SERTRALINE HYDROCHLORIDE

Sertraline hydrochloride capsules contain sertraline hydrochloride, a selective serotonin reuptake inhibitor (SSRI). Sertraline hydrochloride has a molecular weight of 342.7 and has the following chemical name: (1S,4S)-4-(3, 4-dichloro phenyl)-1, 2, 3, 4-tetrahydro-N-methyl-1 naphthylamine hydrochloride. The empirical formula C 17 H 17 Cl 2 N HCI is represented by the following structural formula: Sertraline hydrochloride is a white to off-white, crystalline powder that is sparingly soluble in ethanol, slightly soluble in water and in isopropyl alcohol. 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: colloidal silicon dioxide, croscarmellose sodium, hydroxy propyl cellulose, magnesium stearate, microcrystalline cellulose, titanium dioxide, gelatin, purified water. Ink contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, black iron oxide, potassium hydroxide. 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. formula

Sertraline hydrochloride 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 capsules is a selective serotonin reuptake inhibitor (SSRI) indicated for the treatment of ( 1 ): Major depressive disorder (MDD) Obsessive-compulsive disorder (OCD) in adults and pediatric patients 6 years and older

Do not intiate 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.

Sertraline hydrochioride 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 )

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 [seeWarnings 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 hydrochloride were nausea, diarrhea/loose stool, tremor, dyspepsia, decreased appetite, hyperhidrosis, ejaculation failure, and decreased libido ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Cipla Ltd. at 1-866-604-3268 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 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 SertralineHydrochloride and Greater than or Equal to Twice the Incidence of Placebo) in Pooled Placebo-Controlled Trials* Sertraline Hydrochloride (N=3066) % Placebo (N=2293) % Cardiac disorders 4 2 Palpitations Eye disorders 4 2 Visual impairment 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=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. 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 adversereactions (>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 PooledControlled 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

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 MAOls increases the risk of serotonin syndrome. Intervention: Sertraline hydrochloride 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 hydrochloride capsules is 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 proteinbound 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 Warnings and Precautions ( 5.10 ), Clinical Pharmacology ( 12.2 )] . Intervention: Pimozide is contraindicated for use with sertraline hydrochloride capsules. Avoid the concomitant use of drugs known to prolong the QTc interval. 7.2 Drugs Having No Clinically Important Interactions with Sertraline Hydrochloride Based on pharmacokinetic studies with another sertraline hydrochloride formulation, no dosage adjustment of sertraline hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride capsules. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish sertraline from benzodiazepines.