Indications:
Treatment of major depressive episodes.
Treatment of panic disorder with or without agoraphobia.
Administration, dosage:
Administration:
Citalopram is taken as a single daily dose, either in the morning or in the evening. The tablet is taken with a glass of water, with or without food. The 10 mg dose requires the appropriate dosage form.
Dosage:
Adults:
Treatment of major depressive episodes:
The recommended dose is 20 mg once daily. Dependent on individual patient response, the dose may be increased to a maximum of 40 mg daily. Following treatment initiation, an antidepressant effect should not be expected for at least two weeks. Treatment should continue until the patient has been free of symptom for 4-6 months to prevent the possibility of relapse.
Treatment of panic disorder:
The recommended dose is 10 mg once daily 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. This is to avoid paradox reactions (i.e. panic, anxiety).
The first therapeutic effects usually appear after 2 – 4 weeks. Full therapeutic response may take up to 3 months to develop. It may be necessary to continue treatment for several months. Documentation from clinical efficacy studies exceeding 6 months is insufficient.
Elderly patients (>65 years old):
For elderly patients, the dose should be decreased to half of the recommended dose, e.g. 10-20 mg daily. The recommended maximum dose is 20 mg daily.
Children and adolescents (<18 years old): Citalopram should not be used in the treatment of children and adolescents under the age of 18 years.
Hepatic impairment:
Patients with mild or moderate hepatic impairment:
An initial dose 10 mg daily for the first 2 weeks of treatment.
Dependent on individual patient response, the dose may be increased to a maximum of 20 mg daily.
Patients with severe liver impairment: Caution and extra careful dose titration is advised. These patients should be clinically monitored.
Renal impairment:
Dose adjustment is not necessary for patients with mild to moderate renal failure. The use of citalopram in patients with severe renal failure (creatinine clearance is less than 20 ml/min.) is not recommended as no information is available on use in these patients.
Poor metabolisers regarding CYP2C19:
An initial dose of 10 mg daily during the first two weeks of treatment is recommended for patients who are known to be poor metabolisers with respect to CYP2C19.
The dose may be increased to 20 mg daily depending on individual patient response.
For the different dose regimens suitable strengths should be prescribed.
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. 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.
Some special attention on the handling of the medicine before and after use:
There are no special requirements for handling the drug after use.
Contraindications:
Hypersensitivity to the drug or to any of the excipients.
Citalopram is contraindicated in combination with linezolid unless there are facilities for close observation and monitoring of blood pressure.
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.
Monoamine oxidase inhibitor.
Citalopram should not be given to patients receiving 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 14 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.
Warnings and precautions for use:
Elderly patients, caution should be used in the treatment of patients with reduced kidney and liver function and poor CYP2C19 metabolisers (see dosage and administration).
Use in children and adolescents under 18 years of age:
Citalopram should not be used in the treatment of children and adolescents under age of 18 years. Suicide related behaviours (suicide attempt and suicidal thoughts), and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo.
If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms.
In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking.
Paradoxical anxiety:
Some patients with panic disorder may experience intensified anxiety symptoms at the start of treatment with antidepressants. This paradoxical reaction usually subsides within the first two weeks of starting treatment. A low starting dose is advised to reduce the likelihood of a paradoxical anxiogenic effect.
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 reverses on discontinuation of therapy. Elderly female patients seem to be at particularly high risk.
Suicide/suicidal thoughts or clinical worsening:
Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.
Other psychiatric conditions for which citalopram is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.
Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressant medicinal products 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 pharmacotherapy 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.
Restlessness: 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. If the patient enters a manic phase, citalopram should be discontinued.
Withdrawal symptoms seen on discontinuation of SSRI treatment:
Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt. 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.
Diabetes:
In patients with diabetes, treatment with an SSRI may alter glycaemic control. Insulin and/or oral hypoglycaemic dose may need to be adjusted.
Seizures:
Seizures are a potential risk with antidepressant medicinal products. 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.
ECT (electro-convulsive therapy):
There is limited clinical experience of concurrent administration of SSRIs and ECT, therefore caution is advisable.
Haemorrhage:
There have been reports of prolonged bleeding time and/or bleeding abnormalities such as ecchymosis, gynaecological haemorrhages, gastrointestinal bleedings and other cutaneous or mucous bleedings with SSRIs. Caution is advised in patients taking SSRIs, particularly in concomitant use with active substances known to affect platelet function or other active substances that can increase the risk of haemorrhage as well as in patients with a history of bleeding disorders.
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 medicinal products:
Citalopram should not be used concomitantly with medicinal products with serotonergic effects such as sumatriptan or other triptans, tramadol, oxitriptan and tryptophan.
Psychosis:
Treatment of psychotic patients with depressive episodes may increase psychotic symptoms.
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.
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 hypokalaemia, or with pre-existing QT prolongation or other cardiac diseases.
Caution is advised in patients with significant bradycardia; or in patients with recent acute myocardial infarction or uncompensated heart failure.
If patients with stable cardiac disease are treated, an ECG review should be considered before treatment is started.
If signs of cardiac arrhythmia occur during treatment with citalopram, the treatment should be withdrawn and an ECG should be performed.
Angle-closure glaucoma:
SSRIs including citalopram may have an effect on pupil size resulting in mydriasis. This mydriatic effect has the potential to narrow the eye angle resulting in increased intraocular pressure and angle-closure glaucoma, especially in patients pre-disposed. Citalopram should therefore be used with caution in patients with angle-closure glaucoma or history of glaucoma.
This medicine contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Pregnancy and lactation:
Pregnancy:
Published data on pregnant women (more than 2500 exposed outcomes) indicate no malformative fetus / neonatal toxicity. However, citalopram should not be used during pregnancy unless clearly necessary and only after careful consideration of the risk/benefit.
Neonates should be observed if maternal use of citalopram continues into the later stages of pregnancy, particularly 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, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, 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 cases, 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.
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 (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, consideration should be given to discontinuing breastfeeding.
Effects on ability to drive, use machines:
Citalopram has minor or moderate influence on the ability to drive and use machines. Patients should be informed of these effects and be warned that their ability to drive a car or operate machinery could be affected.
Interactions, incompatibilities of medicine:
Interaction of the drug:
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 the serotonin syndrome.
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, myoclony, 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 derivatives, pimozide, haloperidol). tricyclic antidepressants, certain antimicrobial agents (e.g. sparfloxacin, moxifloxacin, erythromycin IV, pentamidine, anti-malarian treatment particularly halofantrine), certain antihistamines (astemizole, mizolastine), is contraindicated.
Pimozide:
Coadministration 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 contraindicated.
Serotonergic medicinal products:
Lithium and tryptophan:
No pharmacodynamic interactions have been found in clinical studies in which citalopram has been given concomitantly with lithium. However, there have been reports of enhanced effects when SSRIs have been given with lithium or tryptophan and therefore the concomitant use of citalopram with these medicinal products should be undertaken with caution. Routine monitoring of lithium levels should be continued as usual.
Co-administration with serotonergic medicinal products e.g. opioids (including tramadol and buprenorphine) and triptans (including sumatriptan and oxitriptan) 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.
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. 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, dipyridamol, and ticlopidine or other medicinal products (e.g. atypical antipsychotics) that can increase the risk of haemorrhage.
ECT (electroconvulsive therapy):
There are no clinical studies establishing the risks or benefits of the combined use of electroconvulsive therapy (ECT) and citalopram.
Alcohol:
No pharmacodynamic or pharmacokinetic interactions have been demonstrated between citalopram and alcohol. However, the combination of citalopram and alcohol is not advisable.
Medicinal products inducing hypokalaemia/hypomagnesaemia:
Caution is warranted for concomitant use of hypokalaemia/hypomagnesaemia inducing medicinal products as these conditions increase the risk of malignant arrhythmias.
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 [SSRIs], neuroleptics [butyrophenones, thioxanthenes], mefloquin, bupropion and tramadol).
Pharmacokinetic interactions:
Biotransformation of citalopram to demethylcitalopram is mediated by CYP2C19 (approx. 38%), CYP3A4 (approx. 31%) and CYP2D6 (approx. 31%) isozymes of the cytochrome P450 system.
The fact that citalopram is metabolised by more than one CYP means that inhibition of its biotransformation is less likely as inhibition of one enzyme may be compensated by another. Therefore, co-administration of citalopram with other medicinal 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:
Coadministration 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.
Cimetidine:
Cimetidine (potent CYP2D6, 3A4, 1A2 inhibitor) caused a moderate increase in the average steadystate levels of citalopram. Caution is advised when administering citalopram in combination with cimetidine. Dose adjustment may be warranted.
Omeprazole and other CYP2C19 inhibitors:
Coadministration 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). A reduction in the dose of citalopram may be necessary based on monitoring of undesirable effects during concomitant treatment.
Metoprolol:
Caution is recommended when citalopram is coadministered 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. Dose adjustment may be warranted. Co-administration with metoprolol resulted in a twofold increase in the plasma levels of metoprolol, but did not statistically significant increase the effect of metoprolol on the blood pressure and cardiac rhythm.
Effects of citalopram on other medicinal products:
A pharmacokinetic/pharmacodynamic interaction study with concomitant administration of citalopram and metoprolol (a CYP2D6 substrate) showed a twofold increase in metoprolol concentrations, but no statistically significant increase in the effect of metoprolol on blood pressure and heart rate in healthy volunteers. Caution is advised in case of concomitant use of metoprolol and citalopram. Dose adjustment may be necessary.
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:
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).
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.
Incompatibilities:
Because there are no studies of drug incompatibility, do not mix this drug with other drugs.
Undesirable effects:
Adverse reactions observed with citalopram are in general mild and transient. They are most frequent during the first one or two weeks of treatment and usually attenuate subsequently.
For the following reactions a dose-response was discovered: Sweating increased, dry mouth, insomnia, somnolence, diarrhoea, nausea and fatigue.
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.
Undesirable effects are classified according to frequency: Very common (ADR ≥ 1/10), common (1/100 ≤ ADR < 1/10), uncommon (1/1,000 ≤ ADR < 1/100), rare (1/10,000 ≤ ADR < 1/1,000), very rare (ADR < 1/10,000); not known (cannot be estimated from the available data).
| System organ class | Frequency | Adverse reaction |
| Blood and lymphatic disorders | Not known | Thrombocytopenia |
| Immune system disorders | Uncommon | Hypersensitivity |
| Very rare | Anaphylactic reaction | |
| Endocrine disorders | Rare | Vasopressin hypersecretion |
| Not known | Inappropriate ADH secretion | |
| Metabolism and nutrition disorders | Common | Appetite decreased, weight decreased |
| Uncommon | Weight increased, loss of appetite | |
| Rare | Hyponatraemia | |
| Not known | Hypokalaemia | |
| Psychiatric disorders | Very common | Agitation, nervousness |
| Common | Libido decreased, abnormal orgasm (female), anxiety, confusional state, apathy, impaired concentration, abnormal dreams, memory loss | |
| Uncommon | Aggression, depersonalisation, hallucination, mania, euphoria, increased libido | |
| Not known | Panic attack, bruxism, restlessness, suicidal ideation, suicidal behaviour | |
| Nervous system disorders
|
Very common | Lethargy, urge to sleep, insomnia, headache, somnolence |
| Common | Paraesthesia, sleeping disorders, migraine, taste disturbance, attention disturbance | |
| Uncommon | Fainting, cramps, extrapyramidal disorders, syncope | |
| Rare | Convulsion grand mal, dyskinesia, akathisia | |
| Not known | Serotonin syndrome, movement disorders, convulsions | |
| Eye disorders | Very common | Accommodation disorder |
| Common | Visual disturbance | |
| Uncommon | Mydriasis | |
| Ear and labyrinth disorders | Common | Tinnitus |
| Cardiac disorders | Very common | Palpitations |
| Common | Tachycardia | |
| Uncommon | Bradycardia | |
| Not known | Ventricular arrhythmia including torsade de pointes, electrocardiogram QT prolonged | |
| Vascular disorders | Common | Hypotension, hypertension, orthostatic hypotension |
| Rare | Haemorrhage | |
| Respiratory, thoracic and mediastinal disorders | Common | Yawning, rhinitis, sinusitis |
| Uncommon | Coughing | |
| Not known | Epistaxis | |
| Gastrointestinal disorders | Very common | Dry mouth, nausea, constipation |
| Common | Diarrhoea, vomiting, dyspepsia, abdominal pain, flatulence, increased salivation | |
| Not known | Gastrointestinal haemorrhage (including rectal haemorrhage) | |
| Hepatobiliary disorders | Rare | Hepatitis |
| Not known | Liver function test abnormal, | |
| Skin and subcutaneous tissue disorders | Very common | Hyperhidrosis |
| Common | Itching, rash | |
| Uncommon | Urticaria, alopecia, purpura, photosensitivity reaction | |
| Very rare | Angioedema | |
| Not known | Ecchymosis | |
| Musculoskeletal, connective tissue and bone disorders | Common | Myalgia, arthralgia |
| Renal and urinary disorders | Common | Polyuria, micturition disorder |
| Uncommon | Urinary retention | |
| Reproductive system and breast disorders | Common | Impotence, ejaculation disorder, ejaculation failure, dysmenorrhoea |
| Uncommon | Female: Menorrhagia | |
| Very rare | Galactorrhoea | |
| Uncommon | Femal: Abnormal uterine bleeding
Male: Priapism and pain |
|
| General disorders and administration site conditions | Very common | Asthenia |
| Common | Fatigue, pyrexia | |
| Uncommon | Oedema, malaise |
Cases of suicidal ideation and suicidal behaviour have been reported during citalopram therapy or early after treatment discontinuation.
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 hypokalaemia, or with pre-existing QT prolongation or other cardiac diseases.
Withdrawal symptoms seen on discontinuation of SSRI treatment:
Discontinuation of citalopram (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor, confusion, sweating, headache, diarrhoea, palpitations, emotional instability, irritability, and visual disturbances are the most commonly reported reactions. Generally, these events are mild to moderate and are self-limiting, however, in some patients they may be severe and/or prolonged. It is therefore advised that when citalopram treatment is no longer required, gradual discontinuation by dose tapering should be carried out.
Overdose and management:
Overdose:
Toxicity: Comprehensive clinical data on citalopram overdose are limited and many cases involve concomitant overdoses of other medicinal products/alcohol. Fatal cases of citalopram overdose have been reported with citalopram alone, however, the majority of fatal cases have involved overdose with concomitant medicinal products.
Symptoms: The following symptoms have been seen in reported overdose of citalopram: Convulsion, tachycardia, somnolence, QT interval prolongation, coma, vomiting, tremor, hypotension, cardiac arrest, nausea, serotonin syndrome, agitation, bradycardia, dizziness, bundle branch block, QRS prolongation, hypertension, mydriasis, torsade de pointes, stupor, sweating, cyanosis, hyperventilation, atrial, ventricular arrhythmia and rhabdomyolysis.
Management:
Treatment: There is no known specific antidote to citalopram.
Treatment should be symptomatic and supportive. Activated charcoal, osmotically working laxative (such as sodium sulphate) and stomach evacuation should be considered. If consciousness is impaired the patient should be intubated. ECG and vital signs should be monitored.
ECG monitoring is advised in case of overdose in patients with congestive heart failure/bradyarrhythmias, in patients using concomitant medicinal products that prolong the QT interval, or in patients with altered metabolism (e.g. liver impairment).
Pharmacodynamics:
Pharmacological group: Selective serotonin reuptake inhibitors (SSRI).
ATC code: N06AB04
Citalopram is an antidepressant with a strong and selective inhibitory action on the uptake of 5-hydroxytryptamine (5-HT, serotonin).
Mechanism of action and pharmacodynamic effects:
Tolerance to the inhibitory effect of citalopram on 5-HT uptake does not occur during long-term treatment.
The antidepressant effect is probably connected with the specific inhibition of serotonin uptake in the brain neurons.
Citalopram has almost no effect on the neuronal uptake of noradrenaline, dopamine and gamma-aminobutyric acid. Citalopram shows no affinity, or only very little, for cholinergic, histaminergic and a variety of adrenergic, serotonergic and dopaminergic receptors.
Citalopram is a bicyclic isobenzophurane-derivative that is chemically not related to tricyclic and tetracyclic antidepressants or other available antidepressants. The main metabolites of citalopram are also selective serotonin uptake inhibitors, though to a lesser degree. The metabolites are not reported to contribute to the overall antidepressant effect.
In a double-blind, placebo-controlled ECG study in healthy subjects, the change from baseline in QTc (Fridericia-correction) was 7.5 msec (90%CI 5.9-9.1) at the 20 mg/day dose and 16.7 msec (90%CI 15.0-18.4) at the 60 mg/day dose.
Pharmacokinetics:
Absorption:
Citalopram is rapidly absorbed following oral administration: The maximum plasma concentration is reached on average after 4 (1-7) hours. Absorption is independent of food intake. Oral bioavailability is approximately 80%.
Distribution:
The apparent distribution volume is 12-17 L/kg. The plasma-protein binding of citalopram and its metabolites is below 80%.
Metabolism:
Citalopram is metabolised into demethylcitalopram, didemethylcitalopram, citalopram-N-oxide and the deaminated propionic acid-derivative. The propionic acid-derivative is pharmacologically inactive. Demethylcitalopram, didemethylcitalopram and citalopram-N-oxide are selective serotonin uptake inhibitors, although weaker than the parent compound.
The main metabolizing enzyme is CYP2C19. Some contribution from CYP3A4 and CYP2D6 is possible.
Elimination:
The plasma half-life is approximately 1½ days. After systemic administration, the plasma clearance is approximately 0.3-0.4 L/min and after oral administration the plasma clearance is approximately 0.4 L/min.
Citalopram is mainly eliminated via the liver (85%), but also partly (15%) via the kidneys. Of the quantity of citalopram administered, 12-23 % is eliminated unaltered via the urine. Hepatic clearance is approximately 0.3 l/min and renal clearance is 0.05-0.08 L/min.
Steady-state concentrations are reached after 1-2 weeks. A linear relationship has been demonstrated between the steady-state plasma level and the dose administered. At a dose of 40 mg per day, an average plasma concentration of approximately 300 nmol/L is reached. There is no clear relationship between citalopram plasma levels and therapeutic response or adverse reactions.
Characteristics relating to patients:
Longer plasma half-life values and a smaller clearance have been found in older patients due to a reduced metabolism.
The elimination of citalopram progresses more slowly in patients with reduced liver function. The plasma half-life of citalopram is approximately twice as long and the steady-state plasma concentration approximately twice as high in comparison with patients with a normal liver function.
The elimination of citalopram progresses more slowly in patients with a mild to moderate renal function disorder. A longer half-life and a small increase in the exposure of citalopram have been observed without any major impact on the pharmacokinetics of citalopram. No information is available on treatment of patients with severe renal impairment (creatinine clearance less than 20 mL/min).
Polymorphism: Poor metabolisers regarding CYP2C19 have been observed having twice as high plasma concentrations of escitalopram compared to extensive metabolisers. No relevant changes in the exposure were observed in poor metabolisers regarding CYP2D6.
Storage conditions, shelf life, quality specification of the medicine:
Storage conditions: Protect from humidity and light, below 300C.
Shelf life: 36 months from the manufacture date.
Quality specification: In house.
A1202069901
