Consumer medicine information

Celapram

Citalopram

BRAND INFORMATION

Brand name

Celapram

Active ingredient

Citalopram

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Celapram.

What is in this leaflet

This leaflet answers some common questions about Celapram.

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

All medicines have benefits and risks. Your doctor has weighed the risks of you taking Celapram against the benefits expected for you.

If you have any concerns about taking this medicine, talk to your doctor or pharmacist.

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

What Celapram is used for

Celapram is used to treat depression.

Celapram belongs to a group of medicines called selective serotonin reuptake inhibitors (SSRIs). They are thought to work by acting on chemicals in your brain called amines. These amines 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.

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

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

Celapram is available only with a doctor's prescription.

Celapram 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 Celapram.

Before you take Celapram

When you must not take it

Do not take Celapram if you have a condition called 'congenital long QT syndrome. At high doses, Celapram 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 Celapram.

Do not take Celapram if you are allergic to medicines containing citalopram hydrobromide (e.g. Cipramil) 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 or tongue or other parts of the body or rash, itching or hives on the skin.

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

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

Do not take Celapram if the expiry date (EXP) printed on the pack or bottle has passed. If you take this medicine after the expiry date, it may not work as well.

Do not take Celapram if the packaging shows signs of tampering or the tablets do not look quite right.

Before you start to take it

Tell your doctor if:

  • you have allergies to any other medicines, foods, dyes or preservatives.
  • you are pregnant or plan 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 Celapram 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 Celapram.

When taken during pregnancy, particularly in the last three months of pregnancy, medicines like Celapram 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.

Your doctor will discuss the possible risks and benefits of taking Celapram during pregnancy.

If used during pregnancy Celapram should never be stopped abruptly.

Tell your doctor if you are breastfeeding or planning to breastfeed. Do not take Celapram 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 Celapram as it is excreted in breast milk.

Tell your doctor if you have, or have had, any medical conditions, especially the following:

  • 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 test
  • A tendency to bleed or bruise easily
  • bipolar disorder (manic depression)
  • diabetes
  • a history of seizures or fits
  • liver disease
  • kidney disease
  • restlessness and/or a need to move often
  • raised intraocular pressure (fluid pressure in the eye), or if you are a risk of angle-closure glaucoma.

Tell your doctor if you are receiving electroconvulsive therapy.

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

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

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

Taking other medicines

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

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

  • monoamine oxidase inhibitors (MAOIs), medicines used to treat depression.
    Do not take Celapram with MAOIs.
    Celapram can only be started after you have stopped taking:
    - tranylcypromine and phenelzine for at least 14 days
    - moclobemide for at least 1 day
  • other antidepressants, including other SSRIs and tricyclic antidepressants such as imipramine, despiramine
  • medicines used to treat mental illnesses such as schizophrenia, depression and mood swings, including antipsychotics and lithium
  • linezolid, an antibiotic
  • Non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, which are used to treat both pain and inflammation
  • sumatriptan, a medicine used to relieve migraines
  • tryptophan, an amino acid found in sports and dietary supplements
  • ketoconazole, itraconazole, fluconazole, medicines taken to treat fungal infections
  • macrolide antibiotics such as erythromycin and clarithromycin
  • warfarin, a medicine used to prevent blood clots
  • carbamazepine, a medicine used to treat convulsions
  • cimetidine and omeprazole, medicines used to treat reflux and stomach ulcers
  • St John's Wort (Hypericum perforatum), a herbal remedy used for depression
  • tramadol, a medicine used for pain relief
  • selegiline, a medicine used to treat Parkinson's disease
  • beta-blockers, medicines used to treat high blood pressure and other heart problems such as metoprolol
  • antiarrhythmics, medicines used to treat an irregular heart beat
  • digoxin, a medicine used to treat heart failure or to control a fast irregular heart beat
  • any other medicines for depression, anxiety, obsessive-compulsive disorder or pre-menstrual dysphoric disorder.

These medicines may be affected by Celapram or may affect how well it works. You may need different amounts of your medicines, or you may need to 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 Celapram. If it is necessary for you to be on these medicines at the same time as Celapram, your doctor may perform an ECG test to check your heart rate and rhythm.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking Celapram.

How to take Celapram

Follow all directions given to you by your doctor and pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the pack or bottle, ask your doctor or pharmacist for help.

How much to take

The dose varies from person to person.

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

Your doctor may gradually increase this dose depending on how you respond to this medicine.

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 or 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 Celapram greater than 40mg, talk to your doctor about reducing the dose.

Celapram is not recommended for use in children and adolescents below 18 years of age. Its safety and effectiveness in this age group has not been established.

How to take it

Swallow the tablets as a single daily dose with a glass of water. Celapram 20 mg and 40 mg tablets can be divided in half if advised by your doctor or pharmacist.

When to take it

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

Celapram can be taken with or without food, either in the morning or evening.

How long to take it

Continue to take Celapram even if it takes some time before you feel any improvement in your condition. Most medicines of this type take time to work, so do not be discouraged if you do not feel better right away. The treatment of depression may take at least six months.

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 Celapram 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 heartbeats.

When you have completed your course of treatment, the dose of Celapram 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 are less than 12 hours late in taking a tablet, take the missed dose as soon as you remember, and then go back to taking your tablets as you would normally.

If you are more than 12 hours late, then skip the dose you missed and take your next dose when you are meant to.

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

If you are not sure what to do or you have any questions about this, ask your doctor or pharmacist.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think you or anyone else may have taken too much Celapram. 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 changes in heart rhythm, decreased or increased blood pressure, tremor (shaking), agitation, dilated pupils of the eyes, drowsiness and sleepiness. 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 Celapram

Things you must do

Before starting any new medicine, tell your doctor or pharmacist that you are taking Celapram.

Tell all the doctors, dentists and pharmacists who are treating you that you are taking Celapram.

Persons taking Celapram may be more likely to think about killing themselves or actually trying to do so, especially when Celapram 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 taking Celapram who talks about or shows signs of killing him or herself. 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 in children, adolescents and young adults under 25 years of age, and you have not used antidepressant medicines before.

Contact your doctor or a mental health professional right away, or go to the nearest hospital for treatment if you or someone you know is showing any of the following warning signs of suicide:

  • worsening of your depression
  • 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, agitation or any other unusual changes in behaviour or mood.

All mentions of suicide or violence must be taken seriously. Family and carers of people taking Celapram also need to monitor for the above symptoms.

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 immediately if you experience episodes of mania. Some people with manic-depressive illness (bipolar disorder) may enter a manic phase. Symptoms of mania include rapidly changing thoughts or ideas, excessive physical activity and excessive restlessness.

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

If you become pregnant while taking Celapram, tell your doctor immediately. Do not stop taking your tablets until you have spoken to your doctor.

If you plan to have surgery, including dental surgery, tell your doctor or dentist that you are taking Celapram.

Things you must not do

Do not use Celapram to treat any other conditions unless your doctor tells you to.

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

Do not suddenly stop taking Celapram, or change the dose, without checking with your doctor.

Do not let yourself run out of Celapram over weekends or holidays. If you stop Celapram suddenly, you may get unwanted side effects, such as dizziness, headache and nausea.

Your doctor will tell you how to gradually reduce the amount of Celapram you are taking before stopping completely. This is usually done slowly over one to two weeks.

Things to be careful of

Be careful driving or operating machinery until you know how Celapram affects you. Celapram may cause dizziness, visual disturbances or drowsiness in some people. If you experience any of these, 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

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Celapram. Celapram helps most people with depression, but it may have unwanted side effects in some people.

All medicines have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

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

Ask your doctor or pharmacist to answer any questions you may have.

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
  • sleepiness or drowsiness, fatigue, yawning
  • dizziness
  • diarrhoea, constipation, flatulence, indigestion, stomach pain or discomfort
  • increase saliva or dry mouth, taste disturbance
  • nausea (feeling sick) or vomiting
  • loss of appetite or increased appetite, weight gain or weight loss
  • a sense of indifference to everything
  • sexual disturbances (decreased sexual drive, problems with orgasm, problems with ejaculation or erection)
  • migraine, headache
  • restlessness
  • unable to sit or stand still for extended periods of time
  • problems with menstrual periods.

These are the more common yet mild side effects of Celapram. Some of these may occur within the first two weeks of treatment and disappear after a short period of time.

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
  • nervousness, confusion, hallucinations, loss of memory
  • blurred vision
  • dizziness on standing up, especially when getting up from a sitting or lying position
  • 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
  • worsening depression, anxiety, agitation, aggressive behaviour
  • increased tendency to develop bruises
  • passing more urine than normal or difficulty passing urine
  • unusual bleeding, including bleeding from the stomach or bowel
  • tingling or numbness of the hands or feet

These side effects listed above are serious and may need urgent medical attention.

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

  • thoughts of suicide
  • serious allergic reaction (symptoms of an allergic reaction may include shortness of breath, wheezing or trouble breathing; swelling of the face, lips, tongue or other parts of the body, sometimes with itching, skin rash)
  • 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, movements disorders (involuntary movements of the muscles)
  • fast, irregular heart beat with feelings of dizziness or difficulty breathing.

The above list includes very serious side effects, which are uncommon or rare. You may need urgent medical attention or hospitalisation.

Tell your doctor if you notice anything that is making you feel unwell.

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

This is not a complete list of all possible side effects. Other side effects not listed above may also occur in some people.

After taking Celapram

Storage

Keep Celapram 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.

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

Keep your tablets in a cool dry place where the temperature stays below 25°C.

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

Do not leave Celapram in the car or on window stills. Heat and dampness can destroy some medicines.

Disposal

If your doctor tells you to stop taking Celapram, or your tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

Celapram is available in 3 strengths:

  • 10 mg - round, white, film-coated tablet marked "CM" over "10" on one side and "G" on the other. Each pack contains 28 tablets.
  • 20 mg - oval, white, scored film-coated tablet marked "CM breakline 20" on one side and "G" on the other. Each pack and bottle contains 28 tablets.
  • 40 mg - oval, white, scored, film-coated tablet marked "CM breakline 40" on one side and "G" on the other. Each pack contains 28 tablets.

Ingredients

The active ingredient in Celapram is citalopram hydrobromide.

Celapram tablets contain 10 mg, 20 mg or 40 mg of citalopram (as citalopram hydrobromide).

The tablets also contain the following inactive ingredients:

  • maize starch
  • lactose monohydrate
  • microcrystalline cellulose
  • povidone
  • crospovidone
  • macrogol 4000
  • magnesium stearate
  • hypromellose
  • titanium dioxide (E171).

Celapram contains sugars (as lactose). The tablets are gluten free.

Supplier

Celapram is supplied in Australia by:

Alphapharm Pty Ltd
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.mylan.com.au

Australian registration numbers:

  • Celapram 10 mg
    - AUST R 93542 (blister pack)
  • Celapram 20 mg
    - AUST R 82904 (blister pack)
    - AUST R 82905 (bottle)
  • Celapram 40 mg
    - AUST R 93543 (blister pack)

This leaflet was prepared in April 2020.

Published by MIMS May 2020

BRAND INFORMATION

Brand name

Celapram

Active ingredient

Citalopram

Schedule

S4

 

1 Name of Medicine

Citalopram hydrobromide.

6.7 Physicochemical Properties

Chemical structure.

Citalopram hydrobromide is soluble in methanol, sparingly soluble in water and acetone, soluble in ethanol (96%), freely soluble in chloroform and very slightly soluble in diethylether. No polymorphic forms have been observed.
Chemical name: 1-[3-(dimethylamino) propyl]-1-(4-fluorophenyl)- 1,3-dihydro- 5-isobenzofurancarbonitrile monohydrobromide. The active is present as a racemate.
Structural formula:
Molecular formula: C20H21FN2O, HBr. Molecular weight: 405.3.

CAS number.

59729-32-7.

2 Qualitative and Quantitative Composition

Each tablet contains 10 mg, 20 mg or 40 mg of citalopram (as hydrobromide) as the active ingredient.
Celapram also contains sugars (as lactose).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Citalopram hydrobromide is a white or almost white crystalline powder, odourless or practically odourless.

Celapram 10 mg.

5.5 mm, normal convex, white film coated tablet debossed "CM" over "10" on one side and "G" on the other.

Celapram 20 mg.

8 mm x 5.6 mm, oval, white, scored, film-coated tablet marked "CM / 20" and "G" on the other.

Celapram 40 mg.

11.65 mm x 7.13 mm, normal convex, oval white film coated tablet debossed "CM / 40" on one side and "G" of the other. Note that "/" represents a scoreline.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Biochemical and behavioural studies have shown that citalopram is a potent inhibitor of 5-hydroxytryptamine (5HT, serotonin) uptake. Tolerance to the inhibition of 5HT uptake is not induced by long-term treatment with citalopram.
In vitro studies indicate that citalopram is one of the most selective serotonin reuptake inhibitors (SSRIs) yet developed, with little or no effect on the uptake of noradrenaline (NA), dopamine (DA) and gamma aminobutyric acid (GABA). 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 5HT1A, 5HT2, DA D1 and DA D2 receptors, α1, α2 and 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 antinociceptive 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 also 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 prolactin and 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 to 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 1,083 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 (approx. 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 to 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 (Montgomery-Asbury Depression Rating Scale, MADRS ≤ 12) in two six week 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 to 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 tri 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 to 30 mg (N = 187) and 40 to 60 mg (N = 193) citalopram were equally effective as imipramine 100 to 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 as 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 to 40 mg (N = 108)/fluvoxamine 100 to 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 to 17 L/kg. The plasma protein binding is below 80% for citalopram and its main metabolites. After six weeks on 40 to 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 N-desmethylcitalopram (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.

Excretion.

The elimination half-life (t½β) is about 1.5 days, and the systemic citalopram plasma clearance (Cls) is about 0.3 to 0.4 L/min, and total (oral) plasma clearance (Cloral) is about 0.4 L/min.
About 12 to 23% of the daily dose is excreted unchanged in the urine. Hepatic (residual) clearance is about 0.3 L/minute and renal clearance about 0.05 to 0.08 L/min.
The kinetics are linear. Steady-state plasma levels are achieved in 1 to 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

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

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.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of major depression.

4.3 Contraindications

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

Monoamine oxidase inhibitors.

Citalopram 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 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 4.5 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 attempts is inherent in depression and may persist until significant remission occurs. The 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 behaviour (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 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 weeks), 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 the 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 adolescents 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 immediately to healthcare providers. 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 Celapram should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Monoamine oxidase inhibitors.

Simultaneous administration of citalopram and a monoamine oxidase inhibitor (MAOI) may cause serotonin syndrome, a serious, sometimes fatal, reaction in patients receiving an SSRI in combination with a MAOI and in patients treated with an SSRI and a MAOI in close temporal proximity. Some cases presented with features resembling neuroleptic malignant syndrome. Symptoms and signs of serotonin syndrome include: rapid onset, clonus, myoclonus, tremor, shivering, hyper-reflexia, hyperthermia, rigidity, autonomic instability with possible rapid fluctuations of vital signs and mental status changes that include extreme agitation progressing to delirium and coma.
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.

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.

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.

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.

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. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not receive this medicine.

Angle-closure glaucoma.

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

Reduced hepatic function.

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.

Reduced renal function.

Citalopram is eliminated more slowly in patients with mild to moderate reduction of renal function, without any 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).

Elderly patients (> 65 years).

Longer half-lives and decreased clearance values due to a reduced rate of metabolism have been demonstrated in elderly patients.

Haemorrhage.

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

Paediatric use (< 18 years).

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).

Serotonergic drugs.

Co-administration with serotonergic drugs (e.g. tramadol, sumatriptan) may lead to enhancement of 5-HT associated effects. Similarly, Hypericum perforatum (St John's wort) should be avoided as adverse interactions have been reported with a range of drugs including antidepressants.

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.
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).
Citalopram steady state levels were not significantly different in poor metabolisers and extensive 2D6 metabolisers after multiple dose administration of citalopram, suggesting that coadministration, with citalopram, of a drug that inhibits CYP2D6, is unlikely to have clinically significant effects on citalopram metabolism.

Lithium and tryptophan.

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

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 citalopram, combined administration of citalopram and digoxin (single dose of 1 mg) did not significantly affect the pharmacokinetics of either citalopram or digoxin.

Carbamazepine.

Combined administration of citalopram (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 N-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.

Alcohol.

The combination of SSRIs and alcohol is not advisable.

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 the risk. Thus, patients should be cautioned about using such medicines concurrently with Celapram.

Others.

No pharmacodynamic interactions have been noted in clinical studies in which citalopram has been given concomitantly with benzodiazepines, 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.
Neonates exposed to citalopram, other SSRIs (selective serotonin reuptake inhibitors) or SNRIs (serotonin noradrenaline 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.
Neonates 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. Abrupt discontinuation should be avoided during pregnancy.
Epidemiological studies have shown that the use of SSRIs (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.
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.
Citalopram appears in human breast milk in very low concentrations. In breastfeeding mothers, caution is recommended as it is not known whether citalopram excreted in milk may affect the infant.

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 tri 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 statistical 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 citalopram administered and the incidence of adverse events was examined in a fixed dose study in depressed patients receiving placebo or citalopram 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 citalopram (N = 423) was 5.9% and 2.8%, respectively. In female depressed patients receiving citalopram (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.

Citalopram 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 citalopram treatment. In addition, a comparison of supine and standing vital sign measures for citalopram and placebo treatments indicated that citalopram treatment is not associated with orthostatic changes.

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 citalopram in controlled trials experienced a weight loss of about 0.5 kg compared to no change for placebo patients.

Laboratory changes.

Citalopram 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 citalopram 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 citalopram.

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 citalopram at multiple doses in a range of 10 to 80 mg/day during any phase of a trial within the premarketing database of 4,422 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 citalopram 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 discoloration, 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.

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, goiter, 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, leukocytosis, lymphadenopathy. Rare: granulocytopenia, lymphocytosis, lymphopenia.

Platelet, bleeding and clotting disorders.

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

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 citalopram.

Although no causal relationship to citalopram treatment has been found, the following adverse events have been reported to be temporally associated with citalopram 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, mania, pancreatitis, serotonin syndrome, spontaneous abortion, thrombocytopenia, ventricular arrhythmia, priapism, abnormal dreams, insomnia, confusional state and withdrawal syndrome.
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.

4.2 Dose and Method of Administration

Citalopram 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 to 3 weeks' treatment, a possible dose increase should take place with intervals of 2 to 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).

The efficacy and safety 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.

The maximum recommended dose is 20 mg/day.

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 < 20 mL/min).

Poor metabolisers of CYP2C19 and patients taking CYP2C19.

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.

4.7 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.

4.9 Overdose

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

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, 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.
Elimination half-life (t½β) and Tmax are independent of the dose taken. Information on these pharmacokinetic parameters can be found (see Section 5.2 Pharmacokinetic Properties).
In cases of overdosage, it is advisable to contact the Poisons Information Centre (131126) for recommendation on the management and treatment of overdosage.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Excipients in Celapram include maize starch, lactose monohydrate, microcrystalline cellulose, povidone, crospovidone, macrogol 4000, magnesium stearate, hypromellose 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

Celapram 10 mg.

Container type: PVC/PVDC/Al blister pack and HDPE Bottle with PP CRC.
Pack sizes: blister packs of 7's, 28's and bottles of 28's.

Celapram 20 mg.

Container type: PVC/PVDC/Al blister pack and HDPE Bottle with PP CRC.
Pack sizes: blister packs and bottles of 7's and 28's.

Celapram 40 mg.

Container type: PVC/PVDC/Al blister pack and HDPE Bottle with PP CRC.
Pack sizes: blister packs of 7's, 28's and bottles of 28's.
Some strengths, pack sizes and/or pack types may not be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking it to your local pharmacy.

Summary Table of Changes