Document: Citalopram Vitabalans film-coated tablet ENG SmPC change

• Citalopram Vitabalans film-coated tablet SmPC
• Citalopram Vitabalans film-coated tablet ENG SmPC

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RMS comment: Please note that this is the tracked SmPC circulated by the applicant. RMS proposed changes and comments are inserted in the FRAR.

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Citalopram Vitabalans 20 mg film-coated tablets

Citalopram Vitabalans 40 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 20 mg or 40 mgof citalopram (as hydrobromide).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL form

Film-coated tablet.

20 mg: A white, round, convex tablet with a one-side score and logo “2”. Diameter is 8 mm.

40 mg: A white, round, convex tablet with a one-side score and logo “4”. Diameter is 10 mm.

The tablet can be divided into equal doses.

4. Clinical particulars

Treatment of depression. Panic disorder with or without agoraphobia. Obsessive-compulsive disorder. Preventive treatment against relapse/recurrence of depression.

Posology

Adults

Depression

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.

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.

Panic disorder

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. The first therapeutic effects usually appear after 2-4 weeks. Full therapeutic response may take up to 3 months to develop. It may be necessary to continue treatment for several months. Documentation from clinical efficacy studies exceeding 6 months is insufficient.

Obsessive-compulsive disorder

An initial dose of 20 mg daily is recommended. Dependent on individual patient response, the dose may be increased to a maximum of 40 mg daily. The first therapeutic effects usually appear after 2 – 4 weeks and additional improvement appears when the treatment is continued.

Preventive treatment

The treatment period is individual, usually yearlong. Discontinuations should happen under close surveillance to avoid relapse.

Elderly patients (>65 years)

Treatment of major depressive episodes

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.

Treatment of panic disorder

The initial dose is 10 mg once daily. After one week the dose may be increased to 20 mg daily. Depending on individual patients response this may be increased to a maximum of 40 mg daily. Doses above 30 mg should only be administrated after careful consideration.

Paediatric population

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

Reduced renal function

Dosage adjustment is not required if the patient has mild to moderate renal impairment.

Caution is recommended in patients with severe renal impairment (creatinine clearance less than 30 ml/min, see section 5.2).

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.

Poor metabolisers regarding 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).

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.

For the different dosage regimens suitable strengths should be prescribed.

Method of administration

Citalopram should be administrated 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.

4.3 Contraindications

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

MAOIs (monoamine oxidase inhibitors): Some cases presented with features resembling serotonin syndrome.

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 (Reversible Monoamine oxidase type A, RIMA) as stated in the prescribing text of the RIMA. MAOIs should not be introduced for seven days after discontinuation of citalopram (see section 4.5).

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 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).

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

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 a paradoxical anxiogenic effect (see section 4.2).

Hyponatraemia

Hyponatraemia, probably due to inappropriate antidiuretic 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 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.

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.

Mania

In patients with manic-depressive illness a change towards the manic phase may occur. Should the patient enter a manic phase citalopram should be discontinued.

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.

Diabetes

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

Serotonin syndrome

Serotonine syndrome has been reported in rare cases 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 sumatriptan or other triptans, tramadol, oxitriptan, and tryptophan.

Haemorrhage

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 during the treatment with SSRIs (see section 4.8). Caution is advised in patients taking SSRIs, particularly in concomitant use with active substance known to affect the 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).

ECT (electroconvulsive therapy)

There is limited clinical experience of concurrent administration of SSRIs and ECT; therefore caution is advisable.

St. John´s Wort

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).

Withdrawal symptoms seen on discontinuation of SSRI 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 disturbances (including paraesthesia and electric shock sensations), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor, confusion, sweating, headache, diarrhoea, palpitations, emotional instability, irritability, and visual disturbances are the most commonly reported reactions. Generally these symptoms are mild to moderate, however, in some patients they may be severe in intensity.

They usually occur within the first few days of discontinuing treatment, but there have been very rare reports of such symptoms in patients who have inadvertently missed a dose.

Generally these symptoms are self-limiting and usually resolve within 2 weeks, though in some individuals they may be prolonged (2-3 months or more). It is therefore advised that citalopram should be gradually tapered when discontinuing treatment over a period of several weeks or months, according to the patient’s needs (see "Withdrawal Symptoms Seen on Discontinuation of SSRI", section 4.2).

Psychosis

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

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, and 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.

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.

Other warnings and precautions

Citalopram should be prescribed in the smallest effective amount in order to minimize the risk for overdose.

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

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

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. phenotiazine 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.

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 (non-selective) and moclobemide (selective for type A) 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.

If progressing without intervention the condition can be fatal due to rhabdomyolysis, central hyperthermia with multi organ acute impairment, delirium and coma (see section 4.3).

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 C_maxof 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 10 msec. Due to the interaction noted at a low dose of pimozide, concomitant administration of citalopram and pimozide is contraindicated.

Combinations requiring precaution for use

Seleginile (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, sumatriptan or other triptans, oxitriptan and tryptophan) may lead to enhancement of 5-HT associated effects. 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 in patients who are being treated simultaneously with anticoagulants (such as warfarin), medicinal products that affect theplatelet functionsuch as non-steroidal anti-inflammatory drugs (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).

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 (phenothiazines, thioxanthenes and butyrophenones), 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 productsin clinical practice has very low likelihood of producing pharmacokinetic medicinal productinteractions.

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 high doses of citalopram in combination with high doses of 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

Escitalopram (the active enantiomer of citalopram) is an inhibitor of the enzyme CYP2D6. Caution is recommended when escitalopram 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. 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 and CYP2C19 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, digoxin (indicating that citalopram neither induce nor inhibit P-glycoprotein) or carbamazepine and its metabolite carbamazepine-epoxide.

Desipramine, imipramine

In a pharmacokinetic study no effects were 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 in the desipramine plasma concentration has been observed. A reduction of the desipramine dose may be needed.

4.6 Fertility, pregnancy and lactation

Pregnancy

Published 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 the third trimester. Abrupt discontinuation should be avoided during pregnancy.

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 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 SSRI 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 1000 pregnancies. In the general population 1 to 2 cases of PPHN per 1000 pregnancies occur.

Breast-feeding

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.

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 saperm quality is reversible. Impact on human fertility has not been observed so far.

4.7 Effects on ability to drive and use machines

Citalopram Vitabalans 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.

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.

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

Adverse drug reactions associated with SSRIs and/or citalopramseen in either ≥ 1% of patients in double-blind placebo-controlled trials or in the post-marketing period are presented below at the MedDRA Preferred Term Level.

The frequency classification of adverse effects is following:

• Very common (≥ 1/10),

• Common (≥ 1/100 to < 1/10),

• Uncommon (≥ 1/1 000 to < 1/100),

• Rare (≥ 1/10 000 to < 1/1 000),

• Very rare (< 1/10 000),

• Not known (cannot be estimated from the available data).

MedDRA SOC	Frequency	Preferred term
Blood and lymphatic disorders	Not Known	Thrombocytopenia
Immune system disorders	Not Known	Hypersensitivity, anaphylactic reaction
Endocrine disorders	Not Known	Inappropriate ADH secretion
Metabolism and nutrition disorders	Common	Appetite decreased, weight decreased
	Uncommon	Increased appetite, weight increased
	Rare	Hyponatremia (see section 4.4)
	Not Known	Hypokalaemia
Psychiatric disorders	Common	Agitation, libido decreased, anxiety, nervousness, confusional state, abnormal orgasm (female), abnormal dreams
	Uncommon	Aggression, depersonalization, hallucination, mania
	Not Known	Panic attack, bruxism, restlessness, suicidal ideation, suicidal behaviour1
Nervous system disorders	Very common	Somnolence, insomnia, headache
	Common	Tremor, paraesthesia, dizziness, disturbance in attention
	Uncommon	Syncope
	Rare	Convulsion grand mal, dyskinesia, taste disturbance
	Not Known	Convulsions, serotonin syndrome, extrapyramidal disorder, akathisia, movement disorder
Eye disorders	Uncommon	Mydriasis
	Not Known	Visual disturbance
Ear and labyrinth disorders	Common	Tinnitus
Cardiac disorders	Uncommon	Bradycardia, tachycardia
	Not Known	Electrocardiogram QT-prolongation, ventricular arrhythmia including Torsade de pointes
Vascular disorders	Rare	Haemorrhage
	Not Known	Orthostatic hypotension
Respiratory thoracic and mediastinal disorders	Common	Yawning
	Not Known	Epistaxis
Gastrointestinal disorders	Very common	Dry mouth, nausea
	Common	Diarrhoea, vomiting, constipation
	Not Known	Gastrointestinal haemorrhage (including rectal haemorrhage)
Hepatobiliary disorders	Rare	Hepatitis
	Not Known	Liver function test abnormal
Skin and subcutaneous tissue disorders	Very common	Sweating increased
	Common	Pruritus
	Uncommon	Urticaria, alopecia, rash, purpura, photosensitivity reaction
	Not Known	Ecchymosis, angioedemas
Musculoskeletal, connective tissue and bone disorders	Common	Myalgia, arthralgia
Renal and urinary disorders	Uncommon	Urinary retention
Reproductive system and breast disorders	Common	Impotence, ejaculation disorder, ejaculation failure
	Uncommon	Female: Menorrhagia
	Not Known	Female: Metrorrhagia Male: Priapism, galactorrhoea
General disorders and administration site conditions	Common	Fatigue
	Uncommon	Oedema
	Rare	Pyrexia

¹Cases 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 in 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 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, 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 ahould be carried out (see section 4.2 Posology and Method of Administration and section 4.4 Special Warnings and Special Precautions for use).

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 national reporting system listed in Appendix V*.

4.9 Overdose

Toxicity

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

Symptoms of overdose

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, torsade de pointes, stupor, sweating, cyanosis, hyperventilation, atrial and ventricular arrhythmia.

Management

There is no known specific antidote to citalopram. Treatment should be symptomatic and supportive. Activated charcoal, osmotically working laxative (such as sodium sulphate) and stomach evacuation should be considered. If consciousness is impaired the patient should be intubated. 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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Selective serotonin reuptake inhibitors

ATC Code: N06AB04

Citalopram is an antidepressant with strong and selective inhibitory action on the uptake of 5-hydroxytryptamine (5-HT, serotonine).

Mechanism of actions and pharmacodynamic effects

Tolerance to the inhibitory effect of citalopram on the 5-HT uptake does not occur during long-term treatment. The anti-depressant effect is probably connected with specific inhibition of the serotonine uptake in brain neurons.

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

Citalopram is a bicyclic isobenzophurane-derivative, which is not chemically related to tricyclic nor 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 anti-depressant 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 %.

Biotransformation

Citalopram is metabolised into demethylcitalopram, didemethylcitalopram, citalopram-N-oxide and the deaminated propionic acid derivative. The propionic acid-derivate 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 36 hours (28-42 hours). After systematic 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 40 mg per day, an average plasma concentration of approximately 300 nmol/l is reached. There is no clear relationship between citalopram plasma levels and therapeutic response or side effects.

Characteristics relating to patients

Elderly (>65 years)

Longer plasma half-life values and a decreased clearance have been found in elderly patients due to a reduced metabolism. The systemic exposure of escitalopram is approximately 50 % higher in elderly compared to healthy young volunteers (see section 4.2).

Hepatic impairment

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 concentrations approximately twice as high in comparison with patients with a normal liver function.

Renal impairment

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 <30 ml/min) (see section 4.2).

Polymorphism

Poor metabolisers regarding CYP2C19 have been observed having twice as high plasma concentrations of escitalopram compared to extensive metabolisers. No relevant changes in the exposure were observed in poor metabolisers regarding CYP2D6 (see section 4.2).

5.3 Preclinical safety data

Non-clinical data revealed no special hazard for humans based on conventional studies of safety, pharmacology, genotoxicity and carcinogenic potential. Phospholipidosis in several organs has been observed following multiple administrations in rats. The effect is reversible on withdrawal. In animal experiments, accumulation of phospholipids has been seen in long term studies with many cation-amphophilic substances. The clinical relevance of these findings is not clear.

Reproductive toxicological studies in rats have shown skeletal anomalies in the offspring, but no increased incidence of malformations. The effects may be related to the pharmacological activity or a result of maternal toxicity. Peri- and postnatal studies have shown reduced survival rates in the offspring during the lactation period. The potential risk to humans is not known.

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

Cellulose, microcrystalline

Mannitol (E421)

Silica, colloidal anhydrous

Magnesium stearate

Polydextrose

Hypromellose

Titanium dioxide

Macrogol

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

4 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

20 mg: 10, 14, 20, 30, 60 and 100 tablets in blister (PVC/PVdC/Al).

40 mg: 10, 14, 20, 30, 60 and 100 tablets in blister (PVC/PVdC/Al).

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Vitabalans Oy

Varastokatu 8

FI-13500 Hämeenlinna

FINLAND

Tel: +358 (3) 615600

Fax: +358 (3) 6183130

8. MARKETING AUTHORISATION NUMBER(S)

To be completed nationally.

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

To be completed nationally.

10. DATE OF REVISION OF THE TEXT

2015-10-01