SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Citalopram 40 mg Film-coated Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each coated tablet contains 50 mg citalopram hydrobromide equivalent to 40 mg citalopram.

Excipients with known effect: Lactose monohydrate.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Film-Coated Tablet

White to off-white circular biconvex film-coated tablet debossed with '40' on one side and a lip shaped break line on the other side.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Treatment of depressive illness in the initial phase and as maintenance against potential relapse/recurrence.

Citalopram is also indicated in the treatment of panic disorder with or without agoraphobia.

4.2    Posology and method of administration

Posology

Adults

Major depressive episodes

Citalopram should be administered as a single oral dose of 20 mg daily. Dependent on individual patient response, the dose may be increased to a maximum of 40 mg daily.

In general, improvement in patients starts after one week, but may only become evident from the second week of therapy.

As with all antidepressant medicinal products, dosage should be reviewed and adjusted, if necessary, within 3 to 4 weeks of initiation of therapy and thereafter as judged clinically appropriate. Although there may be an increased potential for undesirable effects at higher doses, if after some weeks on the recommended dose insufficient response is seen, some patients may benefit from having their dose increased up to a maximum of 40 mg a day (see section 5.1). Dosage adjustments should be made carefully on an individual patient basis, to maintain the patient at the lowest effective dose.

Patients with depression should be treated for a sufficient period of at least 6 months to ensure that they are free from symptoms.

Panic Disorder Adults

A single oral dose of 10 mg is recommended for the first week before increasing the dose to 20 mg daily. Dependent on individual patient response, the dose may be increased to a maximum of 40 mg daily.

Patients should be started on 10 mg/day and the dose gradually increased in 10 mg steps according to the patient's response up to the recommended dose. A low initial starting dose is recommended to minimise the potential worsening of panic symptoms, which is generally recognised to occur early in the treatment of this disorder. Although there may be an increased potential for undesirable effects at higher doses, if after some weeks on the recommended dose insufficient response is seen some patients may benefit from having their dose increased gradually up to a maximum of 40 mg/day (see section 5.1). Dosage adjustments should be made carefully on an individual patient basis, to maintain the patients at the lowest effective dose.

Patients with panic disorder should be treated for a sufficient period to ensure that they are free from symptoms. This period may be several months or even longer.

Elderly patients (> 65 years old)

For elderly patients the dose should be decreased to half of the recommended dose, e.g. 10-20 mg daily. The recommended maximum dose for the elderly is 20 mg daily.

Paediatric population

Citalopram should not be used in the treatment of children and adolescents under the age of 18 years (see section 4.4).

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. Depending on individual patient response, the dose may be increased to a maximum of 20 mg daily. Caution and extra careful dose titration is advised in patients with severely reduced hepatic function (see section 5.2). These patients should be clinically monitored.

Reduced renal function

Dosage adjustment is not necessary in cases of mild or moderate renal impairment.

No information is available in cases of severe renal impairment (creatinine clearance <20 mL / min).

Withdrawal symptoms seen on discontinuation of citalopram

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 and section 4.8 Undesirable Effects). 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.

Poor metabolisers of 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).

Method of administration

Citalopram Tablets are administered as a single daily dose. Citalopram Tablets can be taken any time of the day without regard to food intake but with fluid.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Citalopram is contraindicated in patients with known QT-interval prolongation or congenital long QT syndrome.

Citalopram is contraindicated together with medicinal products that are known to prolong the QT-interval (see section 4.5).

Monoamine oxidase inhibitors (MAOIs)

Citalopram should not be used in combination with a monoamine oxidase inhibitor (MAOI). Some cases presented with features resembling serotonin syndrome. Citalopram should not be given to patients receiving MAOIs including selegiline in daily doses exceeding 10 mg/day. Citalopram should not be given for fourteen days after discontinuing treatment with an irreversible MAOI or for the time specified after discontinuing treatment with a reversible MAOI (RIMA) as stated in the prescribing text of the RIMA. At least 7 days should elapse after discontinuing citalopram treatment before starting a MAOI or RIMA (see section 4.5).

Cases of serious and sometimes fatal reactions have been reported in patients receiving a selective serotonin reuptake inhibitor (SSRI) in combination with MAOI, including the selective MAOI selegiline and the reversible MAOI (RIMA), moclobemide and in patients who have recently discontinued an SSRI and have been started on a MAOI.

Symptoms of a drug interaction with a MAOI include: hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes that include confusion, irritability and extreme agitation progressing to delirium and coma.

Citalopram is contraindicated in the combination with linezolid unless there are facilities for close observation and monitoring of blood pressure (see section 4.5).

Citalopram should not be used concomitantly with pimozide (see also section 4.5).

4.4 Special warnings and precautions for use

Treatment of elderly patients and patients with reduced kidney and liver function, see section 4.2.

Paediatric population (children and adolescents under 18 years of age)

Antidepressant as Citalopram should not be used in the treatment of children and adolescents under the age of 18 years.

Suicide-related behaviours (suicide attempt and suicidal thoughts), and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo. If, based on clinical need, a decision to treat is nevertheless taken; the patient should be carefully monitored for the appearance of suicidal symptoms. In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking.

Paradoxical anxiety

Some patients with panic disorder may experience intensified anxiety symptoms at the start of treatment with antidepressants. This paradoxical reaction usually subsides within the first two weeks of starting treatment. A low starting dose is advised to reduce the likelihood of of a paradoxical anxiogenic effect (see section 4.2)

Hyponatraemia

Hyponatraemia, probably due to inappropriate anti-diuretic hormone secretion (SIADH) has been reported as a rare adverse reaction with the use of SSRIs and generally reverse on discontinuation of therapy. Elderly female patients seem to be at particularly high risk.

Suicide/suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission occurs.

As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase again in the early stages of recovery.

Other psychiatric conditions for which Citalopram is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.

Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.

Close supervision of patients and in particular those at high risk should accompany drug therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

Elderly patients

Caution should be used in the treatment of elderly patients (see section 4.2).

Reduced kidney and liver function

Caution should be used in the treatment of patients with reduced kidney and liver function (see section 4.2).

The use of citalopram in patients with severe renal impairment (creatinine clearance less than 20 ml/min.) is not recommended as no information is available on use in these patients (see section 4.2).

In cases of impaired hepatic function dose reduction is recommended (see section 4.2) and liver function has to be closely monitored.

Akathisia/psychomotor restlessness

The use of Citalopram 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 Citalopram.

Mania

Citalopram should be used with caution in patients with a history of mania/hypomania. In patients with manic-depressive illness a change towards the manic phase may occur. Citalopram should be discontinued in any patient entering a manic phase.

Seizures

Seizures are a potential risk with antidepressant drugs. 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.

Serotonin syndrome

In rare cases, a serotonin syndrome has been reported in patients using SSRIs. A combination of symptoms, such as agitation, tremor, myoclonus and hyperthermia may indicate the development of this condition. Treatment with citalopram should be discontinued immediately and symptomatic treatment initiated.

Serotonergic medicines

Citalopram should not be used concomitantly with medicinal products with serotonergic effects such as tramadol, tryptophan, oxitriptan, sumatriptan or other triptans (see section 4.3).

St John's Wort

An increase in serotoninergic effects, such as serotonin syndrome, may occur with concomitant use of citalopram and herbal preparations containing St John’s wort (Hypericum perforatum). Therefore citalopram and St John's wort preparations should not be taken concomitantly (see section 4.5).

Psychosis

Treatment of psychotic patients with depressive episodes may increase psychotic symptoms

Diabetes

In patients with diabetes, treatment with an SSRI may alter glycaemic control. Insulin and/ or oral hypoglycaemic dosage may need to be adjusted.

Angle-closure Glaucoma

SSRIs 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 patients pre-disposed. Citalopram should therefore be used with caution in patients with angle-closure glaucoma or history of glaucoma.

Haemorrhage

There have been reports of prolonged bleeding time and/or bleeding abnormalities such as ecchymoses and purpura, gynaecological haemorrhages, gastrointestinal bleedings and other cutaneous or mucous bleedings with SSRIs (see section 4.8). Caution is advised in patients taking Citalopram, particularly in concomitant use with oral anticoagulants, active substances known to affect platelet function or other active substances that can increase the risk of haemorrhage (e.g. atypical antipsychotics and phenothiazines, most tricyclic antidepressants, acetylsalicylic acid, non-steroidal antiinflammatory drugs (NSAIDs), ticlopidine and dipyridamol, as well as in patients with a history of bleeding disorders (see section 4.5).

Electroconvulsive Therapy (ECT)

There is limited clinical experience of concurrent administration of citalopram and ECT, therefore caution is advisable.

QT interval prolongation

Citalopram has been found to cause a dose-dependent prolongation of the QT-interval. Cases of QT interval prolongation and ventricular arrhythmia including torsade de pointes have been reported during the post-marketing period, predominantly in patients of female gender, with hypokalemia, or with pre-existing QT prolongation or other cardiac diseases (see sections 4.3, 4.5, 4.8, 4.9 and 5.1).

Caution is advised in patients with significant bradycardia; or in patients with recent acute myocardial infarction or uncompensated heart failure.

Electrolyte disturbances such as hypokalaemia and hypomagnesaemia increase the risk for malignant arrhythmias and should be corrected before treatment with citalopram is started.

If patients with stable cardiac disease are treated, an ECG review should be considered before treatment is started.

If signs of cardiac arrhythmia occur during treatment with citalopram, the treatment should be withdrawn and an ECG should be performed.

Monoamine Oxidase Inhibitors (MAOIs)

MAOIs should not be used in combination with SSRIs (see section 4.3).

Reversible, selective MAO-A inhibitors

The combination of citalopram with MAO-A inhibitors is generally not recommended due to the risk of onset of a serotonin syndrome (see section 4.5).

For information on concomitant treatment with non-selective, irreversible MAOinhibitors see section 4.5.

Withdrawal symptoms seen on discontinuation of Citalopram treatment Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt (see section 4.8). In a recurrence prevention clinical trial with citalopram, adverse events after discontinuation of active treatment were seen in 40% of patients versus 20% in patients continuing citalopram.

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 disturbance (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 month, according to the patient’s needs (see “Withdrawal Symptoms Seen on Discontinuation of Citalopram”, section 4.2).

Excipients

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

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions

At the pharmacodynamic level cases of serotonin syndrome with citalopram and moclobemide and buspirone have been reported.

Contraindicated combinations

MAO-inhibitors

The simultaneous use of citalopram and MAO-inhibitors can result in severe undesirable effects, including the serotonin syndrome (see section 4.3).

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 and the reversible MAOIs linezolid and moclobemide and in patients who have recently discontinued an SSRI and have been started on a MAOI.

Some cases presented with features resembling serotonin syndrome. Symptoms of an active substance interaction with a MAOI include: agitation, tremor, myoclonus, and hyperthermia.

QT interval prolongation

Pharmacokinetic and pharmacodynamic studies between citalopram and other medicinal products that prolong the QT interval have not been performed. An additive effect of citalopram and these medicinal products cannot be excluded. Therefore, coadministration of citalopram with medicinal products that prolong the QT interval, such as Class IA and III antiarrhythmics, antipsycotics (e.g. phenothiazine derivatives, pimozide, haloperidol), tricyclic antidepressants, certain antimicrobial agents (e.g. sparfloxacin, moxifloxacin, erythromycin IV, pentamidine, anti-malarian treatment particularly halofantrine), certain antihistamines (astemizole, mizolastine) etc., is contraindicated.

Pimozide

Co administration of a single dose of pimozide 2 mg to subjects treated with racemic citalopram 40 mg/day for 11 days caused an increase in AUC and Cmax of pimozide, although not consistently throughout the study. The co-administration of pimozide and citalopram resulted in a mean increase in the QTc interval of approximately 10msec. Due to the interaction noted at a low dose of pimozide, concomitant administration of citalopram and pimozide is contraindicated.

Combinations requiring precaution for use

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 medicinal products Lithium and tryptophan

No pharmacodynamic interactions have been found in clinical studies in which citalopram has been given concomitantly with lithium. However there have been reports of enhanced effects when SSRIs have been given with lithium or tryptophan and therefore the concomitant use of citalopram with these medicinal products should be undertaken with caution. Routine monitoring of lithium levels should be continued as usual.

Co-administration with serotonergic medicinal products (e.g. tramadol, dextromethorphan, pethidine, tryptophan, oxitriptan, sumatriptan and other triptans) may lead to enhancement of 5-HT associated effects; serotonin syndrome.

Until further information is available, the simultaneous use of citalopram and 5-HT agonists, such as sumatriptan and other triptans, is not recommended (see section 4.4).

St. John’s Wort

Dynamic interactions between SSRIs and herbal remedy St John's Wort (Hypericum perforatum) can occur, resulting in an increase in undesirable effects (see section 4.4). Pharmacokinetic interactions have not been investigated.

Haemorrhage

Caution is warranted for patients who are being treated simultaneously with anticoagulants, medicinal products that affect the platelet function, such as non steroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid, dipyridamol, and ticlopidine or other medicines (e.g. atypical antipsychotics) that can increase the risk of haermorrhage (see section 4.4).

ECT (electroconvusive therapy)

There are no clinical studies establishing the risks or benefits of the combined use of electroconvulsive therapy (ECT) and citalopram (see section 4.4).

Alcohol

No pharmacodynamic or pharmacokinetic interactions have been demonstrated between citalopram and alcohol. However, the combination of citalopram and alcohol is not advisable.

Medicinal products inducing hypokalaemia /hypomagnesaemia

Caution is warranted for concomitant use of hypokalaemia/hypomagnesaemia inducing medicinal products as these conditions increase the risk of malignant arrhythmias (see section 4.4).

Medicinal products 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 [butyrophenones, thioxanthenes], mefloquin, bupropion and tramadol].

Pharmacokinetic interactions

Biotransformation of citalopram to demethylcitalopram is mediated by CYP2C19 (approx. 38%), CYP3A4 (approx. 31%) and CYP2D6 (approx. 31%) isozymes of the cytochrome P450 system. The fact that citalopram is metabolised by more than one CYP means that inhibition of its biotransformation is less likely as inhibition of one enzyme may be compensated by another. Therefore co-administration of citalopram with other medicinal products in clinical practice has very low likelihood of producing pharmacokinetic medicinal product interactions.

Food

The absorption and other pharmacokinetic properties of citalopram have not been reported to be affected by food.

Influence of other medicinal _ products on the _ pharmacokinetics of citalopram

Co-administration with ketoconazole (potent CYP3A4 inhibitor) did not change the pharmacokinetics of citalopram.

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

Cimetidine

Cimetidine, a known enzyme-inhibitor, caused a slight rise in the average steady-state citalopram levels. Caution is therefore recommended when administering citalopram in combination with cimetidine. Co-administration of escitalopram (the active enantiomer of citalopram) with omeprazole 30 mg once daily (a CYP2C19 inhibitor) resulted in moderate (approximately 50%) increase in the plasma concentrations of escitalopram. Thus, caution should be exercised when used concomitantly with CYP2C19 inhibitors (e.g. omeprazole, esomeprazole, fluvoxamine, lansoprazole, ticlopidine) or cimetidine Dose adjustment may be warranted.

Metoprolol

Caution is recommended when citalopram is co-administered with medicinal products that are mainly metabolised by this enzyme, and that have a narrow therapeutic index, e.g. flecainide, propafenone and metoprolol (when used in cardiac failure), or some CNS acting medicinal products that are mainly metabolised by CYP2D6, e.g. antidepressants such as desipramine, clomipramine and nortriptyline or antipsychotics like risperidone, thioridazine and haloperidol. Dosage adjustment may be warranted. Co-administration with metoprolol resulted in a twofold increase in the plasma levels of metoprolol, but did not statistically significant increase the effect of metoprolol on the blood pressure and cardiac rhythm.

Effects of citalopram on other medicinal _products

A pharmacokinetic / pharmacodynamic interaction study with concomitant administration of citalopram and metoprolol (a CYP2D6 substrate) showed a twofold increase in metoprolol concentrations, but no statistically significant increase in the effect of metoprolol on blood pressure and heart rate in healthy volunteers.

Citalopram and demethylcitalopram are negligible inhibitors of CYP2C9, CYP2E1 and CYP3A4, and only weak inhibitors of CYP1A2, CYP2C19 and CYP2D6 as compared to other SSRIs established as significant inhibitors.

Levomepromazine, digoxin, carbamazepine

Thus no change or only very small changes of no clinical importance were observed when citalopram was given with CYP1A2 substrates (clozapine and theophylline), CYP2C9 (warfarin), CYP2C19 (imipramine and mephenytoin), CYP2D6 (sparteine, imipramine, amitriptyline, risperidone) and CYP3A4 (warfarin, carbamazepine (and its metabolite carbamazepine epoxid) and triazolam).

No pharmacokinetic interaction was observed between citalopram and levomepromazine, or digoxin, (indicating that citalopram neither induce nor inhibit P-glycoprotein).

Desipramine, imipramine

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. When desipramine is combined with citalopram, an increase of the desipramine plasma concentration has been observed. A reduction of the desipramine dose may be needed.

4.6 Fertility, pregnancy and lactation

Pregnancy

Publised data on pregnant women (more than 2500 exposed outcomes) indicate no malformative feto/ neonatal toxicity. However, citalopram should not be used during pregnancy unless clearly necessary and only after careful consideration of the risk/benefit.

Neonates should be observed if maternal use of citalopram continues into the later stages of pregnancy, particularly in the third trimester. Abrupt discontinuation should be avoided during pregnancy.

The following symptoms may occur in the neonates after maternal SSRI/SNRI use in later stages of pregnancy: respiratory distress, cyanosis, apnoea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycaemia, hypertonia, hypotonia, hyperreflexia, tremor, jitteriness, irritability, lethargy, constant crying, somnolence and difficulty sleeping. These symptoms could be due to either serotonergic effects or discontinuation symptoms. In a majority of instances the complications begin immediately or soon (<24 hours) after delivery.

Epidemiological data have suggested that the use of SSRIs in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). The observed risk was approximately 5 cases per 1000 pregnancies. In the general population 1 to 2 cases of PPHN per 1000 pregnancies occur.

Animal studies showed reproductive toxicity, but did not indicate direct harmful effects with respect to pregnancy, embryonic/foetal development, parturition or postnatal development (see section 5.3).

Lactation

Citalopram is excreted into breast milk. It is estimated that the suckling infant will receive about 5% of the weight related maternal daily dose (in mg/kg). No or only minor events have been observed in the infants. However, the existing information is insufficient for assessment of the risk to the child. Caution is recommended. If treatment with citalopram is considered necessary, discontinuation of breast feeding should be considered.

Male fertility

Animal data have shown that citalopram may affect sperm quality (see section 5.3). Human case reports with some SSRIs have shown that an effect on sperm quality is reversible. Impact on human fertility has not been observed so far.

4.7 Effects on ability to drive and use machines

Citalopram has minor or moderate influence on the ability to drive and use machines. Psychoactive medicinal products can reduce the ability to make judgements and to react to emergencies. Patients should be informed of these effects and be warned that their ability to drive a car or operate machinery could be affected.

4.8 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 adverse reactions are presented at the MedDRA Preferred Term Level.

For the following reactions a dose-response was discovered: Sweating increased, dry mouth, insomnia, somnolence, diarrhoea, nausea and fatigue.

The table below shows the percentage of adverse drug reactions associated with SSRIs and/or citalopram seen in either > 1% of patients in double-blind placebo-controlled trials or in the post-marketing period.

Frequencies are defined as follows: very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1000 to < 1/100), rare (> 1/10000 to < 1/1000), very rare (< 1/10000), not known (cannot be estimated from the available data).

Blood and lymphatic system disorders

Not known: Thrombocytopenia

Immune system disorders

Uncommon: Allergic reactions

Very rare: Anaphylactoid reactions

Not known: Hypersensitivity, anaphylactic reaction

Endocrine disorders

Very rare: Prolactinaemia

Not known: Inappropriate ADH secretion

Metabolism and nutrition disorders

Common: Appetite decreased, weight decreased Uncommon: Increased appetite, weight increased Rare: Hyponatremia Not known: Hypokalaemia

Psychiatric disorders

Common: Agitation, nervousness, sleep disorders, abnormal orgasm (female), abnormal dreams, amnesia, anxiety, decreased libido, apathy and confusion. Uncommon: Aggression, hallucinations, mania, depersonalisation, euphoria and increased libido

Not known: Panic attack (these symptoms may be due to the underlying disease), bruxism, restlessness, suicidal ideation, suicidal behaviour¹

Nervous system disorders

Very common: Somnolence, headache, dizziness, insomnia

Common: Migraine, tremor, dizziness, disturbance in attention and paraesthesia

Uncommon: Syncope

Rare: Convulsion grand mal, dyskinesia, taste disturbance

Not known: Convulsions, serotonin syndrome, extrapyramidal disorder, akathisia,

movement disorder

Eye disorders

Very common: Abnormal accommodation Common: Abnormalities of vision

Uncommon: Mydriasis (which may lead to acute narrow angle glaucoma), see section 4.4 Special warnings and precautions for use)

Not known: Visual disturbance

Ear and labyrinth disorders

Common: tinnitus

Cardiac disorders

Very common: Palpitations

Uncommon: Bradycardia, tachycardia

Very rare: Supraventricular and ventricular arrhythmia

Not known: Ventricular arrhythmia including torsade de pointes, electrocardiogram QT-prolonged

Vascular disorders

Common: Hypotension, hypertension

Rare: Haemorrhage

Not known: Orthostatic hypotension

Respiratory, thoracic and mediastinal disorders

Common: Rhinitis, yawning and sinusitis Uncommon: Coughing Not known: Epistaxis

Gastrointestinal disorders

Very common: Nausea, dry mouth

Common: Dyspepsia, diarrhoea, vomiting, constipation, abdominal pain, flatulence and increased salivation

Not known: Gastrointestinal haemorrhage (including rectal haemorrhage)

Hepatobiliary disorders

Rare: Hepatitis

Not known: Liver function test abnormal

Skin and subcutaneous tissue disorders

Very common: Increased sweating Common: Pruritus

Uncommon: Urticaria, alopecia, rash, purpura, photosensitivity reaction Not known: Ecchymosis, angiodemas

Musculoskeletal and connective tissue disorders

Common: Myalgia, arthralgia

Renal and urinary disorders

Common: Micturition disorder and polyuria Uncommon: Urinary retention

Reproductive system and breast disorders

Common: Ejaculation failure, ejaculation disorder, dysmenorrhoea and impotence Uncommon: Female: Menorrhagia Not known: Female: Metrorrhagia Male: Priapism, galactorrhoea

General disorders and administration site conditions

Very common: Asthenia Common: Fatigue Uncommon: Malaise, oedema

Rare: Pyrexia ¹ Cases of suicidal ideation and suicidal behaviours have been reported during citalopram therapy or early after treatment discontinuation (see section 4.4).

Bone fractures

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.

QT interval prolongation

Cases of QT prolongation and ventricular arrhythmia including torsade de pointes have been reported during the post-marketing period, predominantly in patients of female gender, with hypokalemia, or with pre-existing QT prolongation or other cardiac diseases (see sections 4.3, 4.4, 4.5, 4.9 and 5.1).

Withdrawal symptoms seen on discontinuation of citalopram treatment Discontinuation of citalopram (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbance (include paraesthesia), sleep disturbance (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 events are mild to moderate and are self-limiting, however, in some patients they may be severe and/or prolonged. It is therefore advised that when citalopram treatment is no longer required, gradual discontinuation by dose tapering should be carried out (see sections 4.2 and 4.4).

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Toxicity

Comprehensive clinical data on citalopram overdose are limited and many cases involve concomitant overdoses of other drugs/alcohol. Citalopram is given to patients at potential risk of suicide and some reports of attempted suicide have been received. Detail is often lacking regarding precise dose. Fatal cases of citalopram overdose have been reported with citalopram alone; however, the majority of fatal cases have involved overdose with concomitant medications. Fatal dose is not known. Patients have survived ingestion of up to 2 g citalopram. The effects will be potentiated by alcohol taken at the same time. Potential interaction with tricyclic antidepressants and MAOIs.

Symptoms

The following symptoms have been seen in reported overdose of citalopram: Nausea, drowsiness, dystonia, convulsions, tachycardia, somnolence, QT interval prolongation, coma, vomiting, tremor, hypotension, cardiac arrest, serotonin syndrome, agitation, bradycardia, dizziness, bundle branch block, QRS prolongation, hypertension, mydriasis, torsade de pointes, stupor, sweating, cyanosis, hyperventilation, hyperpyrexia and atrial and ventricular arrythmia. Rarely, features of the "serotonin syndrome" may occur in severe poisoning. This includes alteration of mental status, neuromuscular hyperactivity and autonomic instability. There may be hyperpyrexia and elevation of serum creatine kinase. Rhabdomyolysis is rare.

Management

There is no known specific antidote to citalopram and includes the maintenance of a clear airway and monitoring of ECG and vital signs until stable. Treatment is symptomatic and supportive. If the amount of medicine is large and ingestion very recent, gastric lavage can be considered (if the patient has lost consciousness, intubation must be performed first). Consider oral activated charcoal in adults and children who have ingested more than 5 mg/kg body weight within 1 hour. Activated charcoal given !4 hour after ingestion of citalopram has been shown to reduce absorption by 50%.. Speeding up the passage using osmotically working laxatives, e.g., sodium sulphate can also be considered. ECG and vital signs should be monitored.

ECG monitoring is advisable in case of overdose in patients with congestive heart failure/bradyarrhythmias, in patients using concomitant medications that prolong the QT interval, or in patients with altered metabolism, e.g. liver impairment.

If consciousness is impaired the patient should be intubated.

Control convulsions with intravenous diazepam if they are frequent or prolonged.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Selective Serotonin Reuptake Inhibitors, ATC-Code: N 06A B 04

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.

Citalopram is a very Selective Serotonin Reuptake Inhibitor (SSRI), with no, or minimal, effect on noradrenaline (NA), dopamine (DA) and gamma aminobutyric acid (GABA) uptake.

In contrast to many tricyclic antidepressants and some of the newer SSRIs, citalopram has no or very low affinity for a series of receptors including 5-HT _1A, 5-HT₂, DA Di and D₂ receptors, a₁-, a₂-, ^-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.

This absence of effects on receptors could explain why citalopram produces fewer of the traditional side effects such as dry mouth, bladder and gut disturbance, blurred vision, sedation, cardiotoxicity and orthostatic hypotension.

The main metabolites of citalopram are all SSRIs although their potency and selectivity ratios are lower than those of citalopram. However, the selectivity ratios of the metabolites are higher than those of many of the newer SSRIs. The metabolites do not contribute to the overall antidepressant effect.

Pharmacodynamic effects

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. Although citalopram does not bind to opioid receptors it potentiates the antinociceptive effect of commonly used opioid analgesics. There was potentiation of d-amphetamine-induced hyperactivity following administration of citalopram.

In humans citalopram does not impair cognitive (intellectual function) and psychomotor performance and has no or minimal sedative properties, either alone or in combination with alcohol.

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.

In a double-blind, placebo-controlled ECG study in healthy subjects, the change from baseline in QTc (Fridericia-correction) was 7.5 (90%CI 5.9-9.1) msec at the 20 mg/day dose and 16.7 (90%CI 15.0-18.4) msec at the 60 mg day/dose (see sections 4.3, 4.4, 4.5, 4.8 and 4.9).

5.2 Pharmacokinetic properties

Absorption

Absorption of citalopram is almost complete and independent of food intake (T_max average/mean 3.8 hours). Oral bioavailability is about 80%.

Distribution

The apparent volume of distribution (V_d)p is about 12.3 L/kg. The plasma protein binding is below 80% for citalopram and its main metabolites.

Biotransformation

Citalopram is metabolized to the active demethylcitalopram, didemethylcitalopram, citalopram-N-oxide and an inactive deaminated proprionic 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 (T_/2p) is about 1.5 days and the systemic citalopram plasma clearance (Cl_s) is about 0.33 L/min, and oral plasma clearance (Cl _oral) is about 0.41 L/min.

Citalopram is excreted mainly via the liver (85%) and the remainder (15%) via the kidneys. About 12% of the daily dose is excreted in urine as unchanged citalopram. Hepatic (residual) clearance is about 0.35 L/min and renal clearance about 0.068 L/min.

Linearitv/Non-linearitv

The kinetics is linear. Steady state plasma levels are achieved in 1-2 weeks. Average concentrations of 250 nmol/L (100-500 nmol/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.

Elderly patients (>65 years)

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

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 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. At present no information is available for treatment of patients with severely reduced renal function (creatinine clearance <20 mL/min).

5.3 Preclinical safety data

Citalopram has low acute toxicity. In chronic toxicity studies there were no findings of concern for the therapeutic use of citalopram. Citalopram has no mutagenic or carcinogenic potential. Based on data from reproduction toxicity studies (segment I,

II and III) there is no reason to have special concern for the use of citalopram in women of child-bearing potential. Embryotoxicity studies in rats have shown skeletal anomalies at maternal toxic doses. The effects may be related to the pharmacological activity or could be an indirect effect due to maternal toxicity. Peri- and postnatal studies have revealed reduced survival in offspring during the lactation period.The potential risk for humans is unknown.

Phospholipidosis has been observed in several organs following multiple administrations in rats. The effect was reversible at discontinuation.

Accumulation of phospholipids has been observed in long term animal studies with many cation-amphophilic drugs. The clinical relevance of these results is not clear.

Animal data have shown that citalopram induces a reduction of fertility index and pregnancy index, reduction in number in implantation and abnormal sperm at exposure well in excess of human exposure.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Core Tablets Lactose monohydrate Microcrystalline cellulose Maize starch Copovidone Croscarmellose sodium Magnesium stearate

Film Coating Opadry White 20H 58983 Hypromellose Titanium dioxide E171 Propylene glycol Hydroxypropyl cellulose Talc

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions

6.5 Nature and contents of container

Blister strips comprising of PVC film coated uniformly with PVdC on the inner side with a backing of aluminium foil coated with heat seal lacquer.

Pack sizes of 1, 14, 28, 30, 50, 56, 98, 100 or 250 tablets. Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

7    MARKETING AUTHORISATION HOLDER

Ranbaxy (UK) Limited Building 4, Chiswick Park 566 Chiswick High Road London, W4 5YE United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 14894 / 0165

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

08/09/2008

10    DATE OF REVISION OF THE TEXT

09/07/2013