Drug Safety-related Labeling Changes (SrLC)

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ZOLOFT (NDA-019839)

(SERTRALINE HYDROCHLORIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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08/18/2023 (SUPPL-108)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Serotonin Syndrome

Additions and/or revisions underlined:

Serotonin-norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs), including ZOLOFT, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [See Contraindications (4), Drug Interactions (7.1)].

…

5.3 Increased Risk of Bleeding

Additions and/or revisions underlined:

… Based on data from the published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Use in Specific Populations (8.1)]. Bleeding events related to drugs that interfere with serotonin reuptake have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.

…

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Respiratory, thoracic and mediastinal disorders - pulmonary hypertension, eosinophilic pneumonia, anosmia, hyposmia

…

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

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].

…

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)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Serotonin Syndrome

Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of ZOLOFT with other serotonergic drugs including triptans, tricyclic antidepressants, opioids, lithium, 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 [See Warnings and Precautions (5.2), Drug Interactions (7.1)].

…

Pregnancy

Inform pregnant women that ZOLOFT may cause withdrawal symptoms in the newborn or persistent pulmonary hypertension of the newborn (PPHN) [See Use in Specific Populations (8.1)]. Advise women that there is a pregnancy exposure registry that monitors pregnancy outcomes of women exposed to ZOLOFT during pregnancy.

MEDICATION GUIDE

Additions and/or revisions underlined:

…

What should I tell my healthcare provider before taking ZOLOFT?

…

• are pregnant or plan to become pregnant. Your baby may have withdrawal symptoms after birth or may be at increased risk for a serious lung problem at birth. Talk to your healthcare provider about the benefits and risks of taking ZOLOFT during pregnancy.

  • There is a pregnancy registry for females who are exposed to ZOLOFT during pregnancy. The purpose of the registry is to collect information about the health of females exposed to ZOLOFT and their baby. If you or your child become pregnant during treatment with ZOLOFT, talk to your healthcare provider about registering with the National Pregnancy Registry for Antidepressants. You can register by calling 1-866-961-2388 or by visiting online at https://womensmentalhealth.org/research/pregnancyregistry/antidepressants/.

    …

    Tell your healthcare provider about all the medicines that you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

    Especially tell your healthcare provider if you or your child take:

• medicines used to treat migraine headaches called triptans

• tricyclic antidepressants

• lithium

• tramadol, fentanyl, meperidine, methadone, or other opioids

• tryptophan

• buspirone

• amphetamines

• phenytoin

• St. John’s Wort

• medicines that can affect blood clotting such as aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), other antiplatelet medicines, warfarin, and other anticoagulants

• diuretics

• medicines used to treat mood, anxiety, psychotic, or thought disorders, including selective serotonin reuptake (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs)

  …

01/25/2023 (SUPPL-102)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Respiratory, thoracic and mediastinal disorders - pulmonary hypertension, eosinophilic pneumonia

…

09/20/2021 (SUPPL-100)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.11 Sexual Dysfunction

(Newly added subsection)

Use of SSRIs, including ZOLOFT, 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 ZOLOFT 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.

6 Adverse Reactions

(Addition of the following to the bulleted line listing)

• Sexual Dysfunction [See Warnings and Precautions (5.11)]

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(Additions and/or revisions underlined)

…

Sexual problems (dysfunction). Taking serotonin and norepinephrine reuptake inhibitors (SSRIs), including ZOLOFT, may cause sexual problems.

Symptoms in males may include:

• Delayed ejaculation or inability to have an ejaculation

• Decreased sex drive

• Problems getting or keeping an erection

Symptoms in females may include:

• Decreased sex drive

• Delayed orgasm or inability to have an orgasm

Talk to your healthcare provider if you develop any changes in your sexual function or if you have any questions or concerns about sexual problems during treatment with ZOLOFT. There may be treatments your healthcare provider can suggest.

…

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

…

Sexual Dysfunction

Advise patients that use of ZOLOFT 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)].

…

12/08/2017 (SUPPL-91)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

Musculoskeletal and connective tissue disorders - rhabdomyolysis, trismus

12/08/2017 (SUPPL-93)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.10 QTc Prolongation

Newly added subsection:

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, ZOLOFT should be used with caution in patients with risk factors for QTc prolongation.

7 Drug Interactions

7.1 Clinically Significant Drug Interactions

Table 5. Clinically-Significant Drug Interactions with Zoloft Addition of section entitled Drugs that Prolong the QTc Interval; please refer to label for full information.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Serotonin Syndrome

Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of ZOLOFT with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, St. John’s Wort …

06/15/2017 (SUPPL-88)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

Musculoskeletal and connective tissue disorders - trismus

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

(Additions and/or revisions are underlined)

What is the most important information I should know about ZOLOFT?

1. Low salt (sodium) levels in the blood. Elderly people may be at greater risk for this. Symptoms may include:

• confusion, problems concentrating or memory problems

12/23/2016 (SUPPL-74)

Approved Drug Label (PDF)

Boxed Warning

(Additions and/or revisions are underlined)

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

Antidepressants increased the risk of suicidal thoughts and behavior in pediatric and young adult patients in short- term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors.

4 Contraindications

(Additions and/or revisions are underlined)

ZOLOFT is contraindicated in patients:

• With known hypersensitivity to sertraline (e.g., anaphylaxis, angioedema).

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.

5 Warnings and Precautions

5.1 Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients

(Revised subsection title; Additions and/or revisions are underlined)

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.

…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 (Title added to table)

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…

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 ZOLOFT, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

5.2 Serotonin Syndrome

(Additions and/or revisions underlined)

Serotonin-norepinephrine reuptake inhibitors (SNRIs) and SSRIs, including ZOLOFT, can precipitate serotonin syndrome...

Serotonin syndrome signs and symptoms may include…

Monitor all patients taking ZOLOFT for the emergence of serotonin syndrome…

5.3 Increased Risk of Bleeding

(Revised subsection title; Additions and/or revisions are underlined)

Drugs that interfere with serotonin reuptake inhibition, including ZOLOFT, increase the risk of bleeding events.

Inform patients of the increased risk of bleeding associated with the concomitant use of ZOLOFT and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio.

5.4 Activation of Mania or Hypomania

(Additions and/or revisions are underlined)

In patients with bipolar disorder, treating a depressive episode with ZOLOFT 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 ZOLOFT. Prior to initiating treatment with ZOLOFT, screen patients for any personal or family history of bipolar disorder, mania, or hypomania.

5.5 Discontinuation Syndrome

(Additions and/or revisions are underlined)

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…

5.6 Seizures

(Additions and/or revisions are underlined)

ZOLOFT has not been systematically evaluated in patients with seizure disorders. Patients with a history of seizures were excluded from clinical studies. ZOLOFT should be prescribed with caution in patients with a seizure disorder.

5.7 Angle-Closure Glaucoma

(Revised subsection title; Additions and/or revisions are underlined)

…Avoid use of antidepressants, including ZOLOFT, in patients with untreated anatomically narrow angles.

 

6 Adverse Reactions

(Additions and/or revisions underlined)

The following adverse reactions are described in more detail in other sections of the prescribing information:

• Hypersensitivity reactions to sertraline
• Disulfiram-alcohol reaction when ZOLOFT oral solution is taken with disulfiram
• QT prolongation and ventricular arrhythmias when taken with pimozide
• Suicidal thoughts and behaviors
• Serotonin syndrome
• Increased risk of bleeding
• Activation of mania/hypomania
• Discontinuation syndrome
• Seizures
• Angle-closure glaucoma
• Hyponatremia

6.1 Clinical Trials Experience

(Revised subsection title; Additions and/or revisions are underlined)

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 (greater than 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 (greater than 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* (Table has been revised; please refer to label)

Adverse Reactions Leading to Discontinuation in Placebo-Controlled Clinical Trials

In all placebo-controlled studies in patients with MDD, OCD, PD, PTSD, SAD and PMDD, 368 (12%) of the 3066 patients who received ZOLOFT 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 ZOLOFT-treated patients:

• MDD, OCD, PD, PTSD, SAD and PMDD: nausea (3%), diarrhea (2%), agitation (2%), and insomnia (2%).
• MDD (greater than 2% and twice placebo): decreased appetite, dizziness, fatigue, headache, somnolence, tremor, and vomiting.
• OCD: somnolence.
• PD: nervousness and somnolence

Male and Female Sexual Dysfunction

Table 4 below displays the incidence of sexual adverse reactions reported by at least 2% of ZOLOFT-treated patients and twice placebo from pooled placebo-controlled trials. For men and all indications, the most common adverse reactions (greater than 2% and twice placebo) included: ejaculation failure, decreased libido, erectile dysfunction, ejaculation disorder, and male sexual dysfunction. For women, the most common adverse reaction (greater than or equal to 2% and twice placebo) was decreased libido.

Table 4: Most Common Sexual Adverse Reactions (greater than or equal to 2% and twice placebo) in Men or Women from ZOLOFT Pooled Controlled Trials in Adults with MDD, OCD, PD, PTSD, SAD, and PMDD (Table has been revised; please refer to label)

Adverse Reactions in Pediatric Patients

In 281 pediatric patients treated with ZOLOFT 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 3 (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 ZOLOFT

Other infrequent adverse reactions, not described elsewhere in the prescribing information, occurring at an incidence of less than 2% in patients treated with ZOLOFT were:

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

Reproductive system and breast disorders - galactorrhea, priapism, vaginal hemorrhage

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

(Additions and/or revisions are underlined)

The following adverse reactions have been identified during postapproval use of ZOLOFT. 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)

Endocrine disorders - gynecomastia, hyperprolactinemia, menstrual irregularities, SIADH

Metabolism and nutrition disorders – hyponatremia, hyperglycemia

Nervous system disorders - serotonin syndrome, extrapyramidal symptoms (including akathisia and dystonia), oculogyric crisis

Psychiatric disorders – psychosis, enuresis, paroniria

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)

7 Drug Interactions

7.1 Clinically Significant Drug Interactions

(Newly added subsection title; Additions and/or revisions are underlined)

Table 5 includes clinically significant drug interactions with ZOLOFT. (Table has been added; please refer to label)

7.2 Drugs Having No Clinically Important Interactions with ZOLOFT

(Newly added subsection)

Based on pharmacokinetic studies, no dosage adjustment of ZOLOFT 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 ZOLOFT is administered concomitantly.

7.3 False-Positive Screening Tests for Benzodiazepines

(Revised subsection title)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

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. There are clinical considerations regarding neonates exposed to SSRIs and SNRIs, including ZOLOFT, during the third trimester of pregnancy.

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/m2 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.

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

…Consider the risks of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum.

Fetal/Neonatal adverse reactions

…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.

Data

Human Data

Third Trimester Exposure

Neonates exposed to ZOLOFT 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…

Exposure during late pregnancy to SSRIs may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN)... 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 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. A study of 831,324 infants born in Sweden in 1997-2005 found a PPHN risk ratio of 2.4 (95% CI 1.2-4.3) associated with patient-reported maternal use of SSRIs “in early pregnancy” and a PPHN risk ratio of 3.6 (95% CI 1.2-8.3) 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=0.88-1.17) or cardiac malformations (summary odds ratio=0.93, 95% CI=0.70-1.23) 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/m2 basis in adolescents…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/m2 basis) in rats and 40 mg/kg (3.1 times the MRHD on a mg/m2 basis) in rabbits…These effects occurred at a dose of 20 mg/kg (0.8 times the MRHD on a mg/m2 basis). The no effect dose for rat pup mortality was 10 mg/kg (0.4 times the MRHD on a mg/m2 basis)…

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

Risk Summary

Available data from published literature demonstrate low levels of sertraline and its metabolites in human milk. 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 ZOLOFT 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

(Additions and/or revisions are underlined)

The safety and efficacy of ZOLOFT have been established in the treatment of OCD in pediatric patients aged 6 to 17. Safety and effectiveness in pediatric patients in patients with OCD below the age of 6 have not been established…

Monitoring Pediatric Patients Treated with ZOLOFT

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.

Weight Loss in Studies in Pediatric Patients with MDD

…A subset of patients who completed the randomized controlled trials in patients with MDD (ZOLOFT n=99, placebo n=122) were continued into a 24-week, flexible-dose, open-label, extension study…

Alcohol Content in ZOLOFT Oral Solution

ZOLOFT oral solution contains 12% alcohol.

8.5 Geriatric Use

(Additions and/or revisions are underlined)

Of the total number of patients in clinical studies of ZOLOFT in patients with MDD, OCD, PD, PTSD, SAD and PMDD, 797 (17%) were greater than or equal to 65 years old, while 197 (4%) were greater than or equal to 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 ZOLOFT in MDD placebo-controlled trials, the overall profile of adverse reactions was generally similar to that shown in Table 3, except for tinnitus, arthralgia with an incidence of at least 2% and at a rate greater than placebo in geriatric patients.

8.6 Hepatic Impairment

(Revised subsection title; Additions and/or revisions are underlined)

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 ZOLOFT in patients with moderate (Child-Pugh score 7 to 10) or severe hepatic impairment (Child-Pugh score 10-15) is not recommended, because ZOLOFT is extensively metabolized, and the effects of ZOLOFT in patients with moderate and severe hepatic impairment have not been studied.

8.7 Renal Impairment

(Revised subsection title; Additions and/or revisions are underlined)

No dose adjustment is needed in patients with mild to severe renal impairment.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Revised subsection title; Additions and/or revisions are underlined)

Suicidal Thoughts and Behaviors

Advise patients and caregivers to look for the emergence of suicidality…

Important Administration Instructions for Oral Solution

For patients prescribed ZOLOFT oral solution, inform them that: …

Disulfiram Contraindication for ZOLOFT Oral Solution

Inform patients not to take disulfiram when taking ZOLOFT oral solution. Concomitant use is contraindicated due the alcohol content of the oral solution

Serotonin Syndrome

Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of ZOLOFT with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, 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.

Increased Risk of Bleeding

Inform patients about the concomitant use of ZOLOFT 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.

Activation of Mania/Hypomania

Advise patients and their caregivers to observe for signs of activation of mania/hypomania…

Discontinuation Syndrome

Advise patients not to abruptly discontinue ZOLOFT and to discuss any tapering regimen with their healthcare provider. Adverse reactions can occur when ZOLOFT is discontinued.

Allergic Reactions

Advise patients to notify their healthcare provider if they develop an allergic reaction such as rash, hives, swelling, or difficulty breathing.

Pregnancy

Inform pregnant women that ZOLOFT may cause withdrawal symptoms in the newborn or persistent pulmonary hypertension of the newborn (PPHN).

Medication Guide

(Additions and/or revisions are underlined)

What is the most important information I should know about ZOLOFT?

ZOLOFT and other antidepressant medicines may cause serious side effects. Call your healthcare provider right away if you have any of the following symptoms, or call 911 if there is an emergency.

1. Suicidal thoughts or actions:

• ZOLOFT and other antidepressant medicines may increase suicidal thoughts or actions in some people 24 years of age and younger, especially within the first few months of treatment or when the dose is changed.

2. Serotonin Syndrome. This condition can be life-threatening and symptoms may include:

3. Increased chance of bleeding:

6. Glaucoma (angle-closure glaucoma). Many antidepressant medicines including ZOLOFT may cause a certain type of eye problem called angle-closure glaucoma. Call your healthcare provider if you have eye pain, changes in your vision or swelling or redness in or around the eye…

 

What is ZOLOFT?

ZOLOFT is safe and effective in treating children with OCD age 6 to 17 years.

It is not known if ZOLOFT is safe and effective for use in children under 6 years of age with OCD or children with other behavior health conditions.

 

Who should not take ZOLOFT? Do not take ZOLOFT if you:

• take any other medicines that contain sertraline (such as sertraline HCl or sertraline hydrochloride).

 

What should I tell my healthcare provider before taking ZOLOFT? Before starting ZOLOFT, tell your healthcare provider:

• are pregnant or plan to become pregnant. Your baby may have withdrawal symptoms after birth or may be at increased risk for a serious lung problem at birth.
• are breast-feedingbreastfeeding or plan to breast-feed. A small amount of ZOLOFT may pass into your breast milk.

Tell your healthcare provider about all the medicines that you take, including prescription and over-the- counter medicines, vitamins, and herbal supplements.

 

How should I take ZOLOFT?

• ZOLOFT Oral Solution may look cloudy or hazy after mixing, this is normal.
• ZOLOFT Oral Solution must be diluted before use:
• Do not mix ZOLOFT until you are ready to take it.
• The oral dropper contains latex. If you are sensitive or allergic to latex, ask your healthcare provider or pharmacist about the best way to measure your medicine.

If you take too much ZOLOFT, call your healthcare provider or poison control center right away, or go to the nearest hospital emergency room right away.

 

What are the possible side effects of ZOLOFT?

The most common side effects in adults who take ZOLOFT include:

• Anxiety

How should I store ZOLOFT?

• Store ZOLOFT at room temperature, 68 °F to 77°F (20°C to 25°C).

 

General information about the safe and effective use of ZOLOFT

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide…

 

Inactive ingredients:

Oral solution: glycerin, alcohol (12%)…

Other

(Physician Labeling Rule (PLR) conversion; please refer to label)

12/23/2016 (SUPPL-86)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions are underlined)

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 greater than or equal to 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 – 17 years of age) receiving the maximum recommended dose of sertraline (200 mg/day).

12/23/2016 (SUPPL-87)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Serotonin Syndrome

(Additions and/or revisions are underlined)

…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.