5 WARNINGS AND PRECAUTIONS

5.1 Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients

In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and over 4,400 pediatric patients, the incidence of suicidal thoughts and behaviors in pediatric and young adult patients was greater in antidepressant-treated patients than in placebo-treated patients. The drug- placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 2.

No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about antidepressant drug effect on suicide.

Table 2: Risk Differences of the Number of Cases of Suicidal Thoughts or Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients

Age Range (years)	Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1000 Patients Treated
Increases Compared to Placebo
<18	14 additional patients
18 to 24	5 additional patients
Decreases Compared to Placebo
25 to 64	1 fewer patient
≥65	6 fewer patients

It is unknown whether the risk of suicidal thoughts and behaviors in pediatric and young adult patients 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.

Monitor all antidepressant-treated patients 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 hydrochloride, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

5.2 Serotonin Syndrome

Serotonin-norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs), including sertraline hydrochloride, 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, 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 hydrochloride with MAOIs is contraindicated. In addition, do not initiate sertraline hydrochloride 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 tablets 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 hydrochloride tablets, discontinue sertraline hydrochloride tablets before initiating treatment with the MAOI [See Contraindications (4), Drug Interactions (7.1)].

Monitor all patients taking sertraline hydrochloride for the emergence of serotonin syndrome. Discontinue treatment with sertraline hydrochloride and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of sertraline hydrochloride 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 hydrochloride, 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. Bleeding events related to drugs that interfere with serotonin reuptake have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.

Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride 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 hydrochloride or another antidepressant may precipitate a mixed/manic episode. In controlled clinical trials, patients with bipolar disorder were generally excluded; however, symptoms of mania or hypomania were reported in 0.4% of patients treated with sertraline hydrochloride. Prior to initiating treatment with sertraline hydrochloride, screen patients for any personal or family history of bipolar disorder, mania, or hypomania.

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 (2.6)].

5.6 Seizures

Sertraline hydrochloride has not been systematically evaluated in patients with seizure disorders. Patients with a history of seizures were excluded from clinical studies. Sertraline hydrochloride 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 hydrochloride 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 hydrochloride, in patients with untreated anatomically narrow angles.

5.8 Hyponatremia

Hyponatremia may occur as a result of treatment with SNRIs and SSRIs, including sertraline hydrochloride. Cases with serum sodium lower than 110 mmol/L have been reported. 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 hydrochloride 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 and SNRIs [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 sertraline hydrochloride. 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. Confirmatory tests, such as gas chromatography/mass spectrometry, will help distinguish sertraline hydrochloride 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 hydrochloride should be used with caution in patients with risk factors for QTc prolongation [See Drug Interactions (7.1), Clinical Pharmacology (12.2)].

5.11 Sexual Dysfunction

Use of SSRIs, including sertraline hydrochloride, 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 hydrochloride 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

7.1 Clinically Significant Drug Interactions

Table 5 includes clinically significant drug interactions with sertraline hydrochloride [See Clinical Pharmacology (12.3)] .

Table 5. Clinically-Significant Drug Interactions with Sertraline Hydrochloride

** Monoamine Oxidase Inhibitors (MAOIs)**
Clinical Impact:	The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome.
Intervention:	Sertraline hydrochloride 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 sertraline hydrochloride is contraindicated [See Contraindications (4)].
** Other Serotonergic Drugs**
Clinical Impact:	The concomitant use of serotonergic drugs with sertraline hydrochloride 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 and/or concomitant serotonergic drugs [See Warnings and Precautions (5.2)].
Examples:	other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, 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 sertraline hydrochloride may potentiate the risk of bleeding.
Intervention:	Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride 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:	Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma [See Clinical Pharmacology (12.3)] .
Intervention:	Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted.
Examples:	warfarin
** Drugs Metabolized by CYP2D6**
Clinical Impact:	Sertraline hydrochloride is a CYP2D6 inhibitor [See Clinical Pharmacology (12.3)] . The concomitant use of sertraline hydrochloride 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 use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued.
Examples:	propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thioridazine, tolterodine, venlafaxine
** Phenytoin**
Clinical Impact:	Phenytoin is a narrow therapeutic index drug. Sertraline hydrochloride may increase phenytoin concentrations.
Intervention:	Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. 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.
Examples:	Specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol); specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus).

7.2 Drugs Having No Clinically Important Interactions with Sertraline

Hydrochloride

Based on pharmacokinetic studies, no dosage adjustment of sertraline hydrochloride 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 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 sertraline hydrochloride. 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. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish sertraline from benzodiazepines.

2 DOSAGE AND ADMINISTRATION

2.1 Dosage in Patients with MDD, OCD, PD, PTSD, and SAD

The recommended initial dosage and maximum sertraline hydrochloride 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 sertraline hydrochloride, the recommended interval between dose changes is one week.

Table 1: Recommended Daily Dosage of Sertraline Hydrochloride in Patients with MDD, OCD, PD, PTSD, and SAD
** Indication**	Starting Dose	Therapeutic Range
** Adults**
MDD	50 mg	50 to 200 mg
OCD	50 mg
PD, PTSD, SAD	25 mg
** Pediatric Patients**
OCD (ages 6 to 12 years old)	25 mg	50 to 200 mg
OCD (ages 13 to 17 years old)	50 mg

2.2 Dosage in Patients with PMDD

The recommended starting sertraline hydrochloride dosage in adult women with PMDD is 50 mg per day. Sertraline hydrochloride 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 Sertraline Hydrochloride

Tablets

Prior to initiating treatment with sertraline hydrochloride tablets 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 sertraline hydrochloride tablets in patients with moderate (Child Pugh scores 7 to 9) or severe hepatic impairment (Child Pugh scores 10 to 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 sertraline hydrochloride tablets. In addition, at least 14 days must elapse after stopping sertraline hydrochloride tablets before starting an MAOI antidepressant [See Contraindications (4), Warnings and Precautions (5.2)].

2.6 Discontinuation of Treatment with Sertraline Hydrochloride Tablets

Adverse reactions may occur upon discontinuation of sertraline hydrochloride tablets [See Warnings and Precautions (5.5)]. Gradually reduce the dosage rather than stopping sertraline hydrochloride tablets abruptly whenever possible.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

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 sertraline hydrochloride, 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 2basis 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 to 4% and 15 to 20%, respectively. Advise a pregnant woman of possible risks to the fetus when prescribing sertraline hydrochloride.

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.

Fetal/Neonatal adverse reactions

Exposure to SSRIs and SNRIs, including sertraline hydrochloride 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 during the third trimester, carefully consider both the potential risks and benefits of treatment. Monitor neonates who were exposed to sertraline hydrochloride in the third trimester of pregnancy for PPHN and drug discontinuation syndrome [See Data].

Data

Human Data

Third Trimester Exposure

Neonates exposed to sertraline hydrochloride and other SSRIs or SNRIs 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 and SNRIs 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 thweek 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 3.1 times the maximum recommended human dose (MRHD) of 200 mg/day on a mg/m 2basis in adolescents. There was no evidence of teratogenicity 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 (0.4 times the MRHD on a mg/m 2basis) in rats and 40 mg/kg (3.1 times the MRHD on a mg/m 2basis) 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 (0.8 times the MRHD on a mg/m 2basis). The no effect dose for rat pup mortality was 10 mg/kg (0.4 times the MRHD on a mg/m 2basis). The decrease in pup survival was shown to be due to in uteroexposure to sertraline. The clinical significance of these effects is unknown.

8.2 Lactation

Risk Summary

Available data from published literature demonstrate low levels of sertraline and its metabolites in human milk [See Data]. There are no data on the effects of sertraline on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for sertraline hydrochloride and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition.

Data

In a published pooled analysis of 53 mother-infant pairs, exclusively human milk-fed infants had an average of 2% (range 0% to 15%) of the sertraline serum levels measured in their mothers. No adverse reactions were observed in these infants.

8.4 Pediatric Use

The safety and efficacy of sertraline hydrochloride have been established in the treatment of OCD in pediatric patients aged 6 to 17 [See Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2)] . Safety and effectiveness in pediatric patients in patients with OCD below the age of 6 have not been established. Safety and effectiveness have not been established in pediatric patients for indications other than OCD. Two placebo-controlled trials were conducted in pediatric patients with MDD, but the data were not sufficient to support an indication for use in pediatric patients.

Monitoring Pediatric Patients Treated with Sertraline Hydrochloride

Monitor all patients being treated with antidepressants for clinical worsening, suicidal thoughts, and unusual changes in behavior, especially during the initial few months of treatment, or at times of dose increases or decreases [See Boxed Warning, Warnings and Precautions (5.1)] . Decreased appetite and weight loss have been observed with the use of SSRIs. Monitor weight and growth in pediatric patients treated with an SSRI such as sertraline hydrochloride.

Weight Loss in Studies in Pediatric Patients with MDD

In a pooled analysis of two 10-week, double-blind, placebo-controlled, flexible dose (50 to 200 mg) outpatient trials for MDD (n=373), there was a difference in weight change between sertraline hydrochloride and placebo of roughly 1 kg, for both children (ages 6 to 11) and adolescents (ages 12 to 17), in both age groups representing a slight weight loss for the sertraline hydrochloride group compared to a slight gain for the placebo group. For children, about 7% of the sertraline hydrochloride-treated patients had a weight loss greater than 7% of body weight compared to 0% of the placebo- treated patients; for adolescents, about 2% of sertraline hydrochloride- treated patients had a weight loss > 7% of body weight compared to about 1% of placebo-treated patients.

A subset of patients who completed the randomized controlled trials in patients with MDD (sertraline hydrochloride n=99, placebo n=122) were continued into a 24-week, flexible-dose, open-label, extension study. Those subjects who completed 34 weeks of sertraline hydrochloride treatment (10 weeks in a placebo-controlled trial + 24 weeks open-label, n=68) had weight gain that was similar to that expected using data from age-adjusted peers. However, there are no studies that directly evaluate the long-term effects of sertraline hydrochloride on the growth, development, and maturation in pediatric patients.

Juvenile Animal Data

A study conducted in juvenile rats at clinically relevant doses showed delay in sexual maturation, but there was no effect on fertility in either males or females.

In this study in which juvenile rats were treated with oral doses of sertraline at 0, 10, 40 or 80 mg/kg/day from postnatal day 21 to 56, a delay in sexual maturation was observed in males treated with 80 mg/kg/day and females treated with doses ≥10 mg/kg/day. There was no effect on male and female reproductive endpoints or neurobehavioral development up to the highest dose tested (80 mg/kg/day), except a decrease in auditory startle response in females at 40 and 80 mg/kg/day at the end of treatment but not at the end of the drug-free period. The highest dose of 80 mg/kg/day produced plasma levels (AUC) of sertraline 5 times those seen in pediatric patients (6 to 17 years of age) receiving the maximum recommended dose of sertraline (200 mg/day).

8.5 Geriatric Use

Of the total number of patients in clinical studies of sertraline hydrochloride in patients with MDD, OCD, PD, PTSD, SAD and PMDD, 797 (17%) were ≥ 65 years old, while 197 (4%) were ≥ 75 years old.

No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be conservative, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

In 354 geriatric subjects treated with sertraline hydrochloride in MDD placebo-controlled trials, the overall profile of adverse reactions was generally similar to that shown in Table 3 [See Adverse Reactions (6.1)], except for tinnitus, arthralgia with an incidence of at least 2% and at a rate greater than placebo in geriatric patients.

SNRIs and SSRIs, including sertraline hydrochloride, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [SeeWarnings and Precautions (5.8)].

8.6 Hepatic Impairment

The recommended dosage in patients with mild hepatic impairment (Child-Pugh score 5 or 6) is half the recommended dosage due to increased exposure in this patient population. The use of sertraline hydrochloride in patients with moderate (Child-Pugh score 7 to 10) or severe hepatic impairment (Child-Pugh score 10 to 15) is not recommended, because sertraline hydrochloride is extensively metabolized, and the effects of sertraline hydrochloride in patients with moderate and severe hepatic impairment have not been studied [See Dosage and Administration (2.4), Clinical Pharmacology (12.3)] .

8.7 Renal Impairment

No dose adjustment is needed in patients with mild to severe renal impairment. Sertraline exposure does not appear to be affected by renal impairment [See Clinical Pharmacology (12.3)] .

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

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

Mutagenesis

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

Impairment of Fertility

A decrease in fertility was seen in one of two rat studies at a dose of 80 mg/kg (3.1 times the maximum recommended human dose on a mg/m 2basis in adolescents).

16 HOW SUPPLIED/STORAGE AND HANDLING

Sertraline Hydrochloride Tablets USP,****50 mgare blue colored, biconvex, capsule shaped film coated tablets debossed with ‘A’ on one side and with a score line in between ‘1’ and ‘7’ on the other side.

NDC 42708-124-30 Bottles of 30

Store Sertraline Hydrochloride Tablets USP at 20º to 25ºC(68º to 77ºF); excursions permitted to 15º to 30ºC (59° to 86°F) [See USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling ( Medication Guide).

Suicidal Thoughts and Behaviors

Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dosage is adjusted up or down, and instruct them to report such symptoms to the healthcare provider [See Boxed Warningand Warnings and Precautions (5.1)] .

Serotonin Syndrome

Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of sertraline hydrochloride with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, St. John’s Wort, and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid). Patients should contact their health care provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome [SeeWarnings and Precautions (5.2), Drug Interactions (7.1)] .

Increased Risk of Bleeding

Inform patients about the concomitant use of sertraline hydrochloride with aspirin, NSAIDs, other antiplatelet drugs, warfarin, or other anticoagulants because the combined use has been associated with an increased risk of bleeding. Advise patients to inform their health care providers if they are taking or planning to take any prescription or over-the-­counter medications that increase the risk of bleeding [See Warnings and Precautions (5.3)].

Activation of Mania/Hypomania

Advise patients and their caregivers to observe for signs of activation of mania/hypomania and instruct them to report such symptoms to the healthcare provider [See Warnings and Precautions (5.4)] .

Discontinuation Syndrome

Advise patients not to abruptly discontinue sertraline hydrochloride and to discuss any tapering regimen with their healthcare provider. Adverse reactions can occur when sertraline hydrochloride is discontinued [SeeWarnings and Precautions (5.5)].

Sexual Dysfunction

Advise patients that use of sertraline hydrochloride may cause symptoms of sexual dysfunction in both male and female patients. Inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider [see Warnings and Precautions (5.11)].

Allergic Reactions

Advise patients to notify their healthcare provider if they develop an allergic reaction such as rash, hives, swelling, or difficulty breathing [See Adverse Reactions (6.2)] .

Pregnancy

Inform pregnant women that sertraline hydrochloride may cause withdrawal symptoms in the newborn or persistent pulmonary hypertension of the newborn (PPHN) [See Use in Specific Populations (8.1)] .

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** Dispense with Medication Guide available at: **www.aurobindousa.com/medication-guides