LEXAPRO

Escitalopram oxalate

Chemical name:

S(+)-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile hydrogen oxalate.

Chemical Abstracts No.

219861-08-2

Molecular weight

C₂₀H₂₁FN₂O, C₂H₂O₄ : 414.42

Description

Escitalopram is the active enantiomer of citalopram. Escitalopram oxalate is a fine white to yellow, crystalline material.

Escitalopram oxalate is sparingly soluble in water, slightly soluble in acetone, soluble in ethanol and freely soluble in methanol. No polymorphic forms have been detected.

Excipients in LEXAPRO: cellulose-microcrystalline, silica - colloidal anhydrous, talc, croscarmellose sodium, magnesium stearate, hypromellose, macrogol 400 and titanium dioxide.

Pharmacology

Pharmacodynamics

Biochemical and behavioural studies have shown that escitalopram is a potent inhibitor of serotonin (5-HT)-uptake (in vitro IC₅₀ 2nM). The inhibition of 5-HT uptake is the only recognised mechanism of action of escitalopram capable of explaining the pharmacological and clinical effects of escitalopram.

On the basis of in vitro studies, escitalopram is the most selective Serotonin Reuptake Inhibitor yet developed with no, or minimal effect on noradrenaline (NA), dopamine (DA) and gamma aminiobutyric acid (GABA) uptake.

In contrast to many tricyclic antidepressants and some of the SSRI's, escitalopram has no or very low affinity for a series of receptors including 5-HT_1A, 5-HT₂, DA D₁ and DA D₂ receptors, α_1-, α_2-, β-adrenoceptors, histamine H₁, muscarine cholinergic, benzodiazepine, and opioid receptors. A series of functional in vitro tests in isolated organs as well as functional in vivo tests have confirmed the lack of receptor affinity.

In healthy volunteers and in patients escitalopram did not cause clinically significant changes in vital signs, ECGs, or laboratory parameters.

S-demethylcitalopram, the main plasma metabolite, attains about 30% of parent compound levels after oral dosing and is about 5-fold less potent at inhibiting 5-HT re-uptake than escitalopram in vitro. It is therefore unlikely to contribute significantly to the overall antidepressant effect.

Pharmacokinetics

Absorption

Absorption is expected to be almost complete and independent of food intake (mean T_max is 4 hours after multiple dosing). While the absolute bioavailability of escitalopram has not been studied, it is unlikely to differ significantly from that of racemic citalopram (about 80%).

Distribution

The apparent volume of distribution (V_d,β /F) after oral administration is about 12 to 26 L/kg. The binding of escitalopram to human plasma proteins is independent of drug plasma levels and averages 55 %.

Metabolism

Escitalopram is metabolised in the liver to the demethylated and didemethylated metabolites. Alternatively, the nitrogen may be oxidised to form the N-oxide metabolite. Both parent and metabolites are partly excreted as glucuronides. Unchanged escitalopram is the predominant compound in plasma. After multiple dosing the mean concentrations of the demethyl and didemethyl metabolites are usually 28-31% and <5% of the escitalopram concentration, respectively. Biotransformation of escitalopram to the demethylated metabolite is mediated by a combination of CYP2C19, CYP3A4 and CYP2D6.

Excretion

The elimination half-life (t_{½ β}) after multiple dosing is about 30 hours and the oral plasma clearance (Cl_oral) is about 0.6 L/min.

Escitalopram and major metabolites are - like racemic citalopram - assumed to be eliminated both by the hepatic (metabolic) and the renal routes with the major part of the dose excreted as metabolites in urine. Hepatic clearance is mainly by the P450 enzyme system.

The pharmacokinetics of escitalopram are linear over the clinical dosage range. Steady state plasma levels are achieved in about 1 week. Average steady state concentrations of 50 nmol/L (Range 20 to 125 nmol/L) are achieved at a daily dose of 10 mg.

Elderly patients (>65 years)

A longer half-life and decreased clearance values, due to a reduced rate of metabolism, have been demonstrated in the elderly.

Reduced hepatic function

There is no data on the use of escitalopram in reduced hepatic function. However, based on data for racemic citalopram, escitalopam is expected to be eliminated more slowly in patients with reduced hepatic function. The half-life of escitalopam is expected to be about twice as long and steady state escitalopam concentrations at a given dose will be about twice as high as in patients with normal liver function.

Reduced renal function

While there is no specific data, the use of escitalopram in reduced renal function may be extrapolated from that of racemic citalopram. Escitalopam is expected to be eliminated more slowly in patients with mild to moderate reduction of renal function with no major impact on the escitalopram concentrations in serum. At present no information is available for the treatment of patients with severely reduced renal function (creatinine clearance < 20 mL/min).

Polymorphism

Based on in vitro results with escitalopram and in vivo results with the racemic citalopram, genetic polymorphism with respect to CYP2D6 and CYP2C19 is considered of no clinical relevance. Therefore, there is no need for individualised dosing based on these phenotypes.

Clinical Trials

Two fixed dose studies and one flexible dose study has shown escitalopram in the dose range 10-20 mg/day to be more efficacious than placebo in the treatment of depression. All three studies were randomised, double blind, parallel-group, placebo-controlled multicentre studies. Two of the studies included an active reference (citalopram). All three studies consisted of a 1-week single-blind placebo lead-in period followed by an 8-week double-blind treatment period.

Patients were required to have depression with a minimum score of 22 on the Montgomery-Åsberg Depression Rating Scale (MADRS) at both the screening and baseline visits. The populations studied were therefore defined as suffering from moderate to severe depression. A total of 591 patients received escitalopram in these studies.

All three studies showed escitalopram to be statistically significantly superior to placebo on the ITT LOCF analysis of the mean change from baseline in the MADRS total score (p ≤ 0.01). The magnitude of the difference between escitalopram and placebo in the MADRS change score ranged from 2.7 to 4.6 (mean of these values: 3.6). The magnitude of the difference for citalopram ranged from 1.5 to 2.5 (mean of these values: 2.0). Both ranges are comparable to those reported for development programmes with other SSRIs. The magnitude of the difference is larger with escitalopram than with citalopram.

In the study with two parallel escitalopram dose groups, analysis of subgroups of patients showed a trend toward greater improvement in patients with severe major depressive disorder (HAMD >25) receiving 20 mg/day as compared to 10 mg/day.

In a fourth flexible-dose study with a similar design, the primary analysis did not distinguish a significant drug/placebo difference for either escitalopram or citalopram over 8 weeks on the MADRS change score in the LOCF dataset. However, on the basis of the OC analysis, both escitalopram and citalopram were significantly better than placebo (p ≤ 0.05); difference between escitalopram and placebo: 2.9).

Escitalopram demonstrated efficacy in the treatment of anxiety symptoms associated with depression. In the three positive double-blind placebo-controlled studies escitalopram was shown to be effective compared to placebo on the MADRS anxiety items; inner tension and sleep disturbances. Furthermore in the one study where the Hamilton Anxiety Scale (HAMA) and the anxiety factor of the Hamilton Depression Rating Scale (HAMD scale) were used, results have shown that escitalopram was better than placebo.

Two relapse prevention or maintenance studies of 24 weeks´ duration have been carried out with the racemate. In both studies the racemate showed reduced relapse hazard rates and prolonged time to relapse compared to placebo.

Two placebo-controlled, parallel group studies with the racemate, including one in the elderly, addressed recurrence prevention over a 1 to 2 year recurrence prevention phase. In both patient populations, the racemate led to prolonged time to recurrence in all dose groups compared to placebo.

Although comparative studies have not yet been completed with escitalopram versus tri-/tetracyclic antidepressants or other SSRIs, data with the racemate demonstrate therapeutic efficacy comparable to other SSRIs in the treatment of major depression.

Indications

Treatment of major depression.

Contra-Indications

Hypersensitivity to citalopram and any excipients in Lexapro (see DESCRIPTION).

Monoamine Oxidase Inhibitors

Cases of serious reactions have been reported in patients receiving an SSRI in combination with a monoamine oxidase inhibitor (MAOI) or the reversible MAOI (RIMA), moclobemide, and in patients who have recently discontinued an SSRI and have been started on a MAOI. (see Interactions with Other Drugs). Some cases presented with features resembling serotonin syndrome (see Adverse Reactions).

Escitalopram should not be used in combination with a MAOI. Escitalopram may be started 14 days after discontinuing treatment with an irreversible MAOI and at least one day after discontinuing treatment with the reversible MAOI (RIMA), moclobemide. At least 7 days should elapse after discontinuing escitalopram treatment before starting a MAOI or RIMA.

Precautions

Haemorrhage

There have been reports of cutaneous bleeding abnormalities, such as ecchymoses and purpura, with SSRIs. Caution is advised in patients taking SSRIs, particularly in concomitant use with drugs known to affect platelet function (e.g. most tricyclic antidepressants, aspirin and non-steroidal anti-inflammatory drugs (NSAIDs), as well as in patients with a history of bleeding disorders.

Hyponatraemia

probably due to inappropriate antidiuretic hormone secretion (SIADH), Hyponatraemia has been reported as a rare adverse reaction with the use of SSRIs. Especially elderly patients seem to be a risk group.

Seizures

The drug should be discontinued in any patient who develops seizures. SSRIs should be avoided in patients with unstable epilepsy and patients with controlled epilepsy should be carefully monitored. SSRIs should be discontinued if there is an increase in seizure frequency.

Diabetes

In patients with diabetes, treatment with an SSRI may alter glycaemic control, possibly due to improvement of depressive symptoms. Insulin and/or oral hypoglycaemic dosage may need to be adjusted.

Suicide

As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored during this period. The possibility of a suicide attempt is inherent in depression and may persist until significant therapeutic effect is achieved. It is general clinical experience with all antidepressant therapies that the risk of suicide may increase in the early stages of recovery.

Mania

SSRIs should be used with caution in patients with a history of mania/hypomania. SSRIs should be discontinued in any patient entering a manic phase.

ECT (electroconvulsive therapy)

There is limited published clinical experience of concurrent administration of SSRIs and ECT, therefore caution is advisable.

Effects on ability to drive and use machines

Escitalopram does not impair intellectual function and psychomotor performance. However, as with other psychoactive drugs, patients should be cautioned about their ability to drive a car and operate machinery.

Discontinuation

After prolonged administration abrupt cessation of SSRIs may produce withdrawal reactions in some patients. Although withdrawal reactions may occur on stopping therapy, the available preclinical and clinical evidence does not suggest that SSRIs cause dependence.

Withdrawal reactions have not been systematically evaluated with escitalopram. However, limited withdrawal reactions have been observed with the racemic citalopram; dizziness, headache and nausea.

The withdrawal reactions are mild and self-limiting. It is recommended that treatment should be tapered gradually on discontinuation.

Cardiac disease

Escitalopram has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Like other SSRIs, escitalopram causes a small decrease in heart rate. Consequently, caution should be observed when escitalopram is initiated in patients with pre-existing slow heart rate.

Preclinical Safety

High doses of escitalopram, which resulted in plasma C_max for escitalopram and metabolites at least 10-fold greater than anticipated clinically, have been associated with convulsions and ECG abnormalities in experimental animals.

Carcinogenicity, mutagenicity and impairment of fertility

No carcinogenicity, mutagenicity or impairment of fertility studies were performed with escitalopram. However, other preclinical studies suggest that the effects of escitalopram can be directly predicted from those of the citalopram racemate.

Citalopram did not show any carcinogenic activity in long term oral studies using mice and rats at doses up to 240 and 80mg/kg/day, respectively.

In assays of genotoxic activity, citalopram showed no evidence of mutagenic or clastogenic activity.

In rats, female fertility was unaffected by oral treatment with citalopram doses which achieved plasma drug concentrations slightly in excess of those expected in humans, but effects on male rat fertility have not been tested with adequate oral doses.

Use in pregnancy

Category C.

No relevant epidemiological data or well controlled studies in pregnant women are available for escitalopram. SSRIs have had limited use in pregnancy without a reported increase in birth defects. The use of SSRIs in the third trimester may result in a withdrawal state in the newborn infant.

Oral treatment of rats with escitalopram during organogenesis at maternotoxic doses led to increased post-implantation loss and reduced fetal weight at systemic exposure levels (based on AUC) ca. 11-fold that anticipated clinically, with no effects seen at 6-fold. No teratogenicity was evident in this study at relative systemic exposure levels of ca. 15 (based on AUC).

There were no peri/postnatal effects of escitalopram following oral dosing of pregnant rats (conception through to weaning) at systemic exposure levels (based on AUC) ca. 2-fold that anticipated clinically. However, the number of stillbirths was increased and the size, weight and postnatal survival of offspring was decreased at a relative systemic exposure level ca. 5.

Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Use in lactation

It is expected that escitalopram, like citalopram, will be excreted into human breast milk. Studies in nursing mothers have shown that the mean combined dose of citalopram and demethylcitalopram transmitted to infants via breast milk (expressed as a percentage of the weight-adjusted maternal dose) is 4.4-5.1% (below the notional 10% level of concern). Plasma concentrations of these drugs in infants were very low or absent and there were no adverse effects. Whilst these data support the safety of use of citalopram in breastfeeding women, the decision to breast feed should always be made as an individual risk:benefit analysis.

Interaction with other drugs

Co-administration with MAO inhibitors may cause serotonin syndrome (see Contra indications).

Co-administration with serotonergic drugs (e.g. tramadol, sumatriptan) may lead to an enhancement of serotonergic effects. Similarly, Hypericum perforatum (St John's Wort) should be avoided as adverse interactions have been reported with a range of drugs including antidepressants.

There have been reports of enhanced effects when SSRIs have been given with lithium or tryptophan and therefore concomitant use of SSRIs with these drugs should be undertaken with caution.

Escitalopram has a low potential for clinically significant drug interactions. In vitro studies have shown that the biotransformation of escitalopram to its demethylated metabolites depends on three parallel pathways (cytochrome P450 (CYP) 2C19, 3A4 and 2D6). Escitalopram is a very weak inhibitor of isoenzyme CYP1A2, 2C9, 2C19, 2E1, and 3A, and a weak inhibitor of 2D6.

Effects of other drugs on escitalopram in vivo

The pharmacokinetics of escitalopram was not changed by co-administration with ritonavir (CYP3A4 inhibitor). Furthermore co-administration with ketoconazole (potent CYP3A4 inhibitor) did not change the pharmacokinetics of racemic citalopram.

Co-administration of racemic citalopram with cimetidine (potent CYP2D6, 3A4 and 1A2 inhibitor) resulted in increased plasma concentrations of the racemate (<45% increase). Thus, caution should be exercised at the upper end of the dose range of escitalopram when used concomitantly with high doses of cimetidine.

Effects of escitalopram on other drugs in vivo

Co-administration with desipramine (a CYP2D6 substrate) resulted in a twofold increase in plasma levels of desipramine. Therefore, caution is advised when escitalopram and desipramine are co-administered. A similar increase in plasma levels of desipramine, after administration of imipramine, was seen when given together with racemic citalopram.

Co-administration with metoprolol (a CYP2D6 substrate) resulted in a twofold increase in the plasma levels of metoprolol. However, the combination had no clinically significant effects on blood pressure and heart rate.

The pharmacokinetics of ritonavir (CYP3A4 inhibitor) was not changed by co-administration with escitalopram.

Furthermore, pharmacokinetic interaction studies with racemic citalopram have demonstrated no clinical important interactions with carbamazepine (CYP3A4 substrate), triazolam (CYP3A4 substrate), theophylline (CYP1A2 substrate), warfarin (CYP3A4 and CYP2C9 substrate), levomepromazine (CYP2D6 inhibitor), lithium and digoxin.

Alcohol

The combination of SSRIs and alcohol is not advisable.

Adverse Reactions

Adverse reactions observed with escitalopram are in general mild and transient. They are most frequent during the first one or two weeks of treatment and usually decrease in intensity and frequency with continued treatment and generally do not lead to a cessation of therapy.

Treatment-emergent Adverse Events with an Incidence of ≥1% in placebo-controlled trials

Figures marked with * in below table indicate adverse reactions (incidence with escitalopram statistically significantly different from placebo (P<0.05))

* = Statistically significant difference escitalopram vs placebo (P<0.05) [gs] = gender specific

The following adverse reactions have been observed with escitalopram at an incidence of < 1%:

• Nervous system disorders - taste disturbance, sleep disorder

In addition the following adverse reactions have been reported with racemic citalopram (all of which have also been reported for other SSRIs):

• Disorders of metabolism and nutrition - Hyponatraemia, inappropriate ADH secretion (both especially in elderly women)
• Gastrointestinal disorders - dry mouth
• General disorders - allergic reactions
• Neurological disorders - Convulsions, convulsions grand mal and extrapyramidal disorder, serotonin syndrome (typically characterized by a rapid onset of changes in mental state, with confusion, mania, agitation, hyperactivity, shivering, fever, tremor, ocular movements, myoclonus, hyperreflexia, and inco-ordination)
• Psychiatric disorders - agitation
• Skin disorders - ecchymoses, pruritus, angioedema, purpura

Furthermore a number of adverse reactions have been listed for other SSRIs. Although these are not listed as adverse reactions for escitalopram or citalopram, it cannot be excluded that these adverse reactions may occur with escitalopram. These SSRI class reactions are listed below:

• Cardiovascular disorders - postural hypotension
• Disorders of the eye - abnormal vision
• Gastrointestinal disorders - vomiting
• Hepato-biliary disorders - abnormal liver function tests
• Musculoskeletal disorders - arthralgia, myalgia
• Neurological disorders - seizures, tremor, movement disorders
• Psychiatric disorders - hallucinations, mania, confusion, anxiety, depersonalisation, panic attacks, nervousness
• Renal and Urinary Disorders - urinary retention
• Reproductive disorders - galactorrhoea
• Skin disorders - rash, ecchymoses, pruritus, angioedema

Doasge and Administration

Adults

Lexapro should be administered as a single oral dose of 10 mg daily. Depending on individual patient response, the dose may be increased to a maximum of 20 mg daily.

Usually 2-4 weeks are necessary for antidepressant response, although the onset of therapeutic effect may be seen earlier. The treatment of a single episode of depression requires treatment over the acute and the medium term. After the symptoms resolve during acute treatment, a period of consolidation of the response is required. Therefore, treatment of a depressive episode should be continued for a minimum of 6 months.

When stopping SSRI therapy gradual dose reduction should be considered.

Elderly patients (> 65 years of age)

A longer half-life and a decreased clearance have been demonstrated in the elderly, therefore a lower maximum dose should be considered.

Children

Not recommended, since safety and efficacy have not been established in this population.

Reduced renal function

Dosage adjustment is not necessary in patients with mild or moderate renal impairment. No information is available on the treatment of patients with severely reduced renal function (creatinine clearance < 20 ml/min.).

Reduced hepatic function

Dosages should be restricted to the lower end of the dose range in patients with hepatic insufficiency (group A and B according to modified Child -Turcotte´s score system).

Overdosage

Symptoms

Doses of 190 mg have been taken without any symptoms being reported. Furthermore, no symptoms were reported after intake of 600 mg (dose not confirmed).

Treatment

There is no specific antidote. Establish and maintain an airway, ensure adequate oxygenation and ventilation. Activated charcoal should be given as soon as possible after oral ingestion. Cardiac and vital signs monitoring are recommended along with general symptomatic supportive measures.

Pharmaceutical Considerations

Lexapro tablets have a shelf life of two years. Store below 30°C (86°F).

Presentation

Film-coated tablets in packs of 28 tablets.

Description of tablets

5 mg: Round, white, film-coated tablets marked with "EK" on one side.

10 mg: Oval, white, scored , film-coated tablets marked with "EL" on one side.

15 mg: Oval, white, scored, film-coated tablets marked with "EM" on one side.

20 mg: Oval, white, scored, film-coated tablets marked with "EN" on one side.

Manufactured by

H. Lundbeck A/S
Denmark

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