WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents but also when taken alone.

If it occurs, discontinue Escitalopram and serotonergic agents and initiate supportive treatment ( 4 , 5.2 ) • Discontinuation syndrome: When discontinuing Escitalopram, reduce dosage gradually whenever possible, and monitor for discontinuation symptoms ( 5.3 ) • Seizures: Use with caution in patients with a history of seizure ( 5.4 ) • Activation of Mania/Hypomania: Screen patients for bipolar disorder.

( 5.5 ) • Hyponatremia: Can occur in association with syndrome of inappropriate antidiuretic hormone secretion ( 5.6 ) • Increased Risk of Bleeding: Concomitant use of nonsteroidal anti-inflammatory drugs, aspirin, other antiplatelet drugs, warfarin and other drugs that affect coagulation may increase risk ( 5.7 ) • Interference with Cognitive and Motor Performance: Use caution when operating machinery ( 5.8 ) • Angle Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants ( 5.9 ) • Use in Patients with Concomitant Illness: Use caution in patients with diseases or conditions that produce altered metabolism or hemodynamic responses ( 5.10 ) • Sexual Dysfunction: Escitalopram may cause symptoms of sexual dysfunction ( 5.11 ) 5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in the antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients.

There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied.

There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD.

The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1,000 patients treated are provided in Table 1.

Table 1: Risk Differences of the Number of Patients of Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range Drug-Placebo Difference in Number of Patients of Suicidal Thoughts and Behaviors per 1,000 Patients Treated Increases Compared to Placebo <18 years old 14 additional patients 18 to 24 years old 5 additional patients Decreases Compared to Placebo 25 to 64 years old 1 fewer patient ≥65 years old 6 fewer patients It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults 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 and that depression itself is a risk factor for suicidal thoughts and behaviors.

Monitor all antidepressant-treated patients for any indication 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 escitalopram, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

5.2 Serotonin Syndrome SSRIs, including escitalopram tablets, 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, meperidine, methadone, lithium, tramadol, tryptophan, buspirone, amphetamines, and St.

John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications ( 4 ) and Drug Interactions ( 7 )] .

Serotonin syndrome 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/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

The concomitant use of escitalopram with MAOIs is contraindicated.

In addition, do not initiate Escitalopram in a patient who is 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 Escitalopram, discontinue Escitalopram before initiating treatment with the MAOI [see Contraindications (4) and Dosage and Administration ( 2.7 )] .

Monitor all patients taking escitalopram tablets for the emergence of serotonin syndrome.

Discontinue treatment with escitalopram tablets and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment.

If concomitant use of escitalopram with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

5.3 Discontinuation Syndrome During marketing of escitalopram tablets and other SSRIs, there have been spontaneous reports of adverse reactions occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania.

While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.

Monitor for these symptoms when discontinuing treatment with escitalopram.

A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible.

If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered.

Subsequently, the physician may continue decreasing the dose but at a more gradual rate [see Dosage and Administration ( 2.6 )] .

5.4 Seizures Although anticonvulsant effects of racemic citalopram have been observed in animal studies, escitalopram has not been systematically evaluated in patients with a seizure disorder.

These patients were excluded from clinical studies during the product’s premarketing testing.

In clinical trials of escitalopram, cases of convulsion have been reported in association with escitalopram treatment.

Like other drugs effective in the treatment of major depressive disorder, escitalopram tablets should be introduced with care in patients with a history of seizure disorder.

5.5 Activation of Mania or Hypomania In patients with bipolar disorder, treating a depressive episode with escitalopram or another antidepressant may precipitate a mixed/manic episode.

In placebo-controlled trials of escitalopram in major depressive disorder, activation of mania/hypomania was reported in one (0.1%) of 715 patients treated with escitalopram and in none of the 592 patients treated with placebo.

One additional case of hypomania has been reported in association with escitalopram treatment.

Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorders treated with racemic citalopram and other marketed drugs effective in the treatment of major depressive disorder.

Prior to initiating treatment with escitalopram, screen patients for any personal or family history of bipolar disorder, mania, or hypomania [see Dosage and Administration ( 2.4 )] .

5.6 Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs , including escitalopram.

In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH), and was reversible when escitalopram was discontinued.

Cases with serum sodium 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 Specific Populations ( 8.5 )] .

Consider discontinuation of escitalopram 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.

5.7 Increased Risk of Bleeding Drugs that interfere with serotonin reuptake inhibition, including escitalopram, increase the risk of bleeding events.

Concomitant use of aspirin, nonsteroidal antiinflammatory drugs (NSAIDs), other antiplatelet drugs, warfarin, and other anticoagulants may add to the 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.

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 ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.

Inform patients about the increased risk of bleeding associated with the concomitant use of escitalopram and antiplatelet agents or anticoagulants.

For patients taking warfarin, carefully monitor the international normalized ratio [see Drug Interactions ( 7 )] .

5.8 Interference with Cognitive and Motor Performance In a study in normal volunteers, escitalopram 10 mg daily did not produce impairment of intellectual function or psychomotor performance.

Because any psychoactive drug may impair judgment, thinking, or motor skills, however, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that escitalopram tablets therapy does not affect their ability to engage in such activities.

5.9 Angle Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including escitalopram may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

5.10 Use in Patients with Concomitant Illness Clinical experience with escitalopram in patients with certain concomitant systemic illnesses is limited.

Caution is advisable in using escitalopram tablets in patients with diseases or conditions that produce altered metabolism or hemodynamic responses.

Escitalopram has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable heart disease.

Patients with these diagnoses were generally excluded from clinical studies during the product’s premarketing testing.

In subjects with hepatic impairment, clearance of racemic citalopram was decreased and plasma concentrations were increased.

The recommended dose of escitalopram tablets in hepatically impaired patients is 10 mg daily [see Dosage and Administration ( 2.5 ) and Use in Specific Populations (8.6)] .

Because escitalopram is extensively metabolized, excretion of unchanged drug in urine is a minor route of elimination.

Until adequate numbers of patients with severe renal impairment have been evaluated during chronic treatment with escitalopram tablets, however, it should be used with caution in such patients [see Dosage and Administration ( 2.5 ) and Use in Specific Populations (8.7)] .

5.11 Sexual Dysfunction Use of SSRIs, including escitalopram, 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 escitalopram 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.