ESCITALOPRAM AN escitalopram (as oxalate) 10mg film-coated tablet blister pack

Main information

  • Trade name:
  • ESCITALOPRAM AN escitalopram (as oxalate) 10mg film-coated tablet blister pack
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ESCITALOPRAM AN escitalopram (as oxalate) 10mg film-coated tablet blister pack
    Australia
  • Language:
  • English

Status

  • Source:
  • Dept. of Health,Therapeutic Goods Administration - Australia
  • Authorization status:
  • Registered
  • Authorization number:
  • 190287
  • Last update:
  • 21-05-2019

Public Assessment Report

Public Summary

Summary for ARTG Entry:

190287

ESCITALOPRAM AN escitalopram (as oxalate) 10mg film-coated tablet blister pack

ARTG entry for

Medicine Registered

Sponsor

Amneal Pharma Australia Pty Ltd

Postal Address

12 River Street,SOUTH YARRA, VIC, 3141

Australia

ARTG Start Date

19/02/2013

Product category

Medicine

Status

Active

Approval area

Drug Safety Evaluation Branch

Conditions

Conditions applicable to all therapeutic goods as specified in the document "Standard Conditions Applying to Registered or Listed Therapeutic Goods

Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Conditions applicable to the relevant category and class of therapeutic goods as specified in the document "Standard Conditions Applying to Registered

or Listed Therapeutic Goods Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Products

1. ESCITALOPRAM AN escitalopram (as oxalate) 10mg film-coated tablet blister pack

Product Type

Single Medicine Product

Effective date

12/06/2015

Warnings

See Product Information and Consumer Medicine Information for this product

Standard Indications

Specific Indications

Treatment of major depression.

Additional Product information

Container information

Type

Material

Life Time

Temperature

Closure

Conditions

Blister Pack

PVC/PE/PVDC/Al

48 Months

Store below 25

degrees Celsius

Not recorded

Store in a Dry Place

Pack Size/Poison information

Pack Size

Poison Schedule

28 Tablets

(S4) Prescription Only Medicine

Components

1. ESCITALOPRAM AN escitalopram (as oxalate) 10mg film-coated tablet blister pack

Dosage Form

Tablet, film coated

Route of Administration

Oral

Visual Identification

White to off-white oval biconvex film-coated tablets with break-line on one

side and plain on the other side, having approximate dimensions, length

about 8.0mm and width about 5.5mm

Active Ingredients

escitalopram oxalate

12.776 mg

© Commonwealth of Australia.This work is copyright.You are not permitted to re-transmit, distribute or commercialise the material without obtaining prior

written approval from the Commonwealth.Further details can be found at http://www.tga.gov.au/about/website-copyright.htm.

Public Summary

Page 1 of

Produced at 28.11.2017 at 11:28:27 AEDT

This is not an ARTG Certificate document.

The onus is on the reader to verify the current accuracy of the information on the document subsequent to the date shown.

Visit www.tga.gov.au for contact information

Summary of Product characteristics: dosage, interactions, side effects

Escitalopram AN tablets Product Information

Amneal Pharma Australia Pty Ltd

ESCITALOPRAM AN

(escitalopram oxalate tablets)

PRODUCT INFORMATION

NAME OF THE MEDICINE

The name of the medicine is escitalopram oxalate

Chemical name: S-

+

)-1-[3-(Dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-

dihydroisobenzofuran-5-carbonitrile

hydrogen oxalate

Molecular Formula:

Molecular Weight:

414.42

CAS Registry Number:

[219861-08-2]

DESCRIPTION

Escitalopram is the active enantiomer (

S

-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.

Escitalopram AN tablets 10 mg

are white to off white, oval, biconvex, film-coated tablets with

breakline on one side and plain on the other side having approximate dimensions length about 8.0

mm and width about 5.5 mm.

Escitalopram AN tablets 20 mg

are white to off white, oval, biconvex, film-coated tablets with

breakline on one side and plain on the other side having approximate dimensions, length about

11.5 mm and width about 7.0 mm.

Escitalopram AN tablets

also contain the following excipients: microcrystalline cellulose, colloidal

anhydrous silica, purified talc, croscarmellose sodium, magnesium stearate, hypromellose, macrogol

400 and titanium dioxide.

PHARMACOLOGY

Biochemical and behavioural studies have shown that escitalopram is a potent inhibitor of serotonin

Escitalopram AN PI v3.0

Page 1

Escitalopram AN tablets Product Information

Amneal Pharma Australia Pty Ltd

(5-HT)-uptake (

in vitro

2nM). The antidepressant action of escitalopram is presumably linked

to the potentiation of serotonergic activity in the central nervous system (CNS) resulting from

its inhibitory effect on the reuptake of 5-HT from the synaptic cleft.

Escitalopram is a highly selective Serotonin Reuptake Inhibitor (SSRI). On the basis of

in vitro

studies, escitalopram had no, or minimal effect on noradrenaline (NA), dopamine (DA) and gamma

aminobutyric acid (GABA) uptake.

In contrast to many tricyclic antidepressants and some of the SSRIs, escitalopram has no or very

low affinity for a series of receptors including 5-HT

, 5-HT

, DA D

and DA D

receptors, α

-, α

, β-adrenoceptors, histamine H

, 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.

Escitalopram has high affinity for the primary binding site and an allosteric modulating effect on the

serotonin transporter.

Allosteric modulation of the serotonin transporter enhances binding of escitalopram to the primary

binding site, resulting in more complete serotonin reuptake inhibition.

Escitalopram is the

S

-enantiomer of the racemate (citalopram) and is the enantiomer to which the

therapeutic activity is attributed. Pharmacological studies have shown that the

R

-enantiomer is not

inert but counteracts the serotonin-enhancing properties of the

S

-enantiomer in citalopram.

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 reuptake than escitalopram

in

vitro

. It is therefore unlikely to contribute significantly to the overall antidepressant effect.

Pharmacokinetics

Absorption.

Data specific to escitalopram are unavailable. Absorption is expected to be almost

complete and independent of food intake (mean T

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

metabolites

partly

excreted

glucuronides.

Unchanged

escitalopram

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

Escitalopram AN PI v3.0

Page 2

Escitalopram AN tablets Product Information

Amneal Pharma Australia Pty Ltd

combination of CYP2C19, CYP3A4 and CYP2D6.

Elimination/Excretion.

The elimination half-life (t½

) 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. Approximately 8.0% of escitalopram is eliminated unchanged in urine and 9.6% as the

S

demethylcitalopram metabolite based on 20 mg escitalopram data. 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.

Reduced hepatic function.

In patients with mild or moderate hepatic impairment (Child-Pugh Criteria

A and B), the half-life of escitalopram was about twice as long and the exposure was about 60%

higher than in subjects with normal liver function (

see PRECAUTIONS and DOSAGE AND

ADMINISTRATION).

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. Escitalopram 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).

Elderly patients (> 65 years)

Escitalopram pharmacokinetics in subjects > 65 years of age were compared to younger subjects in

a single-dose and a multiple-dose study. Escitalopram AUC and half-life were increased by

approximately 50% in elderly subjects, and C

was unchanged. 10 mg is the recommended

dose for elderly patients.

Gender.

In a multiple-dose study of escitalopram (10 mg/day for 3 weeks) in 18 male (9 elderly and

9 young) and 18 female (9 elderly and 9 young) subjects, there were no differences in AUC, C

and half-life between the male and female subjects. No adjustment of dosage on the basis of

gender is needed.

Polymorphism.

It has been observed that poor metabolisers with respect to CYP2C19 have twice

as high a plasma concentration of escitalopram as extensive metabolisers. No significant change in

exposure was observed in poor metabolisers with respect to CYP2D6 (

see DOSAGE AND

ADMINISTRATION).

CLINICAL TRIALS

Escitalopram oxalate Tablets should not be used for the treatment of major depression,

generalised anxiety disorder, social anxiety disorder and obsessive-compulsive disorder in

children and adolescents under the age of 18 years since the safety and efficacy in this

population have not been established.

Escitalopram AN PI v3.0

Page 3

Escitalopram AN tablets Product Information

Amneal Pharma Australia Pty Ltd

Major Depression

Escitalopram oxalate tablets should not be used in the treatment of children and adolescents under

the age of 18 years.

Two fixed-dose studies and one flexible-dose study have 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 MADRS

consists

items

that

measure

core

symptoms

depression, such

sadness, tension,

pessimism and suicidal thoughts. Each item is rated on a scale of 0 (no abnormality) to 6 (severe).

The populations studied were therefore defined as suffering from moderate to severe depression

(mean MADRS score 29). 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). The magnitude of the difference is larger with

escitalopram than with citalopram.

Escitalopram demonstrated a significant early difference compared to placebo from week 2 onwards

on the MADRS (week 1 in observed cases analysis). Likewise, the Clinical Global Impression–

Improvement items (CGI-I) differed significantly from placebo from week 1 onwards. These early

differences were not seen with racemic citalopram.

the study with two

parallel escitalopram dose

groups,

analysis of

subgroups

patients

showed a trend towards greater improvement in patients with severe major depressive disorder

(HAM-D > 25) receiving 20 mg/day as compared to 10 mg/day. The Hamilton Rating Scale for

Depression (HAM-D) consists of 17 to 24 items reflecting core symptoms of depression. Each item

is scored on a 3, 4, or 5 point scale with 0 reflecting no symptoms and higher scores reflecting

increasing symptom severity.

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

treatment

anxiety

symptoms

associated

with

depression. In the three positive double-blind placebo-controlled studies escitalopram was shown to

effective

compared

placebo

MADRS

anxiety

items;

inner

tension

sleep

disturbances. Furthermore, in the one study where the Hamilton Anxiety Scale (HAM-A) and the

anxiety factor of the Hamilton Depression Rating Scale (HAM-D scale) were used, results have

shown that escitalopram was significantly better than placebo.

Escitalopram AN PI v3.0

Page 4

Escitalopram AN tablets Product Information

Amneal Pharma Australia Pty Ltd

In a relapse prevention trial, 274 patients meeting (DSM-IV) criteria for major depressive disorder,

who had responded during an initial 8-week open-label treatment phase with escitalopram 10 or 20

mg/day, were randomised to continuation of escitalopram at the same dose, or to placebo, for

up to 36 weeks of observation for relapse. Response during the open- label phase was defined as

a decrease of the MADRS total score to ≤ 12.

Relapse during the double-blind phase was defined as an increase of the MADRS total score to ≥

discontinuation

insufficient

clinical

response.

Patients

receiving

continued

escitalopram experienced a significantly longer time to relapse over the subsequent 36 weeks

compared to those receiving placebo (26% vs. 40%; hazard ratio=0.56, p=0.013).

Further evidence of long-term efficacy is provided in a 6-month study which compared escitalopram

10 mg/day to citalopram 20 mg/day over a 6-month treatment period. Analysis of the primary

endpoint (the development of the MADRS total scores over 24 weeks) demonstrated escitalopram

to be at least as efficacious as citalopram in the long-term treatment of depression. Secondary

analyses showed that, while both treatments resulted in numerical improvements in ratings in the

MADRS, HAM-A and the CGI, escitalopram was statistically superior to citalopram in several

analyses, both during and at the end of the study.

Additional supportive evidence of the sustained efficacy of escitalopram treatment is demonstrated

in an open-label 12-month study. The efficacy of escitalopram was maintained throughout the

study, as measured by the MADRS total score and CGI-S score. Patients showed continued

improvement, with total MADRS scores falling from 14.2 at baseline to 5.8 at last assessment,

and CGI-scores falling from 2.7 at baseline to 1.6 at last assessment.

A study in the elderly did not provide conclusive efficacy results for escitalopram, as the reference

drug (fluoxetine) failed to differentiate from placebo. However, safety data from this study showed

escitalopram to be well tolerated.

INDICATIONS

Treatment of major depression.

CONTRAINDICATIONS

Hypersensitivity to citalopram, escitalopram and any excipients in Escitalopram-AN Tablets

(see

DESCRIPTION).

Monoamine Oxidase Inhibitors -

Escitalopram should not be used in combination with monoamine

oxidase inhibitors (MAOI) or the reversible MAOI (RIMA), moclobemide, or within

14 days of discontinuing treatment with a MAOI, and at least one day after discontinuing treatment

with the reversible MAOI (RIMA), moclobemide. Similarly, at least 14 days should be allowed after

stopping escitalopram before starting a MAOI or RIMA. Cases of serious reactions, such as

potentially life-threatening serotonin syndrome (characterised by neuromuscular excitation, altered

mental status and autonomic dysfunction) 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

Escitalopram AN PI v3.0

Page 5

Escitalopram AN tablets Product Information

Amneal Pharma Australia Pty Ltd

a MAOI (see PRECAUTIONS, Interactions with other medicines).

Pimozide -

Concomitant use in patients taking pimozide is contraindicated

(see Interactions

with other medicines).

PRECAUTIONS

Clinical worsening and suicide risk

The risk of suicide attempt is inherent in depression and may persist until significant remission

occurs. This risk must be considered in all depressed patients.

Patients with depression may experience worsening of their depressive symptoms and/or the

emergence of

suicidal

ideation and

behaviours (suicidality) whether

they

taking

antidepressant medications, and

this

risk

persist

until

significant remission

occurs.

improvement may not occur during the first few weeks or more of treatment, patients should be

closely monitored for clinical worsening and suicidality, especially at the beginning of a course of

treatment, 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.

Patients (and caregivers of patients) should be alerted about the need to monitor for any worsening

of their condition and/or the emergence of suicidal ideation/behaviour or thoughts of harming

themselves and to seek medical advice immediately if these symptoms are present.

Patients with comorbid depression associated with other psychiatric disorders being treated with

antidepressants should be similarly observed for clinical worsening and suicidality.

Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal

ideation prior to commencement of treatment, are at greater risk of suicidal thoughts or suicide

attempts, and should receive careful monitoring during treatment.

Pooled analyses of 24 short-term (4 to 16-week), placebo-controlled trials of nine antidepressant

medicines (SSRIs and others) in 4,400 children and adolescents with major depressive disorder (16

trials), obsessive-compulsive disorder (4 trials), or other psychiatric disorders (4 trials) have

revealed a greater risk of adverse events representing suicidal behaviour or thinking (suicidality)

during the first few months of treatment in those receiving antidepressants. The average risk of such

events in patients treated with an antidepressant was 4%, compared with 2% of patients given

placebo. There was considerable variation in risk among the antidepressants, but there was

tendency towards an increase for almost all antidepressants studied. The risk of suicidality was most

consistently observed in the major depressive disorder trials, but there were signals of risk arising

from trials in

other psychiatric indications (obsessive-compulsive disorder and social anxiety

disorder) as well. No suicides occurred in these trials. It is unknown whether the suicidality risk in

children and adolescent patients extends to use beyond several months. The nine antidepressant

medicines in the pooled analyses included five SSRIs (citalopram, fluoxetine,

fluvoxamine,

paroxetine, sertraline) and four non-SSRIs (buproprion, mirtazapine, nefazodone, venlafaxine).

Pooled analyses of short-term studies of antidepressant medications have also shown an increased

risk of suicidal thinking and behaviour, known as suicidality, in young adults aged 18 to 24 years

Escitalopram AN PI v3.0

Page 6

Escitalopram AN tablets Product Information

Amneal Pharma Australia Pty Ltd

during initial treatment (generally the first one to two months). Short-term studies did not show an

increase in the risk of suicidality with antidepressants compared to placebo in adults beyond the age

of 24 years, and there was a reduction with antidepressants compared to placebo in adults aged 65

years and older.

Symptoms of anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness),

impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in

adults, adolescents and children 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 worsening of depression and/or emergence of suicidal

impulses has not been established, there is concern that such symptoms may be precursors of

emerging suicidality.

Families and caregivers of children and adolescents being treated with antidepressants for major

depressive disorder or for any other condition (psychiatric or non psychiatric) should be informed

about the need to monitor these patients for the emergence of agitation, irritability, unusual

changes in behaviour, and other symptoms described above, as well as the emergence of suicidality,

and to report such symptoms to health care providers immediately. It is particularly

important that monitoring be undertaken during the initial few months of antidepressant treatment or

at times of dose increase or decrease.

Prescriptions for escitalopram should be written for the smallest quantity of tablets consistent

with good patient management, in order to reduce the risk of overdose.

Akathisia/psychomotor restlessness

The use of SSRIs/SNRIs has been associated with the development of akathisia, characterised by a

subjectively unpleasant or distressing restlessness and need to move often accompanied by an

inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In

patients who develop these symptoms, increasing the dose may be detrimental.

Haemorrhage

Bleeding abnormalities of the skin and mucous membranes have been reported with the use of

SSRIs (including purpura, ecchymoses, haematoma, epistaxis, vaginal bleeding and gastrointestinal

bleeding). Escitalopram AN Tablets should therefore be used with caution in patients concomitantly

treated with oral anticoagulants, medicinal products known to affect platelet function (e.g. atypical

antipsychotics and phenothiazines, most tricyclic antidepressants, acetylsalicylic acid and non-

steroidal anti-inflammatory medicinal products (NSAIDs), ticlopidine and dipyridamole) as well

as in patients with a past history of abnormal bleeding or those with predisposing conditions.

Pharmacological gastroprotection should be considered for high risk patients.

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

patients with

unstable epilepsy and

patients with

controlled epilepsy should be carefully

monitored. SSRIs

should

discontinued if

there

increase in

seizure

frequency (see

Escitalopram AN PI v3.0

Page 7

Escitalopram AN tablets Product Information

Amneal Pharma Australia Pty Ltd

Preclinical safety

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.

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 advised.

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

Discontinuation symptoms when stopping treatment are common, particularly if discontinuation is

abrupt. The risk of discontinuation

symptoms may be dependent on several factors including the

duration and dose of therapy and the rate of dose reduction. Dizziness, sensory disturbances

(including paraesthesia and electric shock sensations), sleep disturbances (including insomnia and

intense

dreams),

agitation

anxiety,

nausea

and/or

vomiting,

tremor,

confusion, sweating,

headache, diarrhoea, palpitations, emotional instability, irritability, and visual disturbances are the

most commonly reported reactions. Generally these symptoms are mild to moderate, however, in

some patients they may be severe in intensity.

They usually occur within the first few days of discontinuing treatment, but there have been very

rare reports of such symptoms in patients who have inadvertently missed a dose.

Generally these symptoms are self-limiting and usually resolve within 2 weeks, though in some

individuals they may be prolonged (2 - 3 months or more). It is therefore advised that escitalopram

should be gradually tapered when discontinuing treatment over a period of several weeks or months,

according to the patient’s needs (

see DOSAGE AND ADMINISTRATION).

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.

Impaired hepatic function

subjects

with

hepatic

impairment, clearance

escitalopram was decreased

plasma

concentrations were increased. The dose of escitalopram in hepatically impaired patients should

therefore be reduced (

see Pharmacokinetics and DOSAGE AND ADMINISTRATION).

Escitalopram AN PI v3.0

Page 8

Escitalopram AN tablets Product Information

Amneal Pharma Australia Pty Ltd

Impaired renal function

Escitalopram is extensively metabolised and excretion of unchanged drug in urine is a minor route

of elimination. At present no information is available for the treatment of patients with severely

reduced renal function (creatinine clearance < 20 mL/min) and escitalopram should be used with

caution in such patients (

see DOSAGE AND ADMINISTRATION).

Preclinical safety

High doses of escitalopram, which resulted in plasma C

for escitalopram and metabolites at least

8-fold greater than anticipated clinically, have been associated with convulsions, ECG abnormalities

and cardiovascular changes in experimental animals. Of the cardiovascular changes, cardiotoxicity

(including congestive heart failure) was observed in comparative

toxicological

studies

in rats

following oral escitalopram or citalopram administration for 4 to 13 weeks and appears to correlate

with peak plasma concentrations although its exact mechanism is not clear. Clinical experiences

with citalopram, and the clinical trial experience with escitalopram, do not indicate that these findings

have a clinical correlate.

Effects on fertility

No fertility studies were performed with escitalopram. However, other nonclinical studies suggest

that the effects of escitalopram can be directly predicted from those of the citalopram racemate

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)

Limited clinical data are available regarding exposure to escitalopram during pregnancy. Newborns

should be observed if maternal use of Escitalopram-PS Tablets continues into the later stages of

pregnancy, particularly in the third trimester. If escitalopram is used until or shortly before birth,

discontinuation effects in the newborn are possible.

Newborns exposed to Escitalopram, other SSRIs (Selective Serotonin Reuptake Inhibitors), or

SNRIs (Serotonin Norepinephrine Reuptake Inhibitors), late in the third trimester have developed

complications requiring prolonged hospitalisation, respiratory support, and tube feeding.

Such

complications can

arise immediately upon

delivery. Reported clinical findings have included

respiratory distress, cyanosis, apnoea, seizures, temperature instability, feeding difficulty, vomiting,

hypoglycaemia,

hypotonia,

hypertonia,

hyperreflexia,

tremor,

jitteriness,

irritability,

lethargy,

constant crying, somnolence and difficulty sleeping. These features are consistent with either a direct

toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. In the majority of

cases the complications begin immediately or soon (<24 hours) after delivery.

Epidemiological data have suggested that the use of SSRIS in pregnancy, particularly in late

pregnancy, may increase the risk of persistent pulmonarv hypertension in the newborn (PPHN).

Oral treatment of rats with escitalopram during organogenesis at maternotoxic doses led to increased

post-implantation loss and reduced foetal 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

Escitalopram AN PI v3.0

Page 9

Escitalopram AN tablets Product Information

Amneal Pharma Australia Pty Ltd

(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 were 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 and only after careful consideration of the

risk/benefit.

Australian Categorisation definition of category C:

Drugs which, owing to their pharmacological

effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate

without causing malformations. These effects may be reversible. Accompanying texts should be

consulted for further details.

Use in lactation

It is expected that ecitalopram, like citalopram, will be excreted into human breast milk. Studies in

nursing mothers have shown that the mean combined dose of cilatopram and demethyylcitalopram

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 the citalopram data support the safety of use of escitalopram in breast-

feeding women, the decision to breast-feed should always be made as an individual risk/benefit

analysis.

Paediatric use (children and adolescents < 18 years)

The efficacy and safety of escitalopram has not been established in children and adolescents less

than 18 years of age. Consequently, escitalopram should not be used in children and adolescents

less than 18 years of age.

Use in the elderly (> 65 years)

Escitalopram AUC and half-life were increased in subjects ≥ 65 years of age compared to

younger subjects in

single-dose and

multiple-dose pharmacokinetic study. The

dose

escitalopram

elderly

patients

should

therefore

reduced

see

DOSAGE

AND

ADMINISTRATION).

Carcinogenicity

No carcinogenicity studies were performed with escitalopram. However, other nonclinical 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 80 mg/kg/day, respectively.

Genotoxicity

No genotoxicity studies were performed with escitalopram. However, other nonclinical studies

suggest that the effects of escitalopram can be directly predicted from those of the citalopram

racemate.

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

Escitalopram AN PI v3.0

Page 10

Escitalopram AN tablets Product Information

Amneal Pharma Australia Pty Ltd

INTERACTIONS WITH OTHER MEDICINES

MAOIs -

Co-administration with MAO inhibitors may cause serotonin syndrome

(see

CONTRAINDICATIONS).

Serotonin syndrome

Development of serotonin syndrome may occur in association with treatment with SSRIs and

SNRIs,

particularly when

given

combination with

MAOIs

other

serotonergic

agents.

Symptoms and signs of serotonin syndrome include rapid onset of neuromuscular excitation

(Hyperreflexia, incoordination, myoclonus, tremor), altered mental status (confusion, agitation,

hypomania) and autonomic dysfunction (diaphoresis, diarrhoea, fever, shivering and rapidly

fluctuating vital signs). Treatment with escitalopram should be discontinued if such events occur and

supportive symptomatic treatment initiated.

Pimozide

Co-administration of a single dose of pimozide 2 mg to subjects treated with racemic citalopram 40

mg/day for 11 days caused an increase in AUC and C

of pimozide, although not consistently

throughout the study. The co-administration of pimozide and citalopram resulted

in a

mean increase

in the QTc interval of approximately 10 msec. Due to the interaction with citalopram noted at a

low dose of pimozide, concomitant administration of escitalopram and pimozide is contraindicated

(see CONTRAINDICATIONS).

Serotonergic drugs

Co-administration

with

serotonergic

drugs

(e.g.

tramadol,

sumatriptan)

lead

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.

Lithium and tryptophan

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.

Medicines affecting the central nervous system

Given the primary CNS effects of escitalopram, caution should be used when it is taken in

combination with other centrally acting drugs.

Medicines lowering the seizure threshold

SSRIs can lower the seizure threshold. Caution is advised when concomitantly using other medicinal

products capable of

lowering the

seizure threshold

(e.g.

antidepressants

(tricyclics,

SSRIs),

neuroleptics

(phenothiazines,

thioxanthenes,

butyrophenones),

mefloquine,

bupropion

tramadol).

Hepatic enzymes

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 3A4, and a weak inhibitor of 2D6.

Effects of other drugs on escitalopram in vivo

Escitalopram AN PI v3.0

Page 11

Escitalopram AN tablets Product Information

Amneal Pharma Australia Pty Ltd

pharmacokinetics of

escitalopram was

changed

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 escitalopram with omeprazole (a CYP2C19 inhibitor) resulted in a moderate

(approximately

50%)

increase

plasma

concentrations

escitalopram

small but

statistically significant increase (31%) in the terminal half-life of escitalopram (see also Poor

metabolisers of CYP2C19

under DOSAGE AND ADMINISTRATION

Co-administration of escitalopram with cimetidine (moderately potent general enzyme inhibitor)

resulted in a moderate (approximately 70%) increase in the plasma concentrations of escitalopram.

Thus, caution should be exercised at the upper end of the dose range of escitalopram when used

concomitantly with CYP2C19 inhibitors (e.g. omeprazole, esomeprazole, fluoxetine, fluvoxamine,

lansoprazole, and ticlopidine) or cimetidine. A

reduction in the dose of escitalopram may be

necessary based on clinical judgement (see also Poor metabolisers of CYP2C19 under

DOSAGE

AND ADMINISTRATION

Effects of escitalopram on other drugs in vivo

Escitalopram is an inhibitor of the enzyme CYP2D6. Caution is recommended when escitalopram

is co-administered with medicinal products that are mainly metabolised by this enzyme, and that

have a narrow therapeutic index, e.g. flecainide, propafenone and metoprolol (when used in cardiac

failure), or some CNS acting medicinal products that are mainly metabolised by CYP2D6, e.g.

antidepressants

such

desipramine,

clomipramine

nortriptyline

antipsychotics

like

risperidone, thioridazine and haloperidol. Dosage adjustment may be warranted.

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.

similar

increase

plasma

levels

desipramine,

after

administration

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

clinically important interactions with carbamazepine (CYP3A4 substrate), triazolam (CYP3A4

substrate),

theophylline

(CYP1A2

substrate),

warfarin

(CYP3A4

CYP2C9

substrate),

levomepromazine (CYP2D6 inhibitor), lithium and digoxin.

Medicines that interfere with haemostasis (NSAIDs, aspirin, warfarin, etc)

Serotonin release by platelets plays an important role in haemostasis. There is an association

between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of

abnormal bleeding. Concurrent use of an NSAID, aspirin or warfarin potentiates this risk. Thus,

patients should be cautioned about using such medicines concurrently with Escitalopram.

Escitalopram AN PI v3.0

Page 12

Escitalopram AN tablets Product Information

Amneal Pharma Australia Pty Ltd

Alcohol

The combination of SSRIs and alcohol is not advisable.

ADVERSE EFFECTS

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. Data from

short-term placebo-controlled studies are presented below. The safety data from the long- term

studies showed a similar profile.

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

trials

Figures marked with * in the table below indicate adverse reactions where the incidence

with escitalopram is statistically significantly different from placebo (p<0.05).

System Organ Class and Preferred Term

PLACEBO

n (%)

ESCITALOPRAM

n (%)

Patients Treated

1795

2632

Patients with Treatment Emergent Adverse Event

1135 (63.2)

1891 (71.8)

GASTROINTESTINAL SYSTEM DISORDERS

nausea

151 (8.4)

481 (18.3)*

diarrhoea

91 (5.1)

207 (7.9)*

mouth dry

74 (4.1)

152 (5.8)*

constipation

42 (2.3)

71 (2.7)

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

System Organ Class and Preferred Term

PLACEBO

n (%)

ESCITALOPRAM

n (%)

abdominal pain

68 (2.6)

vomiting

54 (2.1)

dyspepsia

33 (1.3)

flatulence

31 (1.2)

CENTRAL AND PERIPHERAL NERVOUS SYSTEM DISORDERS

headache

305 (17.0)

506 (19.2)

dizziness

147 (5.6)*

paraesthesia

35 (1.3)

migraine

23 (0.8)

tremor

33 (1.3)

PSYCHIATRIC DISORDERS

insomnia

245 (9.3)*

somnolence

217 (8.2)*

Escitalopram AN PI v3.0

Page 13

Escitalopram AN tablets Product Information

Amneal Pharma Australia Pty Ltd

anorexia

56 (2.1)*

libido decreased

102 (3.9)*

anxiety

77 (2.9)

appetite decreased

35 (1.3)*

agitation

33 (1.3)*

nervousness

25 (1.0)

dreaming abnormal

41 (1.6)

impotence [gs]

22 (2.2)*

RESPIRATORY SYSTEM DISORDERS

upper respiratory tract infection

96 (3.6)

coughing

24 (0.9)

rhinitis

146 (5.5)

sinusitis

46 (1.7)

pharyngitis

57 (2.2)

yawning

58 (2.2)*

bronchitis

31 (1.7)*

26 (0.9)

BODY AS A WHOLE - GENERAL DISORDERS

influenza-like symptoms

87 (3.3)

fatigue

230 (8.7)*

back pain

74 (2.8)

SKIN AND APPENDAGES DISORDERS

sweating increased

145 (5.5)*

MUSCULOSKELETAL SYSTEM DISORDERS

arthralgia

27 (1.0)

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

System Organ Class and Preferred Term

PLACEBO

N (%)

ESCITALOPRAM

n (%)

REPRODUCTIVE DISORDERS, FEMALE

anorgasmia [gs]

47 (2.9)*

METABOLIC AND NUTRITIONAL DISORDERS

weight increase

REPRODUCTIVE DISORDERS, MALE

ejaculation disorder [gs]

48 (4.7)*

ejaculation failure [gs]

27 (2.7)*

CARDIOVASCULAR DISORDERS

hypertension

24 (1.3)*

Escitalopram AN PI v3.0

Page 14

Escitalopram AN tablets Product Information

Amneal Pharma Australia Pty Ltd

HEART RATE AND RHYTHM DISORDERS

palpitation

SECONDARY TERMS

inflicted injury (unintended injury)

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

Adverse Events in Relation to Dose

The potential dose dependency of common adverse events (defined as an incidence rate of ≥ 5% in

either the 10 mg or 20 mg escitalopram groups) 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 treated patients (66%) was similar to that of the placebo treated

patients (61%), while the incidence rate in 20 mg/day escitalopram treated patients was greater

(86%). Common adverse events that occurred in the 20 mg/day escitalopram group with an

incidence approximately twice that of the 10 mg/day escitalopram group and approximately

twice that of the placebo group are shown below.

Incidence of common adverse events* in patients with major depression receiving

placebo, 10 mg/day

Adverse Event

Placebo

(n=311)

10 mg/day Escitalopram

Tablets (n=310)

20 mg/day Escitalopram

Tablets (n=125)

Insomnia

Diarrhoea

Dry mouth

Somnolence

Dizziness

Sweating

<

Constipation

Fatigu

Indigestion

*adverse events with an incidence rate of at least 5% in either escitalopram group and with

an incidence rate in the 20 mg/day escitalopram group that was approximately twice that of

the 10 mg/day escitalopram group and the placebo group.

Vital Sign Changes

Escitalopram and placebo groups were compared with respect to (1) mean change from baseline in

vital signs (pulse, systolic blood pressure, and diastolic blood pressure) and (2) the incidence of

patients meeting criteria for potentially clinically significant changes from baseline in these

variables. These analyses did not reveal any clinically important changes in vital signs associated

with escitalopram treatment.

ECG Changes

Cases

prolongation have been reported during the

post-marketing period with both

citalopram and escitalopram. Citalopram can cause dose-dependent QT interval prolongation. In an

ECG study, the observed change from baseline QTc (Fridericia correction) was 7.5 msec at the

20mg/day dose and 16.7 msec at the 60mg/day dose of citalopram. The effect of escitalopram on the

QT interval was similarly studied at doses of 10mg/day and 30mg/day. The change from baseline

QTc (Fridericia correction) was 4.3 msec at the 10mg/day dose and 10.7 msec with the above

Escitalopram AN PI v3.0

Page 15

Escitalopram AN tablets Product Information

Amneal Pharma Australia Pty Ltd

recommended dose of 30mg/day. The QTc interval prolongation observed with 60mg citalopram

exceeded that observed with 30mg escitalopram. It is probable that the R-enantiomer and its

metabolites in racemic citalopram contribute to these effects.

Weight Changes

Patients treated with escitalopram in controlled trials did not differ from placebo-treated patients

with regard to clinically important change in body weight.

Laboratory Changes

In clinical studies, there were no signals of clinically important changes in either various serum

chemistry, haematology, and urinalysis parameters associated with escitalopram treatment compared

to placebo or in the incidence of patients meeting the criteria for potentially clinically significant

changes from baseline in these variables.

For abnormal laboratory changes registered as either

uncommon events

serious adverse events

from

ongoing

trials

observed

during

(but

necessarily

caused

treatment

with

escitalopram,

please

Other

Events

Observed

during

Premarketing

Evaluation

Escitalopram Tablets.

Other changes Observed during the Premarketing Evaluation of Escitalopram Tablets

Following is a list of WHO terms that reflect adverse events occurring at an incidence of < 1% and

serious adverse events from ongoing trials. All reported events are included except those already

listed in the table or elsewhere in the Adverse Effects section, and those occurring in only one

patient. It is important to emphasise that, although the events reported occurred during treatment

with Escitalopram Tablets, they were not necessarily caused by it.

Events are further categorised by body system and are listed below. Uncommon adverse events are

those occurring in less than 1/100 patients but at least 1/1,000 patients.

Application Site Disorders

Uncommon: otitis externa, cellulitis.

Body as a Whole

Uncommon:

allergy, aggravated allergy, allergic reactions, asthenia, carpal tunnel syndrome, chest

pain, chest tightness, fever, hernia, leg pain, limb pain, neck pain, oedema, oedema of extremities,

peripheral oedema, rigors, malaise, syncope, scar.

Cardiovascular Disorders, General

Uncommon: hypertension aggravated, hypotension, hypertension, abnormal ECG

.

Central and Peripheral Nervous System Disorders

Uncommon:

ataxia, dysaesthesia, dysequilibrium, dysgeusia, dystonia, hyperkinesia, hyperreflexia,

hypertonia, hypoaesthesia, leg cramps, lightheadedness, muscle contractions, nerve root lesion,

neuralgia, neuropathy, paralysis, sedation, tetany, tics, twitching, vertigo.

Gastrointestinal System Disorders

Uncommon:

abdominal cramp, abdominal discomfort, belching, bloating, change in bowel habit,

colitis,

colitis

ulcerative,

enteritis,

epigastric

discomfort,

gastritis,

gastroesophageal

reflux,

haemorrhoids, heartburn, increased stool frequency, irritable bowel syndrome, melaena, periodontal

Escitalopram AN PI v3.0

Page 16

Escitalopram AN tablets Product Information

Amneal Pharma Australia Pty Ltd

destruction, rectal haemorrhage, tooth disorder, toothache, ulcerative stomatitis.

Hearing and Vestibular Disorders

Uncommon: deafness, earache, ear disorder, otosalpingitis, tinnitus.

Heart Rate and Rhythm Disorders

Uncommon: bradycardia, tachycardia.

Liver and Biliary System Disorders

Uncommon: bilirubinaemia, hepatic enzymes increased.

Metabolic and Nutritional Disorders

Uncommon: abnormal glucose tolerance, diabetes mellitus, gout, hypercholesterolaemia,

hyperglycaemia, hyperlipaemia, thirst, weight decrease, xerophthalmia.

Musculoskeletal System Disorders

Uncommon:

arthritis, arthropathy, arthrosis, bursitis, costochondritis, fascitis plantar, fibromyalgia,

ischial neuralgia, jaw stiffness, muscle cramp, muscle spasms, muscle stiffness, muscle tightness,

muscle weakness, myalgia, myopathy, osteoporosis, pain neck/shoulder, tendinitis, tenosynovitis.

Myo-, Endo- and Pericardial and Valve Disorders

Uncommon:

myocardial infarction, myocardial ischaemia, myocarditis, angina pectoris.

Neoplasm

Uncommon: female breast neoplasm, ovarian cyst, uterine fibroid.

Platelet, Bleeding and Clotting Disorders

Uncommon:

abnormal bleeding, predominantly of the skin and mucous membranes, including

purpura, epistaxis, haematomas, vaginal bleeding and gastrointestinal bleeding.

Poison Specific Terms

Uncommon:

sting.

Psychiatric Disorders

Uncommon: aggressive reaction, amnesia, apathy, bruxism, carbohydrate craving, concentration

impairment, confusion, depersonalisation, depression, depression aggravated, emotional lability,

excitability, feeling unreal, forgetfulness, hallucination, hypomania, increased appetite,

irritability,

jitteriness,

lethargy,

loss

libido,

obsessive-compulsive disorder,

panic

reaction,

paroniria, restlessness aggravated, sleep disorder, snoring, suicide attempt, thinking abnormal.

Red Blood Cell Disorders

Uncommon:

anaemia hypochromic, anaemia.

Reproductive Disorders / Female

Uncommon:

amenorrhoea, atrophic vaginitis, breast pain, genital infection, intermenstrual bleeding,

menopausal symptoms, menorrhagia, menstrual cramps, menstrual disorder, premenstrual tension,

postmenopausal bleeding,

sexual

function

abnormality, unintended pregnancy, dysmenorrhoea,

vaginal haemorrhage, vaginal candidiasis, vaginitis.

Escitalopram AN PI v3.0

Page 17

Escitalopram AN tablets Product Information

Amneal Pharma Australia Pty Ltd

Reproductive Disorders / Male

Uncommon:

ejaculation delayed, prostatic disorder.

Resistance Mechanism Disorders

Uncommon: moniliasis genital, abscess, infection, herpes simplex, herpes zoster, infection bacterial,

infection parasitic, infection (tuberculosis), moniliasis.

Respiratory System Disorders

Uncommon:

asthma, dyspnoea, laryngitis, nasal congestion, nasopharyngitis, pneumonia, respiratory

tract infection, shortness of breath, sinus congestion, sinus headache, sleep apnoea, tracheitis, throat

tightness.

Skin and Appendages Disorders

Uncommon:

acne, alopecia, dermatitis, dermatitis fungal, dermatitis lichenoid, dry skin, eczema,

erythematous rash, furunculosis, onychomycosis, pruritus, psoriasis aggravated, rash, rash pustular,

skin disorder, urticaria, verruca.

Secondary Terms

Uncommon: accidental injury, bite, burn, fall, fractured neck of femur, alcohol problem, traumatic

haematoma, cyst, food poisoning, lumbar disc lesion, surgical intervention.

Special Senses Other, Disorders

Uncommon: dry eyes, eye irritation, taste alteration, taste perversion, visual disturbance, ear

infection NOS, vision blurred.

Urinary System Disorders

Uncommon:

cystitis, dysuria, facial oedema, micturition frequency, micturition disorder, nocturia,

polyuria,

pyelonephritis,

renal

calculus,

urinary

frequency,

urinary

incontinence,

urinary

tract

infection

.

Vascular (Extracardiac) Disorders

Uncommon:

cerebrovascular disorder, flushing, hot flush [gs], ocular haemorrhage, peripheral

ischaemia, varicose vein, vein disorder, vein distended.

Vision Disorders

Uncommon: accommodation abnormal, blepharospasm, eye infection, eye pain, mydriasis, vision

abnormal, vision blurred, visual disturbance.

White Cell and Reticuloendothelial System Disorders

Uncommon: leucopenia.

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).

Neurological disorders

Convulsions, convulsions grand mal and extrapyramidal disorder, serotonin syndrome (typically

Escitalopram AN PI v3.0

Page 18

Escitalopram AN tablets Product Information

Amneal Pharma Australia Pty Ltd

characterised by a rapid onset of changes in mental state, with confusion, mania, agitation,

hyperactivity, shivering, fever, tremor, ocular movements, myoclonus, hyperreflexia, and inco-

ordination).

Skin disorders

Ecchymoses, angioedema.

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.

Hepatobiliary disorders

Abnormal liver function tests.

Neurological disorders

Movement disorders.

Psychiatric disorders

Mania, panic attacks.

Renal and urinary disorders

Urinary retention.

Reproductive disorders

Galactorrhoea.

Other Events Observed During the Postmarketing Evaluation of Escitalopram

Although no causal relationship to escitalopram treatment has been found, the following adverse

events have been reported in association with escitalopram treatment in at least 3 patients (unless

otherwise noted) and not described elsewhere in the

Adverse Effects section:

Stomatitis, drug interaction NOS, feeling abnormal, hypersensitivity NOS, non-accidental overdose,

injury NOS.

In addition, although no causal relationship to racemic citalopram treatment has been found, the

following adverse events have been reported to be temporally associated with racemic citalopram

treatment subsequent to the marketing of racemic citalopram and were not observed during the

premarketing evaluation of escitalopram or citalopram: acute renal failure, akathisia, anaphylaxis,

choreoathetosis, delirium, dyskinesia, epidermal necrolysis, erythema multiforme, gastrointestinal

haemorrhage, haemolytic anaemia, hepatic necrosis, myoclonus, neuroleptic malignant syndrome,

nystagmus,

pancreatitis,

priapism,

prolactinaemia,

prothrombin

decreased,

prolonged,

rhabdomyolysis,

spontaneous

abortion,

thrombocytopenia,

thrombosis,

Torsades

pointes,

ventricular arrhythmia, and withdrawal syndrome.

Class effect

Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased

Escitalopram AN PI v3.0

Page 19

Escitalopram AN tablets Product Information

Amneal Pharma Australia Pty Ltd

risk of bone fractures in patients receiving SSRIs and TCAs. The mechanism leading to this risk is

unknown.

DOSAGE AND ADMINISTRATION

Adults

Escitalopram is administered as a single oral dose and may be taken with or without food.

Major depression

The recommended dose is 10 mg (one 10 mg tablet) once daily. Depending on individual patient

response, the dose may be increased to a maximum of 20 mg (one 20 mg tablet) 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.

Elderly patients (> 65 years of age)

A longer half-life and a decreased clearance have been demonstrated in the elderly. 10 mg (one 10

mg tablet) is the recommended maximum maintenance dose in the elderly (

see

Pharmacokinetics and PRECAUTIONS

Children and adolescents (< 18 years of age)

Safety and efficacy have not been established in this population. Escitalopram should not be used in

children and adolescents under 18 years of age (

see PRECAUTIONS

Reduced hepatic function

An initial dose of 5 mg (half a 10 mg tablet) daily for the first two weeks of treatment is

recommended. Depending on individual patient response, the dose may be increased to 10 mg (one

10 mg tablet) (

see PRECAUTIONS

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) (

see PRECAUTIONS

Poor metabolisers of CYP2C19

For patients who are known to be poor metabolisers with respect to CYP2C19, an initial dose of

5 mg (half a 10 mg tablet) daily during the first two weeks of treatment is recommended. Depending

on individual patient response, the dose may be increased to 10 mg (one 10 mg tablet) (

see

Pharmacokinetics and Interactions with other medicines under PRECAUTIONS).

Discontinuation

Significant numbers

discontinuation symptoms may

occur with

abrupt discontinuation of

escitalopram. To minimise discontinuation reactions, tapered discontinuation over a period of at

least one to two weeks is recommended. If unacceptable discontinuation symptoms occur following

a decrease in the dose or upon discontinuation of treatment then resuming the previously prescribed

Escitalopram AN PI v3.0

Page 20

Escitalopram AN tablets Product Information

Amneal Pharma Australia Pty Ltd

dose may be considered. Subsequently, the dose may be decreased but at a more gradual rate.

OVERDOSAGE

In general, the main therapy for all overdoses is supportive and symptomatic care Toxicity:

Clinical

data on escitalopram overdose are limited and many cases involve concomitant

overdoses of other

drugs. In the majority of cases mild or no symptoms have been reported. Doses between 400 and

800 mg of escitalopram alone have been taken without any severe symptoms.

fatalities

sequelae were reported in the few cases with a higher dose (one patient survived ingestion of

either 2,400 or 4,800 mg).

Symptoms: Symptoms seen in reported overdose of escitalopram include symptoms mainly related

to the central nervous system (ranging from dizziness, tremor and agitation to rare cases of serotonin

syndrome, convulsion and coma), the gastrointestinal system (nausea/vomiting), the cardiovascular

system (hypotension, tachycardia, arrhythmia and ECG changes (including QT prolongation)), and

electrolyte/fluid balance conditions.

Treatment: There is no specific antidote. Establish and maintain an airway, ensure adequate

oxygenation and respiratory function. The use of activated charcoal should be considered. Activated

charcoal may reduce absorption of the drug if given within one or two hours after ingestion. In

patients who are not fully conscious or have impaired gag reflex, consideration should be given to

administering activated charcoal via a nasogastric tube, once the airway is protected. Cardiac and vital

signs monitoring are recommended along with general symptomatic supportive measures.

For further advice on management of overdose please contact the Poisons Information Centre

(Tel: 13 11 26 for Australia).

PRESENTATION AND STORAGE CONDITIONS

Escitalopram AN Tablets 10 mg /20 mg are presented in clear PVC/PE/PVDC-Aluminium blisters.

Each pack contains 28 Tablets

Escitalopram AN Tablets 10 mg

Film-coated tablets containing 10 mg escitalopram (as oxalate).

Escitalopram AN Tablets 20 mg

Film-coated tablets containing 20 mg escitalopram (as oxalate).

STORAGE:

Store below 25

C. Keep in a dry place.

NAME AND ADDRESS OF THE SPONSOR

Amneal Pharma Australia Pty Ltd

12 River St, South Yarra, 3141 VIC

Australia

Escitalopram AN PI v3.0

Page 21

Escitalopram AN tablets Product Information

Amneal Pharma Australia Pty Ltd

POISON SCHEDULE OF THE MEDICINE

Schedule 4 (Prescription Only Medicine)

DATE

OF

FIRST

INCLUSION

IN

THE

AUSTRALIAN

REGISTER

OF

THERAPEUTIC GOODS (the ARTG)

16 February 2011

DATE OF MOST RECENT AMENDMENT

10 June 2015

Escitalopram AN PI v3.0

Page 22