administration Instructions

Administer Sertraline HCl Capsules orally. Swallow capsules whole; do not open, crush, or chew.

2.3 Screen for Bipolar Disorder Prior to Starting Sertraline HCl Capsules

Prior to initiating treatment with Sertraline HCl Capsules or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions (5.4)].

2.4 Switching Patients to or from a Monoamine Oxidase Inhibitor

Antidepressant

At least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (MAOI) antidepressant and initiation of Sertraline HCl Capsules. In addition, at least 14 days must elapse after stopping Sertraline HCl Capsules before starting an MAOI antidepressant [see Contraindications (4), Warnings and Precautions (5.2)].

2.5 Discontinuation of Treatment with Sertraline HCl Capsules

Adverse reactions may occur upon discontinuation of Sertraline HCl Capsules [see Warnings and Precautions (5.5)]. Gradually reduce the dosage rather than stopping Sertraline HCl Capsules abruptly whenever possible. Given that dosage strengths lower than 150 mg of Sertraline HCl Capsules are not available, gradual dosage reduction will require the use of another sertraline HCl product.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Lifetime carcinogenicity studies were carried out in CD-1 mice and Long-Evans rats at doses up to 40 mg/kg/day. These doses correspond to 1 times (mice) and 2 times (rats) the maximum recommended human dose (MRHD) of 200 mg/day on a mg/m2 basis. There was a dose-related increase of liver adenomas in male mice receiving sertraline at 10 to 40 mg/kg (0.25 to 1.0 times the MRHD on a mg/m2 basis). No increase was seen in female mice or in rats of either sex receiving the same treatments, nor was there an increase in hepatocellular carcinomas. Liver adenomas have a variable rate of spontaneous occurrence in the CD-1 mouse and are of unknown significance to humans. There was an increase in follicular adenomas of the thyroid in female rats receiving sertraline at 40 mg/kg (2 times the MRHD on a mg/m2 basis); this was not accompanied by thyroid hyperplasia. While there was an increase in uterine adenocarcinomas in rats receiving sertraline at 10 to 40 mg/kg (0.5 to 2.0 times the MRHD on a mg/m2 basis) compared to placebo controls, this effect was not clearly drug related.

Mutagenesis

Sertraline had no genotoxic effects, with or without metabolic activation, based on the following assays: bacterial mutation assay; mouse lymphoma mutation assay; and tests for cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes.

Impairment of Fertility

A decrease in fertility was seen in one of two rat studies at a dose of 80 mg/kg (approximately 4 times the maximum recommended human dose on a mg/m2 basis in adults).

14 CLINICAL STUDIES

14.1 Major Depressive Disorder

The efficacy of Sertraline HCl Capsules for the treatment of major depressive disorder (MDD) in adult patients is based upon adequate and well-controlled studies of another sertraline HCl product (referred to as “sertraline” in this section). The results of these adequate and well-controlled studies of sertraline are presented below.

The efficacy of sertraline as a treatment for MDD was established in two randomized, double-blind, placebo-controlled studies and one double-blind, randomized-withdrawal study following an open label study in adult (ages 18 to 65) outpatients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-III) criteria for MDD (studies MDD-1 and MDD-2).

• Study MDD-1 was an 8-week, 3-arm study with flexible dosing of sertraline, amitriptyline, and placebo. Adult patients received sertraline (N=126, in a daily dose titrated weekly to 50 mg, 100 mg, or 200 mg), amitriptyline (N=123, in a daily dose titrated weekly to 50 mg, 100 mg, or 150 mg), or placebo (N= 130).
• Study MDD-2 was a 6-week, multicenter parallel study of three fixed doses of sertraline administered once daily at 50 mg (N=82), 100 mg (N=75), and 200 mg (N=56) doses and placebo (N=76) in the treatment of adult outpatients with MDD.

Overall, these studies demonstrated sertraline to be superior to placebo on the Hamilton Rating Scale for Depression (HAMD-17) and the Clinical Global Impression Severity (CGI-S) of Illness and Global Improvement (CGI-I) scores. Study MDD-2 was not readily interpretable regarding a dose response relationship for effectiveness.

A third study (Study MDD-3) involved adult outpatients meeting the DSM-III criteria for MDD who had responded by the end of an initial 8-week open treatment phase on sertraline 50 to 200 mg/day. These patients (n=295) were randomized to continuation on double-blind sertraline 50 to 200 mg/day or placebo for 44 weeks. A statistically significantly lower relapse rate was observed for patients taking sertraline compared to those on placebo: sertraline [n=11 (8%)] and placebo [n=31 (39%)]. The mean sertraline dose for completers was 70 mg/day.

Analyses for gender effects on outcome did not suggest any differential responsiveness on the basis of sex.

14.2 Obsessive-Compulsive Disorder

The efficacy of Sertraline HCl Capsules for the treatment of OCD in adults and pediatric patients ages 6 to 17 years is based upon adequate and well- controlled studies of another sertraline HCl product (referred to as “sertraline” in this section). The results of these adequate and well- controlled studies of sertraline are presented below.

Adults with OCD

The effectiveness of sertraline in the treatment of OCD was demonstrated in three multicenter placebo-controlled studies of adult (age 18 to 65) non- depressed outpatients (Studies OCD-1, OCD-2, and OCD-3). Patients in all three studies had moderate to severe OCD (DSM-III or DSM-III-R) with mean baseline ratings on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) total score ranging from 23 to 25.

• Study OCD-1 was an 8-week randomized, placebo-controlled study with flexible dosing of sertraline in a range of 50 to 200 mg/day, titrated in 50 mg increments every 4 days to a maximally tolerated dose; the mean dose for completers was 186 mg/day. Patients receiving sertraline (N=43) experienced a mean reduction of approximately 4 points on the Y-BOCS total score which was statistically significantly greater than the mean reduction of 2 points in placebo-treated patients (N=44). The mean change in Y-BOCS from baseline to last visit (the primary efficacy endpoint) was -3.79 (sertraline) and -1.48 (placebo).
• Study OCD-2 was a 12-week randomized, placebo-controlled fixed-dose study, including sertraline doses of 50, 100, and 200 mg/day. Sertraline (N=240) was titrated to the assigned dose over two weeks in 50 mg increments every 4 days. Patients receiving sertraline doses of 50 and 200 mg/day experienced mean reductions of approximately 6 points on the Y-BOCS total score, which were statistically significantly greater than the approximately 3 point reduction in placebo-treated patients (N=84). The mean change in Y-BOCS from baseline to last visit (the primary efficacy endpoint) was -5.7 (pooled results from sertraline 50 mg, 100 mg, and 150 mg) and -2.85 (placebo).
• Study OCD-3 was a 12-week randomized, placebo controlled study with flexible dosing of sertraline in a range of 50 to 200 mg/day; the mean dose for completers was 185 mg/day. Sertraline (N=241) was titrated to the assigned dose over two weeks in 50 mg increments every 4 days. Patients receiving sertraline experienced a mean reduction of approximately 7 points on the Y-BOCS total score which was statistically significantly greater than the mean reduction of approximately 4 points in placebo-treated patients (N=84). The mean change in Y-BOCS from baseline to last visit (the primary efficacy endpoint) was - 6.5 (sertraline) and -3.6 (placebo).

Analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex.

The effectiveness of sertraline was studied in the risk reduction of OCD relapse. In Study OCD-4, patients ranging in age from 18 to 79 meeting DSM- III-R criteria for OCD who had responded during a 52-week single-blind trial on sertraline 50 to 200 mg/day (n=224) were randomized to continuation of sertraline or to substitution of placebo for up to 28 weeks of observation for analysis of discontinuation due to relapse or insufficient clinical response. Response during the single-blind phase was defined as a decrease in the Y-BOCS score of ≥ 25% compared to baseline and a CGI-I of 1 (very much improved), 2 (much improved) or 3 (minimally improved). Insufficient clinical response during the double-blind phase indicated a worsening of the patient’s condition that resulted in study discontinuation, as assessed by the investigator. Relapse during the double-blind phase was defined as the following conditions being met (on three consecutive visits for 1 and 2, and condition 3 being met at visit 3):

• Condition 1: Y-BOCS score increased by ≥ 5 points, to a minimum of 20, relative to baseline;
• Condition 2: CGI-I increased by ≥ one point; and
• Condition 3: Worsening of the patient’s condition in the investigator’s judgment, to justify alternative treatment.

Patients receiving continued sertraline treatment experienced a statistically significantly lower rate of discontinuation due to relapse or insufficient clinical response over the subsequent 28 weeks compared to those receiving placebo. This pattern was demonstrated in male and female subjects.

Pediatric Patients (ages 6 to 17 years) with OCD

The effectiveness of sertraline for the treatment of OCD was demonstrated in a 12-week, multicenter, placebo-controlled, parallel group study in a pediatric outpatient population (ages 6 to 17) (Study OCD-5). Sertraline (N=92) was initiated at doses of either 25 mg/day (pediatric patients ages 6 to 12) or 50 mg/day (pediatric patients ages 13 to 17), and then titrated at 3 and 4 day intervals (25 mg incremental dose for pediatric patients ages 6 to 12) or 1 week intervals (50 mg incremental dose for pediatric patients ages 13 to 17) over the next four weeks to a maximum dose of 200 mg/day, as tolerated. The mean dose for completers was 178 mg/day. Dosing was once a day in the morning or evening. Patients in this study had moderate to severe OCD (DSM-III-R) with mean baseline ratings on the Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) total score of 22. Patients receiving sertraline experienced a mean reduction of approximately 7 units on the CY-BOCS total score which was statistically significantly greater than the 3 unit reduction for placebo patients (n=95). Analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex.

* attempts to commit suicide
* acting aggressive or violent
* new or worse depression
* feeling agitated, restless, angry, or irritable
* an increase in activity and talking more than what is normal for you
* acting on dangerous impulses
* thoughts about suicide or dying
* new or worse anxiety or panic attacks
* trouble sleeping
* other unusual changes in behavior or mood

Revised: 8/2023
MG664-01