Exuber 10

Escitalopram oxalate.

Each film-coated tablet contains: Escitalopram (as oxalate) 10mg.
Escitalopram oxalate tablets are orally administered selective serotonin reuptake inhibitor (SSRI). Escitalopram is the pure S-enantiomer (single isomer) of the racemic bicyclic phthalane derivative citalopram. Escitalopram oxalate is designated S-(+)-1-[3-(dimethyl-amino)propyl]-1-(p-fluorophenyl)-5-phthalancarbonitrile oxalate. The molecular formula is C₂₀H₂₁FN₂OC₂H₂O₄ and the molecular weight is 414.40. Escitalopram oxalate occurs as a white to almost white crystalline powder and is freely soluble in methanol.

Pharmacology: Pharmacodynamics: The mechanism of antidepressant action of Escitalopram, the S-enantiomer of racemic citalopram, is presumed to be linked to potentiation of serotonergic activity in the central nervous system (CNS) resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT). In vitro and in vivo studies in animals suggest that Escitalopram is a highly selective serotonin reuptake inhibitor (SSRI) with minimal effects on norepinephrine and dopamine neuronal reuptake. Escitalopram is at least 100-fold more potent than the R-enantiomer with respect to inhibition of 5-HT reuptake and inhibition of 5-HT neuronal firing rate. Tolerance to a model of antidepressant effect in rats was not induced by long-term (up to 5 weeks) treatment with escitalopram. Escitalopram has no or very low affinity for serotonergic (5-HT_1-7) or other receptors including alpha- and beta-adrenergic, dopamine (D_1-5), histamine (H_1-3), muscarinic (M_1-5), and benzodiazepine receptors. Escitalopram also does not bind to, or has low affinity for, various ion channels including Na⁺, K⁺, Cl^-, and Ca⁺⁺ channels. Antagonism of muscarinic, histaminergic, and adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular side effects of other psychotropic drugs.
Pharmacokinetics: The single and multiple-dose pharmacokinetics of Escitalopram are linear and dose proportional in a dose range of 10 to 30 mg/day. Biotransformation of Escitalopram is mainly hepatic, with a mean terminal half-life of about 27 to 32 hours. With once-daily dosing, steady state plasma concentrations are achieved within approximately one week. At steady state, the extent of accumulation of Escitalopram in plasma in young healthy subjects was 2.2 to 2.5 times the plasma concentrations observed after a single dose.
Absorption and Distribution: Following a single oral dose (20 mg tablet) of Escitalopram, peak blood levels occur at about 5 hours. Absorption of escitalopram is not affected by food. The absolute bioavailability of citalopram is about 80% relative to an intravenous dose, and the volume of distribution of citalopram is about 12 L/kg. The binding of escitalopram to human plasma proteins is approximately 56 %.
Metabolism and Elimination: Following oral administrations of Escitalopram, the fraction of drug recovered in the urine as Escitalopram and S-demethylcitalopram (S-DCT) is about 8% and 10%, respectively. The oral clearance of Escitalopram is 600 mL/min, with approximately 7% of that due to renal clearance. Escitalopram is metabolized to S-DCT and S-didemethylcitalopram (S-DDCT). In humans, unchanged escitalopram is the predominant compound in plasma. At steady state, the concentration of the Escitalopram metabolite S-DCT in plasma is approximately one-third that of Escitalopram. The level of S-DDCT was not detectable in most subjects. In vitro studies show that Escitalopram is at least 7 and 27 times more potent than S-DCT and S-DDCT, respectively, in the inhibition of serotonin reuptake, suggesting that the metabolites of Escitalopram do not contribute significantly to the antidepressant actions of Escitalopram. S-DCT and S-DDCT also have no or very low affinity for serotonergic (5-HT_1-7) or other receptors including alpha and beta-adrenergic, dopamine (D_1-5), histamine (H_1-3), muscarinic (M_1-5), and benzodiazepine receptors. S-DCT and S-DDCT also do not bind to various ion channels including Na⁺, K⁺, Cl^-, and Ca⁺⁺ channels.

It is indicated for the treatment of depression, panic disorder with or without agoraphobia. It is also used in variety of Anxiety disorders including panic attack, obsessive-compulsive disorders and social phobia. In Schizophrenia, it is mainly given in combination of social therapy and antipsychotic drug to reduce the frequency but not the average severity of aggressive incidents.

It is given orally as the oxalate although doses are expressed in term of the basic,escitalopram oxalate 12.8 mg is equivalent to about 10 mg of escitalopram.
In the treatment of depression: Selective serotonin reuptake inhibitors (SSRI) such as Escitalopram are widely used as an alternative to the older tricyclic as they are fewer adverse effects and are safer in overdosage. The usual dose is 10 mg once daily increased, after at least a week, to a maximum of 20 mg once daily if necessary.
In the treatment of Anxiety Disorders: Escitalopram has been given in anxiety disorders including generalized anxiety disorder, panic disorder, obsessive compulsive disorder and social anxiety disorder, phobic disorders. Doses used in the treatment of anxiety disorders are similar to those used in depression.
Administration in hepatic impairment: Patients with mild to moderate hepatic impairment or those who are poor metaboliser with respect to cytochrome P450 isoenzyme CYP2C19 should receive an initial oral dose of 5mg daily increase to 10 mg daily after 2 weeks depending on response; more careful dose titration is advise in those with sever impairment.

Human Experience: During the post-marketing evaluation of Escitalopram, Escitalopram oxalate tablets overdoses involving overdoses of over 1000 mg have been reported. As with other SSRI's, a fatal outcome in a patient who has taken an overdose of Escitalopram has been rarely reported. Symptoms most often accompanying escitalopram overdose, alone or in combination with other drugs and/or alcohol, included convulsions, coma, dizziness, hypotension, insomnia, nausea, vomiting, sinus tachycardia, somnolence, ECG changes (including QT prolongation and very rare cases of torsade de pointes). Acute renal failure has been very rarely reported accompanying overdose.
Management of Overdose: Establish and maintain an airway to ensure adequate ventilation and oxygenation. Gastric evacuation by lavage and use of activated charcoal should be considered. Careful observation and cardiac and vital sign monitoring are recommended, along with general symptomatic and supportive care. Due to the large volume of distribution of escitalopram, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. There are no specific antidotes for Escitalopram oxalate tablets. In managing overdosage, consider the possibility of multiple-drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose.

Concomitant use in patients taking Monoamine Oxidase Inhibitors (MAOIs) is contraindicated. Concomitant use in patients taking pimozide is contraindicated. Escitalopram oxalate tablets are contraindicated in patients with a hypersensitivity to Escitalopram or Citalopram or any of the inactive ingredients in Escitalopram oxalate tablets.

Antidepressants increase the risk of suicidal thinking and behaviour (suicidality) in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders' and those considering use of these agents "must balance risk with the clinical need".

General: Discontinuation of Treatment with Escitalopram Oxalate Tablets: During marketing of Escitalopram oxalate tablets 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 escitalopram oxalate tablets. 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.
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.
Hyponatremia: Cases of hyponatremia and SIADH (syndrome of inappropriate antidiuretic hormone secretion) have been reported in association with Escitalopram oxalate tablets treatment. All patients with these events have recovered with discontinuation of escitalopram 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: One additional case of hypomania has been reported in association with Escitalopram oxalate tablets 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, escitalopram oxalate tablets should be used cautiously in patients with a history of mania.
Seizures: Although anticonvulsant effects of racemic citalopram have been observed in animal studies, Escitalopram oxalate tablets have not been systematically evaluated in patients with a seizure disorder. In clinical trials of Escitalopram oxalate tablets, cases of convulsion have been reported in association with Escitalopram oxalate tablets treatment.
Interference with Cognitive and Motor Performance: In a study in normal volunteers, Escitalopram oxalate tablets 10 mg/day did not produce impairment of intellectual function or psychomotor performance.
Use in Patients with Concomitant Illness: Clinical experience with Escitalopram oxalate tablets in patients with certain concomitant systemic illnesses is limited. Caution is advisable in using Escitalopram oxalate tablets in patients with diseases or conditions that produce altered metabolism or hemodynamic responses. Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Escitalopram oxalate tablets and triptans, tramadol or other serotonergic agents. Patients should be cautioned about the concomitant use of escitalopram oxalate tablets 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.
Use in the Elderly: Approximately 6% of the 1144 patients receiving escitalopram in controlled trials of Escitalopram oxalate tablets in major depressive disorder and GAD were 60 years of age or older; elderly patients in these trials received daily doses of escitalopram oxalate tablets 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 Escitalopram oxalate tablets cannot be ruled out.

Use in Pregnancy: Pregnancy Category C: In a rat embryo/fetal development study, oral administration of Escitalopram (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). 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 Escitalopram oxalate tablets 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. Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN 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 six-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.
When treating a pregnant woman with Escitalopram oxalate tablets during the third trimester, the physician should carefully consider both the potential risks and benefits of treatment. Physicians should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.
Labor and Delivery: The effect of Escitalopram oxalate tablets on labor and delivery in humans is unknown.
Use in Lactation: 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 escitalopram oxalate tablets therapy should take into account the risks of citalopram exposure for the infant and the benefits of Escitalopram oxalate tablets treatment for the mother.

Adverse Events Associated with Discontinuation of Treatment Major Depressive Disorder: Among the 715 depressed patients who received Escitalopram oxalate tablets in placebo-controlled trials, 6% discontinued treatment due to an adverse event, as compared to 2% of 592 patients receiving placebo. In two fixed-dose studies, the rate of discontinuation for adverse events in patients receiving 10 mg/day Escitalopram oxalate tablets was not significantly different from the rate of discontinuation for adverse events in patients receiving placebo. The rate of discontinuation for adverse events in patients assigned to a fixed dose of 20 mg/day Escitalopram oxalate tablets was 10%, which was significantly different from the rate of discontinuation for adverse events in patients receiving 10 mg/day Escitalopram oxalate tablets (4%) and placebo (3%). Adverse events that were associated with the discontinuation of at least 1% of patients treated with Escitalopram oxalate tablets, and for which the rate was at least twice that of placebo, were nausea (2%) and ejaculation disorder (2% of male patients).
Generalized Anxiety Disorder: Adverse events that were associated with the discontinuation of at least 1% of patients treated with Escitalopram oxalate tablets, and for which the rate was at least twice the placebo rate, were nausea (2%), insomnia (1%), and fatigue (1%).
Dose Dependency of Adverse Events: The potential dose dependency of common adverse events was examined on the basis of the combined incidence of adverse events in two fixed-dose trials. The overall incidence rates of adverse events in 10 mg Escitalopram oxalate tablets-treated patients (66 %) was similar to that of the placebo-treated patients (61%), while the incidence rate in 20 mg/day Escitalopram oxalate tablets-treated patients was greater (86%).

Serotonergic Drugs: Based on the mechanism of action of SNRIs and SSRIs including Escitalopram oxalate tablets, and the potential for serotonin syndrome, caution is advised when escitalopram oxalate tablet is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John's Wort. The concomitant use of Escitalopram oxalate tablets with other SSRIs, SNRIs or tryptophan is not recommended.
Triptans: If concomitant treatment of Escitalopram oxalate tablets with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.
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 Escitalopram oxalate tablets 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 Escitalopram oxalate tablets is not recommended.
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 Escitalopram oxalate tablets.
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 escitalopram oxalate tablets and lithium are coadministered.
Pimozide and Celexa: In a controlled study, a single dose of pimozide 2 mg co-administered with racemic citalopram 40 mg given once daily for 11 days was associated with a mean increase in QTc values of approximately 10 msec compared to pimozide given alone. Racemic citalopram did not alter the mean AUC or C_max of pimozide. The mechanism of this pharmacodynamic interaction is not known.
Sumatriptan: There have been rare post-marketing 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 C_max 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.
Drugs Metabolized by Cytochrome P4502D6: 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.
Metoprolol: Coadministration of Escitalopram oxalate tablets 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.

Store at temperatures not exceeding 30°C.

Antidepressants

N06AB10 - escitalopram ; Belongs to the class of selective serotonin reuptake inhibitors. Used in the management of depression.

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