Citalopram 10 Mg Film-Coated Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Citalopram 10mg Film-Coated Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
10mg tablet: Each tablet contains 10mg citalopram (as hydrobromide).
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablet.
10mg tablet: White round tablet, diameter 6 mm.
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
Posology
Major depressive episodes
Adults:
Citalopram should be administered as a single oral dose of 20mg daily. Dependent on individual patient response, the dose may be increased to a maximum of 40mg 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 40mg a day (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
Adults:
A single oral dose of 10mg daily is recommended for the first week before increasing the dose to 20mg daily. Dependent on individual patient response, the dose may be increased to a maximum of 40mg daily.
Patients should be started on 10mg/day and the dose gradually increased in 10mg steps according to the patient's response up to the recommended dose. 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 40mg/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):
For elderly patients the dose should be decreased to half the recommended dose e.g. 10-20mg daily. The recommended maximum dose for the elderly is 20mg daily.
Children and adolescents (< 18 years of age):
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:
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 a maximum of 20mg daily. Caution and extra careful dose titration is advised in patients with severely reduced hepatic function (see section 5.2)
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 <20 mL/min).
Poor metabolisers of CYP2C19
An initial dose of 10mg 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 a maximum of 20mg daily depending on individual patient response, (see section 5.2).
Withdrawal symptoms seen on discontinuation of citalopram
Abrupt discontinuation should be avoided. When stopping treatment with citalopram it is recommended that the dose is 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 prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose, but at a more gradual rate.
Method of administration
Citalopram tablets are administered as a single daily dose. Citalopram tablets can be taken any time of the day without regard to food intake.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Monoamine Oxidase Inhibitors (MAOIs):
Some cases presented with features resembling serotonin syndrome.
Citalopram should not be used in combination with a MAOI, including selegiline, in daily doses exceeding 10mg/day.
Citalopram may be started 14 days after discontinuing treatment with an irreversible MAOI and at least one day or for the time specified after discontinuing treatment with the irreversible MAOI and at least one day or for the time specified after discontinuation of a reversible MAOI (RIMA), as stated in the prescribing text of the RIMA.
At least 7 days should elapse after discontinuing citalopram treatment before starting a MAOI or RIMA (see section 4.5).
Citalopram is contraindicated in combination with linezolid unless there are facilities for close observation and monitoring of blood pressure (see section 4.5).
Citalopram is contraindicated in patients with known QT-interval prolongation or congenital long QT syndrome.
Citalopram is contraindicated together with medicinal products that are known to prolong the QT-interval (see section 4.5).
4.4 Special warnings and precautions for use
Use in children and adolescents under 18 years of age
Citalopram Tablets 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).
Serotonin syndrome
Rarely, the occurrence of “serotonin syndrome” has been reported in patients receiving SSRIs. A combination of symptoms, possibly including agitation, tremor, myoclonus and hyperthermia, may indicate the development of this condition (see section 4.5). Treatment with citalopram should be discontinued immediately and symptomatic treatment initiated.
Serotonergic medicines
Citalopram should not be used concomitantly with medicinal products with serotonergic effects such as sumatriptan or other triptans, tramadol, oxitriptan and tryptophan.
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. Especially elderly female patients seem to be a risk group.
Diabetes
In patients with diabetes, treatment with an SSRI may alter glycaemic control., possibly due to improvement of depressive symptoms. Insulin and or oral hypoglycaemic dosage may need to be adjusted.
Seizures
Seizures are a potential risk with antidepressant drugs. The drug 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 (electroconvulsive therapy)
There is little clinical experience of concurrent administration of citalopram and ECT, therefore caution is advisable.
Reversible, selective MAO-A inhibitors
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).
Mania
In patients with manic-depressive illness a change towards the manic phase may occur. Citalopram should be discontinued in any patient entering a manic phase.
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 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.
Haemorrhage
There have been reports of cutaneous or mucous bleedings, prolonged bleeding time and/or bleeding abnormalities such as ecchymoses, gynaecological haemorrhages, , and gastrointestinal haemorrhage with SSRIs. Caution is advised in patients taking SSRIs, particularly in concomitant use of active substances known to affect platelet function or other active substances that can increase the risk of haemorrhages, as well as in patients with a history of bleeding disorders (see section 4.5).
Paradoxical anxiety
Some patients with panic disorder may experience intensified anxiety symptoms when starting pharmacotherapy with antidepressants. This paradoxical reaction usually subsides within the first two weeks of starting treatment. A low starting dose is advised to (see Posology) reduces the likelihood of this effect.
Angle-closure Glaucoma
As with other SSRIs including citalopram may have an effect on pupil size which can cause 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.
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 of SSRI treatment
Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt (see section 4.8 Undesirable effects). In a recurrence prevention clinical trial with citalopram, adverse events after discontinuation of active treatment were seen in approximately 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 citalopram”, Section 4.2 Posology and Method of Administration).
Psychosis
Treatment of psychotic patients with depressive episodes may increase psychotic symptoms.
Citalopram has been found to cause a dose-dependent prolongation of the QT-interval. Cases of QT interval prolongation and ventricular arrhythmia including torsades de pointes have been reported during the post marketing period, predominantly in patients of female gender, with hypokalemia, or with pre-existing QT prolongation or other cardiac diseases (see sections 4.3, 4.5, 4.8, 4.9 and 5.1)
Caution is advised in patients with significant bradycardia; or in patients with recent acute myocardial infarction or uncompensated heart failure.
Electrolyte disturbances such as hypokalaemia and hypomagnesaemia increase the risk for malignant arrhythmias and should be corrected before treatment with Citalopram is started.
If patients with stable cardiac disease are treated, an ECG review should be considered before treatment is started.
ECG monitoring may be advisable in case of overdose or conditions of altered metabolism with increased peak levels, e.g. liver impairment.
If signs of cardiac arrhythmia occur during treatment with Citalopram, the treatment should be withdrawn and an ECG should be performed.
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 amonoamine oxidase inhibitor (MAOI), including the irreversible MAOI selegiline and the reversible MAOIs linezolid and moclobemide and in patients who have recently discontinued an SSRI and have been started on a MAOI.
Some cases presented with features resembling serotonin syndrome.
Symptoms of an active substance interaction with a MAOI include: agitation, tremor, myoclonus, and hyperthermia.
Pharmacokinetic and pharmacodynamic studies between Citalopram and other medicinal products that prolong the QT interval have not been performed. An additive effect of citalopram and these medicinal products cannot be excluded. Therefore, co-administration of citalopram with medicinal products that prolong the QT interval, such as Class IA ad 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) etc., is contraindicated.
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 coadministration 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 contraindicated.
Serotonergic medicinal products
Lithium & 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 drugs should be undertaken with caution. Routine
monitoring of lithium levels need not be adjusted and should be continued as usual.
Serotonergic drugs: 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
Dynamic interactions between citalopram and the herbal remedy St. John's Wort (Hypericum perforatum) can occur, resulting in an increase in undesirable effects (see section 4.4). Pharmacokinetic interactions have not been investigated.
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) 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 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 [thioxanthenes and butyrophenones]), mefloquine, 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.
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.
Citalopram and demethylcitalopram are negligible inhibitors of CYP2C9, CYP2E1 and CYP3A4, and only weak inhibitors of CYP1A2, CYP2C19 and CYP2D6 as compared to other SSRIs established as significant inhibitors.
No change or only very small changes of clinical importance were observed when citalopram was given with CYP1A2 substrates (clozapine and theophylline), CYP2C9 (warfarin), CYP2C19 (imipramine and mephenytoin), CYP2D6 (sparteine, imipramine, amitriptyline, risperidone) and CYP3A4 (warfarin, carbamazepine (and its metabolite carbamazepine epoxid) and triazolam).
No pharmacokinetic interaction was observed between citalopram and levomepromazine, or digoxin, (indicating that citalopram neither induces nor inhibits P-glycoprotein).
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.
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 (potent CYP2D6, 3A4 and 1A2 inhibitor) caused a moderate increase in the average steady state levels of citalopram. Caution is advised when administering citalopram in combination with cimetidine. Dose adjustment may be warranted.
Co-administration of escitalopram (the active enantiomer of citalopram) with omeprazole 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). 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 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. 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.
4.6 Fertility, pregnancy and lactation
Pregnancy
Published data on pregnant women (more than 2500 exposed outcomes) indicate no malformative foeto / neonatal toxicity, however citalopram should not be used during pregnancy unless clearly necessary and only after careful consideration of risk/benefit.
Neonates should be observed if maternal use of citalopram continues into the later stages of pregnancy, 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, 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.
Breastfeeding
Citalopram is known to be excreted in 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.
Fertility
Animal data have shown that citalopram may affect sperm quality (see section 5.3).
Human case reports with some SSRIs have shown that an effect on sperm quality is reversible.
Impact on human fertility has not been observed so far.
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 either due to the illness itself and psychoactive medicinal products can reduce the ability to make judgements and to react to emergencies. Patients should be informed of these effects and should be warned that their ability to drive a car and operate machinery could be affected.
4.8 Undesirable effects
Adverse effects observed with citalopram are in general mild and transient. They are most frequent during the first one or two weeks of treatment and usually attenuate subsequently. The adverse reactions are presented at the MedDRA Preferred Term Level.
For the following reactions a dose-response was discovered: Sweating increased, dry mouth, insomnia, somnolence, diarrhoea, nausea and fatigue.
The table shows the percentage of adverse drug reactions associated with SSRIs and/or citalopram seen in either >1% of patients in double-blind placebo-controlled trials or in the post-marketing period. Frequencies are defined as: very common ( >1/10); common ( >1/100 to <1/10); uncommon ( >1/1000 to <1/100); rare ( >1/10000 to <1/1000); very rare (<1/10000), not known (cannot be estimated from available data).
|
System organ class |
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 |
Increased appetite, weight increased |
Hyponatra emia |
Hypokalaemia | |
|
Psychiatric disorders |
Sleep disorder |
Agitation, libido decreased, anxiety, nervousness 5 confusional state, abnormal orgasm (female), abnormal dreams, apathy |
Aggression, depersonaliza tion, hallucination, mania, libido increased |
Panic attack, bruxism, restlessness, suicidal ideation, suicidal behaviour1 | |
|
Nervous system disorders |
Somnolenc e, insomnia, headache |
Tremor, dizziness, paraesthesia 5 disturbance in attention, migraine, amnesia |
Syncope |
Convulsio n grand mal, dyskinesia , taste disturbanc e, |
Convulsions, serotonin syndrome, extrapyramidal disorder, akathisia, movement disorder |
|
Eye disorders |
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 |
Palpitations |
Bradycardia, tachycardia |
QT-prolongation ventricular arrhythmia including torsade de pointes | ||
|
Vascular disorders |
Hypotensio n, hypertensio n, Orthostatic hypotension |
Haemorrh age | |||
|
Respiratory thoracic and mediastinal disorders |
Yawning, rhinitis |
Coughing |
Epistaxis | ||
|
Gastrointestina l disorders |
Dry mouth, Nausea |
Diarrhoea, vomiting, constipation , dyspepsia abdominal pain, flatulence, increased salivation |
Gastrointestinal haemorrhage (including rectal haemorrhage) | ||
|
Hepatobiliary disorders |
Hepatitis |
Liver function test abnormal | |||
|
Skin and subcutaneous tissue disorders |
Sweating increased |
Pruritus |
Urticaria, alopecia, rash, purpura, photosensitiv ity reaction |
Ecchymosis, angioedemas |
|
Musculoskelet al, connective tissue and bone disorders |
Myalgia, arthralgia | ||||
|
Renal and urinary disorders |
Urinary retention | ||||
|
Reproductive system and breast disorders |
Impotence, ejaculation disorder, ejaculation failure |
Female: Menorrhagia |
Female: Metrorrhagia Male: Priapism, galactorrhoea | ||
|
General disorders and administration site conditions |
Asthenia |
Fatigue, |
Oedema |
Pyrexia, malaise |
Number of patients: citalopram / placebo = 1346 / 545
1
Cases of suicidal ideation and suicidal behaviours have been reported during citalopram therapy or early after treatment discontinuation (see section 4.4).
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 disease (see sections 4.3, 4.4, 4.5, 4.9 and 5.1).
Class effects
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.
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 (see section 4.2 and section 4.4).
Reporting of suspected adverse reactions:
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
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 2g 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 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. ECG monitoring is advisable in case of overdose in patients with congestive heart failure/bradyarrhythmias, in patients using concomitant medications that prolong the QT interval, or in patients with altered metabolism, e.g. liver impairment.
Consider oral activated charcoal in adults and children who have ingested more than 5 mg/kg body weight within 1 hour. Activated charcoal given V 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
Pharmacotherapeutic group: antidepressants, selective serotonin reuptake inhibitors, ATC code: N 06 AB 04.
Mechanism of action
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 SSRIs, citalopram has no or very low affinity for a series of receptors including 5-HTiA, 5-HT2, DA Dl and D2 receptors, a1-, a2-and P-adrenoceptors, histamine H1, muscarinic 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.
The main metabolites of citalopram are all SSRIs although their potency and
selectivity ratios are lower than those of citalopram. However, the selectivity ratios of the metabolites are higher than those of many of the newer SSRIs. The metabolites do not contribute to the overall antidepressant effect.
Pharmacodynamic effects
Suppression of rapid eye movement (REM) sleep is considered a predictor of antidepressant activity. Like tricyclic antidepressants, other SSRIs and MAO inhibitors, citalopram suppresses REM-sleep and increases deep slow-wave sleep.
Although citalopram does not bind to opioid receptors it potentiates the antinociceptive effect of commonly used opioid analgesics. There was potentiation of d-amphetamine-induced hyperactivity following administration of citalopram.
In humans citalopram does not impair cognitive (intellectual function) and psychomotor performance and has no or minimal sedative properties, either alone or in combination with alcohol.
Citalopram did not reduce saliva flow in a single dose study in human volunteers and in none of the studies in healthy volunteers did citalopram have significant influence on cardiovascular parameters. Citalopram has no effect on the serum levels of prolactin and growth hormone.
In a double-blind, placebo-controlled ECG study in healthy subjects, the change from baseline in QTc (Fridericia-correction) was 7.5 (90%CI 5.9-9.1) msec at the 20mg/day dose and 16.7 (90%CI 15.0-18.4) msec at the 60mg day/dose (see sections 4.3, 4.4, 4.5, 4.8 and 4.9).
5.2 Pharmacokinetic properties
Absorption
Absorption is almost complete and independent of food intake (Tmax average/mean 3.8 hours). Oral bioavailability is about 80%.
Distribution
The apparent volume of distribution (Vd)p is about 12.3 L/kg. The plasma protein binding is below 80% for citalopram and its main metabolites.
Biotransformation
Citalopram is metabolized to the active demethylcitalopram, didemethylcitalopram, citalopram-N-oxide and an inactive deaminated propionic acid derivative. All the active metabolites are also SSRls, although weaker than the parent compound. Unchanged citalopram is the predominant compound in plasma.
Elimination
The elimination half-life (T% p) is about 1.5 days and the systemic citalopram plasma clearance (Cls) is about 0.33 L/min, and oral plasma clearance (Cl oral) is about 0.41 L/min.
Citalopram is excreted mainly via the liver (85%) and the remainder (15%) via the kidneys. About 12% of the daily dose is excreted in urine as unchanged citalopram. Hepatic (residual) clearance is about 0.35 L/min and renal clearance about 0.068 L/min.
The kinetics are linear. Steady state plasma levels are achieved in 1-2 weeks. Average concentrations of 250 nmol/L (100-500 nmol/L) are achieved at a daily dose of 40 mg. There is no clear relationship between citalopram plasma levels and therapeutic response or side-effects.
Elderly patients ( > 65 years):
Longer half-lives and decreased clearance values due to a reduced rate of metabolism have been demonstrated in elderly patients.
Reduced hepatic function:
Citalopram is eliminated more slowly in patients with reduced hepatic function. The half-life of citalopram is about twice as long and steady state citalopram concentrations at a given dose will be about twice as high as in patients with normal liver function.
Reduced renal function:
Citalopram is eliminated more slowly in patients with mild to moderate reduction of renal function, without any major impact on the pharmacokinetics of citalopram. At present no information is available for treatment of patients with severely reduced renal function (creatinine clearance <20 mL/min).
5.3 Preclinical safety data
Acute toxicity
Citalopram has low acute toxicity.
Chronic toxicity
In chronic toxicity studies there were no findings of concern for the therapeutic use of citalopram.
Reproduction studies
Based on data from reproduction toxicity studies (segment I, II and III) there is no reason to have special concern for the use of citalopram in women of childbearing potential.
Animal data have shown that citalopram induces a reduction of fertility index and pregnancy index, reduction in the implantation number and abnormal sperm at exposure well in excess of human exposure.
Mutagenic and carcinogenic potential
Citalopram has no mutagenic or carcinogenic potential.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Core
Mannitol
Colloidal anhydrous silica Microcrystalline cellulose Magnesium stearate
Coating Macrogol Hypromellose Titanium dioxide (E171)
6.2 Incompatibilities
Not applicable.
6.3
Shelf life
6.4 Special precautions for storage
Not applicable.
6.5 Nature and contents of container
Blister strip comprising of PVC/PVdC/Aluminium foil enclosed in an outer carton.
Pack sizes of 28 and 30 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Crescent Pharma Limited
3&4 Quidhampton Business Units
Polhampton Lane
Overton
Hampshire
RG25 3ED
UK
8 MARKETING AUTHORISATION NUMBER(S)
10mg tablet: PL 20416/0301
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
04/08/2010
10
DATE OF REVISION OF THE TEXT
30/09/2016