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Serotonin Syndrome: The development of potentially life-threatening syndromes like serotonin syndrome (SS) or Neuroleptic Malignant Syndrome (NMS) has been reported with selective serotonin reuptake inhibitors (SSRIs), including treatment with sertraline. The risk of SS or NMS with SSRIs is increased with concomitant use of serotonergic drugs (including amphetamines, triptans and fentanyl and its analogues, tramadol, dextromethorphan, tapentadol, meperidine, methadone, pentazocine), with drugs that impair metabolism of serotonin (including MAOIs), antipsychotics and other dopamine antagonists. SS symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Some signs of SS, including hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes resemble NMS. Patients should be monitored for the emergence of signs and symptoms of SS or NMS syndrome (see Contraindications).
Monoamine Oxidase Inhibitors: Cases of serious reactions, sometimes fatal, have been reported in patients receiving sertraline in combination with a MAOI, including the selective MAOI selegiline, the reversible MAOI moclobemide and MAOI drugs, e.g., linezolid [an antibiotic that is a reversible non-selective MAOI] and methylene blue. Some cases presented with features resembling SS, the symptoms of which include: hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes that include confusion, irritability and extreme agitation progressing to delirium and coma. Therefore, sertraline should not be used in combination with an MAOI or within 14 days of discontinuing treatment with an MAOI. Similarly, at least 14 days should elapse after discontinuing sertraline treatment before starting an MAOI (see Contraindications).
Other Serotonergic Drugs: Co-administration of sertraline with other drugs that enhance the effects of serotonergic neurotransmission, such as amphetamines, tryptophan, fenfluramine, and fentanyl, 5-HT agonists, or the herbal medicine St. John's Wort (Hypericum perforatum) should be undertaken with caution and avoided whenever possible due to the potential for pharmacodynamic interaction.
QTc Prolongation/Torsade de Pointes (TdP): Cases of QTc prolongation and TdP have been reported during post-marketing use of sertraline. The majority of reports occurred in patients with other risk factors for QTc prolongation/TdP. Therefore sertraline should be used with caution in patients with risk factors for QTc prolongation (see Interactions and Pharmacology: Pharmacodynamics under Actions).
Switching from Selective Serotonin Reuptake Inhibitors (SSRIs), Antidepressants or Antiobsessional Drugs: There is limited controlled experience regarding the optimal timing of switching from SSRIs, antidepressants or anti-obsessional drugs to sertraline. Care and prudent medical judgment should be exercised when switching, particularly from long-acting agents, such as fluoxetine. The duration of a washout period for switching from one SSRI to another has not been established.
Activation of Mania/Hypomania: During pre-marketing testing, hypomania or mania occurred in approximately 0.4% of sertraline-treated patients. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder treated with other marketed antidepressant and anti-obsessional drugs.
Seizures: Seizures are a potential risk with antidepressant and anti-obsessional drugs. Seizures were reported in approximately 0.08% of patients treated with sertraline in the development program for depression. No seizures were reported in patients treated with sertraline in the development program for panic. During the development program for OCD, four out of approximately 1,800 patients exposed to sertraline experienced seizures (approximately 0.2%). Three of these patients were adolescents, two with a seizure disorder and one with a family history of seizure disorder, none of whom were receiving anticonvulsant medication. In all these cases, the relationship with sertraline therapy was uncertain. Since sertraline has not been evaluated in patients with a seizure disorder, it should be avoided in patients with unstable epilepsy; patients with controlled epilepsy should be carefully monitored. Sertraline should be discontinued in any patient who develops seizures.
Suicide/Suicidal Thoughts or Clinical Worsening: All patients treated with sertraline, in particular those at high risk, should be monitored appropriately and observed closely for clinical worsening and suicidality. Patients, their families, and their caregivers should be encouraged to be alert to the need to monitor for any clinical worsening, suicidal behavior or thoughts and unusual changes in behavior especially when initiating therapy or during any change in dose or dosage regimen. The risk of suicide attempt must be considered, especially in depressed patients, and the smallest quantity of drug, consistent with good patient management, should be provided to reduce the risk of overdose.
Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are strong predictors of suicide. Pooled analyses of short-term placebo-controlled trials of antidepressant medicines (SSRIs and others) showed that these medicines increase the risk of suicidality in children, adolescents, and young adults (aged 18 to 24 years) with major depression and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond the age of 24 years; there was a reduction in the risk of suicidality with antidepressants compared to placebo in adults aged 65 years and older.
Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of Sertraline or any other antidepressant in a child or adolescent for any clinical use must balance the risk of increased suicidality with the clinical need. Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised to closely observe the patient and to communicate with the prescriber. Sertraline is not approved for use in pediatric patients (see Use in Children under Dosage & Administration).
Sexual Dysfunction: Selective serotonin reuptake inhibitors (SSRIs) may cause symptoms of sexual dysfunction (see Adverse Reactions). There have been reports of long lasting sexual dysfunction where the symptoms have continued despite discontinuation of SSRIs.
Abnormal Bleeding/Hemorrhage: There have been reports of bleeding abnormalities with SSRIs from ecchymoses and purpura to life-threatening hemorrhage. Caution is advised in patients taking SSRIs, particularly in concomitant use with drugs known to affect platelet function (e.g., atypical antipsychotics and phenothiazines, most tricyclic antidepressants, aspirin and non-steroidal anti-inflammatory drugs (NSAIDs)) as well as in patients with a history of bleeding disorders (see Interactions).
Hyponatremia: Hyponatremia may occur as a result of treatment with SSRIs or serotonin norephinephrine reuptake inhibitors (SNRIs) including sertraline. In many cases, hyponatremia appears to be the result of a syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases of serum sodium levels lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also patients taking diuretics or who are otherwise volume-depleted may be at greater risk (see Use in the Elderly under Dosage & Administration). Discontinuation of sertraline should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness and unsteadiness that may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest and death.
Because of the well-established comorbidity between OCD and depression, panic disorder and depression, PTSD and depression, and social phobia and depression, the same precautions observed when treating patients with depression should be observed when treating patients with OCD, panic disorder, PTSD or social phobia.
Bone Fractures: Epidemiological studies show an increased risk of bone fractures in patients receiving serotonin reuptake inhibitors (SRIs) including sertraline. The mechanism leading to this risk is not fully understood.
Diabetes/Loss of Glycemic Control: Cases of new onset diabetes mellitus have been reported in patients receiving SSRIs including sertraline. Loss of glycemic control including both hyperglycemia and hypoglycemia has also been reported in patients with and without pre-existing diabetes. Patients should therefore be monitored for signs and symptoms of glucose fluctuations. Diabetic patients especially should have their glycemic control carefully monitored since their dosage of insulin and/or concomitant oral hypoglycemic drug may need to be adjusted.
Laboratory Tests: False-positive urine immunoassay screening tests for benzodiazepines have been reported in patients taking sertraline. This is due to lack of specificity of the screening tests. False positive test results may be expected for several days following discontinuation of sertraline therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish sertraline from benzodiazepines.
Angle-Closure Glaucoma: SSRIs including sertraline may have an effect on pupil size resulting in mydriasis. This mydriatic effect has the potential to narrow the eye angle resulting in increased intraocular pressure and angle-closure glaucoma, especially in patients pre-disposed. Sertraline should therefore be used with caution in patients with angle-closure glaucoma or history of glaucoma.
Effects on Ability to Drive and Use Machines: Clinical pharmacology studies have shown that sertraline has no effect on psychomotor performance. However, as psychotropic drugs may impair the mental or physical abilities required for the performance of potentially hazardous tasks, such as driving a car or operating machinery, the patient should be cautioned accordingly.
Use in Hepatic Insufficiency: Sertraline is extensively metabolized by the liver. A multiple-dose pharmacokinetic study in subjects with mild, stable cirrhosis demonstrated a prolonged elimination half-life and approximately three-fold greater AUC and Cmax in comparison to normal subjects. There were no significant differences in plasma protein binding observed between the two groups. The use of sertraline in patients with hepatic disease should be approached with caution. A lower or less frequent dose should be used in patients with hepatic impairment.
Use in Renal Insufficiency: Sertraline is extensively metabolized. Excretion of unchanged drug in urine is a minor route of elimination. In studies of patients with mild to moderate renal impairment (creatinine clearance 30-60 mL/min) or moderate to severe renal impairment (creatinine clearance 10-29 mL/min), multiple-dose pharmacokinetic parameters (AUC0-24 or Cmax) were not significantly different compared to controls. Half-lives were similar and there were no differences in plasma protein binding in all groups studied. This study indicates that, as expected from the low renal excretion of sertraline, sertraline dosing does not have to be adjusted based on the degree of renal impairment.
Use in Children and Adolescents: Only limited clinical evidence is available concerning long-term safety data in children and adolescents, including effects on growth, sexual maturation and cognitive and behavioral developments (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). Physicians must monitor pediatric patients on long-term treatment for abnormalities in growth and development.
