Zoloft

Warnings and Precautions ( 5.2 , 5.3 ) 8/2023

1 INDICATIONS AND USAGE ZOLOFT is indicated for the treatment of the following [See Clinical Studies (14) ] : • Major depressive disorder (MDD) • Obsessive-compulsive disorder (OCD) • Panic disorder (PD) • Posttraumatic stress disorder (PTSD) • Social anxiety disorder (SAD) • Premenstrual dysphoric disorder (PMDD) ZOLOFT is a selective serotonin reuptake inhibitor (SSRI) indicated for the treatment of ( 1 ): • Major depressive disorder (MDD) • Obsessive-compulsive disorder (OCD) • Panic disorder (PD) • Posttraumatic stress disorder (PTSD) • Social anxiety disorder (SAD) • Premenstrual dysphoric disorder (PMDD)

2 DOSAGE AND ADMINISTRATION Indication Starting Dosage Maximum Dosage MDD ( 2.1 ) 50 mg per day 200 mg per day OCD ( 2.1 ) 25 mg per day (ages 6-12) 50 mg per day (ages ≥ 13) 200 mg per day PD, PTSD, SAD ( 2.1 ) 25 mg per day 200 mg per day PMDD ( 2.2 ) continuous dosing 50 mg per day 150 mg per day PMDD ( 2.2 ) intermittent dosing 50 mg per day during luteal phase only 100 mg per day during luteal phase only • If inadequate response to starting dosage, titrate in 25-50 mg per day increments once weekly in MDD, OCD, PD, PTSD, and SAD ( 2.1 ) • See Full Prescribing Information for titration in PMDD ( 2.2 ) • Hepatic impairment: o Mild: Recommended starting and maximum dosage is half recommended dosage ( 2.4 ) o Moderate or severe: Not recommended ( 2.4 ) • When discontinuing ZOLOFT, reduce dose gradually ( 2.6 , 5.4 ) • Oral solution: Must be diluted before administration ( 2.7 ) 2.1 Dosage in Patients with MDD, OCD, PD, PTSD, and SAD The recommended initial dosage and maximum ZOLOFT dosage in patients with MDD, OCD, PD, PTSD, and SAD are displayed in Table 1 below. A dosage of 25 mg or 50 mg per day is the initial therapeutic dosage. For adults and pediatric patients, subsequent dosages may be increased in case of an inadequate response in 25 to 50 mg per day increments once a week, depending on tolerability, up to a maximum of 200 mg per day. Given the 24-hour elimination half-life of ZOLOFT, the recommended interval between dose changes is one week. Table 1: Recommended Daily Dosage of ZOLOFT in Patients with MDD, OCD, PD, PTSD, and SAD Indication Starting Dose Therapeutic Range Adults MDD 50 mg 50-200 mg OCD 50 mg PD, PTSD, SAD 25 mg Pediatric Patients OCD (ages 6-12 years old) 25 mg 50-200 mg OCD (ages 13-17 years old) 50 mg 2.2 Dosage in Patients with PMDD The recommended starting ZOLOFT dosage in adult women with PMDD is 50 mg per day. ZOLOFT may be administered either continuously (every day throughout the menstrual cycle) or intermittently (only during the luteal phase of the menstrual cycle, i.e., starting the daily dosage 14 days prior to the anticipated onset of menstruation and continuing through the onset of menses). Intermittent dosing would be repeated with each new cycle. • When dosing continuously , patients not responding to a 50 mg dosage may benefit from dosage increases at 50 mg increments per menstrual cycle up to 150 mg per day. • When dosing intermittently , patients not responding to a 50 mg dosage may benefit from increasing the dosage up to a maximum of 100 mg per day during the next menstrual cycle (and subsequent cycles) as follows: 50 mg per day during the first 3 days of dosing followed by 100 mg per day during the remaining days in the dosing cycle. 2.3 Screen for Bipolar Disorder Prior to Starting ZOLOFT Prior to initiating treatment with ZOLOFT 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 Dosage Modifications in Patients with Hepatic Impairment Both the recommended starting dosage and therapeutic range in patients with mild hepatic impairment (Child Pugh scores 5 or 6) are half the recommended daily dosage [See Dosage and Administration (2.1 , 2.2) ] . The use of ZOLOFT in patients with moderate (Child Pugh scores 7 to 9) or severe hepatic impairment (Child Pugh scores 10-15) is not recommended [See Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ] . 2.5 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 ZOLOFT. In addition, at least 14 days must elapse after stopping ZOLOFT before starting an MAOI antidepressant [See Contraindications (4) , Warnings and Precautions (5.2) ] . 2.6 Discontinuation of Treatment with ZOLOFT Adverse reactions may occur upon discontinuation of ZOLOFT [See Warnings and Precautions (5.5) ] …

3 DOSAGE FORMS AND STRENGTHS 25 mg tablets : light green film-coated, engraved on one side with “ZOLOFT” and on the other side scored and engraved with “25 mg” 50 mg tablets : light blue film-coated, engraved on one side with “ZOLOFT” and on the other side scored and engraved with “50 mg” 100 mg tablets : light yellow film-coated, engraved on one side with “ZOLOFT” and on the other side scored and engraved with “100 mg” Oral solution : a clear, colorless solution with a menthol scent containing sertraline hydrochloride equivalent to 20 mg of sertraline per mL and 12% alcohol. It is supplied as a 60 mL bottle with an accompanying calibrated dropper that has 25 mg and 50 mg graduation marks. • Tablets: 25 mg, 50 mg and 100 mg ( 3 ) • Oral solution: 20 mg/mL ( 3 )

4 CONTRAINDICATIONS ZOLOFT is 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 (e.g., anaphylaxis, angioedema) [See Adverse Reactions (6.1 , 6.2) ] . In addition to the contraindications for all ZOLOFT formulations listed above, ZOLOFT oral solution is contraindicated in patients: • Taking disulfiram. ZOLOFT oral solution contains alcohol, and concomitant use of ZOLOFT and disulfiram may result in a disulfiram-alcohol reaction. • 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 , 5.4 ) • ZOLOFT oral solution only: Concomitant use of disulfiram ( 4 )

6 ADVERSE REACTIONS The following adverse reactions are described in more detail in other sections of the prescribing information: • Hypersensitivity reactions to sertraline [See Contraindications (4) ] • Disulfiram-alcohol reaction when ZOLOFT oral solution is taken with disulfiram [See Contraindications (4) ] • QTc prolongation and ventricular arrhythmias when taken with pimozide [See Contraindications (4) , Clinical Pharmacology (12.2) ] • Suicidal thoughts and behaviors [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/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) ] • Sexual Dysfunction [See Warnings and Precautions (5.11) ] Most common adverse reactions (≥5% and twice placebo) in pooled placebo-controlled MDD, OCD, PD, PTSD, SAD and PMDD clinical trials were nausea, diarrhea/loose stool, tremor, dyspepsia, decreased appetite, hyperhidrosis, ejaculation failure, and decreased libido. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Viatris at 1-877-446-3679 (1-877-4-INFO-RX) 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 data described below are from randomized, double-blind, placebo-controlled trials of ZOLOFT (mostly 50 mg to 200 mg per day) in 3066 adults diagnosed with MDD, OCD, PD, PTSD, SAD, and PMDD. These 3066 patients exposed to ZOLOFT for 8 to12 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 ZOLOFT-treated patients with MDD, OCD, PD, PTSD, SAD and PMDD were nausea, diarrhea/loose stool, tremor, dyspepsia, decreased appetite, hyperhidrosis, ejaculation failure, and decreased libido (see Table 3). The following are the most common adverse reactions in trials of ZOLOFT (≥5% and twice placebo) by indication that were not mentioned previously. • MDD: somnolence; • OCD: insomnia, agitation; • PD: constipation, agitation; • PTSD: fatigue; • PMDD: somnolence, dry mouth, dizziness, fatigue, and abdominal pain; • SAD: insomnia, dizziness, fatigue, dry mouth, malaise. Table 3: Common Adverse Reactions in Pooled Placebo-Controlled Trials in Adults with MDD, OCD, PD, PTSD, SAD, and PMDD Adverse reactions that occurred greater than 2% in ZOLOFT-treated patients and at least 2% greater in ZOLOFT-treated patients than placebo-treated patients. ZOLOFT (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 Denominator used was for male patients only (n=1316 ZOLOFT; n=973 placebo). 8% 1% Erectile dysfunction 4% 1% Ejaculation disorder 3% 0% Male sexual dysfunctiom 2% 0% Skin and subcutaneous tissue disorders Hyperhidrosis 7% 3% Adverse Reactions Leading to Discontinuation in Placebo-Controlled Clinical Trials In all placebo-controll …

7 DRUG INTERACTIONS • Protein-bound drugs: Monitor for adverse reactions and reduce dosage of ZOLOFT 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 5 includes clinically significant drug interactions with ZOLOFT [See Clinical Pharmacology (12.3) ] . Table 5. Clinically-Significant Drug Interactions with ZOLOFT Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: The concomitant use of SSRIs including ZOLOFT and MAOIs increases the risk of serotonin syndrome. Intervention: ZOLOFT is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [See Dosage and Administration (2.5) , Contraindications (4) , Warnings and Precautions (5.2) ]. Examples: selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue 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 ZOLOFT is contraindicated [See Contraindications (4) ]. Other Serotonergic Drugs Clinical Impact: The concomitant use of serotonergic drugs with ZOLOFT 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 ZOLOFT and/or concomitant serotonergic drugs [See Warnings and Precautions (5.2) ]. Examples: Other SSRIs, SNRIs, triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, amphetamines, and St. John’s Wort. Drugs that Interfere with Hemostasis (antiplatelet agents and anticoagulants) Clinical Impact: The concurrent use of an antiplatelet agent or anticoagulant with ZOLOFT may potentiate the risk of bleeding. Intervention: Inform patients of the increased risk of bleeding associated with the concomitant use of ZOLOFT and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [See Warnings and Precautions (5.3) ]. Examples: aspirin, clopidogrel, heparin, warfarin Drugs Highly Bound to Plasma Protein Clinical Impact: ZOLOFT is highly bound to plasma protein. The concomitant use of ZOLOFT with another drug that is highly bound to plasma protein may increase free concentrations of ZOLOFT or other tightly-bound drugs in plasma [See Clinical Pharmacology (12.3) ] . Intervention: Monitor for adverse reactions and reduce dosage of ZOLOFT or other protein-bound drugs as warranted. Examples: warfarin Drugs Metabolized by CYP2D6 Clinical Impact: ZOLOFT is a CYP2D6 inhibitor [See Clinical Pharmacology (12.3) ] . The concomitant use of ZOLOFT with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate. Intervention: Decrease the dosage of a CYP2D6 substrate if needed with concomitant ZOLOFT use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if ZOLOFT is discontinued. Examples: propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thioridazine, tolterodine, venlafaxine Phenytoin Clinical Impact: Phenytoin is a narrow therapeutic index drug. ZOLOFT may increase phenytoin concentrations. Intervention: Monitor phenytoin levels when initiating or titrating ZOLOFT. Reduce phenytoin dosage if needed. Examples: phenytoin, fosphenytoin 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 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. Avoid the concomitant use of drugs known to prolong the QTc interval. …

8 USE IN SPECIFIC POPULATIONS • Pregnancy: Third trimester use may increase risk for persistent pulmonary hypertension and withdrawal in the neonate. ( 8.1 ) • Pediatric use: Safety and effectiveness of ZOLOFT in pediatric patients other than those with OCD have not been established. ( 8.4 ) 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 and SNRIs, including ZOLOFT, during the third trimester of pregnancy [See Clinical Considerations ] . Although no teratogenicity was 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 3.1 times the MRHD in rabbits on a mg/m 2 basis in adolescents. 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 2-4% and 15-20%, respectively. Advise a pregnant woman of possible risks to the fetus when prescribing ZOLOFT. ZOLOFT oral solution contains 12% alcohol and is not recommended during pregnancy because there is no known safe level of alcohol exposure during pregnancy. 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 ZOLOFT 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 and SNRIs, including ZOLOFT 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 ZOLOFT during the third trimester, carefully consider both the potential risks and benefits of treatment. Monitor neonates who were exposed to ZOLOFT in the third trimester of pregnancy for PPHN and drug discontinuation syndrome [See Data ] . Data Human Data Third Trimester Exposure Neonates exposed to ZOLOFT and other SSRIs or SNRIs late in the third tr …

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 ZOLOFT contains sertraline hydrochloride, an SSRI. Sertraline hydrochloride has a molecular weight of 342.7 and has the following chemical name: (1S‐cis)‐4‐(3,4‐dichlorophenyl)‐1,2,3,4‐tetrahydro-N‐methyl‐1‐naphthalenamine hydrochloride. The empirical formula C 17 H 17 NCl 2 •HCl is represented by the following structural formula: Sertraline hydrochloride is a white crystalline powder that is slightly soluble in water and isopropyl alcohol, and sparingly soluble in ethanol. ZOLOFT tablets for oral administration contain 28.0 mg, 56.0 mg and 111.9 mg sertraline hydrochloride equivalent to 25, 50 and 100 mg of sertraline and the following inactive ingredients: dibasic calcium phosphate dihydrate, D & C Yellow #10 aluminum lake (in 25 mg tablet), FD & C Blue #1 aluminum lake (in 25 mg tablet), FD & C Red #40 aluminum lake (in 25 mg tablet), FD & C Blue #2 aluminum lake (in 50 mg tablet), hydroxypropyl cellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, synthetic yellow iron oxide (in 100 mg tablet), and titanium dioxide. ZOLOFT oral solution is available in a multidose 60 mL bottle. Each mL of solution contains 22.4 mg sertraline hydrochloride equivalent to 20 mg of sertraline. The solution contains the following inactive ingredients: glycerin, alcohol (12%), menthol, butylated hydroxytoluene (BHT). The oral solution must be diluted prior to administration [See Dosage and Administration (2.7) ] . The dispenser contains dry natural rubber. Sertraline Hydrochloride Structural Formula

10 OVERDOSAGE The following have been reported with sertraline tablet 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 ZOLOFT 25 mg tablets: light green, film-coated, capsular-shaped tablets engraved on one side with “ZOLOFT” and on the other side scored and engraved with “25 mg” NDC 58151-574-93 Bottles of 30 ZOLOFT 50 mg tablets: light blue, film-coated, capsular-shaped tablets engraved on one side with “ZOLOFT” and on the other side scored and engraved with “50 mg” NDC 58151-575-93 Bottles of 30 NDC 58151-575-88 Unit Dose Packages of 100 ZOLOFT 100 mg tablets: light yellow, film-coated, capsular-shaped, tablets engraved on one side with “ZOLOFT” and on the other side scored and engraved with “100 mg” NDC 58151-576-93 Bottles of 30 NDC 58151-576-88 Unit Dose Packages of 100 ZOLOFT oral solution: clear, colorless solution with a menthol scent containing sertraline hydrochloride equivalent to 20 mg of sertraline per mL and 12% alcohol NDC 58151-601-35 Bottles containing 60 mL, each with an accompanying calibrated dropper that has 25 mg and 50 mg graduation marks. Store ZOLOFT at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].