Each tablet contains 40mg Citalopram as citalopram hydrobromide.
film-coated tablet ( scored from one side )
4.1 Therapeutic indications
Treatment of depressive illness in the initial phase and as maintenance against potential relapse/recurrence.
Citalofar tablets are also indicated in the treatment of panic disorder with or without agoraphobia.
4.2 Posology and method of administration
Major depressive episodes
Citalofar 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.
The recommended dose is 20 mg 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 40 mg a day in 20 mg steps according to the patient’s response .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.
A single oral dose of 10 mg is recommended for the first week before increasing the dose to 20 mg daily. Dependent on individual patient response, the dose may be increased to a maximum of 40 mg daily.
Patients should be started on 10 mg/day and the dose gradually increased in 10 mg steps according to the patient’s response up to the recommended dose. The recommended dose is 20-30 mg daily. A low initial starting dose is recommended to minimise the potential worsening of panic symptoms, which is generally recognised to occur early in the treatment of this disorder. Although there may be an increased potential for undesirable effects at higher doses, if after some weeks on the recommended dose insufficient response is seen some patients may benefit from having their dose increased gradually up to a maximum of 40 mg/day. 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 of the recommended dose, e.g. 10-20 mg daily. The recommended maximum dose for the elderly is 20 mg daily.
Children and adolescents (< 18 years of age)
Citalofar should not be used in the treatment of children and adolescents under the age of 18 years.
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.
Dosage should be restricted to the lower end of the dose range.
Reduced renal function
Dosage adjustment is not necessary in cases of mild or moderate renal impairment. No information is available in cases of severe renal impairment (creatinine clearance <20 mL / min).
Poor metabolisers of 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.
Withdrawal symptoms seen on discontinuation of Citalofar
Abrupt discontinuation should be avoided. When stopping treatment with Citalofar the dose should be gradually reduced over a period of at least one to two weeks in order to reduce the risk of withdrawal. 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
Citalofar tablets are administered as a single daily dose. Citalofar tablets can be taken at any time of the day without regard to food intake.
Citalofar should no longer be prescribed at doses greater than 40mg /day – 20mg/day is the maximum recommended dose for patients with hepatic impairment who are greater than 60 years of age, eho are CYP 2C19 poor metabolizers, or who are taking concomitant cimetidine, because these drugs factors lead to increased blood levels of citalopram, increasing the risk of QT interval prolongation and torsade de pointes
Hypersensitivity to active substance or to any of the excipients.
Monoamine Oxidase Inhibitors: Some cases presented with features resembling serotonin syndrome.
Citalofar should not be given to patients receiving Monoamine Oxidase Inhibitors (MAOIs) including selegiline in daily doses exceeding 10 mg/day. .
Citalofar 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 Citalofar. Citalofar is contraindicated in the combination with linezolid unless there are facilities for close observation and monitoring of blood pressure.
Citalofar is contraindicated in patients with known QT-interval prolongation or congenital long QT syndrome.
Citalofar is contraindicated together with medicinal products that are known to prolong the QT-interval.
Citalofar should not be used concomitantly withpimozide
Do not use of citalofar with other medicinal products known to prolong the QT interval
Citalofar is contraindicated in patients with congenital long QT syndrome
4.4 Special warnings and precautions for use
Use in children and adolescents under 18 years of age
Citalofar 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.
Caution should be used in the treatment of elderly patients.
Reduced kidney and liver function
Caution should be used in the treatment of patients with reduced kidney and liver function.
Some patients with panic disorder may experience intensified anxiety symptoms at the start of treatment with antidepressants. This paradoxical reaction usually subsides within the first two weeks of starting treatment. A low starting dose is advised to reduce the likelihood of a paradoxical anxiogenic effect.
Hyponatraemia, probably due to inappropriate ant diuretic hormone secretion (SIADH), has been reported as a rare adverse reaction with the use of SSRIs. Especially elderly female patients seem to be at particularly high risk group.
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 Citalofar 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 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 Citalofar should be discontinued.
Seizures: Seizures are a potential risk with antidepressant drugs. The drug should be discontinued in any patient who develops seizures. Citalofar should be avoided in patients with unstable epilepsy and patients with controlled epilepsy should be carefully monitored. Citalofar 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, serotonin syndrome has been reported in patients using SSRIs. A combination of symptoms, possibly including agitation, confusion, tremor, myoclonus and hyperthermia, may indicate the development of this condition. Treatment with Citalofar should be discontinued immediately and symptomatic treatment initiated.
Serotonergic medicines: Citalofar should not be used concomitantly with medicinal products with serotonergic effects such as sumatriptan or other triptans, tramadol, oxitriptan, and tryptophan.
ECT: There is little clinical experience of concurrent administration of Citalofar and ECT, therefore caution is advisable.
Haemorrhage: There have been reports of prolonged bleeding time and/or bleeding abnormalities such as ecchymoses, gynaecologicalhaemorrhages, gastrointestinal bleedings, and other cutaneous or mucous bleedings with SSRIs. 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.
Reversible, selective MAO-A inhibitors: The combination of Citalofar with MAO-A inhibitors is generally not recommended due to the risk of onset of a serotonin syndrome.
For information on concomitant treatment with non-selective, irreversible MAO-inhibitors see.
St. John’s Wort: Undesirable effects may be more common during concomitant use of Citalofar and herbal preparations containing St John’s wort (Hypericumperforatum). Therefore Citalofar and St John’s wort preparations should not be taken concomitantly.
Glaucoma: As with other SSRIs, Citalofar can cause mydriasis and should be used with caution in patients with narrow angle glaucoma or history of glaucoma.
Withdrawal symptoms seen on discontinuation of SSRI treatment: Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt. In a recurrence prevention clinical trial with Citalofar, adverse events after discontinuation of active treatment were seen in 40% patients versus 20% in patients continuing Citalofar.
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 and headache 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 Citalofar should be gradually tapered when discontinuing treatment over a period of several weeks or months, according to the patient’s
Psychosis: Treatment of psychotic patients with depressive episodes may increase psychotic symptoms.
QT prolongation: Citalofar 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.
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 Citalofar 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 Citalofar, the treatment should be withdrawn and an ECG should be performed.
ECG monitoring may be advisable in case of overdose or conditions of altered metabolism with increased peak levels, e.g. liver impairment.
Patients with congestive heart failure,bradyarrhythmias, myocardial infarction or- predisposition to hypokalemia or hypomagnesaemia because of concomitant illness or drugs are at higher risk of developing torsade de pointes.
(ECG) health care professionals should consider more frequent electrocardiogram monitoring in patients with congestive heart failure, bradyarrhythmias. Hypokalemia and hypomagnesaemia should be corrected before administering citalofar . electrolytes should be monitored as clinically indicated
Patients should contact a healthcare professional immediately if they experience signs and symptoms of an abnormal heart rate or rhythm while taking citalofar .Patients should be advised not to stop taking citalofar or change or reduce the dose without first consulting their healthcare professional, as withdrawal symptoms may occur when citalofartreatment is discontinued,particulary if this is abrupt.
• Excepients: the tablets contain lactose monohydrate, patients with rare hereditary problems of galactose intolerance, the Lappdeficiency of glucose , galactosemalabsorption should not receive the medicine
4.5 Interaction with other medicinal products and other forms of interaction
At the pharmacodynamic level cases of serotonin syndrome with Citalofar and moclobemide and buspirone have been reported.
QT interval prolongation
Pharmacokinetic and pharmacodynamic studies between Citalofar and other medicinal products that prolong the QT interval have not been performed. An additive effect of Citalofar and these medicinal products cannot be excluded. Therefore, co-administration of Citalofar 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.
Monoamine Oxidase Inhibitors (MAOIs):
The simultaneous use of Citalofar and MAO-inhibitors can result in severe undesirable effects, including the serotonin syndrome.
Cases of serious and sometimes fatal reactions have been reported in patients receiving an SSRI in combination with a monoamine oxidase inhibitor (MAOI), including the irreversible MAOI selegiline and the reversible MAOIs linezolid and moclobemide and in patients who have recently discontinued and 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.
Co-administration of a single dose of pimozide 2 mg to subjects treated with racemic Citalofar 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 Citalofar 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 Citalofar and pimozide is contraindicated.
Combinations requiring precaution for use
Selegiline (selective MAO-B inhibitor)
A pharmacokinetic / pharmacodynamic interaction study with concomitantly administered Citalofar (20 mg daily) and selegiline (10 mg daily) (a selective MAO-B inhibitor) demonstrated no clinically relevant interactions. The concomitant use of Citalofar 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 Citalofar has been given concomitantly with lithium. However there are have been reports of enhanced effects when SSRIs have been given with lithium or tryptophan and therefore the concomitant use of Citalofar with these drugs should be undertaken with caution. Routine monitoring of lithium levels need not be adjusted.
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 Citalofar and 5-HT agonists, such as sumatriptan and other triptans, is not recommended (see section 4.4).
St John’s wort
Dynamic interactions between Citalofar and herbal remedy St John’s wort (Hypericumperforatum) can occur, resulting in an increase in undesirable effects. occur, resulting in an increase in undesirable effects. Pharmacokinetic interactions have not been investigated.
Caution is warranted for patients who are being treated simultaneously with anticoagulants, medicinal products that affect the platelet function, such as non steroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid, dipyridamol, and ticlopidine or other medicines (e.g. atypical antipsychotics, phenothiazines, tricyclic depressants) that can increase the risk of haermorrhage.
ECT (electroconvusive therapy)
There are no clinical studies establishing the risks or benefits of the combined use of electroconvulsive therapy (ECT) and Citalofar.
No pharmacodynamic or pharmacokinetic interactions have been demonstrated between Citalofar and alcohol. However, the combination of Citalofar and alcohol is not advisable.
Medicinal products inducing QT prolongation or hypokalaemia/hypomagnesaemia
Caution is warranted for concomitant use of other QT interval prolonging medicines or hypokalaemia/hypomagnesaemia inducing drugs as they, like Citalofar, potentially prolong the QT interval.
Medicinal products lowering the seizure threshold
SSRIs can lower the seizure threshold. Caution is advised when concomitantly using other medicinal products capable of lowering the seizure threshold (e.g. antidepressants [tricyclics, SSRIs], neuroleptics [phenothiazines, thioxanthenes, and butyrophenones]), mefloquin, bupropion and tramadol).
In a pharmacokinetic study no effect was demonstrated on either Citalofar or imipramine levels,although the level of desipramine, the primary metabolite of imipramine was increased. When desipramine is combined with Citalofar, an increase of the desipramine plasma concentration has been observed. A reduction of the desipramine dose may be needed.
Experience with Citalofar has not revealed any clinically relevant interactions with neuroleptics. However, as with other SSRIs, the possibility of a pharmacodynamic interaction cannot be excluded.
No pharmacodynamic interactions have been noted in clinical studies in which Citalofar has been given concomitantly with benzodiazepines, neuroleptics, analgesics, lithium, alcohol, antihistamines, antihypertensive drugs, beta-blockers and other cardiovascular drugs.
Biotransformation of Citalopram to demethyl Citalopram 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.
The absorption and other pharmacokinetic properties of Citalopram have not been reported to be affected by food.
Influence of other medicinal products on the pharmacokinetics of Citalopram
Co-administration with ketoconazole (potent CYP3A4 inhibitor) did not change the pharmacokinetics of Citalopram.
A pharmacokinetic interaction study of lithium and Citalopram did not reveal any pharmacokinetic interactions.
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 30 mg once daily (a CYP2C19 inhibitor) resulted in moderate (approximately 50%) increase in the plasma concentrations of escitalopram. Thus, caution should be exercised when used concomitantly with CYP2C19 inhibitors (e.g. omeprazole, esomeprazole, fluvoxamine, lansoprazole, ticlopidine) or cimetidine. A reduction in the dose of Citalopram may be necessary based on monitoring of undesirable effects during concomitant treatment.
Escitalopram (the active enantiomer of Citalopram) is an inhibitor of the enzyme CYP2D6. Caution is recommended when Citalopram is co-administered with medicinal products that are mainly metabolised by this enzyme, and that have a narrow therapeutic index, e.g. flecainide, propafenone and metoprolol (when used in cardiac failure), or some CNS acting medicinal products that are mainly metabolised by CYP2D6, e.g. antidepressants such as desipramine, clomipramine and nortriptyline or antipsychotics like risperidone, thioridazine and haloperidol. Dosage adjustment may be warranted. Co-administration with metoprolol resulted in a twofold increase in the plasma levels of metoprolol, but did not statistically significant increase the effect of metoprolol on the blood pressure and cardiac rhythm.
Effects of Citalofar 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 demethyl Citalopram 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 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).
4.6 Fertility, pregnancy and lactation
A large amount of data on pregnant women (more than 2500 exposed outcomes) indicate no malformativefeto/ neonatal toxicity. Citalofar can be used during pregnancy if clinically needed, taking into account the aspects mentioned below.
Neonates should be observed if maternal use of Citalofar 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, 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.
Citalofar is excreted into breast milk. It is estimated that the suckling infant will receive about 5% of the weight related maternal daily dose (in mg/kg). No or only minor events have been observed in the infants. However, the existing information is insufficient for assessment of the risk to the child.
Caution is recommended. If treatment with Citalofar is considered necessary, discontinuation of breast feeding should be considered
Animal data have shown that Citalofar may affect sperm quality. 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.of the page
4.7 Effects on ability to drive and use machines
Citalofar has minor or moderate influence on the ability to drive or operate machines. Psychoactive medicinal products can reduce the ability to make judgments 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 Citalofar 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 Citalofar see 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, < 1/10); uncommon (≥1/1000, ≤1/100); rare (≥1/10000, ≤1/1000), very rare (≤ 1/10000), not known (can not be estimated from available data).
|MedDRA SOC||Frequency||Preferred term|
|Blood and lymphatic disorders||Not known||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||Increased appetite, weight increased|
|Psychiatric disorders||Common||Agitation, libido decreased, anxiety, nervousness, confusional state, abnormal orgasm (female), abnormal dreams|
|Uncommon||Aggression, depersonalisation, hallucination, mania|
|Not known||Panic attack, bruxism, restlessness, suicidal ideation, suicidal behaviour²|
|Nervous system disorders||Very common||Somnolence, insomnia|
|Common||Tremor, paraesthesia, dizziness, disturbance in attention|
|Rare||Convulsion grand mal, dyskinesia, taste disturbance|
|Not known||Convulsions, serotonin syndrome, extrapyramidal disorder, akathisia, movement disorder|
|Eye disorder||Uncommon||Mydriasis (which may lead to acutenarrow angle glaucoma, see section 4.4 Special warnings and precautions for use)|
|Not known||Visual disturbance|
|Ear and labyrinth disorders||Common||Tinnitus|
|Cardiac disorders||Uncommon||Bradycardia, tachycardia
|Not known||Ventricular arrhythmia including torsade de pointes|
|Not known||Orthostatic hypotension|
|Respiratory thoracic and mediastinal disorders||Common||Yawning|
|Gastrointestinal disorders||Very common||Dry mouth, Nausea|
|Common||Diarrhoea, vomiting, constipation|
|Not known||Gastrointestinal haemorrhage (including rectal haemorrhage)|
|Not known||Liver function test abnormal|
|Skin and subcutaneous tissue disorders||Very common||Sweating increased|
|Uncommon||Urticaria, alopecia, rash, Purpura, photosensitivity reaction|
|Not known||Ecchymosis, angioedemas|
|Musculoskeletal, connective tissue and bone disorders||Common||Myalgia, arthralgia|
|Renal and urinary disorders||Uncommon||Urinary retention|
|Reproductive system and breast disorders||Common||Impotence, ejaculation disorder, ejaculation failure|
|Not known||Female: Metrorrhagia Male: Priapism, Galactorrhoea|
|General disorders and administration site conditions||Common||Fatigue|
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.
2 Cases of suicidal ideation and suicidal behaviours have been reported during Citalofar therapy or early after treatment discontinuation.
The following adverse events have also been reported in clinical trials:
Very common: Headache, asthenia, sleep disorder.
Common: Migraine, palpitation, taste perversion, impaired concentration, amnesia, anorexia, apathy, dyspepsia, abdominal pain, flatulence, increased salivations, rhinitis.
Rare: Increased libido, coughing, and malaise.
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 Citalofar (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 Citalofar treatment is no longer required, gradual discontinuation by dose tapering should be carried out.
Comprehensive clinical data on Citalofar overdose are limited and many cases involve concomitant overdoses of other drugs/alcohol. Fatal cases of Citalofar overdose have been reported with Citalofar alone; however, the majority of fatal cases have involved overdose with concomitant medications.
Fatal dose is not known. Patients have survived ingestion of more than 2 g Citalofar.
The effects may be potentiated by alcohol taken at the same time.
Potential interaction with TCAs, MAOIs and other SSRIs.
Symptoms of overdose
The following symptoms have been seen in reported overdose of Citalofar: 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.
ECG changes including nodal rhythm, prolonged QT intervals and wide QRS complexes may occur. Fatalities have been reported. 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.
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.
There is no known specific antidote to Citalofar.
Treatment should be symptomatic and supportive and include the maintenance of a clear airway and monitoring of ECG and vital signs until stable.
Consider oral activated charcoal in adults and children who have ingested more than 5 mg/kg body weight within 1 hour. Activated charcoal given ½ hour after ingestion of Citalofar 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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic Group : Selective Serotonergic Reuptake Inhibitors
Biochemical and behavioural studies have shown that Citalofar 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 Citalofar.
Citalofar 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, Citalofar has no or very low affinity for a series of receptors including 5-HT 1A, 5-HT2, DA D1 and D2 receptors, α1-, α2-, β-adrenoceptors, histamine H1, muscarine, cholinergic, benzodiazepine, and opioid receptors. A series of functional in vitro tests in isolated organs as well as functional in vivo tests have confirmed the lack of receptor affinity. This absence of effects on receptors could explain why Citalofar produces fewer of the traditional side effects such as dry mouth, bladder and gut disturbance, blurred vision, sedation, cardiotoxicity and orthostatic hypotension.
Suppression of rapid eye movement (REM) sleep is considered a predictor of antidepressant activity. Like tricyclic antidepressants, other SSRIs and MAO inhibitors, Citalofar suppresses REM-sleep and increases deep slow-wave sleep.
Although Citalofar does not bind to opioid receptors it potentiates the anti-nociceptive effect of commonly used opioid analgesics. There was potentiation of d-amphetamine-induced hyperactivity following administration of Citalofar.
The main metabolites of Citalofar are all SSRIs although their potency and selectivity ratios are lower than those of Citalofar. 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.
In humans Citalofar does not impair cognitive (intellectual function) and psychomotor performance and has no or minimal sedative properties, either alone or in combination with alcohol.
Citalofar did not reduce saliva flow in a single dose study in human volunteers and in none of the studies in healthy volunteers did Citalofar have significant influence on cardiovascular parameters. Citalofar 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 20 mg/day dose and 16.7 (90%CI 15.0-18.4) msec at the 60 mg day/dose 5.
In the fixed dose studies there is a flat dose response curve, providing no suggestion of advantage in terms of efficacy for using higher than the recommended doses. However, it is clinical experience that up-titrating the dose might be beneficial for some patients.
5.2 Pharmacokinetic properties
Absorption of Citalopram is almost complete and independent of food intake (Tmax average/mean 3.8 hours). Oral bioavailability is about 80%.
The apparent volume of distribution (Vdβ) is about 12.3 L/kg. The plasma protein binding is below 80% for Citalopram and its main metabolites.
Citalopram is metabolized to the active demethyl Citalopram, didemethyl Citalopram, Citalopram-N-oxide and an inactive deaminated proprionic acid derivative. All the active metabolites are also SSRIs, although weaker than the parent compound. Unchanged Citalopram is the predominant compound in plasma.
The elimination half-life (T½β) 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).
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