4.3 Contraindications
Hypersensitivity to citalopram or any of the excipients (see section 6.1).
Citalopram should not be given to patients receiving Monoamine Oxidase Inhibitors (MAOIs) including selegiline in daily doses exceeding 10 mg/day.
Citalopram is contraindicated in the combination with linezolid unless there are facilities for close observation and monitoring of blood pressure (see section 4.5).
4.4 Special warnings and precautions for use
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 anti depressants 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.
Elderly patients
Caution should be used in the treatment of elderly patients (see section 4.2).
Reduced kidney and liver function
Caution should be used in the treatment of patients with reduced kidney and liver function (see section 4.2).
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.
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.
Serotonin syndrome
In rare cases, serotonin syndrome has been reported in patients using SSRIs. A combination of symptoms such as agitation, tremor, myoclonus, and hyperthermia may indicate the development of this condition. Treatment with citalopram should be discontinued immediately and symptomatic treatment initiated.
Serotonergic medicines
Citalopram should not be used concomitantly with medicinal products with serotonergic effects such as sumatriptan or other triptans, tramadol, oxitriptan, and tryptophan.
Haemorrhage
There have been reports of prolonged bleeding time and/or bleeding abnormalities such as ecchymoses, gynaecological haemorrhages, gastrointestinal bleedings, and other cutaneous or mucous bleedings with SSRIs (see section 4.8). Caution is advised in patients taking SSRIs, particularly with concomitant use of active substances known to affect platelet function or other active substances that can increase the risk of haemorrhage, as well as in patients with a history of bleeding disorders (see section 4.5).
ECT (electroconvulsive therapy)
There is limited clinical experience of concurrent administration of SSRIs and ECT; therefore caution is advisable.
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.
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), 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 prolongation
Elevated levels of a side metabolite (didemethylcitalopram) can theoretically prolong the QT interval in patients predisposed, patients with congenitally prolonged QT syndrome or in patients with hypokalaemia/hypomagnesiaemia. ECG monitoring may be advisable in case of overdose or conditions of altered metabolism with increased peak levels, e.g. liver impairment.
4.5 Interaction with other medicinal products and other forms of
interaction
Pharmacodynamic interactions
At the pharmacodynamic level cases of serotonin syndrome with citalopram and moclobemide and buspirone have been reported.
Contraindicated combinations
MAO-inhibitors
The simultaneous use of citalopram and MAO-inhibitors can result in severe undesirable effects, including serotonin syndrome (see section 4.3).
Cases of serious and sometimes fatal reactions have been reported in patients receiving an SSRI in combination with a monoamine oxidase inhibitor (MAOI), including the irreversible MAOI selegiline and the reversible MAOIs linezolid and moclobemide and in patients who have recently discontinued an SSRI and have been started on a MAOI.
Some cases presented with features resembling serotonin syndrome. Symptoms of an active substance interaction with a MAOI include: agitation, tremor, myoclonus, and hyperthermia.
Pimozide
Co-administration of a single dose of pimozide 2mg to subjects treated with racemic citalopram 40mg/day for 11 days caused an increase in AUC and Cmax of pimozide, although not consistently throughout the study. The co-administration of pimozide and citalopram resulted in a mean increase in the QTc interval of approximately 10msec. Due to the interaction noted at 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.
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 drugs (e.g. tramadol, sumatriptan) 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
Undesirable effects may be more common during concomitant use of serotonin-reuptake inhibitors and herbal preparations containing St John’s Wort (hypericum perforatum). 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, phenothiazines, tricyclic antidepressants) 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 QT prolongation or hypokalaemia/hypomagnesaemia
Caution is warranted for concomitant use of other QT interval prolonging medicines or hypokalaemia- / hypomagnesaemia-inducing drugs as they, like citalopram, potentially prolong the QT interval.
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]), mefloquine, bupropion and tramadol).
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.
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).
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. 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 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 in healthy volunteers 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.
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 induces nor inhibits P-glycoprotein
4.6 Pregnancy and lactation
Pregnancy
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. 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.
4.7 Effects on ability to drive and use machines
Citalopram has minor or moderate influence on the ability to drive and use machines.
4.8 Undesirable effects
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Frequency
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Very common
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Common
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Uncommon
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Rare
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Not Known
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³1/10
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³1/100 to <1/10
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³1/1,000 to <1/100
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³1/10,000 to <1/1,000
|
|
|
Blood and lymphatic disorders
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|
|
|
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Thrombocytopenia
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Immune system disorders
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|
|
|
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Hypersensitivity, anaphylactic reaction
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|
Endocrine disorders
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|
|
|
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Inappropriate ADH secretion
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|
Metabolism and nutrition disorders
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Appetite decreased, weight decreased, anorexia1
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Increased appetite, weight increased
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Hyponatremia
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Hypokalaemia
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Psychiatric disorders
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Sleep disorder1
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Agitation, nervousness, libido decreased, anxiety, confusional state, abnormal dreams, abnormal orgasm (female) apathy1, impaired concentration1, amnesia1
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Aggression, depersonalisation, hallucination, mania
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Euphoria, increased libido1
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Panic attack, bruxism, restlessness, suicidal ideation and suicidal behavior3
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Nervous system disorders
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Somnolence insomnia, headache1
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Tremor, dizziness, migraine1, paraesthesia, disturbance in attention
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Syncope
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Convulsion grand mal, dyskinesia, taste disturbance
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Convulsions, serotonin syndrome,
extrapyramidal disorder, akathisia, movement disorder
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|
Eye disorders
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|
Abnormal accommodation
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Abnormal vision, mydriasis (which may lead to acute narrow angle glaucoma) see section 4.4 Special warnings and precautions for use
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Visual disturbance
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Ear and labyrinth disorders
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Tinnitus
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|
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Cardiac Disorders
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|
Palpitation1
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Postural hypotension, tachycardia, bradycardia
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|
QT – prolongation2
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|
Vascular disorders
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|
|
|
Haemorrhage
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Orthostatic hypotension
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Respiratory, thoracic and mediastinal disorders
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|
Yawning, Rhinitis1
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Coughing1
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Epistaxis
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Gastro-intestinal disorders
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Nausea, dry mouth
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Constipation, diarrhoea, vomiting, taste perversion1 abdominal pain1, flatulence1, increased saliva1, dyspepsia1
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|
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Gastrointestinal haemorrhage (including rectal haemorrhage)
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Hepato-biliary disorders
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|
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Hepatitis
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Liver function test abnormal
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Skin and subcutaneous disorders
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Sweating Increased
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Pruritus
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Urticaria alopecia, rash, purpura, Photosensitivity
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Ecchymosis, angioedemas
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Musculoskeletal, connective tissue and bone disorders
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Myalgia, arthralgia
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Renal and urinary disorders
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Urinary retention, micturition disorder, polyuria
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|
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Reproductive system and breast disorders
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Impotence ejaculation disorder, ejaculation failure
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Female: Menorrhagia
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Female: Metrorrhagia, Male: Priapism, galactorrhoea
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General Disorders
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Asthenia1
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Fatigue
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Oedema
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Pyrexia
Malaise1
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Withdrawal symptoms seen on discontinuation of citalopram 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 citalopram treatment is no longer required, gradual discontinuation by dose tapering should be carried out (see section 4.2 Posology and method of administration and section 4.4 Special warnings and precautions for use).
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, 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, 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
There is no known specific antidote to citalopram.
Osmotically working laxative (such as sodium sulphate) and stomach evacuation should be considered.
If consciousness is impaired the patient should be intubated.
10 DATE OF REVISION OF THE TEXT
12 September 2011
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