Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Lundbeck Limited, Iveco House, Station Road, Watford, Hertfordshire, WD17 1ET, UK
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Monoamine Oxidase Inhibitors (MAOIs).
Some cases presented with features resembling serotonin syndrome.
Citalopram should not be given to patients receiving MAOIs, including selegiline, in daily doses exceeding 10 mg/day.
Citalopram should not be given for fourteen days after discontinuation of an irreversible MAOI or for the time specified after discontinuation of a reversible MAOI (RIMA) as stated in the prescribing text of the RIMA.
MAOIs should not be introduced for seven days after discontinuation of citalopram (see section 4.5).
Citalopram is contraindicated in 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).
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 Cipramil 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.
Cipramil 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.
Caution should be used in the treatment of elderly patients (see section 4.2).
Caution should be used in the treatment of patients with reduced kidney and liver function (see section 4.2).
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, probably due to inappropriate antidiuretic hormone secretion (SIADH), has been reported as a rare adverse reaction with the use of SSRIs and generally reverses on discontinuation of therapy. Elderly female patients seem to be at particularly high risk.
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.
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 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.
In patients with diabetes, treatment with an SSRI may alter glycaemic control. Insulin and/or oral hypoglycaemic dosage may need to be adjusted.
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.
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 (see section 4.5). Treatment with citalopram should be discontinued immediately and symptomatic treatment initiated.
Citalopram should not be used concomitantly with medicinal products with serotonergic effects such as sumatriptan or other triptans, tramadol, oxitriptan and tryptophan.
There have been reports of prolonged bleeding time and /or bleeding abnormalities such as ecchymoses, gynaecological haemorrhages, gastrointestinal bleeding and other cutaneous or mucous bleedings with SSRIs (see section 4.8). SSRIs/SNRIs may increase the risk of postpartum haemorrhage (see sections 4.6, 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).
There is limited clinical experience of concurrent administration of SSRIs and ECT; therefore caution is advisable.
For information on concomitant treatment with non-selective, irreversible MAO-inhibitors see section 4.5.
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 when treatment is discontinued are common, particularly if discontinuation is abrupt (see section 4.8 Undesirable effects). In a recurrence prevention clinical trial with citalopram, adverse events after discontinuation of active treatment were seen in 40% 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 citalopram”, Section 4.2)
Selective serotonin reuptake inhibitors (SSRIs/serotonin norepinephrine reuptake inhibitors (SNRIs) may cause symptoms of sexual dysfunction (see section 4.8). There have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of SSRIs/SNRI.
Treatment of psychotic patients with depressive episodes may increase psychotic symptoms.
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 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.
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.
The tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
At the pharmacodynamic level cases of serotonin syndrome with citalopram and moclobemide and buspirone have been reported.
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.
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 derivatives, pimozide, haloperidol), tricyclic antidepressants, certain antimicrobial agents (e.g. sparfloxacin, moxifloxacin, erythromycin IV, pentamidine, anti-malarial treatment particularly halofantrine), certain antihistamines (astemizole, mizolastine) etc., is contraindicated.
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.
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.
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) 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).
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.
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).
There are no clinical studies establishing the risks or benefits of the combined use of electroconvulsive therapy (ECT) and citalopram (see section 4.4).
No pharmacodynamic or pharmacokinetic interactions have been demonstrated between citalopram and alcohol. However, the combination of citalopram and alcohol is not advisable.
Caution is warranted for concomitant use of hypokalaemia- / hypomagnesaemia-inducing medicinal products as these conditions increase the risk of malignant arrhythmias.
SSRIs 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).
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.
The absorption and other pharmacokinetic properties of citalopram have not been reported to be affected by food.
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 (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, fluconazole, fluvoxamine, lansoprazole, ticlopidine) or cimetidine. A reduction in the dose of citalopram may be necessary based on monitoring of side- effects during concomitant treatment (see section 4.4).
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.
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.
No change or only very small changes of 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).
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.
Published data on pregnant women (more than 2500 exposed outcomes) indicate no malformative foeto/neonatal toxicity, however, citalopram should not be used during pregnancy unless clearly necessary and only after careful consideration of risk/benefit.
Neonates should be observed if maternal use of citalopram continues into the later stages of pregnancy, particular in the third trimester. Abrupt discontinuation should be avoided during pregnancy.
The following symptoms may occur in the neonates after maternal SSRI/SNRI use in later stages of pregnancy: respiratory distress, cyanosis, apnoea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycaemia, hypertonia, hypotonia, hyperreflexia, tremor, jitteriness, irritability, lethargy, constant crying, somnolence and difficulty sleeping. These symptoms could be due to either serotonergic effects or discontinuation symptoms. In a majority of instances the complications begin immediately or soon (<24 hours) after delivery.
Epidemiological data have suggested that the use of SSRIs in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). The observed risk was approximately 5 cases per 1000 pregnancies. In the general population 1 to 2 cases of PPHN per 1000 pregnancies occur.
Observational data indicate an increased risk (less than 2-fold) of postpartum haemorrhage following SSRI/SNRI exposure within the month prior to birth (see sections 4.4, 4.8).
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.
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.
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 and concentration due to the illness itself 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.
Adverse effects observed with citalopram are in general mild and transient. They are most frequent during the first one or two weeks of treatment and usually attenuate subsequently. The adverse reactions are presented at the MedDRA Preferred Term Level.
For the following reactions a dose-response was discovered: Sweating increased, dry mouth, insomnia, somnolence, diarrhoea, nausea and fatigue.
The table 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 (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000), not known (cannot be estimated from the available data).
| System organ class | Frequency | Undesirable effect |
|---|---|---|
| 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 | Hyponatraemia | |
| Not known | Hypokalaemia | |
| Psychiatric disorders | Very common | Sleep disorder |
| Common | Agitation, libido decreased, anxiety, nervousness, confusional state, abnormal orgasm (female), abnormal dreams, apathy | |
| Uncommon | Aggression, depersonalisation, hallucination, mania, libido increased | |
| 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, migraine, amnesia | |
| Uncommon | Syncope | |
| Rare | Convulsion grand mal, dyskinesia, taste disturbance | |
| Not known | Convulsions, serotonin syndrome, extrapyramidal disorder, akathisia, movement disorder | |
| Eye disorders | Uncommon | Mydriasis (which may lead to acute narrow angle glaucoma), see section 4.4 Special warnings and precautions for use |
| Not known | Visual disturbance | |
| Ear and labyrinth disorders | Common | Tinnitus |
| Cardiac disorders | Common | Palpitations |
| Uncommon | Bradycardia, tachycardia | |
| Not known | QT-prolongation, ventricular arrhythmia including torsade de pointes | |
| Vascular disorders | Rare | Haemorrhage |
| Not known | Orthostatic hypotension | |
| Respiratory thoracic and mediastinal disorders | Common | Yawning, rhinitis |
| Rare | Coughing | |
| Not known | Epistaxis | |
| Gastrointestinal disorders | Very common | Dry mouth, nausea |
| Common | Diarrhoea, vomiting, constipation, dyspepsia, abdominal pain, flatulence, salivary hypersecretion | |
| 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 and, connective tissue 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, postpartum haemorrhage2 Male: Priapism Galactorrhoea | |
| General disorders and administration site conditions | Very common | Asthenia |
| Common | Fatigue | |
| Uncommon | Oedema | |
| Rare | 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).
2 This event has been reported for the therapeutic class of SSRIs/SNRIs (see sections 4.4 and 4.6).
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 pre-existing QT prolongation or other cardiac diseases (see sections 4.3, 4.4, 4.5, 4.9 and 5.1).
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.
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 should be carried out (see section 4.2 and section 4.4).
Not applicable.
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