Citalopram 10mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Citalopram 10mg film-coated tablets.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Citalopram 10mg film-coated tablets Each film-coated tablet contains 12.49 mg citalopram hydrobromide equivalent to 10 mg citalopram.
Excipients: lactose monohydrate
Each tablet Citalopram 10 mg contains 13.334 mg lactose monohydrate.
For a full list of excipients, see section 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 Citalopram should be withdrawn slowly, it is advised that the dose is gradually reduced over 1-2 week periods.
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 (see section 4.4).
Adults:
Citalopram should be administered as a single oral dose of 20 mg daily.
Dependent on individual patient response, the dose may be increased to a maximum of 40 mg daily.
Elderly patients (>65 years of age):
For elderly patients the dose should be decreased to half of the recommended dose, e.g. 10-20 mg daily. The recommended maximum dose for the elderly is 20 mg daily.
Reduced renal function:
Dosage adjustment is not required if the patient has mild to moderate renal impairment. Caution is advised in patients with severe renal impairment (creatinine clearance less than 30mL/min, see section 5.2).
Reduced hepatic function
An initial dose of 10 mg 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 20 mg daily. Caution and extra careful dose titration is advised in patients with severely reduced hepatic function (see section 5.2).
Poor metabolisers regarding CYP2C19
An initial dose of 10 mg daily during the first two weeks of treatment is recommended for patients who are known to be poor metabolisers with respect to CYP2C19. The dose may be increased to a maximum of 20 mg daily depending on individual patient response, (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 (see section 6.1).
• 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).
• MAOI (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)
4.4 Special warnings and precautions for use
Treatment of elderly patients, patients with reduced kidney and liver function and poor CYP2C19 metabolisers, see section 4.2.
Use in children and adolescents under 18 years of age
Antidepressants 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.
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.
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.
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 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.
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.
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 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).
Electroconvulsive Therapy (ECT)
There is little clinical experience of concurrent administration of citalopram and electro-convulsive therapy, 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 (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).
Withdrawal symptoms seen on discontinuation:
Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt (see section 4.8).
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).”
Dose titration
At the beginning of the treatment, insomnia and agitation can occur. A dose titration may be helpful.
Psychosis
Treatment of psychotic patients with depressive episodes may increase psychotic symptoms.
QT interval prolongation
Citalopram has been found to cause a dose-dependent prolongation of the QT-interval. Cases of QT interval prolongation and ventricular arrhythmia including torsade de pointes have been reported during the post-marketing period, predominantly in patients of female gender, with 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.
If signs of cardiac arrhythmia occur during treatment with citalopram, the treatment should be withdrawn and an ECG should be performed.
Renal impairment
The use of citalopram in patients with severe renal impairment (creatinine clearance less than 30 ml/min.) is not recommended as no information is available on use in these patients. (see Section 4.2).
Hepatic impairment
In cases of impaired hepatic function dose reduction is recommended (see Section 4.2) and liver function has to be closely monitored.
Excipients
These tablets contain small amounts of lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
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
QT interval prolongation
Pharmacokinetic and pharmacodynamic studies between citalopram and other medicinal products that prolong the QT interval have not been performed. An additive effect of citalopram and these medicinal products cannot be excluded. Therefore, co-administration of citalopram with medicinal products that prolong the QT interval, such as Class IA and III antiarrhythmics, antipsychotics (e.g. fentiazine 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.
MAO-inhibitors
The simultaneous use of citalopram and MAO-inhibitors can result in severe undesirable 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, 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 (See section 4.3).
Pimozide
Concomitant use of citalopram and pimozide is contra-indicated (see section 4.3).Co administration of a single dose of pimozide 2 mg to subjects treated with racemic citalopram 40 mg/day for 11 days caused an increase in AUC and Cmax of pimozide, although not consistently throughout the study. The co-administration of pimozide and citalopram resulted in a mean increase in the QTc interval of approximately 10 msec. Due to the interaction noted at a low dose of pimozide, concomitant administration of citalopram and pimozide is contraindicated.
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 serotonergic 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
Pharmacodynamic interactions between SSRIs and 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 function of thrombocytes, such as non steroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid, dipyridamol, and ticlopidine or other medicines (e.g. atypical antipsychotics, phenothiazines, tricyclic depressants) that can increase the risk of haemorrhage (see Section 4.4).
ECT (electroconvulsive therapy)
There are no clinical studies establishing the risks or benefits of the combined use of electroconvulsive therapy (ECT) and citalopram (see section Special warnings and precautions for use).
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 rise of malignant arrhythmias (see section 4.4).
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.
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
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). However, there have been reports of enhanced serotonergic effects when SSRIs were administered in combination with lithium or tryptophan. Caution is advised during simultaneous use of citalopram with these active substances. Routine monitoring of lithium levels should be continued as usual.
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.
CYP2C19 inhibitors
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). A reduction in the dose of citalopram may be necessary based on monitoring of undesirable effects during concomitant treatment.
The metabolism of escitalopram is mainly mediated by CYP2C19. CYP3A4 and CYP2D6 may also contribute to the metabolism although to a smaller extent. The metabolism of the major metabolite S-DCT (demethylated escitalopram) seems to be partly catalysed by CYP2D6.
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 induce nor inhibit P-glycoprotein).
In a pharmacokinetic study no effect was demonstrated on either citalopram or imipramine levels, although the level of desipramine, the primary metabolite of imipramine was increased. When desipramine is combined with citalopram, an increase of the desipramine plasma concentration has been observed. A reduction of the desipramine dose may be needed.
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.
Cases of withdrawal symptoms in the newborn child have been described after the use of SSRI at the end of pregnancy. 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
Epidemiological data have suggested that the use of SSRIs in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). The observed risk was approximately 5 cases per 1000 pregnancies. In the general population 1 to 2 cases of PPHN per 1000 pregnancies occur.
Lactation:
Citalopram is excreted into breast milk. It is estimated that the suckling infant will receive about 5% of the weight related maternal daily dose (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. 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.
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 frequent during the first one or two weeks of treatment and usually attenuate subsequently.
For the following reactions a dose-response was discovered: sweating increased, dry mouth, insomnia, somnolence, diarrhoea, nausea and fatigue.
List of adverse reactions
Below is presented 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. The frequencies of adverse events are ranked according to the following: very common (> 1/10), common (> 1/100 to < 1/10),
uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000), very rare (< 1/10,000; including isolated reports), not known (cannot be estimated from the available data).
Infections and infestations Common: Rhinitis
Blood and lymphatic system disorders
Rare: Haemorrhage (for example, gynaecological haemorrhage,
|
Not known: |
gastrointestinal haemorrhage, ecchymosis and other forms of skin haemorrhage or bleeding in the mucous membranes) can occur on rare occasions. Thrombocytopenia |
Immune system disorders
Not known: Hypersensitivity, anaphylactic reaction
Endocrine disorders
Not known: Inappropriate ADH secretion
Metabolism and nutrition disorders
Common: Appetite decreased, weight decreased
|
Uncommon: Rare: Not known: |
Increased appetite, weight increased, anorexia Hyponatraemia Hypokalaemia |
|
Psychiatric disorders Common: |
Agitation, libido decreased, anxiety, nervousness, confusional state, abnormal orgasm (female), abnormal dreams, apathy, |
|
Uncommon: |
Aggression, depersonalization, hallucination, mania, euphoria |
|
Rare: Not known: |
Psychomotor restlessness Panic attack, bruxism, restlessness, suicidal ideation, suicidal behaviour2 |
Nervous system disorders
Very common: Somnolence, insomnia, headache
|
Common: Uncommon: Rare: Not known: |
Tremor, dizziness, paraesthesia, disturbance in attention Syncope Convulsion grand mal, dyskinesia, taste disturbance Convulsions, serotonin syndrome, extrapyramidal disorder, akathisia, movement disorder |
|
Eye disorders Uncommon: Not known: |
Mydriasis Visual disturbance |
Ear and labyrinth disorders
Common: Tinnitus
Cardiac disorders
Very common: Palpitations
Uncommon: Bradycardia, tachycardia
Not known: QT -prolongation, Ventricular arrhythmia including torsade
de pointes1
Vascular disorders
Rare: Haemorrhage
Not known: Orthostatic hypotension
Respiratory, thoracic and mediastinal disorders
Common: Yawning
Uncommon: Coughing
Not known: Epistaxis
Gastrointestinal disorders
Very common: Nausea, dry mouth
Common: Constipation, diarrhoea, dyspepsia, vomiting, abdominal
pain, flatulence, increased salivation
Not known: Gastrointestinal haemorrhage (including rectal haemorrhage)
Hepatobiliary disorders
Rare: Hepatitis
Not known: Liver function test abnormal
Renal and urinary disorders
Common: Micturition disorder
Uncommon: Urinary retention
Reproductive system and breast disorders
Common: Ejaculation failure, ejaculation disorder, impotence
Uncommon: Female: Menorrhagia
Not known: Female: Metrorrhagia Male: Priapism, galactorrhoea
Skin and subcutaneous tissue disorders
Very common: Sweating increased
Common: Pruritus
Uncommon: Urticaria, alopecia, rash, purpura, photosensitivity reaction
Not known: Ecchymosis, angioedemas
Musculoskeletal and connective tissue disorders
Common: Myalgia, arthralgia.
General disorders and administration site conditions
Very common: Asthenia
Common: Fatigue
Uncommon: Oedema, malaise
Rare: Pyrexia
Number of patients: citalopram/placebo = 1346/545
1 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 hypokalemia, or with pre-existing QT prolongation or other cardiac diseases (see sections 4.3, 4.4, 4.5, 4.9 and 5.1).
2 Cases of suicidal ideation and suicidal behaviours have been reported during citalopram therapy or early after treatment discontinuation (see section Special warnings and precautions for use).
Withdrawal symptoms seen on discontinuation of SSRI 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, palpitaions, 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 4.4).
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.
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
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, and atrial and ventricular arrhythmia.
Treatment
There is no known specific antidote to citalopram. Treatment should be symptomatic and supportive. Activated charcoal, osmotically working laxative (such as sodium sulfate) and stomach evacuation should be considered. If consciousness is impaired the patient should be intubated. Vital signs should be monitored. 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.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group:
Antidepressant, Selective serotonin reuptake inhibitors ATC code: N06AB04
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.
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 20 mg/day dose and 16.7 (90%CI 15.0-18.4) msec at the 60 mg day/dose (see sections 4.3, 4.4, 4.5, 4.8 and 4.9).
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.
Citalopram is metabolised primarily by CYP2C19 enzymes (ca.. 60%); and to a lesser extent by CYP3A4 (ca. 30%) and CYP2D6 (ca. 10%) enzymes. Citalopram and demethylcitalopram are weak inhibitors of CYP1A2, CYP2C19 and CYP2D6.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.
Elimination:
The plasma half-life is approximately 1.5 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 undesirable effects.
5.3 Preclinical safety data
Preclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenic potential.
Phospholipidosis has been observed in several organs following multiple administration in rats. The effect was reversible at discontinuation. Accumulation of phospholipids has been observed in long term animal studies with many cation-amphophilic drugs. The clinical relevance of these results is not clear.
Reproduction toxicity studies in rats have demonstrated skeletal anomalies in the offspring, but no increased frequency of malformations. The effects may be related to the pharmacological activity or may be a consequence of maternal toxicity. Peri- and postnatal studies have revealed reduced survival in offspring during the lactation period. The potential risk for humans is unknown.”
Animal data have shown that citalopram induces a reduction of fertility index and pregnancy index, reduction in number in implantation and abnormal sperm at exposure well in excess of human exposure.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Core:
Copovidone
Croscarmellose sodium (E466) Glycerol (E422)
Lactose monohydrate Magnesium stearate (E470b)
Maize starch
Cellulose, microcrystalline(E460i) Coating:
Hypromellose (E464)
Cellulose, microcrystalline (E460i) Macrogol stearate 40 (E431)
Titanium dioxide (E171)
6.2 Incompatibilities
Not applicable
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Do not store above 25°C, store in the original package.
6.5 Nature and contents of container
Packed in PVC/PVDC/Al blisters.
Pack sizes of 10, 14, 20, 28, 30, 50, 56, 98 and 100 tablets per box,
50x1 unit dose blister
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
TEVA UK Limited Brampton Road,
Hampden Park,
Eastbourne,
East Sussex BN22 9AG
8 MARKETING AUTHORISATION NUMBER(S)
PL 00289/0927
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 23/02/2011
10 DATE OF REVISION OF THE TEXT
18/07/2012