Consumer medicine information

Chemmart Escitalopram Tablets

Escitalopram

BRAND INFORMATION

Brand name

Chemmart Escitalopram Tablets

Active ingredient

Escitalopram

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Chemmart Escitalopram Tablets.

What is in this leaflet

Read this leaflet carefully before taking your medicine.

This leaflet answers some common questions about escitalopram.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the last page. More recent information on this medicine may be available.

Ask your doctor or pharmacist:

  • if there is anything you do not understand in this leaflet,
  • if you are worried about taking your medicine, or
  • to obtain the most up-to-date information.

You can also download the most up to date leaflet from www.apotex.com.au.

All medicines have risks and benefits. Your doctor has weighed the risks of you using this medicine against the benefits they expect it will have for you.

Pharmaceutical companies cannot give you medical advice or an individual diagnosis.

Keep this leaflet with your medicine.

You may want to read it again.

What this medicine is used for

The name of your medicine is Chemmart Escitalopram. It contains the active ingredient, escitalopram (as escitalopram oxalate).

It is used to treat

  • depression
  • obsessive-compulsive disorder.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed this medicine for another reason.

This medicine is available only with a doctor's prescription.

How it works

Escitalopram belongs to a group of medicines called Selective Serotonin Reuptake Inhibitors (SSRIs). Escitalopram and other SSRIs are thought to help by increasing the amount of serotonin in your brain.

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.

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

There is no evidence that escitalopram is addictive. However, if you suddenly stop taking it, you may get side effects.

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

Use in children

Do not give this medicine to a child or adolescent.

There is no experience with its use in children and adolescents under 18 years of age.

Before you take this medicine

When you must not take it

Do not take this medicine if:

  • You are taking the following other medicines:
    - pimozide, used to treat disorders which affect the way you think, feel or act
    - monoamine oxidase inhibitors (MAOIs), used to treat depression (phenelzine, tranylcypromine, moclobemide), Parkinson's Disease (selegiline) or infections (linezolid).
    Do not take escitalopram until 14 days after stopping most MAOIs. The exception is the MAOI, moclobemide, where you may take escitalopram one whole day after finishing taking moclobemide. Similarly, do not take any MAOI until at least 14 days after stopping taking escitalopram.
    Taking escitalopram with MAOIs may cause a serious reaction with signs such as a sudden increase in body temperature, very high blood pressure, rigid muscles, nausea/vomiting and/or fits (convulsions). Your doctor will know when it is safe to start escitalopram after the MAOI has been stopped.
  • The expiry date (EXP) printed on the pack has passed.
  • The packaging is torn, shows signs of tampering or it does not look quite right.
  • You have had an allergic reaction to escitalopram, citalopram or any of the ingredients listed at the end of this leaflet.
    Symptoms of an allergic reaction may include cough, shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin; fainting or hayfever-like symptoms.
    If you think you are having an allergic reaction do not take any more of the medicine and contact your doctor immediately or go to the Accident and Emergency department at the nearest hospital.

Before you start to take it

Before you start taking this medicine, tell your doctor if:

  1. You have allergies to:
  • any other medicines
  • any other substances such as foods, preservatives, lactose or dyes.
  1. You have or have had any medical conditions, especially the following:
  • mania, hypomania, bipolar disorder or any other conditions which affect the way you think, feel or act
  • epilepsy or convulsions, fits or seizures (you should avoid taking escitalopram if your epilepsy is not properly controlled; if it is properly controlled your doctor will wish to watch you carefully if you take escitalopram)
  • heart problems
  • liver problems
  • kidney problems
  • problems with blood clotting or abnormal bleeding, i.e. a tendency to bleed or bruise easily
  • thoughts or actions relating to self-harm or suicide
  • diabetes
  • a decreased level of sodium in your blood
  • restlessness and/or a need to move often (akathisia)
  1. You are currently pregnant or you plan to become pregnant.
    There have been reports that babies exposed to certain antidepressants during the third trimester of pregnancy may develop complications after birth.
    Do not take this medicine whilst pregnant until you and your doctor have discussed the risks and benefits involved.
  2. You are currently breast-feeding or you plan to breast-feed.
    It is not recommended that you breast-feed while taking this medicine because escitalopram passes into breast milk and may affect your baby.
    Do not take this medicine whilst breast-feeding until you and your doctor have discussed the risks and benefits involved.
  3. You are receiving electroconvulsive therapy (ECT).
  4. You are planning to have, or have very recently had, surgery or an anaesthetic.
  5. You are currently receiving or are planning to receive dental treatment.
  6. You are taking or are planning to take any other medicines
    This includes vitamins and supplements that are available from your pharmacy, supermarket or health food shop.

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

Therefore some medicines MUST NOT be taken with escitalopram. These include:

  • monoamine oxidase inhibitors, such as moclobemide, phenelzine, tranylcypromine, selegiline and linezolid
  • pimozide

(see also "When you must not take it").

Some other medicines may interact with escitalopram.

These include:

  • tryptophan, contained in some multivitamin and herbal preparations
  • sumatriptan, used to treat migraines
  • tramadol, a strong pain killer
  • sumatriptan and similar medicines used to treat migraines and cluster headaches
  • St John's Wort (Hypericum perforatum), a herbal remedy
  • other medicines used to treat depression, including SSRIs, imipramine, clomipramine, nortriptyline and desipramine
  • lithium, used to treat mood swings and some types of depression
  • any other medicines used to treat anxiety, obsessive-compulsive disorder or pre-menstrual dysphoric disorder.
  • antipsychotics, medicines used to treat psychoses, schizophrenia and other conditions which affect the way you think, feel or act (e.g. risperidone, thioridazine and haloperidol)
  • any other medicines affecting the chemicals in the brain
  • prochlorperazine, used to prevent or treat severe nausea and vomiting
  • bupropion, a medicine helping to treat nicotine dependence
  • mefloquine, an anti-malaria medicine
  • some heart or blood pressure medications, e.g. dipyridamole, flecainide, propafenone, metoprolol
  • medicines known to prolong bleeding e.g. aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs) and anti-coagulants (such as warfarin and ticlopidine), which are used to prevent blood clots
  • medicines used to treat reflux and ulcers, such as cimetidine, omeprazole, esomeprazole and lansoprazole
  • imipramine and desipramine types of antidepressants.

If you are taking any of these you may need a different dose or you may need to take different medicines.

Other medicines not listed above may also interact with escitalopram.

How to take this medicine

Follow carefully all directions given to you by your doctor.

Their instructions may be different to the information in this leaflet.

How much to take

Your doctor will tell you how much of this medicine you should take. This will depend on your condition and whether you are taking any other medicines.

The standard dose for this medicine is 10 mg per day. Your doctor may increase your dose to 20 mg per day depending on how you respond to this medicine.

Elderly people may need smaller doses. The maximum dose for elderly people is 10 mg per day.

Patients with liver disease or with a lack of certain liver enzymes may receive a lower initial dose of 5 mg daily for the first two weeks. Your doctor may increase the dose to 10 mg daily.

Do not stop taking your medicine or change your dosage without first checking with your doctor.

How to take it

Swallow the tablets whole with a full glass of water.

Do not chew them.

When to take it

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

Take this medicine at the same time each day.

Taking it at the same time each day will have the best effect and will also help you remember when to take it.

It does not matter if you take it before, with or after food.

How long to take it for

Continue taking your medicine for as long as your doctor tells you, even if it takes some time before you feel any improvement in your condition.

Make sure you have enough to last over weekends and holidays.

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 escitalopram.

Your doctor will check your progress at regular intervals.

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

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

Occasionally the symptoms of depression or other psychiatric conditions may include thoughts of harming yourself or committing suicide. It is possible that these symptoms may continue or increase until the full anti-depressant effect of your medicine becomes apparent.

You or anyone close to you or caring for you should watch for these symptoms and tell your doctor immediately or go to the nearest hospital if you have any distressing thoughts or experiences during this initial period or at any other time.

Also contact your doctor if you experience any worsening of your depression or other symptoms at any time during your treatment.

Stopping Treatment

Do not stop taking this medicine even if you begin to feel better.

Your doctor may decide that you should continue to take it for some time, even when you have overcome your problem. For best effect, this medicine must be taken regularly.

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 you suddenly stop taking your medicine, you may experience mild, but usually temporary, symptoms such as dizziness, pins and needles, electric shock sensations, sleeping problems (vivid dreams, nightmares, inability to sleep), feeling anxious, restless or agitated, headaches, feeling sick (nausea), vomiting, sweating, tremor (shaking), feeling confused, feeling emotional or irritable, diarrhoea, visual disturbances, or fast or irregular heartbeats.

When you have completed your course of treatment, the dose of escitalopram 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 help avoid getting side effects.

If you forget to take it

If you missed 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 you are more than 12 hours late, 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 missed doses.

This may increase the chance of you experiencing side effects.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints to help you remember.

If you take too much (overdose)

If you think that you or anyone else may have taken too much of this medicine, immediately telephone your doctor or the Poisons Information Centre (Tel: 13 11 26 in Australia) for advice. Alternatively go to the Accident and Emergency Department at your nearest hospital.

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

If you take too much escitalopram, you may get symptoms of drowsiness, sleepiness, dizziness, high or low blood pressure, nausea (feeling sick), vomiting, agitation or tremor (shaking), fast or slow heart beat or change in heart rhythm, dilated pupils or, rarely, temporary paralysis or weakness of muscles, convulsions or coma.

A condition called serotonin syndrome may occur, with high fever, agitation, confusion, trembling and abrupt contraction of muscles.

While you are taking this medicine

Things you must do

People taking escitalopram may be more likely to think about killing themselves or actually trying to do so, especially when escitalopram 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 escitalopram 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.

If you or someone you know or care for demonstrates any of the following warning signs of suicide-related behaviour while taking escitalopram, contact a doctor immediately, or even to 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
  • worsening of depression.

Follow your doctor's instructions. 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 sitting or standing still.

These symptoms can also occur during the first weeks of treatment.

Contact your doctor as soon as possible if you suddenly experience an episode of mania.

Some people with bipolar disorder (manic depression) may enter into a manic phase. Symptoms of mania include lots of rapidly changing thoughts or ideas, exaggerated gaiety, being much more physically active and much more restless.

Sometimes you may not know that you are manic, so it may be helpful to have a friend or relative watch over you for any possible signs of change in your behaviour.

Visit your doctor regularly so they can check on your progress.

Tell your doctor immediately if you become pregnant. If you are a woman of child-bearing age, you should avoid becoming pregnant while taking escitalopram.

Make sure your midwife and/or doctor know you are taking escitalopram. When taken during pregnancy, particularly in the last 3 months of pregnancy, medicines like escitalopram 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 midwife and/or doctor immediately.

Low Sodium
Some people (especially older people or those taking diuretics/water tablets) may experience a lack of sodium in the blood when taking this medicine. Tell your doctor if you get a headache or start to feel sick, restless, irritated, confused or fatigued or if you vomit or have fits, muscle weakness or spasms.

Tell your doctor that you are taking this medicine if:

  • you are about to be started on any new medicine
  • you are breast-feeding or are planning to breastfeed
  • you are about to have any blood tests
  • you are going to have surgery or an anaesthetic or are going into hospital.

Your doctor may occasionally do tests to make sure the medicine is working and to prevent side effects.

Go to your doctor regularly for a check-up.

Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

Tell your doctor if, for any reason, you have not taken your medicine exactly as prescribed.

Otherwise your doctor may think that it was not effective and change your treatment unnecessarily.

Tell your doctor if you feel this medicine is not helping your condition.

If you are being treated for depression, be sure to discuss with your doctor any problems you may have and how you feel, especially any feelings of severe sadness, thoughts of suicide, bursts of unusual energy, anger or aggression, or if you become particularly agitated or restless.

Tell your doctor immediately if you have any suicidal thoughts or other mental/mood changes.

Make sure you have enough tablets to last over weekends and holidays.

Things you must not do

Do not:

  • Give this medicine to anyone else, even if their symptoms seem similar to yours.
  • Take your medicine to treat any other condition unless your doctor or pharmacist tells you to.
  • Stop taking your medicine, or change the dosage, without first checking with your doctor.

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

Suddenly stopping escitalopram may cause unwanted discontinuation symptoms, such as dizziness, headache and nausea. Your doctor will tell you when and how escitalopram should be discontinued. You 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 when driving or operating machinery until you know how this medicine affects you.

This medicine may cause nausea, fatigue, drowsiness, sight problems or 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 best not to drink alcohol while you are being treated for depression.

You should be aware that people over 50 years of age who take antidepressants have an increased risk of having a bone fracture.

Possible side effects

Tell your doctor as soon as possible if you do not feel well while you are taking escitalopram or if you have any questions or concerns.

Do not be alarmed by the following lists of side effects. You may not experience any of them. All medicines can have side effects. Sometimes they are serious, but most of the time, they are not.

Tell your doctor if you notice any of the following:

  • feeling tired and weak (fatigued), hot flushes, fever, feeling unwell, shaking or tremors, migraine, headache, or giddiness
  • muscle, back, bone, nerve or joint pain, stiffness, weakness or cramps, decrease or loss of touch or other senses
  • increased or decreased sensitivity to outside stimuli
  • feeling or being sick, reflux, diarrhoea or loose bowel motions, constipation, indigestion, stomach pain or discomfort, wind, burping, hiccups, problems swallowing, sore mouth, tongue or throat, haemorrhoids (piles)
  • dry mouth, feeling thirsty increased saliva, taste disturbance
  • fatigue, sleepiness or drowsiness, yawning, sleeping difficulties, strange or terrifying dreams
  • teeth grinding or clenching
  • increased or decreased appetite, weight loss
  • excessive and/or abnormal movements
  • increased muscle tension, muscle twitching
  • sexual problems, painful erection, prostate problems
  • symptoms of hyperglycaemia (high blood sugar): feeling hungry, thirsty and/or frequent or excessive urination;
  • problems with eyes or eyesight
  • dizziness when you stand up suddenly, due to low blood pressure
  • unable to tolerate alcohol
  • menstrual irregularities, period pain, breast pain, unusual vaginal bleeding
  • loss of bladder control unusual hair loss or thinning
  • tingling or numbness of the hands or feet
  • breast enlargement or unusual secretion of breast milk in men or women
  • mild rash, or itching or prickling of the skin
  • acne, eczema, dermatitis, dry skin, psoriasis or other skin problem
  • pain of any type
  • ringing or other persistent noise in the ears, problems hearing or earache
  • increased or decreased sweating
  • bruises
  • osteoporosis
  • tooth or jaw problems
  • flu-like symptoms, runny or blocked nose, sneezing, facial pressure or pain, coughing or sore throat

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

These may be serious side effects. You may need medical attention.

  • becoming nervous, confused, forgetful, unable to concentrate, agitated, confused, panicky or anxious
  • feeling restless or unable to sit still
  • stomach pain with nausea and vomiting of blood, or blood in the bowel movements
  • aggression, worsening of depression
  • general swelling or swollen hands, ankles, feet or face or eye area due to fluid build-up
  • problems speaking
  • feelings of not being part of your body, or in a daze
  • feeling sick or unwell with weak muscles or feeling confused (these symptoms may be signs of a rare condition as a result of low levels of sodium in the blood, which may be caused by antidepressants and occurs especially in elderly women) increased tendency to bleed, develop bruises or broken bones
  • passing more or less urine than normal, or problems when urinating, or bladder infection
  • abnormal liver function tests (increased amount of liver enzymes)
  • flushing, varicose veins
  • infection in any part of your body
  • dizziness
  • agitation, anxiety, feeling tense and restless, tired, drowsy, lack of energy, irritable, problems sleeping, headache, nausea and tingling or numbness of the hands and feet after stopping escitalopram.

If you experience any of the following, stop taking your medicine and contact your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

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

  • seizures, tremors, movement disorders (involuntary movements of the muscles or being unco-ordinated).
  • coma (unconsciousness)
  • a collection of symptoms including weight gain (despite loss of appetite), feeling and being sick, muscle weakness and irritability
  • severe rash, with blisters and/ or excessive peeling of skin and also possibly severe blisters and bleeding in the lips, eyes, mouth, nose and genitals
  • a sudden increase in body temperature, very high blood pressure, rigid muscles, nausea/vomiting and/or fits (convulsions). These symptoms may be signs of a rare condition called Serotonin Syndrome.
  • Neuroleptic Malignant Syndrome (a serious reaction to some medicines with a sudden increase in body temperature, extremely high blood pressure and severe convulsions)
  • fast, slow or irregular heartbeat, high blood pressure
  • palpitations, fainting or chest pain or tightness
  • abnormal bleeding
  • kidney pain, difficulty in passing urine, dark coloured urine or blood in the urine
  • a collection of symptoms including fever, sore throat, swollen glands, mouth ulcers, unusual bleeding or bruising under the skin
  • mania (mood of excitement, over-activity and uninhibited behaviour or aggression), hallucinations (hearing, seeing or feeling things that are not there)
  • jaundice (yellowing of the skin and/or eyes), with or without other signs of hepatitis or liver problems (loss of appetite, tiredness, feeling or being sick, dark urine, stomach pain or swelling, confusion, unconsciousness).
  • feeling paranoid, panicky, or "high" or having mood swings or feeling more depressed or in a trance
  • thoughts of suicide or attempting suicide or self-harm
  • sudden, severe breathing problems
  • sudden weakness or numbness of the face, arms or legs, especially on one side, slurred speech

Other side effects not listed above may also occur in some people.

Allergic reactions

If you think you are having an allergic reaction to escitalopram, do not take any more of this medicine and tell your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

Symptoms of an allergic reaction may include some or all of the following:

  • cough, shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue, throat or other parts of the body
  • rash, itching or hives on the skin
  • fainting
  • hayfever-like symptoms

Storage and disposal

Storage

Keep your medicine in its original packaging until it is time to take it.

If you take your medicine out of its original packaging, it may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 30°C.

Do not store your medicine, or any other medicine, in the bathroom, or near a sink.

Do not leave it on a window-sill or in the car. Heat and dampness can destroy some medicines.

Keep this medicine 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 this medicine, or it has passed its expiry date, your pharmacist can dispose of the remaining medicine safely.

Product description

What Chemmart Escitalopram looks like

Chemmart Escitalopram tablets are available in the following strengths:

  • 10 mg tablets: white to off - white, oval, biconvex, film-coated tablets with "C4" embossed on one side and a notch break-line on the other side.
  • 20 mg tablets: white to off - white, oval, biconvex, film-coated tablets with "C3" embossed on one side and a notch break-line on the other side.

Blister packs of 28 tablets.

* Not all strengths may be available.

Ingredients

Each tablet contains 10 mg, or 20 mg of escitalopram (as oxalate) as the active ingredient.

It also contains the following inactive ingredients:

  • microcrystalline cellulose
  • colloidal anhydrous silica
  • hypromellose
  • magnesium stearate
  • croscarmellose sodium
  • purified talc
  • macrogol 400
  • titanium dioxide.

This medicine is gluten-free, lactose free, sucrose-free, tartrazine-free and free of other azo dyes.

Australian Registration Numbers

Chemmart Escitalopram 10 mg tablets (blister pack): AUST R 213723.

Chemmart Escitalopram 20 mg tablets (blister pack): AUST R 213724.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113

This leaflet was last updated in:
January 2017.

BRAND INFORMATION

Brand name

Chemmart Escitalopram Tablets

Active ingredient

Escitalopram

Schedule

S4

 

Name of the medicine

Escitalopram oxalate.

Excipients.

Microcrystalline cellulose, anhydrous colloidal silica, purified talc, croscarmellose sodium, magnesium stearate, hypromellose, macrogol 400 and titanium dioxide.

Description

Chemical name: S(+)-1-[3-(dimethylamino) propyl]-1-(4-flurophenyl)- 1,3-dihydroisobenzofuran-5- carbonitrile hydrogen oxalate. Molecular formula: C20H21FN2O.C2H2O4. MW: 414.42. CAS: 219861-08-2. 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.

Pharmacology

Pharmacological actions.

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.

Pharmacokinetics.

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 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 nanomol/L (range 20 to 125 nanomol/L) are achieved at a daily dose of 10 mg.

Hepatic impairment.

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).

Renal impairment.

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).

Pharmacokinetics in 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 Dosage and Administration).

Clinical Trials

Escitalopram should not be used for the treatment of major depression 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.

Major depression.

Escitalopram 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 8 weeks on the MADRS change score in the LOCF dataset. However, on the basis of the OC analysis, both escitalopram and citalopram were significantly better than placebo (p ≤ 0.05; difference between escitalopram and placebo: 2.9).
Escitalopram demonstrated efficacy in the treatment of anxiety symptoms associated with depression. In the three positive double blind placebo controlled studies, escitalopram was shown to be effective compared to placebo on the MADRS anxiety items; inner tension and sleep disturbances. Furthermore, in the one study where the Hamilton Anxiety Scale (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% 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.

Obsessive compulsive disorder (OCD).

Escitalopram should not be used in the treatment of children and adolescents under the age of 18 years.
Efficacy of escitalopram in the treatment of OCD was investigated in two clinical trials, a 24 week placebo controlled, fixed dose study (with efficacy assessments at week 12 and week 24) and a 16 + 24 week placebo controlled relapse prevention study.
Patients included in these studies were male and female outpatients aged 18-65 years with a diagnosis of OCD according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria and a predefined minimum score of 20 on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). Patients had actual baseline Y-BOCS scores of approx. 27, indicating significant OCD symptomatology. A structured clinical interview, the Mini International Neuropsychiatric Interview (MINI), was used to assist in the diagnosis and to exclude relevant psychiatric comorbidities. In order to avoid the confounding variable of significant concomitant depression, patients with more than mild depressive symptoms, i.e. a score of 22 or more on the Montgomery-Åsberg Depression Rating Scale (MADRS), were excluded. To ensure a relatively homogenous population with OCD, patients currently diagnosed with any other psychiatric disorders as per Axis I of DSM-IV-TR or any clinically significant unstable medical illness were also excluded.
Results at week 12 of the 24 week placebo controlled, fixed dose study are shown in Tables 1 and 2. In the short-term (12 weeks), 20 mg/day escitalopram separated from placebo on the Y-BOCS total score.
Furthermore, escitalopram 20 mg/day was significantly more efficacious than placebo on the Y-BOCS subscale of rituals at week 12. Both escitalopram 10 mg/day and escitalopram 20 mg/day were significantly more efficacious than placebo on the Y-BOCS subscale of obsessions as well as on the NIMH-OCS total score, CGI-I score and CGI-S score.
Results after 24 weeks showed that both escitalopram 10 mg/day (p < 0.05) and escitalopram 20 mg/day (p < 0.01) were significantly more efficacious than placebo as measured by the primary outcome measure, the Y-BOCS total score, as well as on the secondary subscales of Y-BOCS (obsessions and rituals) and the NIMH-OCS score (escitalopram 10 mg/day (p < 0.01) and escitalopram 20 mg/day (p < 0.001)). See Table 3.
The beneficial efficacy of long-term treatment with escitalopram was also demonstrated by the analyses of responders and remitters in this study as shown in Tables 4 and 5.
Maintenance of efficacy and prevention of relapse were investigated in the relapse prevention study. This 24 week relapse prevention study was preceded by a 16 week open label period with patients initially receiving escitalopram 10 mg/day. In case of lack of efficacy (as judged by the investigator), the dose could be increased to a maximum of 20 mg/day. If dose limiting adverse effects occurred, it was permissible to decrease the dose to 10 mg/day. Thus the dose of escitalopram was flexible at 10-20 mg/day from week 2 to 12. Subsequently, the dose was fixed at the dose received at the end of week 12 until week 16 to allow stabilisation of the patient on this dose. Responders to treatment were defined as patients with a decrease in Y-BOCS total score from baseline by ≥ 25% at week 16 and remitters were defined as Y-BOCS ≤ 10. See Table 6 for responder and remitter rates at the end of the 16 week open label phase.
Responders at the end of the above 16 week open label treatment phase (escitalopram 10 mg: 30 responders; escitalopram 20 mg: 133 responders) entered the 24 week randomised, double blind placebo controlled relapse prevention phase. Both escitalopram 10 mg/day (p = 0.014) and 20 mg/day (p < 0.001) showed significantly fewer relapses as seen in Table 7.

Indications

Treatment of major depression.
Treatment of obsessive compulsive disorder.

Contraindications

Hypersensitivity to citalopram, escitalopram and any excipients in the escitalopram tablets (see Excipients).

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 a MAOI (see 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 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 (4-16 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 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 or 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 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 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 Precautions, 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.

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.
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.

Effect 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 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 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.

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 Pharmacology, Pharmocokinetics and Dosage and Administration).

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/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 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.

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 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.

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 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. Abrupt discontinuation should be avoided during pregnancy.
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, 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 perinatal/ 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.

Use in lactation.

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

Paediatric use.

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 a single dose and a multiple dose pharmacokinetic study. The dose of escitalopram in elderly patients should therefore be 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.

Interactions

MAOIs.

Coadministration 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 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 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 isoenzyme 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 also Dosage and 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 and ticlopidine) or cimetidine. A reduction in the dose of escitalopram may be necessary based on clinical judgement (see also Dosage and 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 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 escitalopram.

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 Table 8 indicate adverse reactions where 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 9.

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.

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 escitalopram, please see Other changes observed during the premarketing evaluation of escitalopram.

Other events observed during the premarketing evaluation of escitalopram.

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 Adverse Effects and those occurring in only one patient. It is important to emphasise that, although the events reported occurred during treatment with escitalopram, 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, disequilibrium, 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.

Myocardial, endocardial 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 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 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 in Adverse 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.

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.

Obsessive compulsive disorder.

The recommended starting dose is 10 mg (one 10 mg tablet) once daily. Depending on individual patient response, the dose may be increased to 20 mg (one 20 mg tablet) daily.
Long-term treatment has been studied for a maximum of 40 weeks. Patients responding to a 16 week open label treatment phase were randomised to a 24 week placebo controlled relapse prevention phase, receiving 10 or 20 mg escitalopram daily. As OCD is a chronic disease, patients should be treated for a sufficient period to ensure that they are symptom free. This period may be several months or even longer.

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 Pharmacology, Pharmacokinetics and Precautions).

Paediatric use.

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).

Hepatic impairment.

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).

Renal impairment.

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 Pharmacology, Pharmacokinetics and Interactions with Other Medicines).

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.

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. No fatalities or sequelae were reported in the few cases with a higher dose (one patient survived ingestion of either 2400 or 4800 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 sydrome, 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 131 126 (Australia).

Presentation

Tablets (white to off white, oval, biconvex, film coated, scored on reverse), escitalopram (as oxalate) 10 mg (marked C4 on one side, AUST R 213723), 20 mg (marked C3 on one side, AUST R 213724): 28's (PVC/PVdC/Al blister pack).
Chemmart Escitalopram tablets are intended for oral administration

Storage

Store below 30°C.

Poison Schedule

S4.