SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Citalopram Sandoz 20mg film-coated tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 24,99 mg citalopramhydrobromide, equivalent to 20 mg citalopram

Excipients with known effect:

each film-coated tablet contains 23 mg lactose monohydrate For a full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Film-coated tablet

White oblong biconvex film-coated tablet with a one sided notch and the embossment C20

The tablets can be divided into equal doses.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Treatment of major depressive episodes

4.2    Posology and method of administration

Citalopram should be administered as a single oral dose, either in the morning or in the evening. The tablets can be taken with or without food, but with fluid.

Following treatment initiation, an antidepressant effect should not be expected for at least two weeks. Treatment should continue until the patient has been free of symptoms for 4-6 months. Citalopram should be withdrawn slowly, it is advised that the dose is gradually reduced over a period of at least one to two weeks.

Adults

The recommended starting dose is 20 mg citalopram per day. If necessary, the dose can be increased to a maximum of 40 mg per day, depending on the individual response of the patient.

Elderly patients (>65 years of age)

For elderly patients the dose should be decreased to half of the recommended dose, e.g 10-20 mg per day. Depending on the individual response of the patient, the dose can be increased to a maximum of 20 mg/day.

Children and adolescents under the age of 18

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

Reduced renal function

Dosage adjustment is not required if the patient has mild to moderate renal impairment. No information is available on treatment of patients with severe renal impairment (creatinine clearance less than 20 ml/min).

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).

Poor metabolisers regarding CYP2C19

For known poor CYP2C19 metabolisers an initial dose of 10 mg daily the first two weeks of treatment is recommended. Depending on the outcome of the treatment the dose can thereafter be increased to 20 mg (see section 5.2).

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 and section 4.8 ). If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose, but at a more gradual rate.

4.3 Contraindications

Hypersensitivity to citalopram or to any of the excipients listed in section 6.

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).

Citalopram should not be given to patients receiving Monoamine Oxidase Inhibitors (MAOIs) including selegiline in daily doses exceeding 10 mg/day. Citalopram should not be given for fourteen days after discontinuation of an irreversible MAOI or for the time specified after discontinuation of a reversible MAOI (RIMA) as stated in the prescribing text of the RIMA. MAOIs should not be introduced for seven days after discontinuation of citalopram.

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 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.

Some cases presented with features resembling serotonin syndrome. Symptoms of an active substance 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.

Concommitant treatment with pimozide (see also section 4.5).

4.4 Special warnings and precautions for use

Use in children and adolescents under 18 years of age

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.

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 in the early stages of recovery.

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.

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.

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).

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 and headache 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).

Citalopram should not be used concomitantly with medicinal products with serotonergic effects such as sumatriptan or other triptans, tramadol, oxitriptan and tryptophan.

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

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.

There is little clinical experience of concurrent administration of citalopram and electro-convulsive therapy, therefore caution is advisable.

Citalopram should be used with caution in patients with a history of mania/hypomania. Citalopram should be discontinued in any patient entering a manic phase.

There have been reports of prolonged bleeding time and/or bleeding abnormalities such as ecchymosis, gynaecological haemorrhages, gastrointestinal bleedings and other cutaneous or mucous bleedings with SSRIs (see section 4.8). Caution is advised in patients taking SSRIs, particularly in concomitant use with active substances known to affect platelet function or other active substances that can increase the risk of haemorrhage as well as in patients with a history of bleeding disorders (see section 4.5).

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.

Treatment of psychotic patients with depressive episodes may increase psychotic symptoms.

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.

Hyponatraemia and the syndrome of inappropriate anti-diuretic hormone secretion (SIADH) has been reported rarely, predominantly in the elderly, and generally reverses on discontinuation of therapy.

Undesirable effects may be more common during 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).

At the beginning of the treatment, insomnia and agitation can occur. A dose titration may be helpful.

QT interval prolongationhas 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.

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

4.5 Interaction with other medicinal products and other forms of interaction

Contraindicated combinations

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, co-administration of citalopram with medicinal products that prolong the QT interval, such as Class IA and III antiarrhythmics, antipsycotics (e.g. fentiazine derviatives, 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.

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

Concomitant use of citalopram and pimozide is contra-indicated (see section 4.3). Concomitant administration of a single dose of 2 mg pimozide to healthy volunteers, who were treated with citalopram

40 mg/day for 11 days, caused only a minor increase in the AUC and Cmax of pimozide of approximately 10%, not being statistically significant. Despite the minor increase in plasma pimozide levels, the QTc interval was more prolonged after concomitant administration of citalopram and pimozide (on average 10 ms) as compared to administration of a single dose of pimozide alone (on average 2 ms). Since this interaction was already observed after administration of a single dose of pimozide, concomitant treatment with citalopram and pimozide is contraindicated.

The serotonergic effect of sumatriptan may be potentiated by selective serotonin reuptake inhibitors (SSRIs). 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).

Caution is warranted for patients who are being treated simultaneously with anticoagulants, medicines that affect the function of thrombocytes, such as NSAIDs, acetylsalicylic acid, dipyridamol, and ticlopidine or other medicines (e.g. atypical antipsychotics, phenothiazines, tricyclic depressants) that can increase the risk of haemorrhage (see section 4.4).

Caution is warranted for concomitant use of other QT interval prolonging medicines or hypokalaemia/hypomagnesaemia inducing drugs as they, like Citalopram, also prolong the QT interval.

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 and butyrophenones), mefloquin, bupropion and tramadol).

Experience with citalopram has not revealed any clinically relevant interactions with neuroleptics. However, as with other SSRIs, the possibility of a pharmacodynamic interaction cannot be excluded.

Undesirable effects may be more common during concomitant use of citalopram and herbal preparations containing St John's wort (Hypericum perforatum) (see section 4.4).

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

Pharmacokinetic interactions

Escitalopram (the active enantiomer of citalopram) is an inhibitor of the enzyme CYP2D6. 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 nortryptyline or antipsychotics like risperidone, thioridazine and haloperidol. Coadministration of citalopram and metoprolol (CYP2D6 substrate) resulted in a twofold increase in the plasma levels of metoprolol.

The metabolism of escitalopram is mainly mediated by CYP2C19. CYP3A4 and CYP2D6 may also contribute to the metabolism although to a smaller extent. The metabolism of the major metabolite S-DCT (demethylated escitalopram) seems to be partly catalysed by CYP2D.

Cimetidine, a potent CYP2D6, 3A4 and 1A2-inhibitor, caused a moderate increase in the average steady-state citalopram levels. Caution is advised when administering citalopram in combination with cimetidine. Dose adjustment may be warranted.

Co-administration of escitalopram 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. A reduction in the dose of escitalopram may be necessary based on monitoring of undesirable effects during concomitant treatment.

There is no pharmacokinetic interaction between lithium and citalopram. However, there have been reports of enhanced serotonergic effects when SSRIs were administered in combination with lithium or tryptophan. Caution is advised during simultaneous use of citalopram with these active substances. Routine monitoring of lithium levels should be continued as usual.

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.

No pharmacokinetic interaction was observed between citalopram and levomepromazine, digoxin or carbamazepine and its metabolite carbamazepine-epoxide.

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

4.6 Pregnancy and lactation

Pregnancy

There are limited data from the use of Citalopram in pregnant women. Studies in rats have shown teratogenic effects at high doses which caused maternal toxicity (see section 5.3 Preclinical safety data). The potential risk for humans is unknown. Citalopram should only be used in pregnancy if considered clearly necessary.

Cases of withdrawal symptoms in the newborn child have been described after the use of SSRI at the end of pregnancy. Neonates should be observed if maternal use of citalopram continues into the later stages of pregnancy. Abrupt discontinuation should be avoided during pregnancy.

Epidemiological data have suggested that the use of SSRIs in pregnancy, particular in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). The observed risk was approximately 5 cases per 1,000 pregnancies. In the general population 1 to 2 cases of PPHN per 1,000 pregnancies occur.

The following symptoms may occur in the neonate 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 withdrawal symptoms. In a majority of instances the complications begin immediately or soon (< 24 hours) after delivery.

Lactation

Citalopram is known to be excreted in breastmilk in small quantities. The advantages of breastfeeding should outweigh the potential undesirable effects for the child.

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 reactions observed with citalopram are in general mild and transient. They are most prominent during the first weeks of treatment and usually attenuate as the depressive state improves.

Treatment emergent adverse events reported in clinical trials:

	very common (>1/10)	common (>1/100, < 1/10)	uncommon £1/1,000, < 1/100)	rare £1/10,000, <1/1,000)	Other events reported since authorisation of citalopram
Blood and lymphatic system disorders				Haemorrhage (for example, gynaecological haemorrhage, gastrointestinal haemorrhage, ecchymosis and other forms of skin haemorrhage or bleeding in the mucous membranes
Metabolism and nutrition disorders		weight decrease, weight increase
Psychiatric disorders	somnolence, insomnia, agitation, nervousness	sleep disorders, impaired concentration, abnormal dreaming, amnesia, anxiety, decreased libido, increased appetite, anorexia, apathy, confusion	euphoria, increased libido		hallucinations, mania, depersonalisation, panic attack (these symptoms may be due to the underlying disease), suicidal thoughts/beha-viour (see section 4.4)*
Nervous system disorders	headache, tremor, dizziness	migraine, paraesthesia,	extrapyramidal disorder, convulsions	psychomotor-restlessness/ akathisia (see section 4.4)
Eye disorders	abnormal accommo dation	abnormalities of vision
Ear and labyrinth disorders			tinnitus

	very common (>1/10)	common (>1/100, < 1/10)	uncommon £1/1,000, < 1/100)	rare £1/10,000, <1/1,000)	Other events reported since authorisation of citalopram
Cardiac disorders	palpitations	tachycardia	Bradycardia (may be more frequent in elderly patients > 65 years)		supraventricula r and ventricular arrhythmias including torsade de pointes**
Vascular disorders		postural hypotension, hypotension, hypertension
Respiratory, thoratic and mediastinal disorders		rhinitis, sinusitis	coughing
Gastrointestinal disorders	nausea, dry mouth, constipation, diarrhoea	dyspepsia, vomiting, abdominal pain, flatulence, increased salivation
Hepato-biliary disorders			increased liver enzyme values
Skin and subcutaneous tissue disorders	increased sweating	rash, pruritus	photosensitivit y		angiodema
Musculoskeletal and connective tissue disorders			myalgia		arthralgia
Renal and urinary disorders		micturition disorder, polyuria		Hyponatriaemi a and the syndrome of inappropriate anti-diuretic hormone secretion (SIADH), predominantly in the elderly (see section 4.4)

citalopram therapy or early after treatment discontinuation (see section 4.4)

** 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).

Class effects

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.

Withdrawal symptoms seen on discontinuation of SSRI treatment Discontinuation of citalopram (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor and headache 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 section 4.2 and section 4.4).

4.9 Overdose

Fatal dose 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

Nausea, vomiting, sweating, tachycardia, drowsiness, coma, dystonia, convulsions, hyperventilation and hyperpyrexia have been reported. Cardiac features that have been observed include nodal rhythm, prolonged QT intervals and wide QRS complexes. Prolonged bradycardia with severe hypotension and syncope has also been reported.

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

An ECG should be taken. Consider oral activated charcoal in adults and children who have ingested more than 5 mg/kg body weight within 1 hour.

Control convulsions with intravenous diazepam if they are frequent or prolonged. Management should be symptomatic and supportive and include the maintenance of a clear airway and monitoring of cardiac and vital signs until stable.

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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antidepressant, Selective serotonin reuptake inhibitors ATC code: N06A B04

Citalopram is an antidepressant with a strong and selective inhibitory action on the uptake of

5-hydroxytryptamine (5-HT, serotonin).

Mechanism of action and pharmacodynamic effects

Tolerance to the inhibitory effect of citalopram on 5-HT uptake does not occur during long-term treatment.

The antidepressant effect is probably connected with the specific inhibition of serotonin uptake in the brain neurons.

Citalopram has almost no effect on the neuronal uptake of noradrenaline, dopamine and gamma-aminobutyric acid. Citalopram shows no affinity, or only very little, for cholinergic, histaminergic and a variety of adrenergic, serotonergic and dopaminergic receptors.

Citalopram is a bi-cyclic isobenzophurane-derivative that is chemically not related to tricyclic and tetracyclic antidepressants or other available antidepressants. The main metabolites of citalopram are also selective serotonin uptake inhibitors, though to a lesser degree. The metabolites are not reported to contribute to the overall antidepressant effect.

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

General characteristics of the active substance Absorption

Citalopram is rapidly absorbed following oral administration: the maximum plasma concentration is reached on average after 4 (1-7) hours. Absorption is independent of food intake. Oral bioavailability is approximately 80%.

Distribution

The apparent distribution volume is 12-17 l/kg. The plasma-protein binding of citalopram and its metabolites is below 80%.

Bio-transformation

Citalopram is metabolised into demethylcitalopram, didemethylcitalopram, citalopram-N-oxide and the deaminated propionic acid-derivative. The propionic acid-derivative is pharmacologically inactive. Demethylcitalopram, didemethylcitalopram and citalopram-N-oxide are selective serotonin uptake inhibitors, although weaker than the parent compound.

The main metabolizing enzyme is CYP2C19. Some contribution from CYP3A4 and CYP2D6 is possible.

Elimination

The plasma half-life is approximately 1/ days. After systemic administration, the plasma clearance is approximately 0.3-0.4 l/min and after oral administration the plasma clearance is approximately 0.4 l/min.

Citalopram is mainly eliminated via the liver (85%), but also partly (15%) via the kidneys. Of the quantity of citalopram administered, 12-23 % is eliminated unaltered via the urine. Hepatic clearance is approximately 0.3 l/min and renal clearance is 0.05-0.08 l/min.

Steady-state concentrations are reached after 1-2 weeks. A linear relationship has been demonstrated between the steady-state plasma level and the dose administered. At a dose of 40mg per day, an average plasma concentration of approximately 300nmol/l is reached. There is no clear relationship between citalopram plasma levels and therapeutic response or side effects.

Characteristics relating to patients

Longer plasma half-life values and a smaller clearance have been found in older patients due to a reduced metabolism.

The elimination of citalopram progresses more slowly in patients with reduced liver function. The plasma half-life of citalopram is approximately twice as long and the steady-state plasma concentration approximately twice as high in comparison with patients with a normal liver function.

The elimination of citalopram progresses more slowly in patients with a mild to moderate renal function disorder. A longer half-life and a small increase in the exposure of citalopram have been observed without any major impact on the pharmacokinetics of citalopram. No information is available on treatment of patients with severe renal impairment (creatinine clearance less than 20ml/min).

5.3 Preclinical safety data

In laboratory animals no evidence for a special hazard for humans was found. This is based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. Phospholipidosis in several organs was observed in repeated dose toxicity studies in rats. This reversible effect is known for several lipophilic amines and was not connected with morphological and functional effects. The clinical relevance is not clear. Embryotoxicity studies in rats have shown skeletal anomalies at high maternal toxic doses. The effects could possibly be related

to the pharmacological activity or could be an indirect effect to maternal toxicity. Peri- and postnatal studies have revealed reduced survival in offspring during the lactation period. The potential risk for humans is unknown. 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:

Cellulose, microcrystalline Glycerol 85%

Magnesium stearate Maize starch Lactose monohydrate Copovidone

Sodium starch glycollate (type A)

Coating:

Macrogol 6000

Hypromellose

Talc

Titanium dioxide (E171)

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

The film-coated tablets are packed in

-    PVDC-PVC / aluminium blisters and inserted into a carton

-    HDPE-bottle.

Pack sizes:

12, 14, 20, 28, 30, 50, 56, 98, 100, 250 film-coated tablets in blister; 250 film-coated tablets in HDPE-bottle

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements

7    MARKETING AUTHORISATION HOLDER

Sandoz Limited

Frimley Business Park

Frimley

Camberley

Surrey

GU16 7SR

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 04416/0914

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

04/03/2003 / 27/06/2008

10 DATE OF REVISION OF THE TEXT

29/05/2013