Citalopram 40mg/Ml Oral Drops Solution

Document: spc-doc_PL 00427-0141 change

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Citalopram 40 mg/ml Oral Drops, Solution

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml contains:

Citalopram hydrochloride, corresponding to 40 mg citalopram.

1 drop = 2 mg citalopram; 1 ml = 20 drops = 40 mg citalopram Ethanol = 76mg/ml

Methyl Parahydroxybenzoate = 1mg/ml Propyl Parahydroxybenzoate = 0.1mg/ml

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Oral drops, solution.

Colourless or slightly yellow liquid.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of depressive illness in the initial phase and as maintenance against potential relapse/recurrence.

Citalopram is also indicated in the treatment of panic disorder with or without agoraphobia.

4.2 Posology and method of administration

For oral administration after mixing with water

MAJOR DEPRESSIVE EPISODES Adults:

Citalopram should be administered as a single oral dose of 16 mg (8 drops) daily. Dependent on individual patient response, the dose may be increased to a maximum of 32 mg (16 drops) daily.

In general, improvement in patients starts after one week but may only become evident from the second week of therapy.

As with all antidepressant medicinal products, dosage should be reviewed and adjusted if necessary within 3 to 4 weeks of initiation of therapy and thereafter as judged clinically appropriate. Although there may be an increased potential for undesirable effects at higher doses, if after some weeks on the recommended dose insufficient response is seen, some patients may benefit from having their dose increased up to a maximum of 32mg (16 drops) a day in 16mg (8 drops) steps according to the patient’s response (see section 5.1). Dosage adjustments should be made carefully on an individual patient basis, to maintain the patient at the lowest effective dose.

Patients with depression should be treated for a sufficient period of at least 6 months to ensure that they are free from symptoms.

PANIC DISORDER Adults:

A single oral dose of 8 mg (4 drops) is recommended for the first week before increasing the dose to 16 mg (8 drops) daily. Dependent on individual patient response, the dose may be increased to a maximum of 32 mg (16 drops) daily. A low initial starting dose is recommended to minimise the potential worsening of panic symptoms, which is generally recognised to occur early in the treatment of this disorder. Although there may be an increased potential for undesirable effects at higher doses, if after some weeks on the recommended dose insufficient response is seen some patients may benefit from having their dose increased gradually up to a maximum of 32mg (16 drops)/day (see section 5.1). Dosage adjustments should be made carefully on an individual patient basis, to maintain the patients at the lowest effective dose.

Patients with panic disorder should be treated for a sufficient period to ensure that they are free from symptoms. This period may be several months or even longer.

Elderly Patients (>65 years of age)

For elderly patients the dose should be decreased to half of the recommended dose, e.g. 8 mg (4 drops) to 16 mg (8 drops) daily. The recommended maximum dose for the elderly is 16 mg (8 drops) daily.

Children & Adolescents (<18 years)

Citalopram should not be used in the treatment of children and adolescents under the age of 18 years, (see section 4.4).

Reduced hepatic function

An initial dose of 8 mg (4 drops) 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 16 mg (8 drops) 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 <20mL/min)

Poor metabolisers of CYP2C19

An initial dose of 8 mg (4 drops) 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 16 mg (8 drops) 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 the dose should be gradually reduced over a period of at least one to two weeks in order to reduce the risk of withdrawal reactions (see section

4.4 Special Warnings and Precautions for use and section 4.8 Undesirable Effects). If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously described dose may be considered. Subsequently, the physician may continue decreasing the dose, but at a more gradual rate.

Method of Administration

Citalopram Oral Drops, Solution can be taken as a single daily dose, at any time of day, without regard to food intake.

Citalopram Oral Drops, Solution have approximately 25% higher bioavailability compared to tablets. Consequently doses of tablets correspond to doses of drops as follows:

Tablets/dose Equivalent	Solution
10mg	8mg (4 drops)
20mg	16mg (8 drops)
30mg	24mg (12 drops)
40mg	32mg (16 drops)

4.3 Contraindications

Hypersensitivity to citalopram or any of the excipients (see section 6.1).

MAOIs (monoamine oxidase inhibitors)

Some cases presented with features resembling serotonin syndrome.

Citalopram should not be given to patients receiving Monoamine Oxidase Inhibitors (MAOIs) including selegiline in daily doses exceeding 10 mg/day.

Citalopram should not be given for fourteen days after discontinuation of an irreversible MAOI or for the time specified after discontinuation of a reversible MAOI (RIMA) as stated in the prescribing text of the RIMA. MAOIs should not be introduced for seven days after discontinuation of citalopram (see section 4.5).

Citalopram is contraindicated in the combination with linezolid unless there are facilities for close observation and monitoring of blood pressure (see section 4.5).

Citalopram should no be used concomitantly with pimozide (see also section 4.5).

Sumatriptan’s serotonergic effects are suspected to be enhanced by SSRI’s. Until further evidence is available it is advised not to use citalopram simultaneously with 5-HT agonists e.g. sumatriptan.

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

Suicide/suicidal thoughts - Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.

Other psychiatric conditions for which citalopram is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive disorder .The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.

Patients with a history of suicide-related events, those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with anti depressants compared to placebo in patients less than 25 years old.

Close supervision of patients and in particular those at high risk should accompany drug therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for the emergence of such events and to seek medical advice immediately if these symptoms present.

Use in children and adolescents under 18 years of age

Citalopram should not be used in the treatment of children and adolescents under the age of 18 years. Suicide-related behaviours (suicide attempt and suicidal thoughts), and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo. If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms. In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking.

Elderly patients

Caution should be used in the treatment of elderly patients (see section 4.2).

Reduced kidney and liver function

Caution should be used in the treatment of patients with reduced kidney and liver function (see section 4.2).

Paradoxical anxiety

Some patients with panic disorder may experience intensified anxiety symptoms at the start of treatment with antidepressants. This paradoxical reaction usually subsides within the first two weeks of starting treatment. A low starting dose is advised to reduce the likelihood of a paradoxical anxiogenic effect (see section 4.2).

Hyponatraemia

Hyponatraemia, probably due to inappropriate antidiuretic hormone secretion (SIADH), has been reported as a rare adverse reaction with the use of SSRIs and generally reverse on discontinuation of therapy. Elderly female patients seem to be at particularly high risk.

Akathisia/psychomotor restlessness

The use of SSRIs/SNRIs has been associated with the development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.

Mania

In patients with manic-depressive illness a change towards the manic phase may occur. Should the patient enter a manic phase citalopram should be discontinued.

Seizures

Seizures are a potential risk with antidepressant drugs. Citalopram should be discontinued in any patient who develops seizures. Citalopram should be avoided in patients with unstable epilepsy and patients with controlled epilepsy should be carefully monitored. Citalopram should be discontinued if there is an increase in seizure frequency.

Diabetes

In patients with diabetes, treatment with an SSRI may alter glycaemic control. Insulin and/or oral hypoglycaemic dosage may need to be adjusted.

Glaucoma

As with other SSRIs, citalopram can cause mydriasis and should be used with caution in patients with narrow angle glaucoma or history of glaucoma.

Serotonin syndrome

In rare cases, serotonin syndrome has been reported in patients using SSRIs. A combination of symptoms such as agitation, tremor, myoclonus, and hyperthermia may indicate the development of this condition. Treatment with citalopram should be discontinued immediately and symptomatic treatment initiated.

Serotonergic medicines

Citalopram should not be used concomitantly with medicinal products with serotonergic effects such as sumatriptan or other triptans, tramadol, oxitriptan, and tryptophan.

Haemorrhage

There have been reports of prolonged bleeding time and/or bleeding abnormalities such as ecchymoses, gynaecological haemorrhages, gastrointestinal bleedings, and other cutaneous or mucous bleedings with SSRIs (see section 4.8). Caution is advised in patients taking SSRIs, particularly with concomitant use of active substances known to affect platelet function or other active substances that can increase the risk of haemorrhage, as well as in patients with a history of bleeding disorders (see section 4.5).

ECT (electroconvulsive therapy)

There is limited clinical experience of concurrent administration of SSRIs and ECT; therefore caution is advisable.

Reversible, selective MAO-A inhibitors

The combination of citalopram with MAO-A inhibitors is generally not recommended due to the risk of onset of a serotonin syndrome (see section 4.5).

For information on concomitant treatment with non-selective, irreversible MAO-inhibitors see section 4.5.

St. John's Wort

Undesirable effects may be more common during concomitant use of citalopram and herbal preparations containing St John’s wort (Hypericum perforatum). Therefore citalopram and St John’s wort preparations should not be taken concomitantly (see section 4.5).

Withdrawal symptoms seen on discontinuation of SSRI treatment Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt (see section 4.8). In a recurrence prevention clinical trial with citalopram, adverse events after discontinuation of active treatment were seen in 40% of patients versus 20% in patients continuing citalopram.

The risk of withdrawal symptoms may be dependent on several factors including the duration and dose of therapy and the rate of dose reduction. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor, confusion, sweating, headache, diarrhoea, palpitations, emotional instability, irritability, and visual disturbances are the most commonly reported reactions. Generally these symptoms are mild to moderate, however, in some patients they may be severe in intensity.

They usually occur within the first few days of discontinuing treatment, but there have been very rare reports of such symptoms in patients who have inadvertently missed a dose.

Generally these symptoms are self-limiting and usually resolve within 2 weeks, though in some individuals they may be prolonged (2-3 months or more). It is therefore advised that citalopram should be gradually tapered when discontinuing treatment over a period of several weeks or months, according to the patient’s needs (see “Withdrawal Symptoms Seen on Discontinuation of SSRI, Section 4.2).

Psychosis

Treatment of psychotic patients with depressive episodes may increase psychotic symptoms.

QT 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.

Warnings on excipients:

This medicinal product contains small amounts of ethanol (alcohol), less than 100 mg per ml.

This medicinal product also contains propyl parahydroxybenzoate (E216) and methyl parahydroxybenzoate (E218), which may cause allergic reactions (possibly delayed).

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions

At the pharmacodynamic level cases of serotonin syndrome with citalopram and moclobemide and buspirone have been reported.

Contraindicated combinations MAO-inhibitors

The simultaneous use of citalopram and MAO-inhibitors can result in severe undesirable effects, including serotonin syndrome (see section 4.3).

Cases of serious and sometimes fatal reactions have been reported in patients receiving an SSRI in combination with a monoamine oxidase inhibitor (MAOI), including the irreversible MAOI selegiline and the reversible MAOIs linezolid and moclobemide and in patients who have recently discontinued an SSRI and have been started on a MAOI.

Some cases presented with features resembling serotonin syndrome.

Symptoms of an active substance interaction with a MAOI include: agitation, tremor, myoclonus, and hyperthermia.

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.

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 10msec. Due to the interaction noted at low dose of pimozide, concomitant administration of citalopram and pimozide is contraindicated.

Combinations requiring_precaution _ for use Selegiline (selective MAO-B inhibitor)

A pharmacokinetic / pharmacodynamic interaction study with concomitantly administered citalopram (20 mg daily) and selegiline (10 mg daily) (a selective MAO B inhibitor) demonstrated no clinically relevant interactions. The concomitant use of citalopram and selegiline (in doses above 10 mg daily) is not recommended.

Serotonergic medicinal products

Lithium and tryptophan

No pharmacodynamic interactions have been found in clinical studies in which citalopram has been given concomitantly with lithium. However there have been reports of enhanced effects when SSRIs have been given with lithium or tryptophan and therefore the concomitant use of citalopram with these medicinal products should be undertaken with caution. Routine monitoring of lithium levels should be continued as usual.

Co-administration with serotonergic drugs (e.g. tramadol, sumatriptan) may lead to enhancement of 5-HT associated effects.

Until further information is available, the simultaneous use of citalopram and 5-HT agonists, such as sumatriptan and other triptans, is not recommended (see section 4.4).

St. John's wort

Undesirable effects may be more common during concomitant use of serotonin-reuptake inhibitors and herbal preparations containing St John’s Wort (hypericum perforatum). Pharmacokinetic interactions have not been investigated.

Haemorrhage

Caution is warranted for patients who are being treated simultaneously with anticoagulants, medicinal products that affect the platelet function, such as non steroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid, dipyridamole, and ticlopidine or other medicines (e.g. atypical antipsychotics, phenothiazines, tricyclic antidepressants) that can increase the risk of haemorrhage (see section 4.4).

ECT (electroconvusive therapy)

There are no clinical studies establishing the risks or benefits of the combined use of electroconvulsive therapy (ECT) and citalopram (see section 4.4).

Alcohol

No pharmacodynamic or pharmacokinetic interactions have been demonstrated between citalopram and alcohol. However, the combination of citalopram and alcohol is not advisable.

Medicinal products inducing QT prolongation or hypokalaemia/ hypomagnesaemia

Caution is warranted for concomitant use of other QT interval prolonging medicines or hypokalaemia- / hypomagnesaemia-inducing drugs as they, like citalopram, potentially prolong the QT interval.

Medicinal products lowering the seizure threshold

SSRIs can lower the seizure threshold. Caution is advised when concomitantly using other medicinal products capable of lowering the seizure threshold (e.g. antidepressants [tricyclics, SSRIs], neuroleptics [phenothiazines, thioxanthenes and butyrophenones]), mefloquine, bupropion and tramadol).

Desipramine, imipramine

In a pharmacokinetic study no effect was demonstrated on either citalopram or imipramine levels, although the level of desipramine, the primary metabolite of imipramine, was increased._When desipramine is combined with citalopram, an increase of the desipramine plasma concentration has been observed. A reduction of the desipramine dose may be needed.

Neuroleptics

Experience with citalopram has not revealed any clinically relevant interactions with neuroleptics, However, as with other SSRIs, the possibility of a pharmacodynamic interaction cannot be excluded.

Pharmacokinetic interactions

Biotransformation of citalopram to demethylcitalopram is mediated by CYP2C19 (approx. 38%), CYP3A4 (approx. 31%) and CYP2D6 (approx. 31%) isozymes of the cytochrome P450 system. The fact that citalopram is metabolised by more than one CYP means that inhibition of its biotransformation is less likely as inhibition of one enzyme may be compensated by another. Therefore co-administration of citalopram with other medicinal products in clinical practice has very low likelihood of producing pharmacokinetic medicinal product interactions.

Food

The absorption and other pharmacokinetic properties of citalopram have not been reported to be affected by food.

Influence of other medicinal products on the pharmacokinetics of citalopram

Co-administration with ketoconazole (potent CYP3A4 inhibitor) did not change the pharmacokinetics of citalopram.

A pharmacokinetic interaction study of lithium and citalopram did not reveal any pharmacokinetic interactions (see also above).

Cimetidine

Cimetidine (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.

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.

Effects of citalopram on other medicinal products

A pharmacokinetic/pharmacodynamic interaction study in healthy volunteers with concomitant administration of citalopram and metoprolol (a CYP2D6 substrate) showed a twofold increase in metoprolol concentrations, but no statistically significant increase in the effect of metoprolol on blood pressure and heart rate.

Citalopram and demethylcitalopram are negligible inhibitors of CYP2C9, CYP2E1 and CYP3A4, and only weak inhibitors of CYP1A2, CYP2C19 and CYP2D6 as compared to other SSRIs established as significant inhibitors.

Levomepromazine, digoxin, carbamazepine

Thus no change or only very small changes of no clinical importance were observed when citalopram was given with CYP1A2 substrates (clozapine and theophylline), CYP2C9 (warfarin), CYP2C19 (imipramine and mephenytoin), CYP2D6 (sparteine, imipramine, amitriptyline, risperidone) and CYP3A4 (warfarin, carbamazepine (and its metabolite carbamazepine epoxid) and triazolam).

No pharmacokinetic interaction was observed between citalopram and levomepromazine, or digoxin, (indicating that citalopram neither induces nor inhibits P-glycoprotein)

No pharmacodynamic interactions have been noted in clinical studies in which citalopram has been given concomitantly with benzodiazepines, neuroleptics, analgesics, lithium, alcohol, antihistamines, antihypertensive drugs, beta-blockers and other cardiovascular drugs.

4.6 Fertility, pregnancy and lactation

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.

Pregnancy

A large amount of data on pregnant women (more than 2500 exposed outcomes) indicate no malformative feto/ neonatal toxicity. Citalopram can be used during pregnancy if clinically needed, taking into account the aspects mentioned below.

Neonates should be observed if maternal use of Citalopram Oral Solution continues into the later stages of pregnancy, particularly in the third trimester. Abrupt discontinuation should be avoided in pregnancy.

The following symptoms may occur in the neonates after maternal SSRI/SNRI use in later stages of pregnancy: respiratory distress, cyanosis, apnoea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycaemia, hypertonia, hypotonia, hyperreflexia, tremor, jitteriness, irritability, lethargy, constant crying, somnolence and difficulty sleeping. These symptoms could be due to either serotonergic effects or discontinuation symptoms. In a majority of instances the complications begin immediately or soon (<24 hours) after delivery.

Epidemiological data have suggested that the use of SSRIs in pregnancy, particular in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). The observed risk was approximately 5 cases per 1000 pregnancies. In the general population 1 to 2 cases of PPHN per 1000 pregnancies occur.

Lactation

Citalopram is excreted into breast milk. It is estimated that the suckling infant will receive about 5% of the weight related maternal daily dose (in mg/kg). No or only minor events have been observed in the infants. However, the existing information is insufficient for assessment of the risk to the child.

Caution is recommended. If treatment with Citalopram is considered necessary, discontinuation of breast feeding should be considered.

4.7 Effects on ability to drive and use machines

Citalopram has minor or moderate influence on the ability to drive and use machines.

Patients who are prescribed psychotropic medication may be expected to have some impairment of general attention and concentration due to illness itself and psychoactive medicinal products can reduce the ability to make judgements and to react to emergencies. Patients should be informed of these effects and be warned that their ability to drive a car or operate machinery could be affected.

4.8 Undesirable effects

Adverse effects observed with citalopram are in general mild and transient. They are most prominent during the first one or two weeks of treatment and usually attenuate as the depressive state improves. The adverse reactions are presented at the MedDRA Preferred Term Level.

For the following reactions a dose-response was discovered: Sweating increased, dry mouth, insomnia, somnolence, diarrhoea, nausea and fatigue. The table shows the percentage of adverse drug reactions associated with SSRIs and/or citalopram seen in either 1% of patients in double-blind placebo-controlled trials or in the postmarketing period. Frequencies are defined as: very common (>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).

Frequency	Very common	Common	Uncommon	Rare	Not Known
Frequency	>1/10	>1/100 to <1/10	>1/1,000 to <1/100	>1/10,000 to <1/1,000
Blood and lymphatic disorders					Thromboc ytopenia
Immune system					Hypersensi tivity,

disorders					anaphylact ic reaction
Endocrine disorders					Inappropri ate ADH secretion
Metabolism and nutrition disorders		Appetite decreased, weight decreased, anorexia¹	Increased appetite, weight increased	Hyponatrem ia	Hypokalae mia
Psychiatric disorders	Sleep disorder¹	Agitation, nervousness, libido decreased, anxiety, confusional state, abnormal dreams, abnormal orgasm (female) apathy¹, impaired concentration¹, amnesia¹	Aggression, depersonalisat ion, hallucination, mania	Euphoria, increased libido¹	Panic attack, bruxism, restlessnes s, suicidal ideation and suicidal behavior³
Nervous system disorders	Somnolen ce insomnia, headache¹	Tremor, dizziness, migraine¹, paraesthesia, disturbance in attention	Syncope	Convulsion grand mal, dyskinesia, taste disturbance	Convulsio ns, serotonin syndrome, extrapyram idal disorder, akathisia, movement disorder
Eye disorders		Abnormal accommodatio n	Abnormal vision, mydriasis (which may lead to acute narrow angle glaucoma) see section 4.4 Special warnings and precautions for use		Visual disturbanc e

Ear and labyrinth disorders		Tinnitus
Cardiac Disorders		Palpitation¹	Postural hypotension, tachycardia, bradycardia		QT - prolongatio n, Ventriculara rrhythmia including torsade de pointes²
Vascular disorders				Haemorrhag e	Orthostatic hypotensio n
Respiratory, thoracic and mediastinal disorders		Yawning, Rhinitis¹		Coughing¹	Epistaxis
Gastro-intestinal disorders	Nausea, dry mouth	Constipation, diarrhoea, vomiting, taste perversion¹ abdominal pain¹, flatulence¹, increased saliva¹, dyspepsia¹			Gastrointes tinal haemorrha ge (including rectal haemorrha g^e)
Hepato-biliary disorders				Hepatitis	Liver function test abnormal
Skin and subcutaneous disorders	Sweating Increased	Pruritus	Urticaria alopecia, rash, purpura, Photosensitivi ty		Ecchymosi s, angioedem as
Musculoskeletal, connective tissue and bone disorders		Myalgia, arthralgia
Renal and urinary disorders			Urinary retention, micturition disorder, polyuria

Reproductive system and breast disorders

Impotence

ejaculation

disorder,

ejaculation

failure

Female:

Menorrhagia

Female:

Metrorrhag

ia, Male:

Priapism,

galactorrho

General

Disorders

Asthenia¹

Fatigue

Oedema

Pyrexia

Malaise¹

Number of patients: Citalopram/ placebo = 1346/ 545

'The following adverse events have also been reported in clinical trials.

² 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).

³Suicidal thoughts/behaviour (frequency unknown): Cases of suicidal ideation and suicidal behaviours have been reported during citalopram therapy or early after treatment discontinuation (see section 4.4 Special warnings and Special Precautions for Use)

Withdrawal symptoms seen on discontinuation of citalopram treatment

Discontinuation of citalopram (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia and electric shock sensations), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor, confusion, sweating, headache, diarrhoea, palpitations, emotional instability, irritability and visual disturbances are the most commonly reported reactions. Generally these events are mild to moderate and are self-limiting, however, in some patients they may be severe and/or prolonged. It is therefore advised that when citalopram treatment is no longer required, gradual discontinuation by dose tapering should be carried out (see section

4.2 Posology and method of administration and section 4.4 Special warnings and precautions for use).

Class effects

Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRs and TCAs. The mechanism leading to this risk is unknown.

4.9 Overdose

Toxicity

Comprehensive clinical data on citalopram overdose are limited and many cases involve concomitant overdoses of other drugs/alcohol. Fatal cases of citalopram overdose have been reported with citalopram alone; however, the majority of fatal cases have involved overdose with concomitant medications.

Fatal dose is not known. Patients have survived ingestion of more than 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 known specific antidote to citalopram.

Treatment should be symptomatic and supportive and include the maintenance of a clear airway and monitoring of ECG and vital signs until stable.

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 5mg/kg body weight within 1 hour. Activated charcoal given !4 hour after ingestion of citalopram has been shown to reduce absorption by 50%.

Osmotically working laxative (such as sodium sulphate) and stomach evacuation should be considered.

If consciousness is impaired the patient should be intubated.

Control convulsions with intravenous diazepam if they are frequent or prolonged.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC Code: N06A B04

Pharmacotherapeutic Group: Selective Serotonin Reuptake Inhibitors

Biochemical and behavioural studies have shown that citalopram is a potent inhibitor of serotonin (5-HT)-uptake. Tolerance to the inhibition of 5-HT-uptake is not induced by long-term treatment with citalopram.

Citalopram is the most selective Serotonin Reuptake Inhibitor (SSRI) yet described, with no, or minimal, effect on noradrenaline (NA), dopamine (DA) and gamma aminobutyric acid (GABA) uptake.

In contrast to many tricyclic antidepressants and some of the newer SSRI’s citalopram has no or very low affinity for a series of receptors including 5-HT_1A, 5-HT₂, DA D₁and D₂ receptors, a₁-, a₂-, B-adrenoceptors, histamine H₁, muscarine cholinergic, benzodiazepine, and opioid receptors. A series of functional in vitro tests in isolated organs as well as functional in vivo tests have confirmed the lack of receptor affinity. This absence of effects on receptors could explain why citalopram produces fewer of the traditional side effects such as dry mouth, bladder and gut disturbance, blurred vision, sedation, cardiotoxicity and orthostatic hypotension.

Suppression of rapid eye movement (REM) sleep is considered a predictor of antidepressant activity. Like tricyclic antidepressants, other SSRI’s and MAO inhibitors, citalopram suppresses REM-sleep and increases deep slow-wave sleep.

Although citalopram does not bind to opioid receptors it potentiates the anti nociceptive effect of commonly used opioid analgesics. There was potentiation of d-amphetamine-induced hyperactivity following administration of citalopram.

The main metabolites of citalopram are all SSRIs although their potency and selectivity ratios are lower than those of citalopram. However, the selectivity ratios are lower than 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.

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 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

Absorption

Absorption is almost complete and independent of food intake (T_max mean 2 hours) after ingestion of drops and T_max mean 3 hours after intake of tablets. Oral bioavailability is about 80% after ingestion of tablets. Relative bioavailability of drops is approximately 25% greater than the tablets.

Distribution

The apparent volume of distribution (V_d)e is about 12.3L/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 SSRIs, although weaker than the parent compound. Unchanged citalopram is the predominant compound in plasma.

Elimination

The elimination half-life (T%b) is about 1.5 days and the systemic citalopram plasma clearance (Cl_s) is about 0.33L/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 40mg. There is no clears relationship between citalopram plasma levels an 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 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 <20mL/min).

5.3 Preclinical safety data

Citalopram has low acute toxicity. In chronic toxicity studies there were no findings of concern for the therapeutic use of citalopram. 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 child-bearing potential. Citalopram has no mutagenic or carcinogenic potential.

Animal data have shown that citaolpram 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

• Methyl parahydroxybenzoate (E218)

• Propyl parahydroxyb enzoate (E216)

• Ethanol

• Hydroxyethylcellulose

• Purified water

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

24 months.

A bottle may be used for 16 weeks after first use.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Amber-coloured type III glass bottle with dropper applicator containing 15ml of solution.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Rosemont Pharmaceuticals Ltd

Rosemont House

Yorkdale Industrial Park

Braithwaite Street

Leeds

LS11 9XE

8 MARKETING AUTHORISATION NUMBER(S)

PL 00427/0141

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 29/09/2009

10 DATE OF REVISION OF THE TEXT

07/09/2012