Zoloft (sertraline hydrochloride 50 mg) Dailymed

• Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents (e.g., SSRI, SNRI, triptans), but also when taken alone. If it occurs, discontinue ZOLOFT and initiate supportive treatment. ( 5.2)
• Increased Risk of Bleeding: Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), other antiplatelet drugs, warfarin, and other anticoagulants may increase this risk. ( 5.3)
• Activation of Mania/Hypomania: Screen patients for bipolar disorder. ( 5.4)
• Seizures: Use with caution in patients with seizure disorders. ( 5.6)
• Angle Closure Glaucoma: Avoid use of antidepressants, including ZOLOFT, in patients with untreated anatomically narrow angles. ( 5.7)
• QTc Prolongation: ZOLOFT should be used with caution in patients with risk factors for QTc prolongation. ( 5.10)
• Sexual Dysfunction: ZOLOFT may cause symptoms of sexual dysfunction. ( 5.11)

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
18–24	5 additional patients
	Decreases Compared to Placebo
25–64	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 ZOLOFT, 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 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, 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 ZOLOFT with MAOIs is contraindicated. In addition, do not initiate ZOLOFT 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 ZOLOFT, discontinue ZOLOFT before initiating treatment with the MAOI [See Contraindications (4), Drug Interactions (7.1)] .

Monitor all patients taking ZOLOFT for the emergence of serotonin syndrome. Discontinue treatment with ZOLOFT and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of ZOLOFT 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 ZOLOFT, 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 ZOLOFT 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 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

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

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

The pupillary dilation that occurs following use of many antidepressant drugs including ZOLOFT 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 ZOLOFT, in patients with untreated anatomically narrow angles.

5.8 Hyponatremia

Hyponatremia may occur as a result of treatment with SNRIs and SSRIs, including ZOLOFT. 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 ZOLOFT 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 ZOLOFT. 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 ZOLOFT. Confirmatory tests, such as gas chromatography/mass spectrometry, will help distinguish ZOLOFT 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, ZOLOFT should be used with caution in patients with risk factors for QTc prolongation [See Drug Interactions (7.1), Clinical Pharmacology (12.2)] .

5.11Sexual Dysfunction

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

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 Pfizer, Inc. at 1-800-438-1985 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 dysfunction	2%	0%
Skin and subcutaneous tissue disorders
  Hyperhidrosis	7%	3%

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 (>2% and twice placebo): decreased appetite, dizziness, fatigue, headache, somnolence, tremor, and vomiting.
• OCD: somnolence.
• PD: nervousness and somnolence.

Male and Female Sexual Dysfunction

Although changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of SSRI treatment. However, reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance and satisfaction are difficult to obtain, in part because patients and healthcare providers may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in labeling may underestimate their actual incidence.

Table 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 (>2% and twice placebo) included: ejaculation failure, decreased libido, erectile dysfunction, ejaculation disorder, and male sexual dysfunction. For women, the most common adverse reaction (≥2% and twice placebo) was decreased libido.

Table 4: Most Common Sexual Adverse Reactions (≥2% and twice placebo) in Men or Women from ZOLOFT Pooled Controlled Trials in Adults with MDD, OCD, PD, PTSD, SAD, and PMDD

	ZOLOFT	Placebo
Men only	(N=1316)	(N=973)
  Ejaculation failure	8%	1%
  Libido decreased	7%	2%
  Erectile dysfunction	4%	1%
  Ejaculation disorder	3%	0%
  Male sexual dysfunction	2%	0%
Women only	(N=1750)	(N=1320)
  Libido decreased	4%	2%

Adverse Reactions in Pediatric Patients

In 281 pediatric patients treated with 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 < 2% in patients treated with ZOLOFT were:

• Cardiac disorders – tachycardia
• Ear and labyrinth disorders – tinnitus
• Endocrine disorders - hypothyroidism
• Eye disorders - mydriasis, blurred vision
• Gastrointestinal disorders - hematochezia, melena, rectal hemorrhage
• General disorders and administration site conditions - edema, gait disturbance, irritability, pyrexia
• Hepatobiliary disorders - elevated liver enzymes
• Immune system disorders - anaphylaxis
• Metabolism and nutrition disorders - diabetes mellitus, hypercholesterolemia, hypoglycemia, increased appetite
• Musculoskeletal and connective tissue disorders - arthralgia, muscle spasms, tightness, or twitching
• Nervous system disorders - ataxia, coma, convulsion, decreased alertness, hypoesthesia, lethargy, psychomotor hyperactivity, syncope
• Psychiatric disorders - aggression, bruxism, confusional state, euphoric mood, hallucination
• Renal and urinary disorders - hematuria
• Reproductive system and breast disorders - galactorrhea, priapism, vaginal hemorrhage
• Respiratory, thoracic and mediastinal disorders - bronchospasm, epistaxis, yawning
• Skin and subcutaneous tissue disorders - alopecia; cold sweat; dermatitis; dermatitis bullous; pruritus; purpura; erythematous, follicular, or maculopapular rash; urticaria
• Vascular disorders - hemorrhage, hypertension, vasodilation

6.2 Post-marketing Experience

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)
• Cardiac disorders - AV block, bradycardia, atrial arrhythmias, QTc-interval prolongation, ventricular tachycardia (including Torsade de Pointes) [See Clinical Pharmacology (12.2)]
• Endocrine disorders - gynecomastia, hyperprolactinemia, menstrual irregularities, SIADH
• Eye disorders - blindness, optic neuritis, cataract
• Hepatobiliary disorders - severe liver events (including hepatitis, jaundice, liver failure with some fatal outcomes), pancreatitis
• Hemic and lymphatic disorders - agranulocytosis, aplastic anemia and pancytopenia, leukopenia, thrombocytopenia, lupus-like syndrome, serum sickness
• Immune system disorders - angioedema
• Metabolism and nutrition disorders - hyponatremia, hyperglycemia
• Musculoskeletal and connective tissue disorders - rhabdomyolysis, trismus
• Nervous system disorders - serotonin syndrome, extrapyramidal symptoms (including akathisia and dystonia), oculogyric crisis
• Psychiatric disorders - psychosis, enuresis, paroniria
• Renal and urinary disorders - acute renal failure
• Respiratory, thoracic and mediastinal disorders - pulmonary hypertension
• Skin and subcutaneous tissue disorders - photosensitivity skin reaction and other severe cutaneous reactions, which potentially can be fatal, such as Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN)
• Vascular disorders - cerebrovascular spasm (including reversible cerebral vasoconstriction syndrome and Call-Fleming syndrome), vasculitis