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Section 4.2 Posology and method of administration

Major Depressive Episodes

Adults: (addition of)

Citalopram should be administered as a single oral dose of 20 mg daily.  Dependent on individual patient response, the dose may be increased to a maximum of 40 mg daily.

Panic Disorder

Adults: (addition of)

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.

Elderly patients (> 65 years of age)
For elderly patients the dose should be decreased to half of the recommended dose, e,g, 10-20 mg daily.  The recommended maximum dose for the elderly is 20 mg daily.

Reduced hepatic function

An initial dose of 10 mg daily for the first two weeks of treatment is recommended in patients with mild or moderate hepatic impairment.  Depending on individual patient response, the dose may be increased to a maximum of 20 mg daily.  Caution and extra careful dose titration is advised in patients with severely reduced hepatic function (see section 5.2).

Poor metabolisers 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 (see section 5.2).

Section 4.3 Contraindications

Addition of:

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).

Section 4.4 Special warnings and precautions for use

Addition of:

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 hypokalaemia, 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.

Section 4.5 Interactions

Contraindicated combinations

Addition of:

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.

Influence of other medicinal products on the pharmacokinetics of citalopram

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.

Section 4.8 Undesirable effects

Addition to table:

Frequency not known: ventricular arrhythmia including torsade de pointes

Addition below table:

Cases of QT-prolongation and ventricular arrhythmia including torsade de pointes have been reported during the post-marketing period, predominantly in patients of female gender, with hypokalaemia, or with pre-existing QT prolongation or other cardiac diseases (see sections 4.3, 4.4, 4.5, 4.9 and 5.1).

Section 4.9 Overdose

Addition of:

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.

Section 5.1 Pharmacodynamic properties

Addition of:

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).

As a result of an EU work sharing procedure for citalopram, the SPC for  Cipramil has been revised.

The changes affects Sections, 4.3, 4.4, 4.5, 4.7 and 4.9 with extensive revisions of the text in these sections.

In addition, in Section 4.6 the following text has been added in the section on pregnancy: “A large amount of data on pregnant women (more than 2500 exposed outcomes) indicate no malformative foeto / neonatal toxicity.  Citalopram can be used during pregnancy if clinically needed, taking into account the aspects mentioned below.”

Additionally the following has been added in the Section on lactation: “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.”

In Section 4.8 the table of undesirable effects has been reformatted, with some events moved into different headings: 

 “purpura”, formerly under “Blood and lymphatic disorders”, now appears under “Skin and subcutaneous tissue disorders”;

“abnormal orgasm”, formerly under “Reproductive system and breast disorders” is now included under “Psychiatric disorders”;

“weight decreased” and “weight increased”, formerly under “Investigations ” have been added to the information under “Metabolism and nutrition disorders”;
“dizziness” and “paraesthesia”, formerly under “General disorders and administration site conditions” are now under “Nervous system disorders”.  
  
 The date of revision of th new SmPC is 28 March 2011.

• Minor amendments in layout to sections 1-3, with addition of full tablet descriptions in section 3.
• Addition of the standard lactose warning, in Section 4.4, as per below:

"Excipients
The tablets contain lactose monohydrate.  Patients with rare hereditary problems of galactose intolerance, the Lapp deficiency or glucose-galactose malabrsorption should not receive this medicine."

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.  In addition, there is a possibility of an increased risk of suicidal behaviour in young adults.

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.

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

Addition of paragraphs on 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 clinical trials adverse events seen on treatment discontinuation occurred in approximately 40% of patients treated with 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 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 citalopram should be gradually tapered when discontinuing treatment over a period of several weeks or months, according to the patient’s needs (see “Withdrawal symptoms seen on discontinuation of citalopram”, Section 4.2 Posology and Method of Administration).

TreatmentThere is no specific antidote. An ECG should be taken.

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 citalopram has been shown to reduce absorption by 50%.
Control convulsions with intravenous diazepam if they are frequent or prolonged
Management should be symptomatic and supportive and include the maintenance of a clear airway and monitoring of cardiac and vital signs until stable.