Ciprager 40mg Film Coated Tablets

4.2 Posology and method of administration

 

 

Posology

 

 

 

 

Depression

 

 

Major depressive episodes

 

 

 

 

 

 

Adults:

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.

 

 

 

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 to give adequate protection against the possibility of a relapse.

 

 

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.

 

 

Maximum effectiveness is reached after 3 months. It may be necessary to continue treatment for several months.

 

 

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/da  (see section 5.1). Dosage adjustments should be made carefully on an

 

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 sections 4.4 Special Warnings and Special 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.

 

 

 

Method of administration

 

 

 

For oOral use.
Ciprager 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.

 

4.4 Special warnings and precautions for use

 

 

 

Elderly patients and patients with

 

impaired renal or hepatic impairmentfunction Treatment of elderly patients and patients with reduced kidney and liver function, see section 4.2.

 

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 (see section 4.5). Treatment with citalopram should be discontinued immediately and symptomatic treatment initiated.

 

 

 

 

Serotonergic medicines

 

 

 

Concomitant use of

 

Ccitalopram with medicinal products with serotonergic effects such as tramadol, tryptophan, oxitriptan, sumatriptan or other triptans is contraindicated (see section 4.3).

Reversible, selective MAO-A inhibitors

 

 

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

 

 

 

 

 

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 postmarketing period, predominantly in patients of female gender, with hypokalaemia, 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.

 

 

 

ECG monitoring may be advisable in case of overdose or conditions of altered metabolism with increased peak levels, e.g. liver impairment.

 

 

 

 

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 effecthas 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.

 

 

 

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).

 

 

 

Excipients

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

 

 

 

 

 

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

 

 

 

Monoamine Oxidase Inhibitors (MAOIs)

 

 

 

 

The simultaneous use of citalopram and MAO-inhibitors can result in severe undesirable effects, including 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, 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, co-administration of citalopram with medicinal products that prolong the QT interval, such as Class IA and III antiarrhythmics, antipsychotics (e.g.

 

phenothiazine fentiazine derivatives, pimozide, haloperidol), tricyclic antidepressants , certain antimicrobial agents (e.g. sparfloxacin, moxifloxacin, erythromycin IV, pentamidine, anti-malarian malarial 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 10 msec. Due to the interaction noted at a low dose of pimozide, concomitant administration of citalopram and pimozide is contraindicated.

 

 

 

Monoamine Oxidase Inhibitors (MAOIs)

 

 

 

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 theselective irreversible MAOI, selegiline, the selective reversible MAOIs linezolid and moclobemide, and in patients who have recently discontinued a 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.

 

 

 

 

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 normal.

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

In combination with triptans, there is a potential risk of coronary vasoconstriction and hypertension too. Until further information is available, the simultaneous use of citalopram and 5-HT agonists, such as sumatriptan and other triptans, is contraindicated (see section 4.3 and 4.4).

 

 

 

 

St. John’s wort

 

 

 

 

Dynamic interactions between SSRIs and the 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, dipyridamole, and ticlopidine or other medicines (e.g. atypical antipsychotics) that can increase the risk of haemorrhage (see section 4.4).

 

 

 

 

ECT (electroconvulsive 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

 

 

 

The combination of citalopram and alcohol is not advisable. However clinical studies have revealed no adverse

 

 

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).

 

 

 

Serotonergic medicinal products

 

 

 

Co-administration with serotonergic medicinal product (e.g. tramadol, tryptophan, oxitriyptan, sumatriptan and other triptans) may lead to enhancement of 5-HT associated effects. In combination with triptans, there is a potential risk of coronary vasoconstriction and hypertension too. Until further information is available, the simultaneous use of citalopram and 5-HT agonists, such as sumatriptan and other triptans, is contraindicated (see section 4.3 and 4.4).

 

 

 

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 normal.

 

 

 

St. John’s Wort

 

 

 

Dynamic interactions betweenConcomitant use of SSRIs and the herbal remedyies containing St. John´s Wort (Hypericum perforatum) can occur,may resulting in an increased incidence of 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, dipyridamole, and ticlopidine or other medicines (e.g. atypical antipsychotics) that can increase the risk of haemorrhage (see section 4.4).

 

 

 

 

ECT (electroconvulsive 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).

 

 

 

 

Medicinal products lowering the seizure threshold

 

 

 

SSRIs

 

 

Citalopram can lower the seizure threshold. Caution is advised when concomitantly using other medicinal products capable of lowering the seizure threshold (e.g antidepressants, (SSRIs), neuroleptics, (thioxanthenes and butyrophenones,), mefloquine, 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.

 

 

 

Effect

 

 

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 (potent CYP2D6, 3A4 and 1A2 inhibitor) caused a moderate increase in the average steady state levels of citalopram. Caution is advised when administering citalopram in combination with cimetidine.

Dose adjustment may be warranted.

 

 

 

 

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. A reduction in the dose of citalopram may be necessary based on monitoring of undesirable effects during concomitant treatment.

 

 

 

 

 

Cimetidine

 

 

 

Cimetidine (potent CYP2D6, 3A4 and 1A2 inhibitor) caused a moderate increase in the average steady state levels of citalopram. Caution is advised when administering citalopram in combination with cimetidine.

Dose adjustment may be warranted.

Effects of citalopram on other medicinal products

 

 

 

 

Metoprolol

 

 

 

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 thise enzyme CYP2D6, 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. Coadministration with metoprolol resulted in a two-fold increase in the plasma levels of metoprolol but did not statistically significantly 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 two

 

-fold 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.

 

 

 

 

 

 

Breast

 

 

Breast-feeding

 

Citalopram is excreted into breast milk in small quantities. 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.

 

Patients who are prescribed psychotropic medication may be expected to have  some impairment of general attention andconcentration due to the illness itself

 

 

 

 

 

Psychoactive

 

 

and 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 Me

 

dDRA Preferred term level.

 

For the following reactions a dose-response was discovered:

 

Ssweating increased, dry mouth, insomnia, somnolence, diarrhoea, nausea and fatigue.

 

The table 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: 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), and not known (cannot be estimated from the available clinical trial data).

 

 

 

 

 

 

 

 

 

 

 

Very Common Common Uncommon Rare Not known

Blood and lymphatic

 

system disorders

 

 

 

 

Thrombocytopenia

 

 

 

Immune system disorders

 

Hyper-sensitivity, disorders anaphylactic reaction
Endocrine

 

 

 

 

Inappropriate ADH secretion

 

 

 

Metabolism and nutrition disorders

 

 

 

Appetite decreased,

w

 

 

Weight decreased, appetite decreased,

 

 

 

 

 

Increased appetite, weight increased

Hypo-natraemia Hypokalaemia

 

 

 

Psychiatric disorders

 

 

 

Sleep disorder

 

 

Sleep disorders,

 

 

 

 

 

Agitation,

 

 

 

 

impaired concentration,

 

 

 

abnormal dreams,

amnesia, anxiety,

 

 

 

 

decreased libido,

 

 

 

anxiety,

 

 

anorexia,

 

apathy,

confusional state,

agitation,

 

 

 

 

nervousness,

 

 

 

confusional state,

 

 

 

 

abnormal orgasm (female)

 

,

 

abnormal dreams,

apathy

Aggression,

depersonalisation,

hallucination,

e

 

 

Euphoria,

 

 

 

 

increased libido,

aggression,

depersonalization,

hallucination,

 

 

 

mania

 

, increased libido

 

 

 

 

 

panic attack (these symptoms may be due to the underlying disease),

 

bruxism,

 

restlessness,

 

 

 

 

suicidal ideation

 

, and suicidal behaviours1 bruxism, restlessness

 

 

 

 

 

Nervous systemdisorders

 

 

 

Headache,

 

 

Ssomnolence, insomnia, headache Migraine,Tremor paraesthesia, tremor, dizziness, disturbance in attention, migraine, amnesia

 

 

 

 

 

Syncope Convulsion grand mal, dyskinesia, taste disturbance

 

 

 

Choreoathetosis,

 

 

 

 

C

 

 

convulsions, serotonin syndrome, extrapyramidal disorder, akathisia, movement disorder

 

 

 

 

Eye disorders

 

Abnormal accommodation

 

 

 

 

 

Mydriasis

 

(which may lead to acute narrow angle glaucoma), see section 4.4 )

 

 

 

 

 

Visual disturbance

 

 

 

Ear and labyrinth disorders

 

 

 

T

 

 

tinnitus

 

 

 

 

Cardiac disorders

 

 

 

Palpitations

 

 

Palpitations Bradycardia, tachycardia

Electrocadiogram

 

 

 

 

 

QT-prolongation, Ventricular arrhythmia including torsade de pointes

 

 

 

Vascular disorders

 

 

 

Hypotension, hypertension

 

 

 

 

Haemorrhage Orthostatic

hypotension

 

 

 

Respiratory, thoracic and mediastinal disorders

 

 

 

Yawning,

r

 

 

Rhinitis, sinusitis, yawning

 

Coughing

 

 

Coughing Epistaxis

 

 

 

 

Gastrointestinal disorders

 

 

 

Nausea, d

 

 

Dry mouth, nausea

 

Diarrhoea,

 

 

Dyspepsia, vomiting, constipation, dyspepsia,

 

 

 

 

 

Gastro

 

-intestinal

 

haemorrhage (including rectal haemorrhage)

 

 

 

 

 

 

 

 

 

 

 

 

 

abdominal pain, flatulence, increased salivation

 

, diarrhoea, constipation

 

 

 

 

 

Hepato

 

-biliary disorders

 

 

 

 

Hepatitis

 

Cholestasis, lLiver function test abnormal

 

 

 

 

Skin and subcutaneous tissue disorders

 

 

 

Increased sweating

Pruritus

 

Photo-sensitivity reaction, uUrticaria, alopecia, rash, purpura, photosensitivity reaction

 

 

 

 

 

Angiodema,

 

 

Eecchymosis, angioedema

 

 

 

 

 

Musculoskeletal and connective tissue disorders

 

 

 

Myalgia, arthralgia

 

 

 

Renal and urinary disorders

 

 

 

Micturition disorder, polyuria

 

 

 

 

Urinary retention

 

 

 

Reproductive system and breast disorders

 

 

 

Ejaculation failure, female anorgasmia, dysmenorrhoea,

 

 

Iimpotence, ejaculation disorder, ejaculation failure

 

 

 

 

 

Female:

Menorrhagia

 

 

 

Female:

Metrorrhagia

 

 

 

 

Male: Priapism,

 

galactorrhoea

 

Female:

Metrorrhagia

 

 

Gala ctorrhoea

 

 

 

 

 

General disorders and administration site conditions

 

 

 

Asthenia Fatigue

 

 

 

Yawning, taste abnormalities Malaise,

 

 

Ooedema

 

Pyrexia

 

, malaise

 

 

 

 

 

Number of patients: citalopram / placebo = 1346 / 545

 

 

 

 

1

 

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

 

 

 

 

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 hypokalaemia, or with preexisting QT prolongation or other cardiac diseases (see sections 4.3, 4.4, 4.5, 4.9 and 5.1).

 

 

 

 

Class effects (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 preexisting QT prolongation or other cardiac disease (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 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 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 citalopramtreatment is no longer required, gradual discontinuation by dose tapering should be carried out (see section 4.2 and section 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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971

 

 

FREE; Fax: +353 1 6762517. Website: www.hpra.ie; Ee-mail: medsafety@hpra.ie.

 

 

 

 

 

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 IMB Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.imb.ie; e-mail: imbpharmacovigilance@imb.ie

 

 

 

 

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.

 

 

 

Fatal dose is not known. Patients have survived ingestion of more than 2 g citalopram. The effects may be potentiated by alcohol taken at the same time. Potential interaction with TCAs, MAOIs and other SSRIs.

 

 

 

 

Symptoms

 

:

 

 

 

 

 

The following symptoms have been seen in reported overdose of citalopram: convulsion, tachycardia, somnolence, seizures, QT interval prolongation, coma, vomiting, tremor, hypotension, cardiac arrest, nausea, serotonin syndrome (particularly when other substances are co-ingested), transpiration, agitation, bradycardia, dizziness, bundle branch block, QRS prolongation, hypertension, mydriasis, torsade de pointes

 

, stupor, sweating, cyanosis, hyperventilation, hyperpyrexia and atrial and ventricular arrhythmia.

 

 

 

 

ECG changes including nodal rhythm, prolonged QT intervals and wide QRS complexes may occur. Fatalities have been reported. 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.

Treatment

 

 

Management:

 

 

 

 

 

There is no known specific antidote to citalopram. Treatment should be symptomatic and supportive

 

. and include the maintenance of a clear airway and monitoring of ECG 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.

 

 

 

 

 

 

 

Consider oral a

 

 

Activated charcoal in adults and children who have ingested more than 5 mg/kg body weight within 1 hour. Activated charcoal given ½ hour after ingestion of citalopram has been shown to reduce absorption by 50%.,

 

 

 

 

 

O

 

 

osmotically working laxative (such as sodium sulphate) and stomach evacuation should be considered.

 

If consciousness is impaired the patient should be intubated.

 

 

 

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

 

 

 

 

ECG and vital signs should be monitored.

ECG monitoring is advised 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.

 

 

 

 

5.1 Pharmacodynamic properties

 

 

Pharmacotherapeutic group: antidepressants, selective serotonin reuptake inhibitors, ATC code: N 06A B04.

 

Mechanism of action

Biochemical and

 

 

behavioralbehavioural studies have shown that cCitalopram is has been demonstrated to be a potent inhibitor of serotonin (5-HT) - uptake. Long-term treatment with citalopram does not induce tolerance to the inhibition of 5-HT–uptake.

 

Citalopram is

 

a verythe most Selective Serotonin Reuptake Inhibitor (SSRI) with no or yet described, with 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, cCitalopram has no or very low affinity for a series of receptors including 5-HT1A, 5-HT2, dopamine D1 and D2 receptors, αalpha1-, αalpha2- and  βbeta-adrenoceptors, histamine H1, muscarine cholinergic, benzodiazepine, and opioid receptors. This is in contrast to many tricyclic antidepressants and some of the other SSRI’s. Lack of receptor affinity has been confirmed using a series of functional in vitro tests in isolated organs as well as functional in vivo tests. 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 orthostatichypotension.

 

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 newer SSRIs. The metabolites do not contribute to the overall antidepressant effect.

Pharmacodynamic effects

 

 

 

 Like tricyclic antidepressants, other SSRI’s and MAO inhibitors, citalopram suppresses REM –-sleep and increases deep slow-wave sleep. Suppression of rapid eye movement (REM) sleep is considered a predictor of antidepressant activity. 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.

 

 

 

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 for Citalopram are higher than many of the other SSRIs. The metabolites do not contribute to the overall antidepressant effect.

 

 

 

 

 

Clinical efficacy and Safety

 

 

 

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 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)ß is about 12.3 L/kg. The plasma protein binding is below 80% for citalopram and its main metabolites.

 

 

 

 

Biotransformation

 

:

 

 

 

 

 

Citalopram is metabolised 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. The main metabolising enzyme is CYP2C19. Some contribution from CYP3A4 and CYP2D6 is possible.

 

 

 

Elimination

 

:

 

 

 

 

 

The elimination half-life (T

 

1/2 ß) is about 1.5 days and the systemic citalopram plasma clearance (CIs) is about 0.33 L/min, and oral plasma clearance (CIoral) is about 0.41 L/min. Citalopram is excreted mainly via the liver (85%) and the remainder (15%) via the kidneys. About 12% - 23% 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.

 

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.

 

 

 

 

Hepatic impairment

 

 

Reduced hepatic function:

 

 

 

 

 

Citalopram is eliminated more slowly

 

infor 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

 

 

: 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 <20 mL/min).

 

 

 

5.3 Preclinical safety data

 

 

 

Acute toxicity

 

 

 

 

Citalopram has low acute toxicity.

 

 

 

 

Chronic toxicity

 

 

 

 

In chronic toxicity studies there were no findings of concern for the therapeutic use of citalopram.

 

 

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.

 

 

 

 

 

Reproduction studies

 

 

 

 

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.

 

 

 

 

Phospholipidosis in several organs was observed in repeated dose toxicity studies in rats. This reversibleeffect 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 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.

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.

 

 

 

Mutagenic and carcinogenic potential
Citalopram has no mutagenic or carcinogenic potential.

 

 

 

 

8

 

. MARKETING AUTHORISATION NUMBER(S)

 

 

 

 

PA

 

0577/047/03

 

 

 

 

10

 

. DATE OF REVISION OF THE TEXT

 

 

 

 

March

 

 

November 2015

 

 

 

 

 

May 2014

 

 

 

Extensive list of changes made to the SPC. Please refer to the uploaded SPC for corrections.

4.2 Posology and method of administration
Added:
Method of administration
Oral use.
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.

4.6 Fertility, pregnancy and lactation
Added:
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.

4.8 Undesirable effects
Added:
The following are all the ADRs that were reported in clinical trials and post-marketing. The following terms and frequencies are applied: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), and not known (cannot be estimated from the available clinical trial data).

5.3 Preclinical safety data
Added:
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.

(internal ref: UK/H/0531/IB/040)

following text outlined were added to the updated smpc

SECTION 4.2
Depression
Adults: 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.

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. 

OCD
Adults: 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.

Elderly (> 65 years of age)
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.

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 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).

SECTION 4.3
Monoamine Oxidase Inhibitors:
Cases of serious and sometimes fatal reactions have been reported in patients receiving an SSRI in combination with monoamine oxidase inhibitors (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.

Citalopram is contraindicated in 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).

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).

SECTION 4.4
Elderly patients and patients with impaired renal or hepatic function
Treatment of elderly patients and patients with impaired renal or hepatic function, see section 4.2.

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 MAO-inhibitors see section 4.5.

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

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.

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

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).

SECTION 4.5
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, antipsychotics (e.g.  fentiazine 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.

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 reactions, sometimes fatal, have been reported in patients receiving an SSRI in combination with a monoamine oxidase inhibitor (MAOI), including the selective irreversible MAOI, selegeline, the selective reversible MAOIs, moclobemide and linezolid, and in patients who have recently discontinued a 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.

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 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
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 not recommended.

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 normal.

St. John’s Wort
Concomitant use of SSRIs and herbal remedies containing St. John´s Wort (Hypericum perforatum) may result in an increased incidence of undesirable effects (see section 4.4). Pharmacokinetic interactions have not been investigated.

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.

Haemorrhage
Caution is warranted for patients who are being treated simultaneously with anticoagulants, medicinal products that affect platelet function, such 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 (electroconvulsive 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).

Medicinal products lowering the seizure threshold
Citalopram 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).

Neuroleptics
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

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).

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. A reduction in the dose of citalopram may be necessary based on monitoring of undesirable effects during concomitant treatment.

Metoprolol
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 nortriptyline or antipsychotics like risperidone, thioridazine and haloperidol. Dosage adjustment may be warranted. Co-administration with metoprolol resulted in a two-fold 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).

Influence of other medicinal products on the pharmacokinetics of citalopram
Cimetidine (potent CYP2D6, 3A4 and 1A2 inhibitor) caused a moderate increase in the average steady state levels of citalopram. Caution is advised when administering citalopram in combination with cimetidine. Dose adjustment may be warranted

SECTION 4.6
A large amount of data on pregnant women (more than 2500 exposed outcomes) indicate no malformative feto/ neonatal toxicity. . Citalopram can be used during pregnancy if clinically needed, taking into account the aspects mentioned below

Lactation
Citalopram is excreted into breast milk in small quantities. 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.

SECTION 4.7
Citalopram has minor or moderate influence on the ability to drive and use machines.

Patients prescribed sychoactive 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.

SECTION 4.8
For the following reactions a dose-response was discovered: Sweating increased, dry mouth, insomnia, somnolence, diarrhoea, nausea and fatigue.

The table 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.

 

	Very Common (> 1/10)	Common (>1/100 to <1/10)	Uncommon (>1/1000 to <1/100)	Rare (>1/10,000 to <1/1000	Not known (cannot be estimated from available data)
Blood and lymphatic disorders					Thrombocyto-penia
Immune system disorders					Hyper-sensitivity, anaphylactic reaction
Endocrine disorders					Inappropriate ADH secretion
Metabolism and nutrition disorders		Weight decreased, appetite decreased,	Increased appetite, weight increased	Hypo-natraemia	Hypokalaemia
Psychiatric disorders		Sleep disorders, impaired concentration, abnormal dreams, amnesia, anxiety, decreased libido, anorexia, apathy, confusional state, agitation, nervousness,  abnormal orgasm (female)	Euphoria, increased libido, aggression, depersonalization, hallucination, mania		panic attack (these symptoms may be due to the underlying disease), suicidal ideation and suicidal behaviours2 bruxism, restlessness
Nervous system disorders	Headache, somnolence, insomnia	Migraine, paraesthesia, tremor, dizziness, disturbance in attention	Syncope	Convulsion grand mal, dyskinesia, taste disturbance	Choreoathetosis, convulsions, serotonin syndrome, extrapyramidal disorder, akathisia, movement disorder
Eye disorders	Abnormal accommodation		Mydriasis		Visual disturbance
Ear and labyrinth disorders		tinnitus
Cardiac disorders	Palpitations		Bradycardia, , tachycardia		QT-prolongation Ventricular arrhythmia including torsade de pointes1
Vascular disorders		Hypotension, hypertension		Haemorrhage	Orthostatic hypotension
Respiratory, thoracic and mediastinal disorders		Rhinitis, sinusitis, yawning	Coughing		Epistaxis
Gastrointestinal disorders	Nausea, dry mouth	Dyspepsia, vomiting, abdominal pain, flatulence, increased salivation, diarrhoea, constipation			Gastro-intestinal haemorrhage (including rectal haemorrhage)
Hepato-biliary disorders				Hepatitis	Cholestasis, liver function test abnormal
Skin and subcutaneous tissue disorders	Increased sweating	Pruritus	Photo-sensitivity reaction, urticaria, alopecia, rash, purpura		Angiodema, ecchymosis
Musculoskeletal, connective tissue and bone disorders		Myalgia, arthralgia
Renal and Urinary disorders		Micturition disorder, polyuria	Urinary retention
Reproductive system and breast disorders		Ejaculation failure, female anorgasmia, dysmenorrhoea, impotence, ejaculation disorder	Female: Menorrhagia		Male: Priapism, galactorrhoea; Female: Metrorrhagia
General disorders and administration site conditions	Asthenia	Fatigue Yawning, taste abnormalities	Malaise, oedema	Pyrexia

Number of patients: Citalopram / placebo = 1346 / 545

 

¹ 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 disease (see sections 4.3, 4.4, 4.5, 4.9 and 5.1).

² Cases of suicidal ideation and suicidal behaviours have been reported during citalopram therapy or early after treatment discontinuation (see section 4.4).

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:
Discontinuation of citalopram (particularly when abrupt) commonly leads to withdrawal symptoms. 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 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).

SECTION 4.9
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..

The following symptoms have been seen in reported overdose of citalopram: convulsion, tachycardia, somnolence, coma, stupor, seizures,  QT prolongation, atrial and ventricular arrhythmia, nausea, vomiting, tremor, hypotension, cardiac arrest, transpiration, cyanosis, hyperventilation, agitation, bradycardia, dizziness, bundle branch block, QRS prolongation, hypertension, mydriasis, torsade de pointes and sweating. Features of serotonin syndrome may occur, particularly when other substances are co-ingested.

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.

SECTION 5.1
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).

4.6 Pregnancy and lactation

Paragraph added:

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


4.8 Undesirable effects

Paragraph added:

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

Sections 4.3, 4.4, 4.5 of the SmPC updated to include information on  a contraindication with Linezolid (MAOI)

Sections 4.4 and 4.8 updated with the recommended PhVWP wording re: suicide/suicidal thoughts

The renewal for Ciprager was approved June 07. The SmPC changes reflect changes during renewal assessment

 

Section 2. –      The quantity of Lactose monohydrate is now listed under Excipients.

 

Section 3. –      Text debossed on tablets has changed to: “CM scoreline 40”

 

Section 4.2 –    Section on Withdrawal Symptoms added.

-        Section on Poor CYP2C19 Metabolisers added.

 

Section 4.4 -   ‘Use in children & adolescents under 18 years of age’ paragraph 

                         moved to start of section 4.4.

-        Section on Suicide/suicidal thoughts added. Previous paragraph removed.

-        Section on Akathisia/psychomotor Restlessness added.

-        Section on Withdrawal Symptoms added.

 

Section 4.5 -     Section on QT prolongation added.

-        Section on Seizures added.

-        Section on Escitalopram added.

 

Section 4.6 -    This section has been entirely updated.

 

Section 4.8 -    This section has been entirely updated. Table has new column and        

                         data added.          

 

Section 4.9 -     Symptoms and Treatment sections updated.                  

 

Section 5.2 -    Biotransformation section updated.

 

Section 5.3 -    Section on Embryotoxicity studies updated.

 

Section 6.4 -    Wording changed.

 

Sections 9 & 10 – Dates are changed