Addition of:

4.4. Special warnings and precautions for use
SSRIs/SNRIs may increase the risk of postpartum haemorrhage (see sections 4.6, 4.8).

4.6. Fertility, pregnancy and lactation
Observational data indicate an increased risk (less than 2-fold) of postpartum haemorrhage following SSRI/SNRI exposure within the month prior to birth (see sections 4.4, 4.8).

 

4.8. Undesirable effects
Reproductive system and breast disorders: postpartum haemorrhage*; frequency not known
* This event has been reported for the therapeutic class of SSRIs/SNRIs (see sections 4.4, 4.6).

Section 2 warnings and precautions - Addition of:
• History of bleeding disorders […], or if you are pregnant (see ‘Pregnancy’2)
Pregnancy2
If you take Cipramil near the end of your pregnancy there may be an increased risk of heavy vaginal bleeding shortly after birth, especially if you have a history of bleeding disorders. Your doctor or midwife should be aware that you are taking Cipramil so they can advise you.

 

Section 4 possible side effects - Addition of:
Frequency not known
• Heavy vaginal bleeding shortly after birth (postpartum haemorrhage), see Pregnancy2 in section 2 for more information

Change in section 4.4. Special warnings and precautions for use

Selective serotonin reuptake inhibitors (SSRIs)/serotonin norepinephrine reuptake inhibitors
(SNRIs) may cause symptoms of sexual dysfunction (see section 4.8). There have been reports
of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation
of SSRIs/SNRI.

Change in section 2. Warnings and precautions

Medicines like Cipralex (so called SSRIs/SNRIs) may cause symptoms of
sexual dysfunction (see section 4). In some cases, these symptoms have
continued after stopping treatment.

The change is administration and reflects office address change

Update IMB details to HPRA.

 

In section 4.4: Angle-Closure Glaucoma and Lactose intolerance sections have been included

In section 4.5: The concomitant use of citalopram and selegiline (in doses above 10 mg daily) is contraindicated (see section 4.3).

Added: Medicinal products inducing hypokalaemia/hypomagnesaemia

Deleted: Desipramine, imipramine, neuroleptics

Effect of other medicinal products on the pharmacokinetics of citalopram: further information about cimetidine and CYP2C19 inhibitors has been added

Effects of citalopram on other medicinal products; further information on concomitant use with metoprolol, desipramine and imipramine

 

In section 4.6: lactaction was changed to breast-feeding

In section 4.8: headache is included as very common undesirable effect

Reporting of suspected adverse reactions and IMB contact details included.

 

 

 

Section 4.6 Fertility, pregnancy and lactation. Addition of following paragraph:

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.

               

Section 5.3 Preclinical safety data. Addition of following paragraph:

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.

Change in date of revision of text to November 2012

4. CLINICAL PARTICULARS

 

4.1. Therapeutic Indications

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

 

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

 

4.2. Posology and Mmethod of Administration

Adults

Treating Depression

Adults:

Citalopram drops should be administered as a single oral dose of 16 mg (8 drops) daily. Dependent on individual patient response and severity of depression the dose may be increased to a maximum of 48 mg (24 drops) daily. Depending on individual patient response, the dose may be increased to a maximum of 32 mg (16 drops) daily.

 

Duration of treatment:

The antidepressant effect usually sets in after 2 to 4 weeks. Treatment with antidepressants is symptomatic and must therefore be continued for an appropriate length of time, usually up to 6 months after recovery in order to prevent relapse. In patients with recurrent depression (unipolar) maintenance therapy may need to be continued for a number of years to prevent new episodes.

 

Treating Panic Disorder

Adults:

A single oral dose of 8 mg (4 drops) daily is recommended for the first week before increasing the dose to 16 mg (8 drops) daily.  The dose may be further increased, up to a maximum of 48 mg (24 drops) daily, dependent on individual patient response. Depending on individual patient response, the dose may be increased to a maximum of 32 mg (16 drops) daily.

 

Duration of treatment:

Maximum effectiveness of citalopram in treating panic disorder is reached after about 3 months and the response is maintained during continued treatment.

 

 Elderly patients ( > 65 years of age)

In elderly patients the dose may be increased to a maximum of 32 mg (16 drops) daily.  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)

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

 

Reduced renal function

Dosage adjustment is not necessary in patients with mild or moderate renal impairment.  No information is available on treatment of patients with severely reduced renal function (creatinine clearance <20 mL/min). 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 30 ml/min, see section 5.2).

 

Reduced hepatic function

Patients with reduced hepatic function should receive dosages of no more than 24 mg/day (12 drops/day). 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).

 

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 SSRI.

Abrupt discontinuation should be avoided. When stopping treatment with citalopram the dose should be gradually reduced over a period of at least one or two weeks in order to reduce the risk of withdrawal reactions (see section 4.4 and 4.8). If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently the physician may continue decreasing the dose, but at a more gradual rate.

 

Method of administration

Citalopram oral drops, solution is administered as a single daily dose.

Citalopram oral drops, solution can be taken any time of the day without regard to food intake.

Citalopram oral drops, solution can be mixed with water, orange juice or apple juice.

 

Citalopram oral drops, solution have an approximately 25% higher bioavailability compared to tablets.  Consequently doses of tablets correspond to doses of drops as follows:

 

Tablets	Drops
10 mg	8 mg  (4mg (4 drops)
20 mg	16 mg  (8mg (8 drops)
30 mg	24 mg (12 drops)
40 mg	32 mg (16 drops)
60 mg	48 mg (24 drops)

 

Duration of treatment

The antidepressant effect usually sets in after 2 to 4 weeks.  Treatment with antidepressants is symptomatic and must therefore be continued for an appropriate length of time, usually up to 6 months after recovery in order to prevent relapse.  In patients with recurrent depression (unipolar) maintenance therapy may need to be continued for a number of years to prevent new episodes.

 

Maximum effectiveness of citalopram in treating panic disorder is reached after about 3 months and the response is maintained during continued treatment.Withdrawal symptoms seen on discontinuation of SSRI.

Abrupt discontinuation should be avoided. When stopping treatment with citalopram the dose should be gradually reduced over a period of at least one or 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 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.

 

4.3. Contraindications

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

 

MAOIs (monoamine oxidase inhibitors)

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

 

Some cases presented with features resembling serotonin syndrome.

Citalopram must not be used in combination with a MAOI including selegiline in doses above 10 mg daily.

Treatment with citalopram may be instituted 14 days after discontinuation of non-selective MAOIs and minimum one day after discontinuation of moclobemide.  Treatment with MAOIs may be introduced 7 days after discontinuation of citalopram (see section 4.5 Interactions with other Medicaments and other forms of Interactions).

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 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).

 

Concomitant treatment with pimozide (see section 4.5).

 

4.4. Special warnings and precautions for use

Paradoxical anxiety

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

 

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 especially seem to be at particularly high risk. Elderly female patients especially seem to be a risk group.

 

Suicide/suicidal thoughts or clinical worsening

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.

 

Seizures

Although animal experiments have shown that citalopram has no epileptogenic potential it should, like other antidepressants, be used with caution in patients with a history of 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

As described for other psychotropics citalopram may modify insulin and glucose responses calling for adjustment of the antidiabetic therapy in diabetic patients; in addition the depressive illness itself may affect patients´ glucose balance. 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

If citalopram is used concomitantly with medicinal products with serotonergic effects such as sumatriptan or other triptans, tramadol and tryptophan, caution is advisable.

Rarely, the occurrence of “serotonin syndrome” has been reported in patients receiving SSRIs.  A combination of symptoms, possibly including agitation, confusion, tremor, myoclonus and hyperthermia, may indicate the development of this condition (see section 4.5 Interactions with other medicinal products and other forms of Interactions). 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 cutaneous bleeding abnormalities such as ecchymoses and purpura with SSRIs. Caution is advised in patients taking SSRIs, particularly with concomitant use of oral anticoagulants; medicinal products known to affect platelet function (e.g. atypical antipsychotics and phenothiazines, most tricyclic antidepressants, phenothiazines, most tricyclic antidepressants, acetylsalicyclic acid and non-steroidal anti-inflammatory medicinal products (NSAIDs), ticlopidine and dipyridamole) as well as in patients with a history of bleeding disorders (see section 4.5 Interactions with other medicinal products and other forms of interactions). There have been reports of cutaneous 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).

 

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 Interactions with other medicinal products and other forms of interactions).

 

St John’s Wort

Concomitant use of SSRIs and herbal remedies containing St John’s Wort (Hypericum perforatum) may result in an increased incidence of adverse reactions (see section 4.5 Interaction with other medicinal products and other forms of interactions). 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 Undesirable Effects). 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.

 

 

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 SSRIs’ section 4.2, Posology and method of administration).

 

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.

 

 Excipients

The oral solution contains 9.0% v/v alcohol (76 mg/ml).

The solution also contains Methyl parahydroxybenzoate (E218), and propyl parahydroxybenzoate (E216). Methyl- and propyl parahydroxybenzoate (E218, E216) which may cause allergic reactions (possibly delayed).

 

4.5. Interactions with other medicinal products and other forms of interactions

Pharmacodynamic interactions

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

 

Contraindicated combinations

MAOIs (non-selective as well as selective A (moclobemide) - risk of “serotonin syndrome” (see section 4.3 Contraindications).

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, 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: 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).

 

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-malarial treatment particularly halofantrine), certain antihistamines (astemizole, mizolastine) etc., 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. Patients tolerated the selegiline-citalopram combination well. 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 medicinal products (e.g. tramadol, sumatriptan) may lead to enhancement of 5-HT associated effects.

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

 

St. John’s Wort

Dynamic interactions between SSRIs and herbal remedy St John’s wWort (Hypericum perforatum) can occur, resulting in an increase in undesirable effects (see section 4.4). Pharmacokinetic interactions have not been investigated.

 

Haemorrhage

There have been reports of cutaneous bleeding abnormalities such as ecchymoses and purpura with SSRIs. Caution is advised in patients taking SSRIs, particularly with concomitant use of oral anticoagulants; medicinal products known to affect platelet function (e.g. atypical antipsychotics and phenothiazines, most tricyclic antidepressants, acetylsalicyclic acid and non-steroidal anti-inflammatory medicinal products (NSAIDs), ticlopidine and dipyridamole) as well as in patients with a history of bleeding disorders (see section 4.4 Special warnings and special precautions for use). 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 (electroconvulsive therapy)

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

 

Alcohol

The combination of SSRIs and alcohol is not advisable.  However, clinical studies have revealed no adverse pharmacodynamic interactions between citalopram and 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 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

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 enzyme means that inhibition of its biotransformation is less likely as inhibition of one enzyme may be compensated by another. Therefore and 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 (potent CYP2D6, 3A4 and 1A2 inhibitor) caused a moderate increase in the average steady state levels of citalopram. No general dose reduction for citalopram is recommended during co-administration with cimetidine Cimetidine, a known enzyme-inhibitor, caused a slight rise in the average steady-state citalopram levels. Caution is therefore recommended when administering high doses of citalopram in combination with high doses of cimetidine. Co-administration of escitalopram (the active enantiomer of citalopram) with omeprazole 30 mg once daily (a CYP2C19 inhibitor) resulted in a 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.

 

 

Effects of citalopram on other medicinal products

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

 

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 epoxide) and triazolam).

 

In a pharmacokinetic interaction study citalopram did not cause any changes in the pharmacokinetics of digoxin meaning that citalopram neither induces nor inhibits P-glycoprotein.

 

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

Pregnancy

Clinical experience of use in pregnant women is limited but no reports, which may cause concern have been received.

 

Based on data from reproduction toxicity studies (segment I, II and III) there is no reason to have special concern for the use of citalopram in women of childbearing potential. A large amount of data on pregnant women (more than 2500 exposed outcomes) indicate no malformative feto/neonatal toxicity. Citalopram can be used in pregnancy if clinically needed, taking into account the aspects mentioned below.

 

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

 

4.7. Effects on ability to drive and use machines

Citalopram does not impair intellectual function and psychomotor performance.  However, patients who are prescribed psychotropic medication may be expected to have some impairment of general attention and concentration either due to the illness itself, the medication or both and should be cautioned about their ability to drive a car and operate machinery. 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

 

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
	Rare	Hyponatraemia
	Not known	Hypokalaemia
Psychiatric disorders	Common	Agitation, libido decreased, anxiety, nervousness, confusional state, abnormal orgasm (female), abnormal dreams
	Uncommon	Aggression, depersonalization, hallucination, mania
	Not Known	Panic attack, bruxism, restlessness, Suicide-related events (see section 4.4) suicidal ideation, suicidal behaviour1
Nervous system disorders	Very common	Somnolence, insomnia
	Common	Tremor, paraesthesia, dizziness, disturbance in attention
	Uncommon	Syncope
	Rare	Convulsion grand mal, dyskinesia, taste disturbance
	Not Known	Convulsions, serotonin syndrome, extrapyramidal disorder, akathisia, movement disorder
Eye disorders	Uncommon	Mydriasis
	Not Known	Visual disturbance
Ear and labyrinth disorders	Common	Tinnitus
Cardiac disorders	Uncommon	Bradycardia, tachycardia
	Not Known	Electrocardiogram QT prolonged, ventricular arrhythmia including Torsade de Pointes
Vascular disorders	Rare	Haemorrhage
	Not known	Orthostatic hypertension
Respiratory thoracic and mediastinal disorders	Common	Yawning
	Not Known	Epistaxis
Gastrointestinal disorders	Very common	Dry mouth, nausea
	Common	Diarrhoea, vomiting, constipation
	Not Known	Gastrointestinal haemorrhage (including rectal haemorrhage)
Hepatobiliary disorders	Rare	Hepatitis
	Not Known	Liver function test abnormal
Skin and subcutaneous tissue disorders	Very common	Sweating increased
	Common	Pruritus
	Uncommon	Urticaria, alopecia, rash, purpura, photosensitivity
	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
	Uncommon	Female: Menorrhagia
	Not Known	Female: Metrorrhagia Male: Priapism, galactorrhoea
General disorders and administration site conditions	Common	Fatigue, pyrexia
	Uncommon	Oedema

 

Number of patients: citalopram / placebo = 1346 / 545

 

Cases of QT-prolongation have been reported during the post-marketing period, predominantly in patients with pre-existing cardiac disease. ¹Cases of suicidal ideation and suicidal behaviours have been reported during citalopram therapy or early after treatment discontinuation (see section 4.4).

 

QT Prolongation

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).

 

Bone Fractures

Epidemiological studies, mainly 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 Ccitalopram (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor, confusion, sweating, headache, diarrhoea, palpitations, emotional instability, irritability, and visual disturbances are the most commonly reported reactions. Generally these events are mild to moderate and are self-limiting, however, in some patients they may be severe and/or prolonged. It is therefore advised that when citalopram treatment is no longer required, gradual discontinuation by dose tapering should be carried out (see section 4.2 and 4.4).

 

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 specific antidote. Establish and maintain an airway, ensure adequate oxygenation and respiratory function. Gastric lavage and the use of activated charcoal might be considered. Gastric lavage should be carried out as soon as possible after oral ingestion.  Cardiac and vital signs monitoring are recommended along with general symptomatic supportive measures. There is no known specific antidote to citalopram. Treatment should be symptomatic and supportive. Activated charcoal, osmotically working laxative (such as sodium sulphate) and gastric lavage should be considered. If consciousness is impaired the patient should be intubated. ECG and 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

 

In contrast to many tricyclic antidepressants and some of the newer SSRIs, cCitalopram has no or very low affinity for a series of receptors including 5-HT_1A, 5-HT₂, DA D₁ and 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.

 

Added as last paragraph:

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 3 hours). Oral bioavailability is about 80%.

 

Citalopram oral drops, solution have an approximately 25% higher bioavailability compared to tablets.

 

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 < 230 mL/min).

 

Pharmacokinetic / pharmacodynamic relationship

There is no clear relationship between citalopram plasma levels and therapeutic response or side effects.

The metabolites do not contribute to the overall antidepressant effect.

Citalopram oral drops, solution have an approximately 25% higher bioavailability compared to tablets.

 

Cadiac Section previously missing

Section 4.2
Depression, Panic Disorder - maximum dosage reduced from 48mg (24 drops) to 32mg (16 drops) daily

Elderly - maximum dosage reduced from 32mg (16 drops) to 16mg (8 drops) daily

Reduced hepatic function - maximum dosage reduced from 24mg (12 drops) to 16mg (8 drops) daily

Poor metabolisers of CYP2C19 - Maximum dosage of 16mg (8 drops) daily

Method of administration - 60 mg Tablets 48mg Solution (24 drops) line deleted

Section 4.4
QT interval prolongation section added
Previous QT and ECG sentences deleted.

Section 4.5
QT interval prolongation section added
Previous QT sentences deleted

Cimetidine section wording amended

Section 4.8
Ventricular arrhythmia including Torsade de Pointes added to Not Known Cardiac Disorders

QT Porolngation section amended to include ventricular arrhythmia including Torsade de Pointes, females with hypokalaemia and QT prolongation. 'See sections' included.

Section 4.9
ECG monitoring wording added

Section 5.1
ECG study findings included

Section 5.2
Pharmacokinetic/Pharmacodynamic relationship deleted

 

Section 4.6 addition:

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.

Section 4.8 addition:

Epidemiological studies, mainly 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.

Remove duplicate 'phenothiazines, most tricyclic antidepressants'

Minor spelling corrections

Core Text update changes to Section 4

Section 4.4

 

Deleted Text:

As improvement of the depressive state may not occur during the first few weeks or more of treatment, patients should be closely monitored during this period.  It is general clinical experience with all antidepressants that the risk of suicide may increase in the early stages of recovery.

 

The possibility of suicide attempt is inherent in depression and may persist until significant remission occurs.  Potentially suicidal patients should not have access to large quantities of drugs.

 

Added Text:

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 Cipramil 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.

 

Section 4.8

 

Added Text:

 

Frequency Not Known

 

Cases of suicidal ideation and suicidal behaviours have been reported during Cipramil therapy or early after treatment discontinuation (see Section 4.4).

Section 4.4

 

Deleted Text:

As improvement of the depressive state may not occur during the first few weeks or more of treatment, patients should be closely monitored during this period.  It is general clinical experience with all antidepressants that the risk of suicide may increase in the early stages of recovery.

 

The possibility of suicide attempt is inherent in depression and may persist until significant remission occurs.  Potentially suicidal patients should not have access to large quantities of drugs.

 

Added Text:

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 Cipramil 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.

 

Section 4.8

 

Added Text:

 

Frequency Not Known

 

Cases of suicidal ideation and suicidal behaviours have been reported during Cipramil therapy or early after treatment discontinuation (see Section 4.4).