Sertraline Hydrochloride

Warnings and Precautions ( 5.2 , 5.3 ) 8/2023

1 INDICATIONS & 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 hydrochloride capsules. Use another sertraline hydrochloride 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 hydrochloride capsules, reduce dose gradually whenever possible. Gradual dosage reduction will require use of another sertraline hydrochloride product ( 2.5 , 5.5 ) 2.1 Dosage in Patients with MDD and OCD Do not initiate treatment with sertraline hydrochloride capsules because the only available dose strengths are 150 mg and 200 mg. Use another sertraline hydrochloride product for initial dosage, titration, and dosages below 150 mg once daily. Refer to Prescribing Information of the other sertraline hydrochloride products for the recommended dosage for those products. Sertraline hydrochloride capsules can be initiated in patients receiving 100 mg or 125 mg of sertraline hydrochloride for at least one week. The recommended dosage of sertraline hydrochloride capsules is 150 mg or 200 mg once daily. The maximum recommended dosage is 200 mg once daily. 2.2 Administration Instructions Administer sertraline hydrochloride capsules orally. Swallow capsules whole; do not open, crush, or chew. 2.3 Screen for Bipolar Disorder Prior to Starting sertraline hydrochloride capsules Prior to initiating treatment with sertraline hydrochloride 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 hydrochloride capsules. In addition, at least 14 days must elapse after stopping sertraline hydrochloride capsules before starting an MAOI antidepressant [ see Contraindications ( 4 ), Warnings and Precautions ( 5.2 ) ]. 2.5 Discontinuation of Treatment with sertraline hydrochloride capsules Adverse reactions may occur upon discontinuation of sertraline hydrochloride capsules [ see Warnings and Precautions ( 5.5 ) ]. Gradually reduce the dosage rather than stopping sertraline hydrochloride capsules abruptly whenever possible. Given that dosage strengths lower than 150 mg of sertraline hydrochloride capsules are not available, gradual dosage reduction will require the use of another sertraline hydrochloride product.

3 DOSAGE FORMS AND STRENGTHS 150 mg capsules : Size 2 hard gelatin capsules, with yellow opaque cap imprinted with SER1 in black and white opaque body imprinted with 'ZN27' in black, filled with white to off-white granular powder. 200 mg capsules : Size 1 hard gelatin capsules, with yellowish green opaque cap imprinted with SER2 in black and white opaque body imprinted with 'ZN28' in black, filled with white to off-white granular powder. Dosage strengths are based on the active moiety, sertraline. The 150 mg capsules contain 168.0 mg of Sertraline Hydrochloride. The 200 mg capsules contain 224.0 mg of Sertraline Hydrochloride. Capsules: 150 mg and 200 mg ( 3 )

4 CONTRAINDICATIONS Sertraline hydrochloride 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 hydrochloride 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 )

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 hydrochloride 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 )] Sexual Dysfunction [see Warnings and Precautions ( 5.12 )] Most common adverse reactions (≥5% and twice placebo) in pooled placebo-controlled clinical trials with sertraline hydrochloride capsules were nausea, diarrhea/loose stool, tremor, dyspepsia, decreased appetite, hyperhidrosis, ejaculation failure, and decreased libido ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 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 hydrochloride capsules for the treatment of MDD and OCD is based on adequate and well-controlled studies of another sertraline hydrochloride product. Below is a display of adverse reactions of sertraline hydrochloride (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 3,066 adults. These 3,066 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* Sertraline Hydrochloride (N=3,066) % Placebo (N=2,293) % 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 (1) Denominator used was for male patients only (n=1,316 sertraline; n=973 placebo). * Adverse reactions that occurred greater than 2% in sertraline hydrochloride-treated patients and at lea …

7 DRUG INTERACTIONS Protein-bound drugs: Monitor for adverse reactions and reduce dosage of sertraline hydrochloride 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 hydrochloride capsules [see Clinical Pharmacology ( 12.3 )] . Table 4. Clinically-Significant Drug Interactions with Sertraline Hydrochloride Capsules Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: The concomitant use of SSRIs, including sertraline hydrochloride capsules, and MAOIs increases the risk of serotonin syndrome. Intervention: Sertraline hydrochloride capsules are 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 hydrochloride capsules are contraindicated [see Contraindications ( 4 )] . Other Serotonergic Drugs Clinical Impact: Concomitant use of sertraline hydrochloride 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 hydrochloride 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 hydrochloride capsules may potentiate the risk of bleeding. Intervention: Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride 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 hydrochloride 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 hydrochloride capsules or other protein-bound drugs as warranted. Drugs Metabolized by CYP2D6 Clinical Impact: Sertraline hydrochloride capsules are a CYP2D6 inhibitor [see Clinical Pharmacology ( 12.3 )] . The concomitant use of sertraline hydrochloride 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 hydrochloride capsules use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride capsules are discontinued. Phenytoin Clinical Impact: Phenytoin is a narrow therapeutic index drug. Sertraline hydrochloride capsules may increase phenytoin concentrations. Intervention: Monitor phenytoin levels when initiating or titrating sertraline hydrochloride 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 hydrochloride capsules with other drugs which prolong the QTc interval [see Warn …

8 USE IN SPECIFIC POPULATIONS Pregnancy: Third trimester use may increase risk for persistent pulmonary hypertension and symptoms of poor adaptation (respiratory distress, temperature instability, feeding difficulty, hypotonia, irritability) in the neonate ( 8.1 ) Pediatric use: Safety and effectiveness in pediatric patients other than those with OCD (6 to 17 years) have not been established ( 8.4 ) Hepatic Impairment: Not recommended ( 8.6 ) 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 hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride 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 …

12.1 Mechanism of Action Sertraline potentiates serotonergic activity in the central nervous system through inhibition of neuronal reuptake of serotonin (5-HT).

11 DESCRIPTION Sertraline hydrochloride capsules contain sertraline hydrochloride, USP a selective serotonin reuptake inhibitor (SSRI). Sertraline hydrochloride has a molecular weight of 342.69 and has the following chemical name: ( 1S,4S )-4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydro- N -methyl-1-naphthylamine hydrochloride. The empirical formula C 17 H 17 Cl 2 N • HCl is represented by the following structural formula: Sertraline hydrochloride, USP is a white or off-white crystalline powder that is sparingly soluble or slightly soluble in absolute alcohol; slightly soluble in water and in isopropanol; and slightly or very slightly soluble in acetone. Sertraline hydrochloride capsules is for oral administration and contain 168 mg and 224 mg sertraline hydrochloride, equivalent to 150 mg and 200 mg sertraline, and the following inactive ingredients: croscarmellose sodium, gelatin, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, silicon dioxide and titanium dioxide. The 150 mg capsules contain FD&C Yellow No. 5 as a color additive. The 200 mg capsules contain FD&C Blue No. 1 and FD&C Yellow No. 5 as color additives. The Imprint ink contains black iron oxide, potassium hydroxide, propylene glycol and shellac. sertraline-spl-structure

10 OVERDOSAGE The following have been reported with sertraline hydrochloride capsules overdosage: Seizures, which may be delayed, and altered mental status including coma. Cardiovascular toxicity, which may be delayed, including QRS and QTc interval prolongation. Hypertension most commonly seen, but rarely can see hypotension alone or with co-ingestants including alcohol. Serotonin syndrome (patients with a multiple drug overdosage with other proserotonergic drugs may have a higher risk). Gastrointestinal decontamination with activated charcoal should be considered in patients who present early after a sertraline overdose. Consider contacting a Poison Center (1-800-221-2222) or a medical toxicologist for additional overdosage management recommendations.

16 HOW SUPPLIED/STORAGE AND HANDLING Sertraline hydrochloride capsules are supplied as: 150 mg Capsules: White to off white granular powder filled in size "2" empty hard gelatin capsules having a cream colored opaque cap imprinted with "1948" in blank ink and a cream colored opaque body. NDC 70710-1948-3 Bottles of 30 with child-resistant closure. 200 mg Capsules: White to off white granular powder filled in size "1" empty hard gelatin capsules having a light green colored opaque cap imprinted with "1949" in blank ink and a light green colored opaque body. NDC 70710-1949-3 Bottles of 30 with child-resistant closure. Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].