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.
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.
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)] .
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.
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.
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)] .
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)] .
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)] .
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)]
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.
|ZOLOFT (N=3066)||Placebo (N=2293)|
|General disorders and administration site conditions|
|Metabolism and nutrition disorders|
|Nervous system disorders|
|Reproductive system and breast disorders|
|Ejaculation failure †||8%||1%|
|Erectile dysfunction †||4%||1%|
|Ejaculation disorder †||3%||0%|
|Male sexual dysfunction †||2%||0%|
|Skin and subcutaneous tissue disorders|
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.
|Male sexual dysfunction||2%||0%|
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
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