1. Name Of The Medicinal Product
Citalopram 10 mg Tablets
2. Qualitative And Quantitative Composition
Citalopram 10mg Tablets: 1 film-coated tablet contains 12.495 mg citalopramhydrobromide, equivalent to 10 mg Citalopram.
For a full list of excipients, see 6.1
3. Pharmaceutical Form
Film-coated tablet
Round, white tablets with a diameter of 6 mm.
4. Clinical Particulars
4.1 Therapeutic Indications
Treatment of major depressive episodes.
4.2 Posology And Method Of Administration
Citalopram should be administered as a single oral dose, either in the morning or in the evening. The tablets can be taken with or without food, but with fluid.
Following treatment initiation, an antidepressant effect should not be expected for at least two weeks. Treatment should continue until the patient has been free of symptoms for 4-6 months. Citalopram should be withdrawn slowly, it is advised that the dose is gradually reduced over 1-2 week periods.
Children and adolescents under the age of 18:
Citalopram should not be used in the treatment of children and adolescents under the age of 18 years (see section 4.4).
Adults:
The recommended starting dose is 20mg per day. If necessary, the dose can be increased up to 40mg per day, depending on the individual response of the patient. The maximum dose is 60mg per day.
Elderly patients (>65 years of age):
For elderly patients the dose should be decreased to half of the recommended dose, e.g. 10-20mg per day. Depending on the individual response of the patient, the dose can be increased. The recommended maximum dose for the elderly is 40mg/day.
Reduced renal function:
Dosage adjustment is not required if the patient has mild to moderate renal impairment. No information is available on treatment of patients with severe renal impairment (creatinine clearance less than 20ml/min).
Reduced hepatic function:
An initial dose of 10mg daily for the first two weeks of treatment is recommended in patients with mild or moderate hepatic impairment. Depending on individual patient response, the dose may be increased to 30mg daily. Caution and extra careful dose titration is advised in patients with severely reduced hepatic function (see section 5.2).
Poor metabolisers regarding CYP2C19
For known poor CYP2C19 metabolisers an initial dose of 10mg daily the first two weeks of treatment is recommended. Depending on the outcome of the treatment the dose can thereafter be increased to 20mg (see section 5.2).
Withdrawal symptoms seen on discontinuation
Abrupt discontinuation should be avoided. When stopping treatment with Citalopram the dose should be gradually reduced at intervals of one to two weeks in order to reduce the risk of withdrawal reactions (see section 4.4 and section 4.8). If intolerable symptoms occur following a decrease in the dose 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.
4.3 Contraindications
Hypersensitivity to citalopram or to any of the excipients.
Citalopram should not be given to patients receiving Monoamine Oxidase Inhibitors (MAOIs) including selegiline in daily doses exceeding 10mg/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).
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 selective MAOI selegiline and the reversible MAOI (RIMA), moclobemide and in patients who have recently discontinued an SSRI and have been started on a MAOI.
Some cases presented with features resembling serotonin syndrome. Symptoms of an active substance interaction with a MAOI include: hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes that include confusion, irritability, and extreme agitation progressing to delirium and coma.
Citalopram is contraindicated in the combination with linezolid unless there are facilities for close observation and monitoring of blood pressure (see section 4.5).
Concomitant treatment with pimozide (see also section 4.5)
4.4 Special Warnings And Precautions For Use
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).
Diabetes
In patients with diabetes, treatment with an SSRI may alter glycaemic control. Insulin and/or oral hypoglycaemic dosage may need to be adjusted.
Seizures
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.
Electroconvulsive Therapy (ECT)
There is little clinical experience of concurrent administration of citalopram and electroconvulsive therapy, therefore caution is advisable.
Mania
Citalopram should be used with caution in patients with a history of manic/hypomanic-depressive illness as a change towards the manic phase may occur. Citalopram should be discontinued in any patient entering a manic phase.
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 (see section 4.8). 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 (see section 4.5).
Serotonin syndrome
In rare cases a serotonin syndrome has been reported in patients using SSRIs. A combination of symptoms, such as agitation, tremor, myoclonus and hyperthermia may indicate the development of this condition. 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.
Psychosis
Treatment of psychotic patients with depressive episodes may increase psychotic symptoms.
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 behavioural development are lacking.
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 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.
Akathisia/psychomotor restlessness
The use of citalopram 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.
Withdrawal symptoms seen on discontinuation
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", section 4.2).”
Renal and hepatic impairment
The use of citalopram in patients with severe renal impairment (creatinine clearance less than 20ml/min.) is not recommended as no information is available on use in these patients. (see section 4.2)
In cases of impaired hepatic function dose reduction is recommended (see section 4.2) and liver function has to be closely monitored.
Hyponatraemia
Hyponatraemia and the syndrome of inappropriate anti-diuretic hormone secretion (SIADH) has been reported rarely, predominantly in the elderly (female patients seem to be at particularly high risk), and generally reverses on discontinuation of therapy.
St John's wort (Hypericum perforatum)
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).
Insomnia and agitation
At the beginning of the treatment, insomnia and agitation can occur. A dose titration may be helpful.
QT prolongation
Consideration should be given to factors which may affect the disposition of a minor metabolite of citalopram (didemethylcitalopram) since increased levels of this metabolite could theoretically prolong the QTc interval in susceptible individuals, patients with congenital 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.
Consideration should be given to factors which may affect the disposition of a minor metabolite of citalopram (didemethylcitalopram) since increased levels of this metabolite could theoretically prolong the QTc interval in susceptible individuals, patients with congenital prolonged QT syndrome or in patients with hypokalaemia/hypomagnesiaemia. ECG monitoring may be advisable in case of overdose or conditions of altered metabolism with increased peak levels, e.g. liver impairment.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Pharmacodynamic interactions
At the Pharmacodynamic level cases of serotonin syndrome with citalopram and moclobemide and buspirone have been reported.
Contraindicated combination:
MAO-inhibitors
The simultaneous use of citalopram and MAO-inhibitors can result in severe side effects, including the serotonin syndrome (see section 4.3).
Cases of serious and sometimes fatal reactions have been reported in patients receiving an SSRI in combination with a monoamine oxidase inhibitor (MAOI), including 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 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 (20mg daily) and selegiline (10mg daily) (a selective MAO-B inhibitor) demonstrated no clinically relevant interactions. The concomitant use of citalopram and selegiline (in doses above 10mg 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.
The 5-HT effect of serotonergic drugs such as tramadol and sumatriptan may be potentiated by selective serotonin re-uptake inhibitors (SSRIs). Until further information is available, the simultaneous use of citalopram and 5-HT agonists, (sumatriptan and other triptans) is not recommended (see section 4.4).
Haemorrhage
Caution is warranted for patients who are being treated simultaneously with anticoagulants, medicines that affect the function of thrombocytes, such as NSAIDs, acetylsalicylic acid, dipyridamole, and ticlopidine or other medicines (e.g. atypical antipsychotics, phenothiazines, tricyclic depressants) that can increase the risk of haemorrhage (see section 4.4).
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.
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) due to dynamic interactions (see section 4.4). Pharmacokinetic interactions have not been investigated.
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 including 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, also 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), mefloquin, 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.
Pharmacokinetic interactions
Biotransformation of citalopram to demethylcitalopram is mediated by CYP2C19 (approx. 38%), CYP3A4 (approx. 31%) and CYP2D6 (approx. 31%) isoenzymes 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.
Influence of other medicinal products on the pharmacokinetics of citalopram
Pharmacokinetic interactions based on plasma-protein binding should not be expected. Citalopram is a weak inhibitor of CYP2D6. Although clinically relevant medicinal interactions with citalopram are unusual, an interaction cannot be excluded if citalopram is administered simultaneously with another medicinal product that is metabolised by CYP2D6.
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 30mg 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 escitalopram may be necessary based on monitoring of undesirable effects during concomitant treatment.
There is no pharmacokinetic interaction between lithium and citalopram. However, there have been reports of enhanced serotonergic effects when SSRIs were administered in combination with lithium or tryptophan.
Co-administration with ketoconazole (potent CYP3A4 inhibitor) did not change the pharmacokinetics of citalopram.
Food
The absorption and other pharmacokinetic properties of citalopram have not been reported to be affected by food.
Effects of citalopram on other medicinal products
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.
A pharmacokinetic/pharmacodynamic interaction study with concomitant administration of citalopram and metoprolol (a CYP2D6 substrate) showed a twofold increase in metoprolol concentrations, but no statistically significant increase in the effect of metoprolol on blood pressure and heart rate in healthy volunteers.
Citalopram and demethylcitalopram are negligible inhibitors of CYP2C9, CYP2E1 and CYP3A4, and only weak inhibitors of CYP1A2, CYP2C19 and CYP2D6 as compared to other SSRIs established as significant inhibitors.
Levomepromazine, digoxin, carbamazepine
Thus no change or only very small changes of no clinical importance were observed when citalopram was given with CYP1A2 substrates (clozapine and theophylline), CYP2C9 (warfarin), CYP2C19 (imipramine and mephenytoin), CYP2D6 (sparteine, imipramine, amitriptyline, risperidone) and CYP3A4 (warfarin, carbamazepine (and its metabolite carbamazepine epoxid) and triazolam.
No pharmacokinetic interaction was observed between citalopram and levomepromazine or digoxin (indicating that citalopram neither induces nor inhibits P-glycoprotein).
4.6 Pregnancy And Lactation
Pregnancy
A large amount of data on pregnant women (more than 2500 exposed outcomes) indicate no malformative feto/ neonatal toxicity. Citalopram can be used during pregnancy if clinically needed, taking into account the aspects mentioned below
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 neonate 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 withdrawal symptoms. In a majority of instances the complications begin immediately or soon (< 24 hours) after delivery. information is insufficient for assessment of the risk to the child.
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
Caution is recommended.
4.7 Effects On Ability To Drive And Use Machines
Citalopram has minor or moderate influence on the ability to drive and use machines.
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 reactions observed with citalopram are in general mild and transient. They are most prominent during the first 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
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Number of patients: Citalopram / placebo = 1346 / 545
1 Cases of QT-prolongation have been reported during the post-marketing period, predominantly in patients with pre-existing cardiac disease
2 Cases of suicidal ideation and suicidal behaviours have been reported during citalopram therapy or early after treatment discontinuation (see section 4.4).
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 and headache 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).
4.9 Overdose
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.
Symptoms of overdose
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, and atrial and ventricular arrythmia.
Treatment of an overdose
There is no known specific antidote to citalopram. Treatment should be symptomatic and supportive.
If possible, the patient should be made to vomit, after which activated carbon and an osmotically working laxative (such as sodium sulfate) should be given. Stomach evacuation should be considered. If consciousness is impaired the patient should be intubated. Monitoring of cardiac and vital signs is recommended together with general symptomatic supportive measures.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group
Antidepressant
ATC code: N06A B04
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 bi-cyclic 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.
5.2 Pharmacokinetic Properties
General characteristics of the active substance
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%.
Bio-transformation:
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 metabolising 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 side effects.
Characteristics relating to patients
Elderly patients
Longer plasma half-life values and a smaller clearance have been found in older patients due to a reduced metabolism.
Patients with reduced hepatic function
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.
Patients with reduced renal function
The elimination of citalopram progresses more slowly in patients with a mild to moderate renal function disorder, 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 30 ml/min).
5.3 Preclinical Safety Data
In laboratory animals no evidence for a special hazard for humans were found. This is based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.
Phospholipidosis in several organs was observed in repeated dose toxicity studies in rats. This reversible effect is known for several lipophilic amines and was not connected with morphological nor functional effects. The clinical relevance is not clear.
Embryotoxicity studies in rats have shown skeletal anomalies at high maternally toxic doses. The effects could possibly be related to the pharmacological activity, or could be an indirect effect of the maternal toxicity. Peri- and postnatal studies have revealed reduced survival in offspring during the lactation period. The potential risk for humans is unknown.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Core:
Mannitol
microcrystalline cellulose
colloidal silica, anhydrous
magnesium stearate
Coating:
hypromellose
macrogol 6000
titanium dioxide (E171)
6.2 Incompatibilities
Not applicable
6.3 Shelf Life
48 months
6.4 Special Precautions For Storage
No special precautions for storage.
6.5 Nature And Contents Of Container
Citalopram 10mg, 20 mg and 40 mg tablets, packed in PVC/PVDC/Al blisters are available in pack sizes of 10, 14, 20, 28, 30, 50, 56, 98 and 100 tablets per box,
100x1 unit dose blister
HDPE tablet container with a LDPE tamper evident cap containing 250, 500 tablets.
Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
No special requirements.
7. Marketing Authorisation Holder
Actavis UK Limited (Trading style: Actavis)
Whiddon Valley
BARNSTAPLE
N Devon EX32 8NS
United Kingdom
8. Marketing Authorisation Number(S)
PL 0142/0543
9. Date Of First Authorisation/Renewal Of The Authorisation
Date of first authorisation: 26/07/2002
Date of last renewal: 20/12/2006
10. Date Of Revision Of The Text
17/09/2010
11 DOSIMETRY
(IF APPLICABLE)
12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS
(IF APPLICABLE)
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