1. Name Of The Medicinal Product
Citalopram 40 mg/ml Oral Drops, Solution
2. Qualitative And Quantitative Composition
Each ml contains:
Citalopram hydrochloride, corresponding to 40 mg citalopram.
1 drop = 2 mg citalopram; 1 ml = 20 drops = 40 mg citalopram
Ethanol = 76mg/ml
Methyl Parahydroxybenzoate = 1mg/ml
Propyl Parahydroxybenzoate = 0.1mg/ml
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Oral drops, solution.
Colourless or slightly yellow liquid.
4. Clinical Particulars
4.1 Therapeutic Indications
Treatment of depressive illness in the initial phase and as maintenance against potential relapse/recurrence.
Citalopram is also indicated in the treatment of panic disorder with or without agoraphobia.
4.2 Posology And Method Of Administration
For oral administration after mixing with water
MAJOR DEPRESSIVE EPISODES
The recommended dose is 16mg (8 drops) 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 48mg (24 drops) a day in 16mg (8 drops) steps according to the patient's response (see section 5.1). Dosage adjustments should be made carefully on an individual patient basis, to maintain the patient at the lowest effective dose.
Patients with depression should be treated for a sufficient period of at least 6 months to ensure that they are free from symptoms.
PANIC DISORDER
Patients should be started on 8mg (4 drops)/day and the dose gradually increased in 8mg (4 drops) steps according to the patient's response up to the recommended dose. The recommended dose is 16-24mg (8 to 12 drops) daily. 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 48mg (24 drops)/day (see section 5.1). Dosage adjustments should be made carefully on an individual patient basis, to maintain the patients at the lowest effective dose.
Patients with panic disorder should be treated for a sufficient period to ensure that they are free from symptoms. This period may be several months or even longer.
Elderly Patients (>65 years of age)
The recommended daily dose is 16mg (8 drops). Dependent on individual patient response this may be increased to a maximum of 32mg (16 drops) daily.
Children & Adolescents (<18 years)
Citalopram should not be used in the treatment of children and adolescents under the age of 18 years, (see section 4.4).
Reduced hepatic function
Dosage should be restricted to the lower end of the dose range.
Reduced renal function
Dosage adjustment is not necessary in cases of mild or moderate renal impairment. No information is available in cases of severe renal impairment (creatinine clearance <20mL/min)
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 section 4.4 Special Warnings and 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 described dose may be considered. Subsequently, the physician may continue decreasing the dose, but at a more gradual rate.
Citalopram Oral Drops can be taken as a single daily dose, at any time of day, without regard to food intake.
Citalopram Oral Drops have approximately 25% increased bioavailability compared to tablets. The tablet corresponds to the number of drops as follows:
Tablets/dose Equivalent
|
Drops
|
10mg
|
8mg (4 drops)
|
20mg
|
16mg (8 drops)
|
30mg
|
24mg (12 drops)
|
40mg
|
32mg (16 drops)
|
60mg
|
48mg (24 drops)
|
4.3 Contraindications
Hypersensitivity to citalopram or any of the excipients (see section 6.1).
MAOIs (monoamine oxidase inhibitors)
Some cases presented with features resembling serotonin syndrome.
Citalopram should not be given to patients receiving Monoamine Oxidase Inhibitors (MAOIs) including selegiline in daily doses exceeding 10 mg/day.
Citalopram should not be given for fourteen days after discontinuation of an irreversible MAOI or for the time specified after discontinuation of a reversible MAOI (RIMA) as stated in the prescribing text of the RIMA. MAOIs should not be introduced for seven days after discontinuation of citalopram (see section 4.5).
Citalopram is contraindicated in the combination with linezolid unless there are facilities for close observation and monitoring of blood pressure (see section 4.5).
Citalopram should no be used concomitantly with pimozide (see also section 4.5).
Sumatriptan's serotonergic effects are suspected to be enhanced by SSRI's. Until further evidence is available it is advised not to use citalopram simultaneously with 5-HT agonists e.g. sumatriptan.
4.4 Special Warnings And Precautions For Use
Suicide/suicidal thoughts – 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, 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 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. Patients (and caregivers of patients) should be alerted about the need to monitor for the emergence of such events and to seek medical advice immediately if these symptoms present.
Use in children and adolescents under 18 years of age
Citalopram should not be used in the treatment of children and adolescents under the age of 18 years. Suicide-related behaviours (suicide attempt and suicidal thoughts), and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo. If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms. In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking.
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.
Seizures
Seizures are a potential risk with antidepressant drugs. Citalopram should be discontinued in any patient who develops seizures. Citalopram should be avoided in patients with unstable epilepsy and patients with controlled epilepsy should be carefully monitored. Citalopram should be discontinued if there is an increase in seizure frequency.
Diabetes
In patients with diabetes, treatment with an SSRI may alter glycaemic control. Insulin and/or oral hypoglycaemic dosage may need to be adjusted.
Glaucoma
As with other SSRIs, citalopram can cause mydriasis and should be used with caution in patients with narrow angle glaucoma or history of glaucoma.
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.
Warnings on excipients:
This medicinal product contains small amounts of ethanol (alcohol), less than 100 mg per ml.
This medicinal product also contains propyl parahydroxybenzoate (E216) and methyl parahydroxybenzoate (E218), which may cause allergic reactions (possibly delayed).
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)
No pharmacodynamic interactions have been noted in clinical studies in which citalopram has been given concomitantly with benzodiazepines, neuroleptics, analgesics, lithium, alcohol, antihistamines, antihypertensive drugs, beta-blockers and other cardiovascular drugs.
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
Neonates should be observed if maternal use of Citalopram Oral Solution continues into the later stages of pregnancy, particularly in the third trimester. Abrupt discontinuation should be avoided in 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, 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.
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.
Patients who are prescribed psychotropic medication may be expected to have some impairment of general attention and concentration due to 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.
4.8 Undesirable Effects
Adverse effects observed with citalopram are in general mild and transient. They are most prominent during the first one or two weeks of treatment and usually attenuate as the depressive state improves. 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 postmarketing period. Frequencies are defined as: very common (
Frequency
|
Very common
|
Common
|
Uncommon
|
Rare
|
Not Known
|
|
|
|
|
|
|
Blood and lymphatic disorders
|
|
|
|
|
Thrombocytopenia
|
Immune system disorders
|
|
|
|
|
Hypersensitivity, anaphylactic reaction
|
Endocrine disorders
|
|
|
|
|
Inappropriate ADH secretion
|
Metabolism and nutrition disorders
|
|
Appetite decreased, weight decreased, anorexia1
|
Increased appetite, weight increased
|
Hyponatremia
|
Hypokalaemia
|
Psychiatric disorders
|
Sleep disorder1
|
Agitation, nervousness, libido decreased, anxiety, confusional state, abnormal dreams, abnormal orgasm (female) apathy1, impaired concentration1, amnesia1
|
Aggression, depersonalisation, hallucination, mania
|
Euphoria, increased libido1
|
Panic attack, bruxism, restlessness, suicidal ideation and suicidal behavior3
|
Nervous system disorders
|
Somnolence insomnia, headache1
|
Tremor, dizziness, migraine1, paraesthesia, disturbance in attention
|
Syncope
|
Convulsion grand mal, dyskinesia, taste disturbance
|
Convulsions, serotonin syndrome,
extrapyramidal disorder, akathisia, movement disorder
|
Eye disorders
|
|
Abnormal accommodation
|
Abnormal vision, mydriasis (which may lead to acute narrow angle glaucoma) see section 4.4 Special warnings and precautions for use
|
|
Visual disturbance
|
Ear and labyrinth disorders
|
|
Tinnitus
|
|
|
|
Cardiac Disorders
|
|
Palpitation1
|
Postural hypotension, tachycardia, bradycardia
|
|
QT – prolongation2
|
Vascular disorders
|
|
|
|
Haemorrhage
|
Orthostatic hypotension
|
Respiratory, thoracic and mediastinal disorders
|
|
Yawning, Rhinitis1
|
|
Coughing1
|
Epistaxis
|
Gastro-intestinal disorders
|
Nausea, dry mouth
|
Constipation, diarrhoea, vomiting, taste perversion1 abdominal pain1, flatulence1, increased saliva1, dyspepsia1
|
|
|
Gastrointestinal haemorrhage (including rectal haemorrhage)
|
Hepato-biliary disorders
|
|
|
|
Hepatitis
|
Liver function test abnormal
|
Skin and subcutaneous disorders
|
Sweating Increased
|
Pruritus
|
Urticaria alopecia, rash, purpura, Photosensitivity
|
|
Ecchymosis, angioedemas
|
Musculoskeletal, connective tissue and bone disorders
|
|
Myalgia, arthralgia
|
|
|
|
Renal and urinary disorders
|
|
|
Urinary retention, micturition disorder, polyuria
|
|
|
Reproductive system and breast disorders
|
|
Impotence ejaculation disorder, ejaculation failure
|
Female: Menorrhagia
|
|
Female: Metrorrhagia, Male: Priapism, galactorrhoea
|
General Disorders
|
Asthenia1
|
Fatigue
|
Oedema
|
Pyrexia
Malaise1
|
|
Number of patients: Citalopram/ placebo = 1346/ 545
1The following adverse events have also been reported in clinical trials.
2Cases of QT-prolongation have been reported during the post-marketing period, predominantly in patients with pre-existing cardiac disease.
3Suicidal thoughts/behaviour (frequency unknown): Cases of suicidal ideation and suicidal behaviours have been reported during citalopram therapy or early after treatment discontinuation (see section 4.4 Special warnings and Special Precautions for Use)
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).
Class effects
Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRs and TCAs. The mechanism leading to this risk is unknown.
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.
Treatment should be symptomatic and supportive and include the maintenance of a clear airway and monitoring of ECG and vital signs until stable.
Consider oral activated charcoal in adults and children who have ingested more than 5mg/kg body weight within 1 hour. Activated charcoal given ½ hour after ingestion of citalopram has been shown to reduce absorption by 50%.
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.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
ATC Code: N06A B04
Pharmacotherapeutic Group: Selective Serotonin Reuptake Inhibitors
Biochemical and behavioural studies have shown that citalopram is a potent inhibitor of serotonin (5-HT)-uptake. Tolerance to the inhibition of 5-HT-uptake is not induced by long-term treatment with citalopram.
Citalopram is the most selective Serotonin Reuptake Inhibitor (SSRI) yet described, with no, or minimal, effect on noradrenaline (NA), dopamine (DA) and gamma aminobutyric acid (GABA) uptake.
In contrast to many tricyclic antidepressants and some of the newer SSRI's citalopram has no or very low affinity for a series of receptors including 5-HT1A, 5-HT2, DA D1 and D2 receptors, α1-, α2-, ß-adrenoceptors, histamine H1, muscarine cholinergic, benzodiazepine, and opioid receptors. A series of functional in vitro tests in isolated organs as well as functional in vivo tests have confirmed the lack of receptor affinity. 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 orthostatic hypotension.
Suppression of rapid eye movement (REM) sleep is considered a predictor of antidepressant activity. Like tricyclic antidepressants, other SSRI's and MAO inhibitors, citalopram suppresses REM-sleep and increases deep slow-wave sleep.
Although citalopram does not bind to opioid receptors it potentiates the anti nociceptive effect of commonly used opioid analgesics. There was potentiation of d-amphetamine-induced hyperactivity following administration of citalopram.
The main metabolites of citalopram are all SSRIs although their potency and selectivity ratios are lower than those of citalopram. However, the selectivity ratios are lower than thos
