WARNINGS
POTENTIAL FOR INTERACTION WITH MONOAMINE OXIDASE INHIBITORS
In patients receiving serotonin reuptake inhibitor drugs in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued SSRI treatment and have been started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Furthermore, limited animal data on the effects of combined use of SSRIs and MAOIs suggest that these drugs may act synergistically to elevate blood pressure and evoke behavioral excitation. Therefore, it is recommended that LEXAPRO 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 be allowed after stopping LEXAPRO before starting an
MAOI. Serotonin syndrome has been reported in two patients who were concomitantly receiving linezolid, an antibiotic which is a reversible non-selective MAOI.
CLINICAL WORSENING AND SUICIDE RISK
Patients with major depressive disorder, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality), whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs.
Although there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients, a causal role for antidepressants in inducing such behaviors has not been established. Nevertheless, patients being treated with antidepressants should be observed closely for clinical worsening and suicidality, especially at the beginning of a course of drug therapy, or at the time of dose changes, either increases or decreases. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or whose emergent suicidality is severe, abrupt in onset, or was not part of the patient's presenting symptoms.
Because of the possibility of co-morbidity between major depressive disorder and other psychiatric and nonpsychiatric disorders, the same precautions observed when treating patients with major depressive disorder should be observed when treating patients with other psychiatric and nonpsychiatric disorders.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients for whom such symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Prescriptions for LEXAPRO should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION, Discontinuation of Treatment with LEXAPRO, for a description of the risks of discontinuation of LEXAPRO).
It should be noted that LEXAPRO is not approved for use in treating any indications in the pediatric population.
A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that LEXAPRO is not approved for use in treating bipolar depression.
PRECAUTIONS
GENERAL
Discontinuation of Treatment with LEXAPRO
During marketing of Lexapro and other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events 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.
Patients should be monitored for these symptoms when discontinuing treatment with LEXAPRO. 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).
Abnormal Bleeding
Published case reports have documented the occurrence of bleeding episodes in patients treated with psychotropic drugs that interfere with serotonin reuptake. Subsequent epidemiological studies, both of the case-control and cohort design, have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. In two studies, concurrent use of a nonsteroidal anti-inflammatory drug (NSAID) or aspirin potentiated the risk of bleeding (see Drug Interactions). Although these studies focused on upper gastrointestinal bleeding, there is reason to believe that bleeding at other sites may be similarly potentiated. Patients should be cautioned regarding the risk of bleeding associated with the concomitant use of LEXAPRO with NSAIDs, aspirin, or other drugs that affect coagulation.
Hyponatremia
One case of hyponatremia has been reported in association with LEXAPRO treatment. Several cases of hyponatremia or SIADH (syndrome of inappropriate antidiuretic hormone secretion) have been reported in association with racemic citalopram. All patients with these events have recovered with discontinuation of escitalopram or citalopram and/or medical intervention. Hyponatremia and SIADH have also been reported in association with other marketed drugs effective in the treatment of major depressive disorder.
Activation of Mania/Hypomania
In placebo-controlled trials of LEXAPRO in major depressive disorder, activation of mania/hypomania was reported in one (0.1%) of 715 patients treated with LEXAPRO and in none of the 592 patients treated with placebo. One additional case of hypomania has been reported in association with LEXAPRO 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. As with all drugs effective in the treatment of major depressive disorder, LEXAPRO should be used cautiously in patients with a history of mania.
Seizures
Although anticonvulsant effects of racemic citalopram have been observed in animal studies, LEXAPRO 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 LEXAPRO, cases of convulsion have been reported in association with LEXAPRO treatment. Like other drugs effective in the treatment of major depressive disorder, LEXAPRO should be introduced with care in patients with a history of seizure disorder.
Interference with Cognitive and Motor Performance
In a study in normal volunteers, LEXAPRO 10 mg/day 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 LEXAPRO therapy does not affect their ability to engage in such activities.
Use in Patients with Concomitant Illness
Clinical experience with LEXAPRO in patients with certain concomitant systemic illnesses is limited. Caution is advisable in using LEXAPRO in patients with diseases or conditions that produce altered metabolism or hemodynamic responses.
LEXAPRO 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 LEXAPRO in hepatically impaired patients is 10 mg/day (see DOSAGE AND ADMINISTRATION).
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 LEXAPRO, however, it should be used with caution in such patients (see DOSAGE AND ADMINISTRATION).
INFORMATION FOR PATIENTS
Physicians are advised to discuss the following issues with patients for whom they prescribe LEXAPRO.
In a study in normal volunteers, LEXAPRO 10 mg/day did not impair psychomotor performance. The effect of LEXAPRO on psychomotor coordination, judgment, or thinking has not been systematically examined in controlled studies. Because psychoactive drugs may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that LEXAPRO therapy does not affect their ability to engage in such activities.
Patients should be told that, although LEXAPRO has not been shown in experiments with normal subjects to increase the mental and motor skill impairments caused by alcohol, the concomitant use of LEXAPRO and alcohol in depressed patients is not advised.
Patients should be made aware that escitalopram is the active isomer of Celexa (citalopram hydrobromide) and that the two medications should not be taken concomitantly.
Patients should be advised to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, as there is a potential for interactions.
Patients should be cautioned about the concomitant use of LEXAPRO and NSAIDs, aspirin, or other drugs that affect coagulation since the combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding.
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.
Patients should be advised to notify their physician if they are breastfeeding an infant.
While patients may notice improvement with LEXAPRO therapy in 1 to 4 weeks, they should be advised to continue therapy as directed.
Patients and their families should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, mania, worsening of depression, and suicidal ideation, especially early during antidepressant treatment. Such symptoms should be reported to the patient's physician, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
LABORATORY TESTS
There are no specific laboratory tests recommended.
CONCOMITANT ADMINISTRATION WITH RACEMIC CITALOPRAM
Citalopram--Since escitalopram is the active isomer of racemic citalopram (Celexa), the two agents should not be coadministered.
DRUG INTERACTIONS
CNS Drugs--Given the primary CNS effects of escitalopram, caution should be used when it is taken in combination with other centrally acting drugs.
Alcohol--Although LEXAPRO did not potentiate the cognitive and motor effects of alcohol in a clinical trial, as with other psychotropic medications, the use of alcohol by patients taking LEXAPRO is not recommended.
Monoamine Oxidase Inhibitors (MAOIs)--See CONTRAINDICATIONS and WARNINGS.
DRUGS THAT INTERFERE WITH HEMOSTASIS (NSAIDS, ASPIRIN, WARFARIN, ETC.)
Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin potentiated the risk of bleeding. Thus, patients should be cautioned about the use of such drugs concurrently with LEXAPRO.
Cimetidine--In subjects who had received 21 days of 40 mg/day racemic citalopram, combined administration of 400 mg/day cimetidine for 8 days resulted in an increase in citalopram AUC and Cmax of 43% and 39%, respectively. The clinical significance of these findings is unknown.
Digoxin--In subjects who had received 21 days of 40 mg/day racemic citalopram, combined administration of citalopram and digoxin (single dose of 1 mg) did not significantly affect the pharmacokinetics of either citalopram or digoxin.
Lithium--Coadministration of racemic citalopram (40 mg/day for 10 days) and lithium (30 mmol/day for 5 days) had no significant effect on the pharmacokinetics of citalopram or lithium. Nevertheless, plasma lithium levels should be monitored with appropriate adjustment to the lithium dose in accordance with standard clinical practice. Because lithium may enhance the serotonergic effects of escitalopram, caution should be exercised when LEXAPRO and lithium are coadministered.
Sumatriptan--There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of an SSRI and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, escitalopram) is clinically warranted, appropriate observation of the patient is advised.
Theophylline--Combined administration of racemic citalopram (40 mg/day for 21 days) and the CYP1A2 substrate theophylline (single dose of 300 mg) did not affect the pharmacokinetics of theophylline. The effect of theophylline on the pharmacokinetics of citalopram was not evaluated.
Warfarin--Administration of 40 mg/day racemic citalopram for 21 days did not affect the pharmacokinetics of warfarin, a CYP3A4 substrate. Prothrombin time was increased by 5%, the clinical significance of which is unknown.
Carbamazepine--Combined administration of racemic citalopram (40 mg/day for 14 days) and carbamazepine (titrated to 400 mg/day for 35 days) did not significantly affect the pharmacokinetics of carbamazepine, a CYP3A4 substrate. Although trough citalopram plasma levels were unaffected, given the enzyme-inducing properties of carbamazepine, the possibility that carbamazepine might increase the clearance of escitalopram should be considered if the two drugs are coadministered.
Triazolam--Combined administration of racemic citalopram (titrated to 40 mg/day for 28 days) and the CYP3A4 substrate triazolam (single dose of 0.25 mg) did not significantly affect the pharmacokinetics of either citalopram or triazolam.
Ketoconazole--Combined administration of racemic citalopram (40 mg) and ketoconazole (200 mg), a potent CYP3A4 inhibitor, decreased the Cmax and AUC of ketoconazole by 21% and 10%, respectively, and did not significantly affect the pharmacokinetics of citalopram.
Ritonavir--Combined administration of a single dose of ritonavir (600 mg), both a CYP3A4 substrate and a potent inhibitor of CYP3A4, and escitalopram (20 mg) did not affect the pharmacokinetics of either ritonavir or escitalopram.
CYP3A4 and -2C19 Inhibitors-- In vitro studies indicated that CYP3A4 and -2C19 are the primary enzymes involved in the metabolism of escitalopram. However, coadministration of escitalopram (20 mg) and ritonavir (600 mg), a potent inhibitor of CYP3A4, did not significantly affect the pharmacokinetics of escitalopram. Because escitalopram is metabolized by multiple enzyme systems, inhibition of a single enzyme may not appreciably decrease escitalopram clearance.
Drugs Metabolized by Cytochrome P4502D6-- In vitro studies did not reveal an inhibitory effect of escitalopram on CYP2D6. In addition, steady state levels of racemic citalopram were not significantly different in poor metabolizers and extensive CYP2D6 metabolizers after multiple-dose administration of citalopram, suggesting that coadministration, with escitalopram, of a drug that inhibits CYP2D6, is unlikely to have clinically significant effects on escitalopram metabolism. However, there are limited in vivo data suggesting a modest CYP2D6 inhibitory effect for escitalopram, i.e., coadministration of escitalopram (20 mg/day for 21 days) with the tricyclic antidepressant desipramine (single dose of 50 mg), a substrate for CYP2D6, resulted in a 40% increase in Cmax and a 100% increase in AUC of desipramine. The clinical significance of this finding is unknown. Nevertheless, caution is indicated in the coadministration of escitalopram and drugs metabolized by CYP2D6.
Metoprolol--Administration of 20 mg/day LEXAPRO for 21 days in healthy volunteers resulted in a 50% increase in Cmax and 82% increase in AUC of the beta-adrenergic blocker metoprolol (given in a single dose of 100 mg). Increased metoprolol plasma levels have been associated with decreased cardioselectivity. Coadministration of LEXAPRO and metoprolol had no clinically significant effects on blood pressure or heart rate.
Electroconvulsive Therapy (ECT)--There are no clinical studies of the combined use of ECT and escitalopram.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
Carcinogenesis
Racemic citalopram was administered in the diet to NMRI/BOM strain mice and COBS WI strain rats for 18 and 24 months, respectively. There was no evidence for carcinogenicity of racemic citalopram in mice receiving up to 240 mg/kg/day. There was an increased incidence of small intestine carcinoma in rats receiving 8 or 24 mg/kg/day racemic citalopram. A no-effect dose for this finding was not established. The relevance of these findings to humans is unknown.
Mutagenesis
Racemic citalopram was mutagenic in the in vitro bacterial reverse mutation assay (Ames test) in 2 of 5 bacterial strains (Salmonella TA98 and TA1537) in the absence of metabolic activation. It was clastogenic in the in vitro Chinese hamster lung cell assay for chromosomal aberrations in the presence and absence of metabolic activation. Racemic citalopram was not mutagenic in the in vitro mammalian forward gene mutation assay (HPRT) in mouse lymphoma cells or in a coupled in vitro/in vivo unscheduled DNA synthesis (UDS) assay in rat liver. It was not clastogenic in the in vitro chromosomal aberration assay in human lymphocytes or in two in vivo mouse micronucleus assays.
Impairment of Fertility
When racemic citalopram was administered orally to 16 male and 24 female rats prior to and throughout mating and gestation at doses of 32, 48, and 72 mg/kg/day, mating was decreased at all doses, and fertility was decreased at doses >/= 32 mg/kg/day. Gestation duration was increased at 48 mg/kg/day.
PREGNANCY
Pregnancy Category C
In a rat embryo/fetal development study, oral administration of escitalopram (56, 112, or 150 mg/kg/day) to pregnant animals during the period of organogenesis resulted in decreased fetal body weight and associated delays in ossification at the two higher doses (approximately >/= 56 times the maximum recommended human dose [MRHD] of 20 mg/day on a body surface area [mg/m2] basis). Maternal toxicity (clinical signs and decreased body weight gain and food consumption), mild at 56 mg/kg/day, was present at all dose levels. The developmental no-effect dose of 56 mg/kg/day is approximately 28 times the MRHD on a mg/m2 basis. No teratogenicity was observed at any of the doses tested (as high as 75 times the MRHD on a mg/m2 basis).
When female rats were treated with escitalopram (6, 12, 24, or 48 mg/kg/day) during pregnancy and through weaning, slightly increased offspring mortality and growth retardation were noted at 48 mg/kg/day which is approximately 24 times the MRHD on a mg/m2 basis. Slight maternal toxicity (clinical signs and decreased body weight gain and food consumption) was seen at this dose. Slightly increased offspring mortality was seen at 24 mg/kg/day. The no-effect dose was 12 mg/kg/day which is approximately 6 times the MRHD on a mg/m2 basis.
In animal reproduction studies, racemic citalopram has been shown to have adverse effects on embryo/fetal and postnatal development, including teratogenic effects, when administered at doses greater than human therapeutic doses.
In two rat embryo/fetal development studies, oral administration of racemic citalopram (32, 56, or 112 mg/kg/day) to pregnant animals during the period of organogenesis resulted in decreased embryo/fetal growth and survival and an increased incidence of fetal abnormalities (including cardiovascular and skeletal defects) at the high dose. This dose was also associated with maternal toxicity (clinical signs, decreased body weight gain). The developmental no-effect dose was 56 mg/kg/day. In a rabbit study, no adverse effects on embryo/fetal development were observed at doses of racemic citalopram of up to 16 mg/kg/day. Thus, teratogenic effects of racemic citalopram were observed at a maternally toxic dose in the rat and were not observed in the rabbit.
When female rats were treated with racemic citalopram (4.8, 12.8, or 32 mg/kg/day) from late gestation through weaning, increased offspring mortality during the first 4 days after birth and persistent offspring growth retardation were observed at the highest dose. The no-effect dose was 12.8 mg/kg/day. Similar effects on offspring mortality and growth were seen when dams were treated throughout gestation and early lactation at doses >/= 24 mg/kg/day. A no-effect dose was not determined in that study.
There are no adequate and well-controlled studies in pregnant women; therefore, escitalopram should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
PREGNANCY-NONTERATOGENIC EFFECTS
Neonates exposed to LEXAPRO and other SSRIs or SNRIs, late in the third trimester, have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS).
When treating a pregnant woman with LEXAPRO during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION).
LABOR AND DELIVERY
The effect of LEXAPRO on labor and delivery in humans is unknown.
NURSING MOTHERS
Racemic citalopram, like many other drugs, is excreted in human breast milk. There have been two reports of infants experiencing excessive somnolence, decreased feeding, and weight loss in association with breastfeeding from a citalopram-treated mother; in one case, the infant was reported to recover completely upon discontinuation of citalopram by its mother and, in the second case, no follow-up information was available. The decision whether to continue or discontinue either nursing or LEXAPRO therapy should take into account the risks of citalopram exposure for the infant and the benefits of LEXAPRO treatment for the mother.
PEDIATRIC USE
Safety and effectiveness in pediatric patients have not been established (see WARNINGS -- Clinical Worsening and Suicide Risk).
GERIATRIC USE
Approximately 6% of the 1144 patients receiving escitalopram in controlled trials of LEXAPRO in major depressive disorder and GAD were 60 years of age or older; elderly patients in these trials received daily doses of LEXAPRO between 10 and 20 mg. The number of elderly patients in these trials was insufficient to adequately assess for possible differential efficacy and safety measures on the basis of age. Nevertheless, greater sensitivity of some elderly individuals to effects of LEXAPRO cannot be ruled out.
In two pharmacokinetic studies, escitalopram half-life was increased by approximately 50% in elderly subjects as compared to young subjects and Cmax was unchanged (see CLINICAL PHARMACOLOGY). 10 mg/day is the recommended dose for elderly patients (see DOSAGE AND ADMINISTRATION). Of 4422 patients in clinical studies of racemic citalopram, 1357 were 60 and over, 1034 were 65 and over, and 457 were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but again, greater sensitivity of some elderly individuals cannot be ruled out.
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