Sertraline HCL

1 INDICATIONS AND USAGE Sertraline Hydrochloride (HCl) Capsules is indicated for the treatment of the following [see Clinical Studies ( 14 )] : Major depressive disorder (MDD) in adults Obsessive-compulsive disorder (OCD) in adults and pediatric patients 6 years and older Sertraline Hydrochloride (HCl) Capsules is a selective serotonin reuptake inhibitor (SSRI) indicated for the treatment of ( 1 ): Major depressive disorder (MDD) in adults Obsessive-compulsive disorder (OCD) in adults and pediatric patients 6 years and older

2 DOSAGE AND ADMINISTRATION Do not initiate treatment with Sertraline HCl Capsules. Use another sertraline HCl product for initial dosage, titration, and dosages below 150 mg once daily ( 2.1 ) Recommended dosage is 150 mg or 200 mg once daily ( 2.1 ) Maximum recommended dosage is 200 mg once daily ( 2.1 ) Swallow capsules whole. Do not open, crush, or chew ( 2.2 ) When discontinuing Sertraline HCl Capsules, reduce dose gradually whenever possible. Gradual dosage reduction will require use of another sertraline HCl product ( 2.5 , 5.5 ) 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.

4 CONTRAINDICATIONS Sertraline HCl Capsules are contraindicated in patients: Taking, or within 14 days of stopping, MAOIs, (including the MAOIs linezolid and intravenous methylene blue) because of an increased risk of serotonin syndrome [see Warnings and Precautions ( 5.2 ), Drug Interactions ( 7.1 )] . Taking pimozide [see Drug Interactions ( 7.1 )] . With known hypersensitivity to sertraline or the excipients in Sertraline HCl Capsules (e.g., anaphylaxis, angioedema) [see Adverse Reactions ( 6.1 , 6.2 )] . Concomitant use of monoamine oxidase inhibitors (MAOIs), or use within 14 days of stopping MAOIs ( 4 , 7.1 ) Concomitant use of pimozide ( 4 , 7.1 ) Known hypersensitivity to sertraline or excipients ( 4 )

5 WARNINGS AND PRECAUTIONS Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents, but also when taken alone. If it occurs, discontinue Sertraline HCl Capsules and serotonergic agents and initiate supportive treatment ( 4 , 5.2 , 7.1 ) Increased Risk of Bleeding: Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), other antiplatelet drugs, warfarin, and other anticoagulants may increase this risk ( 5.3 ) Activation of Mania or Hypomania: Screen patients for bipolar disorder ( 5.4 ) Discontinuation Syndrome: When discontinuing Sertraline HCl Capsules, reduce dosage gradually whenever possible, and monitor for discontinuation symptoms. Gradual reduction will require use of another sertraline HCl product ( 5.5 ) Seizures: Use with caution in patients with seizure disorders ( 5.6 ) Angle Closure Glaucoma: Avoid use of antidepressants, including Sertraline HCl Capsules, in patients with untreated anatomically narrow angles ( 5.7 ) QTc Prolongation: Sertraline HCl Capsules should be used with caution in patients with risk factors for QTc prolongation ( 5.10 ) Allergic Reactions to FD&C Yellow No. 5 (Tartrazine): Contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons ( 5.11 ) Sexual Dysfunction: Sertraline HCl Capsules may cause symptoms of sexual dysfunction ( 5.12 ) 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. Table 1: Risk Differences of the Number of Patients of Suicidal Thoughts or Behavior in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1,000 Patients Treated Increases Compared to Placebo <18 years old 14 additional patients 18 to 24 years old 5 additional patients Decreases Compared to Placebo 25 to 64 years old 1 fewer patient ≥65 years old 6 fewer patients 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.

7 DRUG INTERACTIONS Protein-bound drugs: Monitor for adverse reactions and reduce dosage of Sertraline HCl Capsules or other protein-bound drugs (e.g., warfarin) as warranted ( 7.1 , 12.3 ) CYP2D6 substrates: Reduce dosage of drugs metabolized by CYP2D6 ( 7.1 , 12.3 ) 7.1 Clinically Significant Drug Interactions Table 4 includes clinically significant drug interactions with Sertraline HCl Capsules [see Clinical Pharmacology ( 12.3 )] . Table 4. Clinically-Significant Drug Interactions with Sertraline HCl Capsules Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: The concomitant use of SSRIs, including Sertraline HCl Capsules, and MAOIs increases the risk of serotonin syndrome. Intervention: Sertraline HCl Capsules is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Dosage and Administration ( 2.4 ), Contraindications ( 4 ), Warnings and Precautions ( 5.2 )] . Pimozide Clinical Impact: Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QTc prolongation and ventricular arrhythmias. Intervention: Concomitant use of pimozide and Sertraline HCl Capsules is contraindicated [see Contraindications ( 4 )] . Other Serotonergic Drugs Clinical Impact: Concomitant use of Sertraline HCl Capsules with other serotonergic drugs (including other SSRIs, SNRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John's Wort) increases the risk of serotonin syndrome. Intervention: Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of Sertraline HCl Capsules and/or concomitant serotonergic drugs [see Warnings and Precautions ( 5.2 )] . Drugs that Interfere with Hemostasis (antiplatelet agents and anticoagulants) Clinical Impact: The concurrent use of an antiplatelet agent or anticoagulant with Sertraline HCl Capsules may potentiate the risk of bleeding. Intervention: Inform patients of the increased risk of bleeding associated with the concomitant use of Sertraline HCl Capsules and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [see Warnings and Precautions ( 5.3 )] . Drugs Highly Bound to Plasma Protein Clinical Impact: Sertraline is highly bound to plasma protein. The concomitant use of Sertraline HCl Capsules with another drug that is highly bound to plasma protein may increase free concentrations of sertraline or other tightly-bound drugs in plasma [see Clinical Pharmacology ( 12.3 )] . Intervention: Monitor for adverse reactions and reduce dosage of Sertraline HCl Capsules or other protein-bound drugs as warranted. Drugs Metabolized by CYP2D6 Clinical Impact: Sertraline HCl Capsules are a CYP2D6 inhibitor [see Clinical Pharmacology ( 12.3 )] . The concomitant use of Sertraline HCl Capsules with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate. Intervention: Decrease the dosage of a CYP2D6 substrate if needed with concomitant Sertraline HCl Capsules use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if Sertraline HCl Capsules are discontinued. Phenytoin Clinical Impact: Phenytoin is a narrow therapeutic index drug. Sertraline HCl Capsules may increase phenytoin concentrations. Intervention: Monitor phenytoin levels when initiating or titrating Sertraline HCl Capsules. Reduce phenytoin dosage if needed. Drugs that Prolong the QTc Interval Clinical Impact: The risk of QTc prolongation and/or ventricular arrhythmias (e.g., TdP) is increased with concomitant use of Sertraline HCl Capsules with other drugs which prolong the QTc interval [see Warnings and Precautions ( 5.10 ), Clinical Pharmacology ( 12.2 )] . Intervention: Pimozide is contraindicated for use with Sertraline HCl Capsules. Avoid the concomitant use of drugs known to prolong the QTc interval. 7.2 Drugs Having No Clinically Important Interactions with Sertraline HCl Based on pharmacokinetic studies with another sertraline HCl formulation, no dosage adjustment of Sertraline HCl Capsules is necessary when used in combination with cimetidine. Additionally, no dosage adjustment is required for diazepam, lithium, atenolol, tolbutamide, digoxin, and drugs metabolized by CYP3A4, when Sertraline HCl Capsules is administered concomitantly [see Clinical Pharmacology ( 12.3 )] . 7.3 False-Positive 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 distinguish sertraline from benzodiazepines.

6 ADVERSE REACTIONS The following adverse reactions are described in more detail in other sections of the prescribing information: Hypersensitivity reactions to sertraline or excipients of Sertraline HCl Capsules [see Contraindications ( 4 )] Suicidal Thoughts and Behaviors in Adolescent and Young Adults [see Warnings and Precautions ( 5.1 )] Serotonin Syndrome [see Contraindications ( 4 ), Warnings and Precautions ( 5.2 ), Drug Interactions ( 7.1 )] Increased Risk of Bleeding [see Warnings and Precautions ( 5.3 )] Activation of Mania or Hypomania [see Warnings and Precautions ( 5.4 )] Discontinuation Syndrome [see Warnings and Precautions ( 5.5 )] Seizures [see Warnings and Precautions ( 5.6 )] Angle-Closure Glaucoma [see Warnings and Precautions ( 5.7 )] Hyponatremia [see Warnings and Precautions ( 5.8 )] QTc Prolongation [see Warnings and Precautions ( 5.10 )] Allergic reactions to FD&C Yellow No. 5 (Tartrazine) [see Warnings and Precautions ( 5.11 )] Sexual Dysfunction [see Warnings and Precautions ( 5.12 )] Most common adverse reactions (≥5% and twice placebo) in pooled placebo-controlled clinical trials with sertraline HCl were nausea, diarrhea/loose stool, tremor, dyspepsia, decreased appetite, hyperhidrosis, ejaculation failure, and decreased libido ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Almatica Pharma LLC at 1-877-447-7979 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of Sertraline HCl Capsules for the treatment of MDD and OCD is based on adequate and well-controlled studies of another sertraline HCl product. Below is a display of adverse reactions of sertraline HCl (referred to as “sertraline” in this section) from those adequate and well-controlled studies in MDD, OCD, and other conditions. The data described below reflect exposure in randomized, double-blind, placebo-controlled trials of sertraline in 3066 adults. These 3066 patients exposed to sertraline for 8 to 12 weeks represent 568 patient-years of exposure. The mean age was 40 years; 57% were females and 43% were males. The most common adverse reactions (≥5% and twice placebo) in all pooled placebo-controlled clinical trials of all sertraline-treated patients (MDD, OCD, and other conditions) were nausea, diarrhea/loose stool, tremor, dyspepsia, decreased appetite, hyperhidrosis, ejaculation failure, and decreased libido (see Table 2). The following are the most common adverse reactions in trials of sertraline (≥5% and twice placebo) by indication that were not mentioned previously. MDD: somnolence OCD: insomnia, agitation Table 2: Common Adverse Reactions (Greater than 2% of Adults with MDD, OCD, and Other Conditions Treated with Sertraline Hydrochloride and Greater than or Equal to Twice the Incidence of Placebo) in Pooled Placebo-Controlled Trials* (1) Denominator used was for male patients only (n=1316 sertraline; n=973 placebo). * Adverse reactions that occurred greater than 2% in sertraline hydrochloride-treated patients and at least 2% greater in sertraline hydrochloride-treated patients than placebo-treated patients. Sertraline Hydrochloride (N=3066) % Placebo (N=2293) % Cardiac disorders Palpitations 4 2 Eye disorders Visual impairment 4 2 Gastrointestinal Disorders Nausea 26 12 Diarrhea/Loose Stools 20 10 Dry mouth 14 9 Dyspepsia 8 4 Constipation 6 4 Vomiting 4 1 General disorders and administration site conditions Fatigue 12 8 Metabolism and nutrition disorders Decreased appetite 7 2 Nervous system disorders Dizziness 12 8 Somnolence 11 6 Tremor 9 2 Psychiatric Disorders Insomnia 20 13 Agitation 8 5 Libido Decreased 6 2 Reproductive system and breast disorders Ejaculation failure (1) 8 1 Erectile dysfunction (1) 4 1 Ejaculation disorder (1) 3 0 Male sexual dysfunction (1) 2 0 Skin and subcutaneous tissue disorders Hyperhidrosis 7 3 Adverse Reactions Leading to Discontinuation in Placebo-Controlled Clinical Trials In all placebo-controlled studies, 368 (12%) of the 3066 patients who received sertraline discontinued treatment due to an adverse reaction, compared with 93 (4%) of the 2293 placebo-treated patients. In placebo-controlled studies, the following were the common adverse reactions leading to discontinuation in sertraline-treated patients: All sertraline -treated patients (MDD, OCD, and Other Conditions): nausea (3%), diarrhea (2%), agitation (2%), and insomnia (2%). MDD (>2% and twice placebo): decreased appetite, dizziness, fatigue, headache, somnolence, tremor, and vomiting. OCD: somnolence. Male and Female Sexual Dysfunction 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 SSRI treatment. However, reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance and satisfaction are difficult to obtain, in part because patients and healthcare providers may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in labeling may underestimate their actual incidence. Table 3 below displays the incidence of sexual adverse reactions reported by at least 2% of sertraline -treated patients and twice placebo from pooled placebo-controlled trials of MDD, OCD, and other conditions. For men and all indications, the most common adverse reactions (>2% and twice placebo) included: ejaculation failure, decreased libido, erectile dysfunction, ejaculation disorder, and male sexual dysfunction. For women, the most common adverse reaction (≥2% and twice placebo) was decreased libido. Table 3: Most Common Sexual Adverse Reactions (≥2% and twice placebo) in Men or Women from Sertraline Hydrochloride Pooled Controlled Trials in Adults with MDD, OCD, and Other Conditions Sertraline Hydrochloride % Placebo % Men only (N=1316) (N=973) Ejaculation failure 8 1 Libido decreased 7 2 Erectile dysfunction 4 1 Ejaculation disorder 3 0 Male sexual dysfunction 2 0 Women only (N=1750) (N=1320) Libido decreased 4 2 Adverse Reactions in Pediatric Patients In 281 pediatric patients treated with sertraline in placebo-controlled studies, the overall profile of adverse reactions was generally similar to that seen in adult studies. Adverse reactions that do not appear in Table 2 (most common adverse reactions in adults) yet were reported in at least 2% of pediatric patients and at a rate of at least twice the placebo rate include fever, hyperkinesia, urinary incontinence, aggression, epistaxis, purpura, arthralgia, decreased weight, muscle twitching, and anxiety. Other Adverse Reactions Observed During the Premarketing Evaluation of Sertraline Other infrequent adverse reactions, not described elsewhere in the prescribing information, occurring at an incidence of < 2% in patients treated with sertraline were: Cardiac disorders – tachycardia Ear and labyrinth disorders – tinnitus Endocrine disorders - hypothyroidism Eye disorders - mydriasis, blurred vision Gastrointestinal disorders - hematochezia, melena, rectal hemorrhage General disorders and administration site conditions - edema, gait disturbance, irritability, pyrexia Hepatobiliary disorders - elevated liver enzymes Immune system disorders - anaphylaxis Metabolism and nutrition disorders - diabetes mellitus, hypercholesterolemia, hypoglycemia, increased appetite Musculoskeletal and connective tissue disorders – arthralgia, muscle spasms, tightness, or twitching Nervous system disorders - ataxia, coma, convulsion, decreased alertness, hypoesthesia, lethargy, psychomotor hyperactivity, syncope Psychiatric disorders - aggression, bruxism, confusional state, euphoric mood, hallucination Renal and urinary disorders - hematuria Reproductive system and breast disorders - galactorrhea, priapism, vaginal hemorrhage Respiratory, thoracic and mediastinal disorders - bronchospasm, epistaxis, yawning Skin and subcutaneous tissue disorders - alopecia; cold sweat; dermatitis; dermatitis bullous; pruritus; purpura; erythematous, follicular, or maculopapular rash; urticaria Vascular disorders - hemorrhage, hypertension, vasodilation 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of another sertraline product. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Bleeding or clotting disorders - increased coagulation times (altered platelet function) Cardiac disorders - AV block, bradycardia, atrial arrhythmias, QTc-interval prolongation, ventricular tachycardia (including Torsade de Pointes) [see Clinical Pharmacology ( 12.2 )] Endocrine disorders - gynecomastia, hyperprolactinemia, menstrual irregularities, SIADH Eye disorders - blindness, optic neuritis, cataract Hepatobiliary disorders - severe liver events (including hepatitis, jaundice, liver failure with some fatal outcomes), pancreatitis Hemic and lymphatic disorders - agranulocytosis, aplastic anemia and pancytopenia, leukopenia, thrombocytopenia, lupus-like syndrome, serum sickness Immune system disorders - angioedema Metabolism and nutrition disorders - hyponatremia, hyperglycemia Musculoskeletal and connective tissue disorders - rhabdomyolysis, trismus Nervous system disorders - serotonin syndrome, extrapyramidal symptoms (including akathisia and dystonia), oculogyric crisis Psychiatric disorders - psychosis, enuresis, paroniria Renal and urinary disorders - acute renal failure Respiratory, thoracic and mediastinal disorders - pulmonary hypertension, anosmia, hyposmia Skin and subcutaneous tissue disorders - photosensitivity skin reaction and other severe cutaneous reactions, which potentially can be fatal, such as Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) Vascular disorders - cerebrovascular spasm (including reversible cerebral vasoconstriction syndrome and Call-Fleming syndrome), vasculitis

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers should encourage patients to enroll by calling the National Pregnancy Registry for Antidepressants at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry/antidepressants. Risk Summary Based on data from 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 Warnings and Precautions ( 5.3 ) and Clinical Considerations] . Overall, available published epidemiologic studies of pregnant women exposed to sertraline in the first trimester suggest no difference in major birth defect risk compared to the background rate for major birth defects in comparator populations. Some studies have reported increases for specific major birth defects; however, these study results are inconclusive (see Data) . There are clinical considerations regarding neonates exposed to SSRIs, including Sertraline HCl Capsules, during the third trimester of pregnancy (see Clinical Considerations) . Although no malformations were observed in animal reproduction studies, delayed fetal ossification was observed when sertraline was administered during the period of organogenesis at doses less than the maximum recommended human dose (MRHD) in rats and doses approximately 4 times the MRHD in rabbits on a mg/m 2 basis in adults. When sertraline was administered to female rats during the last third of gestation, there was an increase in the number of stillborn pups and pup deaths during the first four days after birth at the MRHD (see Data) . The background risk of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Advise a pregnant woman of possible risks to the fetus when prescribing Sertraline HCl Capsules. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk A prospective longitudinal study followed 201 pregnant women with a history of major depression who were euthymic taking antidepressants at the beginning of pregnancy. The women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants. Consider the risks of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Maternal Adverse Reactions Use of Sertraline HCl Capsules in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions ( 5.3 )] . Fetal/Neonatal Adverse Reactions Exposure to SSRIs, including Sertraline HCl Capsules, in late pregnancy may lead to an increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding, and/or persistent pulmonary hypertension of the newborn (PPHN). When treating a pregnant woman with Sertraline HCl Capsules during the third trimester, carefully consider both the potential risks and benefits of treatment. Monitor neonates who were exposed to sertraline in the third trimester of pregnancy for PPHN and drug discontinuation syndrome (see Data) . Data Human Data Third Trimester Exposure Neonates exposed to sertraline and other SSRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. These findings are based on post-marketing reports. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs or, possibly, a drug discontinuation syndrome. In some cases, the clinical picture was consistent with serotonin syndrome [see Warnings and Precautions ( 5.2 )] . Exposure during late pregnancy to SSRIs may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20 th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. A study of 831,324 infants born in Sweden in 1997 to 2005 found a PPHN risk ratio of 2.4 (95% CI 1.2 to 4.3) associated with patient-reported maternal use of SSRIs “in early pregnancy” and a PPHN risk ratio of 3.6 (95% CI 1.2 to 8.3) associated with a combination of patient-reported maternal use of SSRIs “in early pregnancy” and an antenatal SSRI prescription “in later pregnancy”. First Trimester Exposure The weight of evidence from epidemiologic studies of pregnant women exposed to sertraline in the first trimester suggest no difference in major birth defect risk compared to the background rate for major birth defects in pregnant women who were not exposed to sertraline. A meta-analysis of studies suggest no increase in the risk of total malformations (summary odds ratio=1.01, 95% CI=0.88 to 1.17) or cardiac malformations (summary odds ratio=0.93, 95% CI=0.70 to 1.23) among offspring of women with first trimester exposure to sertraline. An increased risk of congenital cardiac defects, specifically septal defects, the most common type of congenital heart defect, was observed in some published epidemiologic studies with first trimester sertraline exposure; however, most of these studies were limited by the use of comparison populations that did not allow for the control of confounders such as the underlying depression and associated conditions and behaviors, which may be factors associated with increased risk of these malformations. Animal Data Reproduction studies have been performed in rats and rabbits at doses up to 80 mg/kg/day and 40 mg/kg/day, respectively. These doses correspond to approximately 4 times the maximum recommended human dose (MRHD) of 200 mg/day on a mg/m 2 basis in adults. There was no evidence of malformation at any dose level. When pregnant rats and rabbits were given sertraline during the period of organogenesis, delayed ossification was observed in fetuses at doses of 10 mg/kg (0.5 times the MRHD on a mg/m 2 basis) in rats and 40 mg/kg (3.9 times the MRHD on a mg/m 2 basis) in rabbits. When female rats received sertraline during the last third of gestation and throughout lactation, there was an increase in stillborn pups and pup deaths during the first 4 days after birth. Pup body weights were also decreased during the first four days after birth. These effects occurred at a dose of 20 mg/kg (1 times the MRHD on a mg/m 2 basis). The no effect dose for rat pup mortality was 10 mg/kg (0.5 times the MRHD on a mg/m 2 basis). The decrease in pup survival was shown to be due to in utero exposure to sertraline. The clinical significance of these effects is unknown.