Consumer medicine information

Cipramil

Citalopram

BRAND INFORMATION

Brand name

Cipramil

Active ingredient

Citalopram

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Cipramil.

What is in this leaflet

This leaflet contains answers to some common questions about Cipramil.

It does not contain all the information that is known about Cipramil. 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 Cipramil is used for

Cipramil 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.

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

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.

Cipramil 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 Cipramil.

Before you take it

When you must not take it

Do not take Cipramil if you have a condition called 'congenital long QT syndrome'. At high doses, Cipramil can cause changes in the way that your heart beats.

See your doctor immediately if you experience an irregular heartbeat, shortness of breath, dizziness or fainting while taking Cipramil.

Do not take Cipramil if you are allergic to it 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 Cipramil at the same time as the following other medicines:

  • pimozide, a medicine used to treat mental disorders
  • monoamine oxidase inhibitors (MAOIs), which are also used for the treatment of depression.
  • monoamine oxidase inhibitors such as selegiline which is used in the treatment of Parkinson's Disease
    Do not take Cipramil when you are taking a MAOI or when you have been taking a MAOI within the last 14 days.
    Taking Cipramil 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 Cipramil after the MAOI has been stopped.
  • the antibiotic linezolid
    Do not take Cipramil when you are taking the antibiotic linezolid, or have recently stopped taking linezolid in the last 14-days.

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.
Citalopram has 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 Cipramil 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 Cipramil.
When taken during pregnancy, particularly in the last three months of pregnancy, medicines like Cipramil 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 Cipramil should never be stopped abruptly.
Ask your doctor or pharmacist for advice before taking any medicine.
  1. you are breast-feeding or planning to breast-feed.
Do not take Cipramil 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 Cipramil as it is excreted in breast milk.
  1. you have, or have had, the following medical conditions:
  • congenital long QT syndrome or other heart conditions. Your doctor may occasionally need to check your heart beat and rhythm with an ECG test
  • illnesses which require you to have regular blood tests
  • a tendency to bleed or bruise easily
  • diabetes
  • 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.
  • epilepsy
  1. you are receiving electroconvulsive therapy.

If you are lactose intolerant, contact your doctor before taking Cipramil. Cipramil tablets contain lactose.

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

Cipramil can be given to elderly patients over 65 years of age with a reduced dose. The effects of Cipramil 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 Cipramil.

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 Cipramil may interfere with each other. These include:

  • ketoconazole and itraconazole, medicines used to treat fungal infections
  • macrolide antibiotics, e.g. erythromycin and clarithromycin
  • medicines used to treat reflux and ulcers, such as cimetidine and omeprazole
  • medicines known to prolong bleeding, e.g. aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs)
  • warfarin, a medicine used to prevent blood clots
  • sumatriptan, used to treat migraines
  • tramadol, used to relieve pain
  • carbamazepine, a medicine used to treat convulsions
  • some heart medications, such as beta-blockers (e.g. metoprolol) or antiarrhythmics
  • selegiline, a medicine used to treat Parkinson's disease
  • tryptophan, an amino-acid
  • lithium, used to treat mood swings and some types of depression
  • linezolid, an antibiotic
  • fluconazole, an anti-fungal medicine
  • antipsychotics, a class of medicines used to treat certain mental and emotional conditions
  • 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 Cipramil, 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.

Drugs that are known to affect the way the heart beats (for example some heart medicines , antibiotics, asthma medicines, antihistamines) should be avoided while taking Cipramil. If it is necessary for you to be on these medicines at the same time as Cipramil, your doctor may perform an ECG test to check your heart rate and rhythm.

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

How to take it

How much to take

Your doctor will decide what dose you will receive.

The standard dose for adults for this medicine is between 20 mg and 40 mg (one to two tablets) per day.

The recommended starting dose in elderly patients is 10 mg (half a tablet) per day but may be increased to a maximum of 20 mg (one tablet) per day by your doctor if needed.

If you have liver problems, or are taking medicines such as cimetidine and omeprazole, the recommended starting dose is 10mg (half a tablet) per day. The dose can be increased to a maximum of 20mg (one tablet) per day.

Your doctor may have prescribed a different dose. If you have been prescribed or are currently taking doses of Cipramil greater than 40mg, talk to your doctor about reducing the 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, Cipramil 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 Cipramil as a single dose either in the morning or in the evening.

Take Cipramil with or without food.

How long to take it

Continue to take Cipramil 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 Cipramil. 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 Cipramil is stopped suddenly you may experience mild, but usually temporary, symptoms such as dizziness, pins and needles, 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 Cipramil 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 for Australia and Tel: 0800 764 766 for New Zealand), or go to Accident and Emergency at your nearest hospital, if you think you or anyone else may have taken too much Cipramil.

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

Symptoms of an overdose may include nausea (feeling sick), vomiting, dizziness, fast or slow heart beat or change in heart rhythm, decreased or increased blood pressure, tremor (shaking), agitation, dilated pupils of the eyes, drowsiness, sleepiness, lethargy, sweating, blueish discoloration of the skin, and an increase in rate of breathing. Convulsions or coma may occur. A condition called serotonin syndrome may occur with high fever, agitation, confusion, trembling and abrupt contractions of muscles.

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 Cipramil.

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

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

Persons taking Cipramil may be more likely to think about killing themselves or actually trying to do so, especially when Cipramil 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 Cipramil 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 Cipramil. 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 Cipramil to treat any other complaints unless your doctor tells you to.

Do not stop taking Cipramil, 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 Cipramil may cause unwanted discontinuation symptoms such as dizziness, headache and nausea. Your doctor will tell you when and how Cipramil 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 Cipramil affects you. It may cause 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 Cipramil. It helps most people with depression, but it may have unwanted side effects in a few people.

The side effects of Cipramil 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:

  • itching
  • ringing or other persistent noise in the ears
  • aching muscles or joint pain
  • flu-like symptoms, fever, runny or blocked nose, sneezing, facial pressure or pain, coughing or sore throat
  • increased sweating
  • increased saliva or dry mouth, taste disturbance
  • loss of appetite or increased appetite, weight decrease or weight increase
  • diarrhoea, constipation, flatulence, indigestion, stomach pain or discomfort
  • dizziness
  • nausea (feeling sick) or vomiting
  • migraine, headache
  • sleepiness or drowsiness, fatigue, yawning
  • a sense of indifference to everything
  • sexual disturbances (decreased sexual drive, problems with orgasm; problems with ejaculation or erection)
  • problems with menstrual periods
  • Restlessness or difficulty keeping still

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

  • chest pain
  • a fast heart rate or decrease in heart rate or irregular heartbeat
  • shortness of breath
  • fainting
  • dizziness when you stand up due to low blood pressure
  • blurred vision
  • low sodium levels in the blood (the symptoms are feeling sick and unwell with weak muscles or feeling confused) which may be caused by SSRI antidepressants, especially in elderly patients
  • increased tendency to develop bruises
  • unusual bleeding, including bleeding from the stomach or bowel
  • passing more urine than normal or problems when urinating
  • tingling or numbness of the hands or feet
  • nervousness, confusion, problems with concentration, loss of memory
  • agitation, anxiety, worsening of depression.

These may be serious side effects of Cipramil. 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 suicide
  • 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 which has been reported with the combined use of antidepressants)
  • 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.

An increased risk of bone fractures has been observed in patients taking medicines like Cipramil.

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

After taking it

Storage

Keep Cipramil 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 Cipramil tablets in a cool dry place where the temperature stays below 25°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 the tablets, or the tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Return any unused medicine to your pharmacist.

Product description

What it looks like

Cipramil 20 mg film-coated tablets are oval, white, scored and marked with "C" and "N".

A box contains 28 tablets.

Ingredients

Active ingredient(s):

  • Cipramil 20 mg tablets - 20 mg citalopram (as hydrobromide) per tablet

Inactive ingredients:

  • microcrystalline cellulose
  • croscarmellose sodium
  • glycerol
  • hypromellose
  • lactose
  • macrogol 400
  • magnesium stearate
  • copovidone
  • maize starch
  • titanium dioxide

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

Manufacturer/Sponsor

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

Distributed in Australia by:

Lundbeck Australia Pty Ltd
1 Innovation Road
North Ryde NSW 2113
Ph: +61 2 8669 1000

Distributed in New Zealand by:

Healthcare Logistics
PO Box 62027
Mt Wellington, Auckland
Ph: +64 9 918 5100

This leaflet was prepared on
12-11-2020

Australian Registration Number:

Cipramil tablets
20 mg AUST R 61164

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

AU-NZ-069-22-20-13417-PIL

Published by MIMS January 2021

BRAND INFORMATION

Brand name

Cipramil

Active ingredient

Citalopram

Schedule

S4

 

1 Name of Medicine

Citalopram hydrobromide.

2 Qualitative and Quantitative Composition

Each film-coated tablet contains citalopram 20 mg (as hydrobromide).
Excipients with known effect: lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Citalopram hydrobromide is a fine white to off white, crystalline material.
Citalopram hydrobromide is sparingly soluble in water, soluble in ethanol (96%), freely soluble in chloroform and very slightly soluble in diethylether. No polymorphic forms have been detected.
Cipramil 20 mg tablets are oval, white, scored, film-coated tablets marked "C" and "N".

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of major depression.

4.2 Dose and Method of Administration

Cipramil should be administered as a single daily dose. The dose may be taken in the morning or evening without regard for food.

Adults.

The starting dose is 20 mg/day. The dose can be increased in increments of 10 mg, until satisfactory clinical response is achieved. The maximum dose is 40 mg/day. As the treatment result in general can be evaluated only after 2-3 weeks' treatment, a possible dose increase should take place with intervals of 2-3 weeks.

Elderly patients.

The starting dose is 10 mg/day. The dose can be increased by 10 mg to a maximum of 20 mg/day. As the treatment result in general can be evaluated only after 2-3 weeks' treatment, a possible dose increase should take place after an interval of 2-3 weeks.

Children and adolescents (< 18 years of age).

The safety and efficacy of citalopram for the treatment of major depressive disorder have not been established in this population. Citalopram should not be used in children and adolescents under the age of 18 years.

Reduced hepatic function.

An initial dose of 10 mg daily for the first two weeks of treatment is recommended in patients with mild or moderate hepatic impairment. The maximum recommended dose is 20 mg/day. Caution and extra careful dose titration is advised in patients with severely reduced hepatic function.

Reduced renal function.

Dosage adjustment is not necessary in patients with mild or moderate renal impairment. No information is available on treatment of patients with severely reduced renal function (creatinine clearance < 30 mL/min).

Poor metabolisers of CYP2C19 and patients taking CYP2C19 inhibitors.

An initial dose of 10 mg daily during the first two weeks of treatment is recommended for patients who are known to be poor metabolisers with respect to CYP2C19. The dose may be increased to a maximum of 20 mg daily depending on individual patient response (see Section 5.2 Pharmacokinetic Properties). Patients taking cimetidine or other CYP2C19 inhibitors should not exceed the maximum dose of 20 mg/day.

Duration of treatment.

In treating depression, a treatment period of at least six months is usually necessary to provide adequate maintenance against the potential for relapse.

Withdrawal symptoms seen on discontinuation of SSRI.

Abrupt discontinuation should be avoided. When stopping treatment with citalopram, the dose should be gradually reduced over a period of at least one to two weeks in order to reduce the risk of withdrawal reactions (see Section 4.4 Special Warnings and Precautions for Use). If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose, but at a more gradual rate.

4.3 Contraindications

Hypersensitivity to citalopram and any excipients in Cipramil (see Section 6.1 List of Excipients).
Congenital long QT syndrome (see Section 4.4 Special Warnings and Precautions for Use).

Monoamine oxidase inhibitors.

Cipramil should not be used in combination with monoamine oxidase inhibitors (MAOI) (including selegiline in daily doses exceeding 10 mg/day). Cipramil should not be used in combination with 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 citalopram 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).

Linezolid.

Citalopram is contraindicated in combination with linezolid unless there are facilities for close observation and monitoring of blood pressure (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Pimozide.

Concomitant administration of citalopram and pimozide is contraindicated due to the risk of QT interval prolongation (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Use with caution in the following circumstances.

QT prolongation and torsade de pointes.

Citalopram can cause a dose dependent increase in the QT interval and should not be dosed above 40 mg/day. Torsade de pointes has been reported postmarketing. Citalopram should not be used in patients with congenital long QT syndrome. Patients at higher risk of developing prolongation of the QT interval include those with congestive heart failure, bradyarrhythmias or a predisposition to hypokalaemia or hypomagnesaemia because of concomitant illness or drugs. Hypokalaemia and hypomagnesaemia should be corrected prior to initiation of treatment and periodically monitored. Consider more frequent ECG monitoring in these patients and those with other risk factors for QT prolongation. Dose escalations over 20 mg/day in elderly patients (> 65 years), patients with hepatic dysfunction, CYP2C19 poor metabolisers or patients taking concomitant cimetidine or another CYP2C19 inhibitor are not recommended.
The influence of citalopram on QT interval at doses of 20 mg and 60 mg per day was evaluated in a randomised, placebo and active (moxifloxacin 400 mg) controlled crossover, escalating multiple dose study in 119 healthy subjects. The change from baseline in QTC (Fridericia correction) was 7.5 msec at the 20 mg/day dose and 16.7 msec at the 60 mg/day dose.
Citalopram has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were generally excluded from clinical studies during the product's premarketing testing.

Clinical worsening and suicide risk associated with psychiatric disorders.

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 improvements 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 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; 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 Cipramil should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Haemorrhage.

Bleeding abnormalities of the skin and mucous membranes have been reported with the use of SSRIs (including purpura, ecchymosis, haematoma, epistaxis, vaginal bleeding and gastrointestinal bleeding). Cipramil 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.

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

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 and it may be necessary to review the use of SSRIs/ SNRIs.

Seizures.

Although animal experiments have shown that citalopram has no epileptogenic potential it should, like other antidepressants, be used with caution in patients with a history of seizures. Citalopram should be discontinued in any patient who develops seizures. Citalopram should be avoided in patients with unstable epilepsy and patients with controlled epilepsy should be carefully monitored. Citalopram should be discontinued if there is an increase in seizure frequency.

Diabetes.

As described for other psychotropics, citalopram may modify insulin and glucose responses, calling for adjustment of the antidiabetic therapy in diabetic patients; in addition, the depressive illness itself may affect patients' glucose balance.

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 little clinical experience of concurrent use of citalopram and ECT, therefore, caution is advised.

Discontinuation/ withdrawal.

Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt.
The risk of withdrawal 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), 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 citalopram 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).

Use in patients with cardiac disease.

Citalopram 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, citalopram causes a small decrease in heart rate. Consequently, caution should be observed when citalopram is initiated in patients with pre-existing slow heart rate.

Excipients.

The tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose/ galactose malabsorption should not receive this medicine.

Preclinical safety.

High doses of citalopram, which resulted in high plasma concentrations of citalopram and metabolites, has been associated with convulsions and ECG abnormalities in experimental animals.

Angle-closure glaucoma.

Antidepressants including Cipramil 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. Cipramil should therefore be used with caution in patients with raised intraocular pressure and in those at risk of angle-closure glaucoma.

Use in hepatic impairment.

Citalopram is eliminated more slowly in patients with reduced hepatic function. The half-life of citalopram is about twice as long and steady state citalopram concentrations at a given dose will be about twice as high as in patients with normal liver function.

Use in renal impairment.

Citalopram is eliminated more slowly in patients with mild to moderate reduction of renal function, without major impact on the pharmacokinetics of citalopram.

Polymorphism.

There was no clinically relevant difference in the AUC between poor and extensive metabolisers with respect to CYP2D6 following administration of citalopram. The AUC for poor metabolisers with respect to CYP2C19 was less than 2-fold higher than the AUC observed in the extensive metabolisers (see Section 4.2 Dose and Method of Administration).

Use in the elderly.

Longer half-lives and decreased clearance values due to a reduced rate of metabolism have been demonstrated in elderly patients. Steady state mean values were about twice as high and ranged up to four times higher in the elderly than in younger patients treated with the same dose.

Paediatric use.

The efficacy and safety of citalopram for the treatment of major depressive disorder has not been established in children and adolescents less than 18 years of age. Consequently, citalopram should not be used in children and adolescents less than 18 years of age.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Drugs that prolong the QT interval.

More frequent ECG monitoring is recommended in patients on concomitant medications that prolong the QT interval (see Section 4.4 Special Warnings and Precautions for Use, QT prolongation and torsade de pointes).

MAOIs.

Monoamine oxidase inhibitors (MAOIs) should not be used in combination with SSRIs (see Section 4.3 Contraindications).
Cases of serious and sometimes fatal reactions have been reported in patients receiving an SSRI in combination with a monoamine oxidase inhibitor (MAOI), including the irreversible MAOI selegiline the reversible MAOIs linezolid and moclobemide and in patients who have recently discontinued SSRI and have been started on a MAOI.
Treatment with citalopram may be instituted 14 days after discontinuation of irreversible MAOIs and a minimum of one drug free day after discontinuation of moclobemide. Treatment with MAOIs may be introduced 14 days after discontinuation of citalopram.

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 citalopram 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 noted at a low dose of pimozide, concomitant administration of citalopram and pimozide is contraindicated (see Section 4.3 Contraindications).

Selegiline (selective MAO-B inhibitor).

A pharmacokinetic/ pharmacodynamic interaction study with concomitantly administered citalopram (20 mg daily) and selegiline (10 mg daily) (a selective MAO-B inhibitor) demonstrated no clinically relevant interactions. The concomitant use of citalopram and selegiline (in doses above 10 mg daily) is contraindicated (see Section 4.3).

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. A pharmacokinetic interaction study of lithium and citalopram (N=8) did not reveal any pharmacokinetic interactions (see also above).

Imipramine and other tricyclic antidepressants (TCAs).

In a pharmacokinetic study, no effect was demonstrated on either citalopram or imipramine levels, although the level of desipramine, the primary metabolite of imipramine, was increased. The clinical significance of the desipramine change is unknown. Nevertheless, caution is indicated in the coadministration of citalopram and tricyclic antidepressants.

Medicines affecting the central nervous system.

Given the primary CNS effects of citalopram, 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).

Digoxin.

In subjects who had received 21 days of 40 mg/day Cipramil, combined administration of Cipramil and digoxin (single dose of 1 mg) did not significantly affect the pharmacokinetics of either citalopram or digoxin.

Carbamazepine.

Combined administration of Cipramil (40 mg/day for 14 days) and carbamazepine (titrated to 400 mg/day for 35 days) did not significantly affect the pharmacokinetics of carbamazepine, a CYP3A4 substrate. Although trough citalopram plasma levels were unaffected, given the enzyme inducing properties of carbamazepine, the possibility that carbamazepine might increase the clearance of citalopram should be considered if the two drugs are coadministered.

Metoprolol.

A pharmacokinetic interaction between citalopram and metoprolol was observed, resulting in a twofold increase in metoprolol concentrations. The change in metabolism of metoprolol suggests an interaction between metoprolol and demethylcitalopram related to the CYP2D6 isoenzyme. There was no statistically significant increase in the effect of metoprolol on blood pressure and heart rate in healthy volunteers by adding citalopram.

Cimetidine.

Cimetidine caused a moderate increase in the average steady state levels of citalopram. Citalopram 20 mg/day is the maximum recommended dose for patients taking concomitant cimetidine because of the risk of QT prolongation.

Hepatic enzymes.

The metabolism of citalopram is only partly dependent on the hepatic cytochrome P450 isozyme CYP2D6 and, unlike some other SSRIs, citalopram is only a weak inhibitor of this important enzyme system which is involved in the metabolism of many drugs (including antiarrhythmics, neuroleptics, beta-blockers, tricyclic antidepressants and some SSRIs).
In vitro enzyme inhibition data did not reveal an inhibitory effect of citalopram on CYP3A4, but did suggest that it is a weak inhibitor of CYP1A2, 2D6, and 2C19. Citalopram would be expected to have little inhibitory effect on in vivo metabolism mediated by these isoenzymes. However, in vivo data to address this question are very limited.
Citalopram steady state levels were not significantly different in poor metabolisers and extensive -2D6 metabolisers after multiple dose administration of Cipramil, suggesting that coadministration, with Cipramil, of a drug that inhibits CYP2D6, is unlikely to have clinically significant effects on citalopram metabolism.
Since CYP3A4 and -2C19 are the primary enzymes involved in the metabolism of citalopram, it is expected that potent inhibitors of -3A4 (e.g. ketoconazole, itraconazole and macrolide antibiotics) and potent inhibitors of CYP2C19 (e.g. omeprazole, fluconazole, and cimetidine) might decrease the clearance of citalopram. Citalopram 20 mg/day is the maximum recommended dose for patients taking concomitant cimetidine or another CYP2C19 inhibitor because of the risk of QT prolongation (see Section 4.2 Dose and Method of Administration).

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 Cipramil.

Alcohol.

The combination of SSRIs and alcohol is not advisable.

Others.

No pharmacodynamic interactions have been noted in clinical studies in which citalopram has been given concomitantly with benzodiazepines, neuroleptics, analgesics, lithium, alcohol, antihistamines, antihypertensive drugs, beta-blockers and other cardiovascular drugs.
Experience with citalopram has not revealed any clinically relevant interactions with neuroleptics with the exception of pimozide (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Pimozide). However, as with other SSRIs, the possibility of a pharmacodynamic interaction cannot be excluded.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

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 citalopram induces a reduction of fertility index and pregnancy index, reduction in number in implantation and abnormal sperm.
Animal data have shown that citalopram may affect sperm quality.
(Category C)
Limited clinical data are available regarding exposure to citalopram during pregnancy.
Reproduction studies performed in rats and rabbits at oral doses of up to 112 and 32 mg/kg, respectively, have revealed no evidence of teratogenic effects. Studies in rats have shown increased postimplantation loss, reduced foetal weight and foetal developmental changes. A no effect oral dose of 56 mg/kg/day was established for foetal development. There are no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Newborns should be observed if maternal use of citalopram had continued into the later stages of pregnancy, particularly into the third trimester. If citalopram is used until or shortly before birth, discontinuation effects in the newborn are possible.
Newborns exposed to citalopram, 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.
Epidemiological studies have shown that the use of SSRI's (including citalopram) 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.
Citalopram appears in human breast milk in very low concentrations. In nursing mothers, caution is recommended as it is not known whether citalopram excreted in milk may affect the infant.

4.7 Effects on Ability to Drive and Use Machines

Patients who are prescribed psychotropic medication may be expected to have some impairment of general attention and concentration and should be cautioned about their ability to drive a car and operate machinery.

4.8 Adverse Effects (Undesirable Effects)

Adverse effects observed with citalopram are in general mild and transient. They are most frequent during the first one or two weeks of treatment and usually attenuate subsequently.
The most commonly observed adverse events associated with the use of citalopram in double blind, placebo controlled trials and not seen at an equal incidence among placebo treated patients were: nausea, somnolence, dry mouth, increased sweating, tremor, diarrhoea and ejaculation disorder. The incidence of each in excess over placebo is low.
In comparative double blind clinical trials with tricyclic and tetracyclic antidepressants (TTCAs), the incidence of 10 adverse events was statistically significantly higher on TTCAs (dry mouth, increased sweating, constipation, tremor, dizziness, somnolence, abnormal accommodation, postural hypotension, palpitation, perverted taste) compared to citalopram. For two events (nausea, ejaculation disorder) the incidence was statistically higher on citalopram compared to TTCAs.
In the comparative trials versus other SSRIs no statistically significant differences between the groups were found.
Adverse events reported in clinical trials with citalopram treated patients include (see Table 1):

Dose dependency of adverse events.

The potential relationship between the dose of Cipramil administered and the incidence of adverse events was examined in a fixed dose study in depressed patients receiving placebo or Cipramil 10, 20, 40, and 60 mg. Jonckheere's trend test revealed a positive dose response (p < 0.05) for the following adverse events: fatigue, impotence, insomnia, sweating increased, somnolence and yawning.

Male and female sexual dysfunction with SSRIs.

While sexual dysfunction is often part of depression and other psychiatric disorders, there is increasing evidence that treatment with selective serotonin reuptake inhibitors (SSRIs) may induce sexual side effects. This is a difficult area to study because patients may not spontaneously report symptoms of this nature, and, therefore, it is thought that sexual side effects with the SSRIs may be underestimated. In placebo controlled clinical trials (see Table 1), the reported incidence of decreased libido for the whole population was 2.5%; ejaculation disorder (primarily ejaculatory delay) and impotence in male depressed patients receiving Cipramil (N = 423) was 5.9% and 2.8%, respectively. In female depressed patients receiving Cipramil (N = 660), the reported incidence of anorgasmia was 0.5%. The reported incidence of decreased libido was 0.4% among depressed patients receiving placebo, whilst sex specific adverse events were not reported among male and female depressed patients receiving placebo.
While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects.

Vital sign changes.

Cipramil 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 Cipramil treatment.

Mydriasis and angle-closure glaucoma.

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

Weight changes.

Patients treated with Cipramil in controlled trials experienced a weight loss of about 0.5 kg compared to no change for placebo patients.

Laboratory changes.

Cipramil and placebo groups were compared with respect to (1) mean change from baseline in various serum chemistry, haematology and urinalysis variables and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses revealed no clinically important changes in laboratory test parameters associated with Cipramil treatment.

ECG changes.

Electrocardiograms from citalopram (n = 802) and placebo (n = 241) groups were compared with respect to outliers defined as subjects with QTc changes over 60 msec from baseline or absolute values over 500 msec postdose, and subjects with heart rate increases to over 100 bpm or decreases to less than 50 bpm with a 25% change from baseline (tachycardic or bradycardic outliers respectively). In the citalopram group 1.9% of the patients had a change from baseline in QTcF > 60 msec compared to 1.2% of the patients in the placebo group. None of the patients in the placebo group had a postdose QTcF > 500 msec compared to 0.5% of the patients in the citalopram group. The incidence of tachycardic outliers was 0.5% in the citalopram group and 0.4% in the placebo group. The incidence of bradycardic outliers was 0.9% in the citalopram group and 0.4% in the placebo group.
In a thorough QT study, citalopram was found to be associated with a dose dependent increase in the QTc interval (see Section 4.4 Special Warnings and Precautions for Use, QT prolongation and torsade de pointes).

Other events observed during the premarketing evaluation of Cipramil.

Following is a list of WHO terms that reflect treatment emergent adverse events, as defined in the introduction (see Section 4.8 Adverse Effects (Undesirable Effects)), reported by patients treated with Cipramil at multiple doses in a range of 10 to 80 mg/day during any phase of a trial within the premarketing database of 4422 patients. All reported events are included except those already listed in Table 1 or elsewhere (see Section 4.8 Adverse Effects (Undesirable Effects)), those events for which a drug cause was remote, those event terms which were so general as to be uninformative and those occurring in only one patient. It is important to emphasise that, although the events reported occurred during treatment with Cipramil, they were not necessarily caused by it.
Events are further categorised by body system and listed in order of decreasing frequency according to the following definitions: very common adverse events are those occurring on one or more occasions in at least 1/10 patients; common adverse events are those occurring in less than 1/10 but at least 1/100; uncommon adverse events are those occurring in less than 1/100 patients but at least 1/1,000 patients; rare events are those occurring in fewer than 1/1,000 patients; unknown cannot be estimated from available data.

Skin and appendages disorders.

Uncommon: photosensitivity reaction, urticaria, acne, eczema, skin discolouration, alopecia, dermatitis, skin dry, psoriasis, rash. Rare: hypertrichosis, decreased sweating, melanosis, keratitis, pruritus ani. Unknown: ecchymosis, angioedema.

Musculoskeletal system disorders.

Uncommon: arthritis, muscle weakness, skeletal pain. Rare: bursitis, osteoporosis.

Central and peripheral nervous system disorders.

Common: migraine. Uncommon: vertigo, leg cramps, involuntary muscle contractions, speech disorder, abnormal gait, hypoaesthesia, neuralgia, ataxia, convulsions. Rare: abnormal coordination, hyperaesthesia, ptosis, stupor.

Vision disorders.

Common: abnormal accommodation. Uncommon: conjunctivitis, eye pain. Rare: mydriasis, photophobia, abnormal lacrimation, cataract, diplopia. Unknown: visual disturbance.

Special senses other, disorders.

Common: taste perversion. Rare: taste loss.

Psychiatric disorders.

Common: amnesia, apathy, depression, increased appetite, aggravated depression. Uncommon: aggressive reaction, increased libido, paroniria, drug dependence, depersonalisation, hallucination, euphoria, psychotic depression, delusion, paranoid reaction, emotional lability, panic reaction, psychosis, mania. Rare: catatonic reaction, melancholia, suicide related events. Unknown: bruxism, restlessness.

Gastrointestinal system disorders.

Common: saliva increased. Uncommon: gastritis, gastroenteritis, eructation, haemorrhoids, dysphagia, gingivitis, stomatitis, teeth grinding, oesophagitis. Rare: colitis, gastric ulcer, duodenal ulcer, gastroesophageal reflux, diverticulitis, glossitis, hiccups, rectal haemorrhage. Unknown: gastrointestinal haemorrhage.

Immune system disorders.

Unknown: anaphylactic reaction, hypersensitivity NOS.

Liver and biliary system disorders.

Uncommon: ALT increased, gamma-GT increased, AST increased. Rare: cholecystitis, cholelithiasis, bilirubinaemia, jaundice, hepatitis. Unknown: liver function test abnormal.

Metabolic and nutritional disorders.

Common: increased weight, decreased weight. Uncommon: thirst, dry eyes, increased alkaline phosphatase, abnormal glucose tolerance. Rare: hypokalaemia, obesity, hypoglycaemia, dehydration.

Endocrine disorders.

Rare: hypothyroidism, goitre, gynaecomastia.

Cardiovascular disorders, general.

Common: postural hypotension, hypotension. Uncommon: hypertension, oedema (extremities), cardiac failure, bradycardia, tachycardia. Unknown: orthostatic hypotension.

Myo-, endo-, pericardial and valve disorders.

Uncommon: angina pectoris, myocardial infarction, myocardial ischaemia.

Heart rate and rhythm disorders.

Common: tachycardia. Uncommon: bradycardia, extrasystoles, atrial fibrillation. Rare: bundle branch block, cardiac arrest, QT prolongation, torsade de pointes.

Vascular (extracardiac) disorders.

Uncommon: cerebrovascular accident, flushing, transient ischaemic attack. Rare: phlebitis.

Respiratory system disorders.

Uncommon: bronchitis, dyspnoea, pneumonia. Rare: asthma, laryngitis, bronchospasm, pneumonitis, sputum increased.

Red blood cell disorders.

Uncommon: anaemia. Rare: hypochromic anaemia.

White cell and reticuloendothelial system disorders.

Uncommon: leucopenia, leucocytosis, lymphadenopathy. Rare: granulocytopenia, lymphocytosis, lymphopenia.

Platelet, bleeding and clotting disorders.

Uncommon: abnormal bleeding, predominantly of the skin and mucous membranes, including purpura, epistaxis, haematomas, vaginal bleeding and gastrointestinal bleeding. Rare: pulmonary embolism, coagulation disorder, gingival bleeding. Unknown: thrombocytopaenia.

Urinary system disorders.

Common: polyuria. Uncommon: micturition frequency, urinary incontinence, urinary retention, dysuria. Rare: facial oedema, haematuria, oliguria, pyelonephritis, renal calculus, renal pain.

Reproductive disorders/ female.

Common: amenorrhoea. Uncommon: lactation nonpuerperal, breast pain, breast enlargement, vaginal haemorrhage, menorrhagia. Unknown: metrorrhagia.

Reproductive system and breast disorders/ male.

Unknown: priapism, galactorrhoea.

Body as a whole.

Uncommon: hot flushes, rigors, alcohol intolerance, syncope. Rare: hayfever.

Other events observed during the postmarketing evaluation of Cipramil.

Although no causal relationship to Cipramil treatment has been found, the following adverse events have been reported to be temporally associated with Cipramil treatment in at least 3 patients (unless otherwise noted) and not described elsewhere (see Section 4.8 Adverse Effects (Undesirable Effects)): choreoathetosis, epidermal necrolysis (3 cases), erythema multiforme, hepatic necrosis (2 cases), cholestatic hepatitis, hyponatraemia, neuroleptic malignant syndrome, pancreatitis, serotonin syndrome, spontaneous abortion, thrombocytopenia, ventricular arrhythmia, priapism, abnormal dreams, insomnia, confusional state, withdrawal syndrome, disturbance in attention, inappropriate ADH secretion, appetite decreased, abnormal orgasm female, syncope and grand mal convulsion.
Akathisia has been reported very rarely (< 1/10,000).
Cases of QT prolongation have been reported during the postmarketing period, predominantly in patients with pre-existing cardiac disease.

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.

4.9 Overdose

In general, the main therapy for all overdoses is supportive and symptomatic care.
Cipramil is given to depressed patients who are at potential risk of suicide and some reports of attempted suicide with Cipramil treated patients have been received. Detail is often lacking regarding precise dose or combination with other drugs and/or alcohol.

Toxicity.

Comprehensive clinical data on citalopram overdose are limited and many cases involve concomitant overdoses of other drugs/alcohol. Fatal cases of citalopram overdose have been reported with citalopram alone; however, the majority of fatal cases have involved overdose with concomitant medications.

Symptoms.

The following symptoms have been seen in reported overdose of citalopram: convulsion, tachycardia, somnolence, QT prolongation, coma, vomiting, tremor, hypotension, cardiac arrest, nausea, serotonin syndrome, agitation, bradycardia, dizziness, bundle branch block, QRS prolongation, hypertension, mydriasis, stupor, sweating, cyanosis, hyperventilation, atrial and nodal rhythm, ventricular arrhythmia, and very rare cases of torsade de pointes.

Treatment.

There is no specific antidote. Treatment is symptomatic and supportive. 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. Medical surveillance is advisable. ECG monitoring is recommended when more than 600 mg have been ingested. Convulsions may be treated with diazepam.
ECG monitoring is advisable in case of overdose.
Elimination half-life (t1/2β) and Tmax are independent of the dose taken. Information on these pharmacokinetic parameters can be found (see Section 5 Pharmacological Properties).
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia) and 0800 764 766 (New Zealand).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Biochemical and behavioural studies have shown that citalopram is a potent inhibitor of serotonin (5-HT)-uptake. Tolerance to the inhibition of 5-HT-uptake is not induced by long-term treatment with citalopram.
On the basis of in vitro studies, citalopram is one of the most selective serotonin reuptake inhibitor (SSRI) yet developed, with no or minimal effect on noradrenaline (NA), dopamine (DA) and gamma aminobutyric acid (GABA) uptake. In comparison with other SSRIs the decreasing order of selectivity is escitalopram, citalopram, sertraline, paroxetine, fluvoxamine and fluoxetine. The clinical relevance of this in vitro finding has not been established.
In contrast to many tricyclic antidepressants and some of the newer SSRIs, citalopram has no or very low affinity for a series of receptors including 5-HT1A, 5-HT2, DA D1 and DA D2receptors, α1receptors, α2receptors, 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.
Suppression of rapid eye movement (REM) sleep is considered a predictor of antidepressant activity. Like tricyclic antidepressants, other SSRIs and MAO inhibitors, citalopram suppresses REM sleep and increases deep slow wave sleep (based upon a five week single blind study in 16 depressed patients given doses up to 40 mg daily).
Although citalopram does not bind to opioid receptors, it potentiates the anti-nociceptive effect of commonly used opioid analgesics in rats. The clinical significance of this finding has not been established.
The main metabolites of citalopram are all SSRIs although their potency and selectivity ratios are lower than those of citalopram but higher than those of many of the newer SSRIs. The metabolites do not contribute to the overall antidepressant effect.
In humans, citalopram does not impair cognitive function or psychomotor performance to the same extent as amitriptyline and it has slight sedative properties. There were results suggestive of impairment in some tests (critical flicker fusion, coding skills, body sway, immediate memory recall).
Citalopram did not reduce saliva flow in a single dose study in human volunteers and in none of the studies in healthy volunteers did citalopram have significant influence on cardiovascular parameters. Citalopram has no effect on the serum levels of growth hormone. Like other SSRIs, citalopram increases plasma prolactin, an effect secondary to the prolactin stimulating role of serotonin.

Clinical trials.

Citalopram in the dose range 20-80 mg/day is more effective than placebo in the treatment of depression in the majority of trials, including relapse prevention trials. In the double blind, placebo controlled trials a total of 1083 patients received citalopram and 486 received placebo. There were three fixed dose trials of 6 weeks duration. In one trial a total of 650 patients with major depression were randomly allocated in approximately equal groups (~ 130 per group) to receive placebo or 10 mg, 20 mg, 40 mg or 60 mg citalopram. In the other two fixed dose studies, placebo was compared with 20 mg or 40 mg citalopram. Between 88 and 97 patients were treated in each group in one trial and approximately 48 in each group in the other. The remaining 5 trials of 4 or 6 weeks duration used flexible doses in the range of 20-80 mg/day.
In two relapse prevention or maintenance studies of 24 weeks duration, 257 patients were treated with citalopram and 116 with placebo. In one study, 147 citalopram treated patients who were responders (MADRS ≤ 12) in two 6 weeks fixed dose studies were rerandomised to receive placebo (N = 42) or continue their previous treatment with 20 mg (N = 48) or 40 mg citalopram (N = 57). In the other study MADRS responders (score ≤ 12) continued from an open 8-week trial and were randomised to receive placebo (N = 74) or continue with their optimal dose of citalopram (range 20-60 mg daily, N = 152). In both studies citalopram, independent of dose, reduced relapse rates and prolonged time to relapse compared to placebo.
The majority of the patients in the placebo controlled trials received 40 mg/day. The minimal effective dose was 20 mg/day. Analyses of subgroups of patients showed that patients experiencing their first episode of depression or with less severe depression responded well to the minimal effective dose of 20 mg while patients suffering from severe or recurrent depression achieved better results with 40 or 60 mg/day.
Citalopram demonstrates an equivalent therapeutic efficacy to tricyclic and tetracyclic antidepressants and other SSRIs in the treatment of major depression. The active comparator studies were chiefly randomised double blind studies. In the trials versus tricyclic and tetracyclic antidepressants (TTCA), a total of 682 patients received citalopram and 389 TTCAs. In the comparative trials versus other SSRIs, there were 439 citalopram treated patients and 451 treated with other SSRIs. In the 6 week comparison to imipramine, 20-30 mg (N = 187) and 40-60 mg (N = 193) citalopram were equally effective as imipramine 100-150 mg (N = 92). In an 8-week comparison carried out in hospital settings with fixed doses, 40 mg citalopram (N = 158) was equally effective to 20 mg fluoxetine (N = 158). Likewise in a general practice study, 20 mg citalopram (N = 173) was equally effective to 20 mg fluoxetine (N = 184). A 6-week comparison to fluvoxamine in flexible doses (citalopram 20-40 mg (N = 108)/ fluvoxamine 100-200 mg (N = 109)) also demonstrated equal efficacy.

5.2 Pharmacokinetic Properties

Absorption.

Oral bioavailability is about 80% and independent of food intake (Tmax mean 3.8 hours). The bioavailability of each enantiomer has not been studied separately, but the pharmacokinetics of each enantiomer is different.

Distribution.

The apparent volume of distribution (Vd)β is about 12-17 L/kg. The plasma protein binding is below 80% for citalopram and its main metabolites. After six weeks on 40-60 mg/day in 10 patients, the mean serum concentration of S-(+)-citalopram was about 50% of the R-(-)-citalopram concentration and the mean serum concentration of R-(-)-DCIT was 1.5 times that of S-(+)-DCIT.

Metabolism.

Citalopram is metabolised to the active demethylcitalopram (DCIT), didemethylcitalopram, citalopram-N-oxide and an inactive deaminated propionic acid derivative. All the active metabolites are also SSRIs, although weaker than the parent compound. Unchanged citalopram is the predominant compound in plasma.

Elimination.

The elimination half-life (T1/2β) is about 1½ days and the systemic citalopram plasma clearance (Cls) is about 0.3-0.4 L/min, and total (oral) plasma clearance(Cloral) is about 0.4 L/min.
About 12-23% of the daily dose is excreted unchanged in the urine. Hepatic (residual) clearance is about 0.3 L/min and renal clearance about 0.05-0.08 L/min.
The kinetics are linear. Steady-state plasma levels are achieved in 1-2 weeks. Average concentrations of 250 nanomol/L (100 to 500 nanomol/L) are achieved at a daily dose of 40 mg. There is no clear relationship between citalopram plasma levels and therapeutic response or side effects in a study of 650 patients.

5.3 Preclinical Safety Data

Genotoxicity.

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

Carcinogenicity.

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.

6 Pharmaceutical Particulars

6.1 List of Excipients

The tablets contain the following excipients: maize starch, lactose, microcrystalline cellulose, copovidone, glycerol, croscarmellose sodium, magnesium stearate, 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 25°C.

6.5 Nature and Contents of Container

Blister packs of 28 film-coated tablets containing 20 mg citalopram (as hydrobromide).

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical name.

1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile hydrobromide. The active is present as a racemate.

Molecular formula.

C20H21FN2O, HBr.

Molecular weight.

405.32.

Chemical structure.


CAS number.

59729-32-7.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription only medicine.

Summary Table of Changes