Consumer medicine information

Esipram

Escitalopram

BRAND INFORMATION

Brand name

Esipram

Active ingredient

Escitalopram

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Esipram.

What is in this leaflet

This leaflet contains answers to some common questions about Esipram.

It does not contain all the information that is known about Esipram. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risk of you using this medicine against the benefits he/she expects it will have for you.

If you have any concerns about using this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Esipram is used for

Esipram is used to treat depression.

It belongs to a group of medicines called selective serotonin reuptake inhibitors (SSRIs). They are thought to work by their actions on brain chemicals called amines which are involved in controlling mood.

Depression is longer lasting or more severe than the "low moods" everyone has from time to time due to the stress of everyday life. It is thought to be caused by a chemical imbalance in parts of the brain. This imbalance affects your whole body and can cause emotional and physical symptoms such as feeling low in spirit, loss of interest in activities, being unable to enjoy life, poor appetite or overeating, disturbed sleep, often waking up early, loss of sex drive, lack of energy and feeling guilty over nothing.

Esipram corrects this chemical imbalance and may help relieve the symptoms of depression.

Esipram may also be used to treat patients who may avoid and/or are fearful of social situations.

Esipram may also be used to treat patients who have excessive anxiety and worry.

Esipram may also be used to treat irrational fears or obsessional behaviour (obsessive-compulsive disorder). Obsessive-compulsive disorder involves having both obsessions and compulsions. Obsessions are unwanted thoughts that occur over and over again. Compulsions are the ongoing need to repeat certain actions as a result of these thoughts.

Your doctor, however, may prescribe it for another purpose.

Ask your doctor if you have any questions about why it has been prescribed for you. This medicine is only available with a doctor's prescription.

Esipram is not addictive. However, if you suddenly stop taking it, you may get side effects.

Tell your doctor if you get any side effects after stopping Esipram.

Before you take it

When you must not take it

Do not take Esipram if you are allergic to it, to any medicine containing escitalopram, citalopram, or any of the ingredients listed at the end of this leaflet. Symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing, swelling of the face, lips, tongue or other parts of the body, or rash, itching or hives on the skin.

Do not take Esipram at the same time as the following other medicines:

  • pimozide, a medicine used to treat mental disorders
  • monoamine oxidase inhibitors (MAOIs), such as phenelzine, tranylcypromine and moclobemide which are also used for the treatment of depression.
    One day must elapse after you have finished taking moclobemide before you start taking Esipram. If you have taken any other MAOI you will need to wait 14 days. After stopping Esipram you must allow 14 days before taking any MAOI including moclobemide.
    Taking Esipram with MAOIs may cause a serious reaction with a sudden increase in body temperature, extremely high blood pressure and severe convulsions. Your doctor will know when it is safe to start Esipram after the MAOI has been stopped.

Do not take it after the expiry date printed on the pack. If you take it after the expiry date has passed, it may not work as well. The expiry date refers to the last day of the month.

Do not take it if the packaging is torn or shows signs of tampering.

Before you start to take it

Tell your doctor if:

  1. you have allergies to any other substances such as foods, preservatives or dyes.
  2. you are pregnant or intend to become pregnant.
Medicines like Esipram have been shown to reduce the quality of sperm in animal studies, which theoretically could affect fertility. If you are intending to start a family, ask your doctor for advice.
Do not take Esipram if you are pregnant unless you and your doctor have discussed the risks and benefits involved.
Make sure your doctor and/or midwife know you are on Esipram.
When taken during pregnancy, particularly in the last three months of pregnancy, medicines like Esipram may affect the general condition of your newborn baby and may increase the risk of a serious condition in babies, called persistent pulmonary hypertension of the newborn (PPHN), making the baby breathe faster and appear bluish. These symptoms usually begin during the first 24 hours after the baby is born. If this happens to your baby you should contact your doctor and/or midwife immediately.
If used during pregnancy Esipram should never be stopped abruptly.
  1. you are breast-feeding or planning to breast-feed.
Do not take Esipram if you are breast-feeding unless you and your doctor have discussed the risks and benefits involved. It is not recommended that you breast-feed while taking Esipram as it is excreted in breast milk.
  1. you have, or have had, the following medical conditions:
  • a tendency to bleed or bruise easily
  • diabetes
  • heart disease
  • kidney disease
  • liver disease
  • bipolar disorder (manic depression)
  • a history of seizures or fits
  • restlessness and/or a need to move often
  • raised intraocular pressure (fluid pressure in the eye), or if you are at risk of angle-closure glaucoma.
  1. you are receiving electroconvulsive therapy.

Do not give Esipram to a child or adolescent. There is no experience with its use in children or adolescents under 18 years old.

Esipram can be given to elderly patients over 65 years of age with a reduced dose. The effects of Esipram in elderly patients are similar to that in other patients.

If you have not told your doctor about any of the above, tell them before you use Esipram.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and Esipram may interfere with each other. These include:

  • bupropion, a medicine helping to treat nicotine dependence
  • medicines used to treat reflux and ulcers, such as cimetidine, omeprazole, esomeprazole and lansoprazole
  • medicines known to prolong bleeding, e.g. aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs)
  • ticlopidine and warfarin, medicines used to prevent blood clots
  • fluconazole, an anti-fungal medicine
  • mefloquine, an anti-malaria medicine
  • sumatriptan, used to treat migraines
  • tramadol, used to relieve pain
  • medicines affecting the chemicals in the brain
  • some heart medications, e.g. flecainide, propafenone, metoprolol
  • tryptophan, an amino-acid
  • lithium, used to treat mood swings and some types of depression
  • antipsychotics, a class of medicines used to treat certain mental and emotional conditions, e.g. risperidone, thioridazine and haloperidol
  • tricyclic antidepressants, e.g. imipramine, desipramine
  • St John's Wort (Hypericum perforatum), a herbal remedy
  • any other medicines for depression, anxiety, obsessive-compulsive disorder or pre-menstrual dysphoric disorder

These medicines may be affected by Esipram, or may affect how well it works. You may need to use different amounts of your medicines, or take different medicines. Your doctor will advise you.

Some combinations of medicines may increase the risk of serious side effects and are potentially life threatening.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking Esipram.

How to take it

How much to take

Your doctor will decide what dose you will receive.

The standard dose for this medicine is 10 mg per day. This may be increased by your doctor to 20 mg per day.

The recommended maximum dose in elderly patients is 10 mg per day.

It is recommended that patients with liver disease receive an initial dose of 5 mg daily for the first two weeks. Your doctor may increase the dose to 10 mg daily.

Your doctor may have prescribed a different dose.

Ask your doctor or pharmacist if you are unsure of the correct dose for you. They will tell you exactly how much to take.

Follow the instructions they give you. If you take the wrong dose, Esipram may not work as well and your condition may not improve.

How to take it

Swallow the tablets whole with a full glass of water.

Do not chew them.

When to take it

Take Esipram as a single dose either in the morning or in the evening.

Take Esipram with or without food.

How long to take it

Continue to take Esipram even if it takes some time before you feel any improvement in your condition. As with other medicines for the treatment of these conditions it may take a few weeks before you feel any improvement.

Individuals will vary greatly in their response to Esipram. Your doctor will check your progress at regular intervals.

The duration of treatment may vary for each individual, but is usually at least 6 months.

In some cases the doctor may decide that longer treatment is necessary.

Continue taking your medicine for as long as your doctor tells you, even if you begin to feel better. The underlying illness may persist for a long time and if you stop your treatment too soon, your symptoms may return.

Do not stop taking this medicine suddenly. If Esipram is stopped suddenly you may experience mild, but usually temporary, symptoms such as dizziness, pins and needles, electric shock sensations, sleep disturbances (vivid dreams, inability to sleep), feeling anxious or agitated, headaches, feeling sick (nausea), vomiting, sweating, tremor (shaking), feeling confused, feeling emotional or irritable, diarrhoea, visual disturbances, or fast or irregular heart beats.

When you have completed your course of treatment, the dose of Esipram is gradually reduced over a couple of weeks rather than stopped abruptly.

Your doctor will tell you how to reduce the dosage so that you do not get these unwanted effects.

If you forget to take it

If you miss a dose and remember in less than 12 hours, take it straight away, and then go back to taking it as you would normally.

Otherwise, if it is almost time for your next dose, skip the dose you missed and take the next dose when you are meant to.

Do not take a double dose to make up for the dose you have missed.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering when to take your medicine, ask your pharmacist for hints.

If you take too much (overdose)

Immediately telephone your doctor, or the Poisons Information Centre (Tel: 13 11 26), or go to Accident and Emergency at your nearest hospital, if you think you or anyone else may have taken too much Esipram.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Symptoms of an overdose may include dizziness, low blood pressure, nausea (feeling sick), vomiting, agitation, tremor (shaking) and rarely convulsions and coma.

While you are taking it

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Esipram.

Tell any other doctors, dentists and pharmacists who treat you that you are taking this medicine.

If you become pregnant while taking Esipram, tell your doctor immediately.

Persons taking Esipram may be more likely to think about killing themselves or actually trying to do so, especially when Esipram is first started or the dose is changed. Tell your doctor immediately if you have thoughts about killing yourself or if you are close to or care for someone using Esipram who talks about or shows signs of killing him or herself.

All mentions of suicide or violence must be taken seriously.

Occasionally, the symptoms of depression may include thoughts of suicide or self-harm. It is possible that these symptoms continue or get worse until the full antidepressant effect of the medicine becomes apparent. This is more likely to occur if you are a young adult, i.e. 18 to 24 years of age, and you have not used antidepressant medicines before.

Patients and care givers should pay attention for any of the following warning signs of suicide-related behaviour while taking Esipram. Tell your doctor immediately, or even go to the nearest hospital for treatment:

  • thoughts or talk of death or suicide
  • thoughts or talk of self-harm or harm to others
  • any recent attempts of self-harm
  • increase in aggressive behaviour, irritability or agitation

Do not stop taking this medicine or change the dose without consulting your doctor, even if you experience increased anxiety at the beginning of treatment. At the beginning of treatment, some patients may experience increased anxiety which will disappear during continued treatment.

Tell your doctor immediately if you experience symptoms such as restlessness or difficulty in sitting or standing still. These symptoms can occur during the first weeks of treatment.

Contact your doctor as soon as possible if you suddenly experience an episode of mania. Some patients with bipolar disorder (manic depression) may enter into a manic phase. This is characterised by profuse and rapidly changing ideas, exaggerated gaiety and excessive physical activity.

Sometimes you may be unaware of the above-mentioned symptoms and therefore you may find it helpful to ask a friend or relative to help you to observe the possible signs of change in your behaviour.

Things you must not do

Do not give the tablets to anyone else, even if they have the same condition as you.

Do not take Esipram to treat any other complaints unless your doctor tells you to.

Do not stop taking Esipram, or lower the dosage, without checking with your doctor.

Do not let yourself run out of medicine over the weekend or on holidays.

Suddenly stopping Esipram may cause unwanted discontinuation symptoms such as dizziness, headache and nausea. Your doctor will tell you when and how Esipram should be discontinued. Your doctor will gradually reduce the amount you are using, usually over a period of one to two weeks, before stopping completely.

Things to be careful of

Be careful driving or operating machinery until you know how Esipram affects you. It may cause visual disturbance (such as blurred vision), nausea, fatigue and dizziness in some people, especially early in the treatment. If you have any of these symptoms, do not drive, operate machinery, or do anything else that could be dangerous.

Avoid alcohol while you are taking this medicine. It is not advisable to drink alcohol while you are being treated for depression.

Side effects

All medicines may have some unwanted side effects. Sometimes they are serious, but most of the time they are not. Your doctor has weighed the risks of using this medicine against the benefits he/she expects it will have for you.

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Esipram. It helps most people with depression, social anxiety disorder (social phobia), generalised anxiety disorder and obsessive-compulsive disorder, but it may have unwanted side effects in a few people.

The side effects of Esipram are, in general, mild and disappear after a short period of time.

Tell your doctor if you notice any of the following and they worry you:

  • decreased appetite or loss of appetite
  • dry mouth
  • diarrhoea
  • nausea (feeling sick)
  • sleeplessness
  • fatigue, sleepiness or drowsiness, yawning
  • increased sweating
  • sexual disturbances (decreased sexual drive; problems with ejaculation or erection; women may experience difficulties achieving orgasm)

*The side effects marked with an asterisk (*) are a number of rare side effects that are known to occur with medicines that work in a similar way to Esipram

Tell your doctor as soon as possible if you notice any of the following:

  • agitation, confusion, panic attacks*, anxiety, restlessness*
  • dizziness
  • dizziness when you stand up due to low blood pressure*
  • a fast heart rate or decrease in heart rate or irregular heart beat
  • low sodium levels in the blood (the symptoms are feeling sick and unwell with weak muscles or feeling confused)*
  • abnormal liver function tests (increased amounts of liver enzymes in the blood)*
  • difficulties urinating*
  • unusual secretion of breast milk*
  • bleeding disorders including skin and mucous bleeding (e.g. bruising*) and a low level of blood platelets*
  • rash, itching, patches of circumscribed swellings
  • an increased risk of bone fractures has been observed in patients taking this type of medicine*

These may be serious side effects of Esipram. You may need urgent medical attention.

Tell your doctor immediately, or go to Accident and Emergency at your nearest hospital, if you notice any of the following:

  • thoughts of harming yourself or thoughts of suicide*, see also section "Things you must do"
  • serious allergic reaction
    (symptoms of an allergic reaction may include swelling of the face, lips, mouth or throat which may cause difficulty in swallowing or breathing, or hives)
  • high fever, agitation, confusion, trembling and abrupt contractions of muscles
    (these symptoms may be signs of a rare condition called serotonin syndrome)*
  • mania (i.e.: elevated mood and associated symptoms)*
  • hallucinations
  • seizures, tremors, movement disorders (involuntary movements of the muscles)*
  • fast, irregular heart beat with feelings of dizziness or difficulty breathing

These are very serious side effects. You may need urgent medical attention or hospitalisation.

.

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed above may occur in some people.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After taking it

Storage

Keep Esipram tablets in the blister pack until it is time to take them. If you take the tablets out of the box or the blister pack they may not keep well.

Keep Esipram tablets in a cool dry place where the temperature stays below 30°C.

Do not store it or any other medicine in the bathroom, near a sink, or on a window-sill.

Do not leave it in the car. Heat and damp can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking Esipram, or the medicine has passed its expiry date, ask your pharmacist what to do with any that is left over.

Return any unused medicine to your pharmacist.

Product description

What it looks like

Esipram comes in two types of tablets:

  • Esipram 10 mg film-coated tablets - oval, white, scored and marked with "E" and "L" on each side of the score on one side of the tablet
  • Esipram 20 mg film-coated tablets - oval, white, scored and marked with "E" and "N" on each side of the score on one side of the tablet

A box contains 28 tablets.

Ingredients

Active ingredient(s):

  • Esipram 10 mg tablets - 10 mg escitalopram (as oxalate) per tablet
  • Esipram 20 mg tablets - 20 mg escitalopram (as oxalate) per tablet

Inactive ingredients (tablets):

  • microcrystalline cellulose
  • croscarmellose sodium
  • opadry OY-S28849 PI (4748) (contains: hypromellose, macrogol 400 and titanium dioxide)
  • magnesium stearate
  • colloidal anhydrous silica
  • purified talc

Esipram does not contain lactose, gluten, sucrose, tartrazine or any other azo dyes.

Manufacturer/Sponsor

Esipram is made by H. Lundbeck A/S, Denmark.

Esipram is supplied in Australia by:

CNS Pharma Pty Ltd
Level 5
Deutsche Bank Place
126 Phillip Street
Corner Hunter and Phillip Streets
Sydney NSW 2000
Tel: +61 2 8669 1068

This leaflet was prepared on
26-02-2020

Australian Registration Numbers:

Esipram tablets

10 mg - AUST R 128781

20 mg - AUST R 128783

"Esipram" is the registered trademark of H. Lundbeck A/S.

Published by MIMS April 2020

BRAND INFORMATION

Brand name

Esipram

Active ingredient

Escitalopram

Schedule

S4

 

1 Name of Medicine

Escitalopram oxalate.

6.7 Physicochemical Properties

Chemical name.

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

Molecular formula and weight.

C20H21FN2O, C2H2O4; 414.42.

Chemical structure.


CAS number.

219861-08-2.

2 Qualitative and Quantitative Composition

Esipram tablets 10 mg and 20 mg.

Film-coated tablets containing 10 mg and 20 mg escitalopram (as oxalate).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Esipram 10 mg tablets: Oval, white, scored, film-coated tablets marked with "E" and "L" on one side.
Esipram 20 mg tablets: Oval, white, scored, film-coated tablets marked with "E" and "N" on one side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Biochemical and behavioural studies have shown that escitalopram is a potent inhibitor of serotonin (5HT) uptake (in vitro IC50 2 nanomolar).
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 5HT 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 5HT1A, 5HT2, DA D1 and DA D2 receptors, α1, α2, 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.
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 5HT reuptake than escitalopram in vitro. It is therefore unlikely to contribute significantly to the overall antidepressant effect.

Clinical trials.

Esipram should not be used for the treatment of major depression, generalised anxiety disorder and social anxiety disorder in children and adolescents under the age of 18 years since the safety and efficacy in this population have not been established.

Major depression.

Esipram 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 of 10 items that measure core symptoms of depression, such as 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.
In the study with two parallel escitalopram dose groups, analysis of subgroups of 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 eight 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 (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.
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 ≥ 22, or discontinuation due to 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% versus 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.

Generalised anxiety disorder (GAD).

Esipram should not be used in the treatment of children and adolescents under the age of 18 years.
The efficacy of escitalopram in the treatment of generalised anxiety disorder was demonstrated in three eight week placebo controlled flexible dose studies (10 to 20 mg/day) and one twelve week fixed dose, active reference (paroxetine 20 mg/day), study (5, 10 and 20 mg/day).
In the four studies, the mean HAM-A total scores at baseline ranged from 22.1 to 27.7 and the CGI-S scores were 4.2 or higher, indicating significant GAD symptomatology.
In all three placebo controlled, flexible dose studies, escitalopram was significantly better than placebo at endpoint on the primary efficacy measure (mean change from baseline to endpoint in HAM-A total score), and the results were supported by secondary efficacy measures.
In the fixed dose study, over a 12 week period, escitalopram in doses of 10 and 20 mg/day was statistically significantly more effective than placebo on the primary measure of efficacy, with an effect size at least as high as that of the reference treatment paroxetine. The 5 mg dose of escitalopram was numerically, but not statistically significantly, superior to placebo. 10 mg escitalopram was statistically significantly superior to the reference treatment paroxetine (LOCF) based on the HAM-A and CGI-I. (See Table 3.)
In the pooled analysis, of these three placebo controlled, flexible dose studies of similar design, the mean change from baseline in HAM-A total score improved statistically significantly (LOCF) over time in the escitalopram group relative to the placebo group. The separation from placebo was first observed at week 1 and continued through to the end of the study (week 8). The treatment difference to placebo at week 8 was -2.3 in favour of escitalopram (p ≤ 0.01).
The results of the primary analysis (pooled data) were supported by secondary LOCF analyses (pooled data), where escitalopram was statistically significantly superior to placebo on the HAM-A psychic anxiety subscale score (p ≤ 0.001), the HAM-A item 1 (anxious mood) score (p ≤ 0.001), and the HAM-A item 2 (tension) score (p ≤ 0.01). Escitalopram was also more effective than placebo on the CGI-S score (p ≤ 0.01) and on the CGI-I score at week 8 (p ≤ 0.001). The results on the HAD anxiety subscale, the HAM-A somatic subscale, the HAM-D anxiety scale, the Covi Anxiety Scale (OC), and the QoL (OC) also showed superior efficacy of escitalopram relative to placebo at week 8 (p ≤ 0.05).
The long-term efficacy of escitalopram in the treatment of GAD is based on the results from the double blind active comparator study, an open label extension study and a double blind, randomised, placebo controlled relapse prevention study.
The active comparator study demonstrated numerically superior efficacy of escitalopram over paroxetine both on the primary efficacy measure (mean change from baseline in HAM-A total score) and on the secondary efficacy measures (mean change from baseline in HAM-A psychic anxiety, CGI-S, QoL, HAM-A somatic anxiety, HAM-A item 1 (anxious mood), HAM-A item 2 (tension), HAM-D anxiety and Covi scores, and mean CGI-I score) at week 24. For all but one (QoL) of the efficacy measures, a further improvement was seen from week 8 to week 24. In the primary efficacy analysis, the extra improvement in mean HAM-A total score over the last 16 weeks of treatment was 2.3 points for escitalopram compared with 1.6 points for paroxetine.
Further evidence of long-term efficacy is provided by an open label extension study, which showed a beneficial effect of continued treatment with escitalopram. In this study, escitalopram treatment was associated with additional improvement beyond the response observed during the initial 8 weeks of treatment in the lead-in studies. The mean change in HAM-A total score from baseline (final visit of the lead-in study) to week 24 (LOCF) was -3.8, with greater improvement observed in patients who were switched from placebo in the lead-in study to escitalopram in the extension study (4.9 points versus 2.7 points for those previously treated with escitalopram). Similar positive results were seen in the analyses of secondary efficacy measures.
Escitalopram 20 mg/day significantly reduced the risk of relapse in a 24 to 76 week randomised, continuation study in 373 patients who had responded during the initial 12 week open label treatment.

Social anxiety disorder (SAD).

Esipram should not be used in the treatment of children and adolescents under the age of 18 years.
The efficacy of escitalopram in the treatment of SAD was demonstrated in three placebo controlled clinical studies. A short-term, flexible dose (10 to 20 mg/day) study, a long-term, fixed dose (5, 10 and 20 mg/day), active reference (paroxetine 20 mg/day) study, and a relapse prevention study.
Approximately two-thirds of patients in the studies were markedly or severely ill (score of 5 or 6 on the CGI-S) and one-third were moderately ill (score of 4 or less on the CGI-S). The mean baseline LSAS total score ranged from 92 to 96 in the three studies.
In the short-term, flexible dose study, over a 12 week period, escitalopram was statistically significantly better than placebo on the primary, and almost all the secondary measures of efficacy (see Table 4).
In the placebo controlled, active reference study, escitalopram was effective both in the short and in the long-term (see Table 4), with an effect size at least as high as that of the reference treatment paroxetine (escitalopram 20 mg/day was significantly superior to the reference treatment paroxetine 20 mg/day from week 16 and onwards (OC)). Thus, continued treatment with escitalopram improves treatment response. At week 24 of the study, all three doses of escitalopram also produced significant improvements in the LSAS subscale scores for fear/anxiety and avoidance, the CGI-I score (except for the 10 mg dose of escitalopram), the CGI-S score, and the SDS subscale scores for work, social life and family life.
The beneficial effect of long-term treatment with escitalopram was also reflected in the analyses of responders and remitters in this study. The analyses showed a further increase both in the proportion of responders and in the proportion of remitters from week 12 to week 24, especially in the escitalopram 20 mg group. At week 24, a statistically significantly greater proportion of responders and remitters were seen in all three escitalopram dose groups (except for the proportion of responders in the 10 mg group) than in the placebo group (p ≤ 0.01) (see Tables 5 and 6).
In the relapse prevention study, the primary efficacy analysis showed a statistically significantly superior effect of escitalopram relative to placebo on the time to relapse of SAD (log-rank test, p ≤ 0.001). Furthermore, patients treated with escitalopram had fewer protocol defined relapses than those treated with placebo. In addition, patients treated with escitalopram showed a further improvement in mean LSAS total score during the double blind period, while patients treated with placebo showed deterioration. Escitalopram was also statistically significantly superior to placebo at week 24 on all the secondary efficacy measures in this study: the LSAS total score, the LSAS subscale scores for fear/anxiety and avoidance, the CGI-S score, and the SDS subscale scores for work, social life and family life (p ≤ 0.001).

5.2 Pharmacokinetic Properties

Absorption.

Data specific to escitalopram are unavailable. Absorption is expected to be almost complete and independent of food intake (mean Tmax 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 (Vd,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 (t1/2β) after multiple dosing is about 30 hours and the oral plasma clearance (Cloral) 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.

Special population.

The pharmacokinetics of escitalopram is linear over the clinical dosage range. Steady state plasma levels are achieved in about 1 week. Average steady state concentrations of 50 nanomol/L (range 20 to 125 nanomol/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 Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of 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 Cmax 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, Cmax 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 Section 4.2 Dose and Method of Administration).

5.3 Preclinical Safety Data

High doses of escitalopram, which resulted in plasma Cmax 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.

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.

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.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of major depression.
Treatment of social anxiety disorder (social phobia).
Treatment of generalised anxiety disorder.

4.3 Contraindications

Hypersensitivity to citalopram, escitalopram and any excipients in Esipram (see Section 6.1 List of Excipients).

Monoamine oxidase inhibitors.

Esipram 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 a MAOI (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Pimozide.

Concomitant use in patients taking pimozide is contraindicated (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

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 or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. As 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 4400 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 a 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 (bupropion, 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 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 nonpsychiatric) 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 Esipram 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). Esipram 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 nonsteroidal 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 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 (see Section 5.3 Preclinical Safety Data).

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.

A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed that treating such an episode with an antidepressant alone can increase the likelihood of precipitation of a mixed/manic episode in patients at risk of bipolar disorder. Prior to initiating treatment with an antidepressant, patients should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder and depression.

Angle-closure glaucoma.

Antidepressants including Esipram may have an effect on pupil size resulting in mydriasis. This mydriatic effect has the potential to narrow the eye angle resulting in increased intraocular pressure and angle-closure glaucoma, especially in pre-disposed patients. Escitalopram should therefore be used with caution in patients with raised intraocular pressure and in those at risk of angle-closure glaucoma.

ECT (electroconvulsive therapy).

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

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 or 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 Section 4.2 Dose and Method of 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.

Use in hepatic impairment.

In subjects with hepatic impairment, clearance of escitalopram was decreased and plasma concentrations were increased. The dose of escitalopram in hepatically impaired patients should, therefore, be reduced (see Section 5.2 Pharmacokinetic Properties; Section 4.2 Dose and Method of Administration).

Use in renal impairment.

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/minute) and escitalopram should be used with caution in such patients (see Section 4.2 Dose and Method of Administration).

Use in the elderly (> 65 years).

Escitalopram AUC and half-life were increased in subjects ≥ 65 years of age compared to younger subjects in a single dose and a multiple dose pharmacokinetic study. The dose of escitalopram in elderly patients should, therefore, be reduced (see Section 4.2 Dose and Method of Administration).

Paediatric use.

The efficacy and safety of escitalopram have 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.

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects).

4.5 Interactions with Other Medicines and Other Forms of Interactions

MAOIs.

Coadministration with MAO inhibitors may cause serotonin syndrome (see Section 4.3 Contraindications).

Serotonin syndrome.

Development of serotonin syndrome may occur in association with treatment with SSRIs and SNRIs, particularly when given in combination with MAOIs or other serotonergic agents. Symptoms and signs of serotonin syndrome include rapid onset of neuromuscular excitation (hyper-reflexia, 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.

Coadministration 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 Cmax of pimozide, although not consistently throughout the study. The coadministration 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 Section 4.3 Contraindications).

Serotonergic drugs.

Coadministration 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.

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 and 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 isoenzymes CYP1A2, 2C9, 2C19, 2E1, and 3A4, and a weak inhibitor of 2D6.

Effects of other drugs on escitalopram in vivo.

The pharmacokinetics of escitalopram was not changed by coadministration with ritonavir (CYP3A4 inhibitor). Furthermore coadministration with ketoconazole (potent CYP3A4 inhibitor) did not change the pharmacokinetics of racemic citalopram.
Coadministration of escitalopram with omeprazole (a CYP2C19 inhibitor) resulted in a moderate (approximately 50%) increase in plasma concentrations of escitalopram and a small but statistically significant increase (31%) in the terminal half-life of escitalopram (see Section 4.2 Dose and Method of Administration, Poor metabolisers of CYP2C19).
Coadministration 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, fluconazole and ticlopidine) or cimetidine. A reduction in the dose of escitalopram may be necessary based on clinical judgment (see Section 4.2 Dose and Method of Administration, Poor metabolisers of CYP2C19).

Effects of escitalopram on other drugs in vivo.

Escitalopram is an inhibitor of the enzyme CYP2D6. Caution is recommended when escitalopram is coadministered 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 as desipramine, clomipramine and nortriptyline or antipsychotics like risperidone, thioridazine and haloperidol. Dosage adjustment may be warranted.
Coadministration with desipramine (a CYP2D6 substrate) resulted in a twofold increase in plasma levels of desipramine. Therefore, caution is advised when escitalopram and desipramine are coadministered. A similar increase in plasma levels of desipramine, after administration of imipramine, was seen when given together with racemic citalopram.
Coadministration 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 coadministration 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 and 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 Esipram.

Alcohol.

The combination of SSRIs and alcohol is not advisable.

4.6 Fertility, Pregnancy and Lactation

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.
Animal data have shown that some SSRIs induce a reduction of fertility index and pregnancy index, reduction in number in implantation and abnormal sperm. No animal data related to this aspect are available for escitalopram.
Animal data have shown that some SSRIs may affect sperm quality.
(Category C)
Limited clinical data are available regarding exposure to escitalopram during pregnancy.
Newborns should be observed if maternal use of Esipram 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 Esipram, 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, hyper-reflexia, 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 studies have shown that the use of SSRIs (including escitalopram) in pregnancy, particularly use in late pregnancy, was associated with an increased risk of persistent pulmonary hypertension of the newborn (PPHN). The risk of PPHN among infants born to women who used SSRIs late in pregnancy was estimated to be 4 to 5 times higher than the rate of 1 to 2 per 1000 pregnancies observed in the general population.
Oral treatment of rats with escitalopram during organogenesis at maternotoxic doses led to increased postimplantation 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 (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.
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 the citalopram data support the safety of use of escitalopram in breastfeeding women, the decision to breast feed should always be made as an individual risk/benefit analysis.

4.8 Adverse Effects (Undesirable 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 Table 1 indicate adverse reactions where the incidence with escitalopram is statistically significantly different from placebo (p < 0.05).

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 in Table 2.

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 of QT prolongation have been reported during the postmarketing 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 20 mg/day dose and 16.7 msec at the 60 mg/day dose of citalopram. The effect of escitalopram on the QT interval was similarly studied at doses of 10 mg/day and 30 mg/day. The change from baseline QTc (Fridericia correction) was 4.3 msec at the 10 mg/day dose and 10.7 msec with the above recommended dose of 30 mg/day. The QTc interval prolongation observed with 60 mg citalopram exceeded that observed with 30 mg escitalopram. It is probable that the R-enantiomer and its metabolites in racemic citalopram contribute to these effects.

Mydriasis and angle-closure glaucoma.

Cases of mydriasis and angle-closure glaucoma have been reported in the postmarketing period (see Section 4.4 Special Warnings and Precautions for Use).

Weight changes.

Patients treated with escitalopram in controlled trials did not differ from placebo treated patients with regard to clinically important change in bodyweight.

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 or serious adverse events from ongoing trials and observed during (but not necessarily caused by) treatment with Esipram, please see Section 4.8 Adverse Effects (Undesirable Effects)), Other events observed during the premarketing evaluation of Esipram.

Other events observed during the premarketing evaluation of Esipram.

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 (see Section 4.8 Adverse Effects (Undesirable Effects)), and those occurring in only one patient. It is important to emphasise that, although the events reported occurred during treatment with Esipram, 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 1/1000 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, hyper-reflexia, 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 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 of 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.

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 disorder.

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 characterised by a rapid onset of changes in mental state, with confusion, mania, agitation, hyperactivity, shivering, fever, tremor, ocular movements, myoclonus, hyper-reflexia and incoordination).

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, see Section 4.8 Adverse Effects (Undesirable Effects):
Stomatitis, drug interaction NOS, feeling abnormal, hypersensitivity NOS, nonaccidental overdose, injury NOS, psychotic disorder.
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, QT prolonged, rhabdomyolysis, spontaneous abortion, thrombocytopenia, thrombosis, torsades de pointes, ventricular arrhythmia and withdrawal syndrome.

Class effect.

Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRIs and TCAs. The mechanism leading to this risk is unknown.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of 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.

Social anxiety disorder.

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. Social anxiety disorder is a disease with a chronic course and long-term treatment is therefore warranted to consolidate response and prevent relapse.

Generalised anxiety disorder.

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. Generalised anxiety disorder is a disease with a chronic course and long-term treatment is therefore warranted to consolidate response and prevent relapse.

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 Section 5.2 Pharmacokinetic Properties; Section 4.4 Special Warnings and Precautions for Use).

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 Section 4.4 Special Warnings and Precautions for Use).

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/minute) (see Section 4.4 Special Warnings and Precautions for Use).

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 Section 4.4 Special Warnings and Precautions for Use).

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 Section 5.2 Pharmacokinetic Properties; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Discontinuation.

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

4.7 Effects on Ability to Drive and Use Machines

Escitalopram does not impair intellectual function and psychomotor performance. However, adverse effects of Esipram include visual disturbances (such as blurred vision) and dizziness which could affect the ability to drive or use machines (see Section 4.8 Adverse Effects (Undesirable Effects)).
As with other psychoactive drugs, patients should be cautioned about their ability to drive a car and operate machinery.

4.9 Overdose

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. No fatalities or 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 information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia) and 0800 764 766 (New Zealand).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Excipients in tablets: microcrystalline cellulose, colloidal anhydrous silica, purified talc, croscarmellose sodium, magnesium stearate, opadry OY-S28849 PI (4748) (contains: hypromellose, macrogol 400 and titanium dioxide).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf-life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Film-coated tablets in blister packs of 28 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

Summary Table of Changes