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Serotonin Syndrome (SS) or Neuroleptic Malignant Syndrome (NMS): The development of potentially life-threatening syndromes eg, SS or NMS has been reported with SSRIs, including treatment with sertraline. The risk of SS or NMS with SSRIs is increased with concomitant use of serotonergic drugs (including triptans), with drugs which impair metabolism of serotonin (including MAOIs), antipsychotics and other dopamine antagonists. SS symptoms may include mental status changes (eg, agitation, hallucinations, coma), autonomic instability (eg, tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (eg, hyperreflexia, incoordination) and/or gastrointestinal symptoms (eg, 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).
MAOIs: 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 eg, linezolid. Some cases presented with features resembling the serotonin syndrome, 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 a MAOI or within 14 days of discontinuing treatment with a MAOI. Similarly, at least 14 days should elapse after discontinuing sertraline treatment before starting a MAOI (see Contraindications).
Other Serotonergic Drugs: Co-administration of sertraline with other drugs which enhance the effects of serotonergic neurotransmission eg, tryptophan, fenfluramine, 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.
Switching from SSRIs, Antidepressants or Anti-Obsessional 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 judgement should be exercised when switching, particularly from long-acting agents eg, fluoxetine. The duration of a washout period for switching from one SSRI to another has not been established.
Activation of Mania/Hypomania: During premarketing 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, 4 out of approximately 1800 patients exposed to sertraline experienced seizures (approximately 0.2%). Three of these patients were adolescents, 2 with a seizure disorder and 1 with a family history of seizure disorder, none of whom were receiving anticonvulsant medication. In all these cases, the relationship to 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: Since the possibility of a suicide attempt is inherent in depression and may persist until significant remission occurs, patients should be closely supervised during the early course of therapy.
Abnormal Bleeding/Hemorrhage: There have been reports of cutaneous bleeding abnormalities eg, ecchymoses and purpura with SSRIs. Caution is advised in patients taking SSRIs, particularly in concomitant use with drugs known to affect platelet function (eg, atypical antipsychotics and phenothiazines, most tricyclic antidepressants, aspirin and nonsteroidal 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 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 <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 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 which 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.
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 3-fold greater AUC and Cmax in comparison to normal subjects. There were no significant differences in plasma protein-binding observed between the 2 groups. The use of sertraline in patients with hepatic disease must 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 with 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.
Effects on the Ability to Drive or Operate Machinery: 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 eg, driving a car or operating machinery, the patient should be cautioned accordingly.
Use in pregnancy & lactation: Reproduction studies have been performed in rats and rabbits at doses up to approximately 20 and 10 times the maximum daily human mg/kg dose, respectively. There was no evidence of teratogenicity at any dose level. At the dose level corresponding to approximately 2.5-10 times the maximum daily human mg/kg dose, however, sertraline was associated with delayed ossification in fetuses, probably secondary to effects on the dams.
There was decreased neonatal survival following maternal administration of sertraline at doses approximately 5 times the maximum human mg/kg dose. Similar effects on neonatal survival have been described for other antidepressant drugs. The clinical significance of these effects is unknown.
There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, sertraline should be used during pregnancy only if the perceived benefits outweigh the risks.
Isolated studies in small numbers of nursing mothers and their infants indicated negligible or undetectable levels of sertraline in infant serum, although levels in breast milk were more concentrated than in maternal serum. Use in nursing mothers is not recommended unless, in the judgment of the physician, the benefit outweighs the risk.
If sertraline is used during pregnancy and/or lactation, the physician should be aware of post-marketing reports of symptoms, including those compatible with withdrawal reactions, in some neonates whose mothers had been on SSRI antidepressants, including sertraline.
Women of childbearing potential should employ an adequate method of contraception if taking sertraline.
Exposure during late pregnancy to SSRIs may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). Pulmonary hypertension of the newborn occurs in 1-2 per 1000 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 6-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".
