EMERDYNE Film-coated tablet Ref.[51194] Active ingredients: Escitalopram

QT interval prolongation

EMERDYNE has been found to cause a dose-dependent prolongation of the QT interval. Cases of QT interval prolongation and ventricular prolongation and ventricular dysrhythmia 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 interval prolongation or other cardiac diseases.

Caution is advised in patients with significant bradycardia; or in patients with recent acute myocardial infarction or uncompensated heart failure.

Electrolyte disturbances such as hypokalaemia and hypomagnesaemia increase the risk of malignant dysrhythmia and should be corrected before treatment with EMERDYNE is started.

If patients with stable cardiac disease are treated, an ECG review should be considered before treatment is started.

If signs of cardiac dysrhythmia occur during treatment with EMERDYNE, the treatment should be withdrawn and an ECG should be performed.

Mania

EMERDYNE should be discontinued in any patient entering a manic phase.

EMERDYNE should be used with caution in patients with a history of mania/hypomania.

Paradoxical anxiety

Some patients with panic disorder may experience increased anxiety symptoms at the start of treatment with EMERDYNE.

This paradoxical reaction usually subsides within two weeks during continued treatment. A low starting dose is advised to reduce the likelihood of a paradoxical anxiogenic effect.

Seizures

EMERDYNE should be discontinued in any patient who develops seizures. EMERDYNE should be avoided in patients with unstable epilepsy and patients with controlled epilepsy should be carefully monitored. EMERDYNE should be discontinued if there is an increase in seizure frequency.

Diabetes mellitus

In patients with diabetes mellitus, treatment with EMERDYNE may alter glycaemic control, possibly due to improvement of depressive symptoms. The doses of insulin and/or oral hypoglycaemic medications may need to be adjusted.

Suicide

As an improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored during this period. The possibility of a suicide attempt is inherent in depression and may persist until significant therapeutic effect is achieved.

Haemorrhage

There have been reports of cutaneous bleeding abnormalities, such as ecchymoses and purpura, with escitalopram. Caution is advised in patients taking EMERDYNE, particularly in concomitant use with medicines known to affect platelet function [e.g. atypical antipsychotics and phenothiazines, most tricyclic antidepressants, aspirin and non-steroidal anti-inflammatory medicines (NSAIDS)], as well as in patients with a history of bleeding disorders.

ECT (electroconvulsive therapy)

There is limited published clinical experience of concurrent administration of EMERDYNE and ECT, therefore caution is advisable.

Post-partum haemorrhage

There has been evidence of an association between antidepressants [particularly selective serotonin reuptake inhibitors (SSRIs) and serotonin non-selective reuptake inhibitors (SNRIs)] and post-partum haemorrhage (PPH). Observational data indicate an increased risk (less than 2- fold) of postpartum haemorrhage PPH following SSRI/SNRI exposure within the month prior to birth. Healthcare professionals should be aware of the potential risk of PPH while making treatment decisions for prescribing SSRI/SNRI towards the end of pregnancy.

Patients should be advised to inform their doctors before taking SSRI/SNRI if they have history of bleeding disorders, such as von Willebrand disease (VWD) or haemophilia or if they are pregnant.

Excipients

Lactose intolerance

EMERDYNE contains lactose. Patients with rare hereditary problems of galactose intolerance and Lapp lactase deficiency, or glucose-galactose malabsorption should not take EMERDYNE.

In vitro studies have shown that the biotransformation of escitalopram to its demethylated metabolites depends on three parallel pathways (cytochrome P450 (CYP) 2C19, 3A4 and 2D6). Escitalopram is a weak inhibitor of isoenzymes CYP1A2, 2C9, 2C19, 2E1 and 3A, and a weak inhibitor of 2D6.

Ritonavir

The pharmacokinetics of single doses of EMERDYNE is not changed by co-administration with a single dose of ritonavir (CYP3A4 inhibitor).

Ketoconazole

Co-administration with ketoconazole (potent CYP3A4 inhibitor) has no effect on the pharmacokinetics of EMERDYNE.

Cimetidine

Co-administration of racemic citalopram with cimetidine (potent CYP2D6, 3A4 and 1A2 inhibitor) resulted in increased plasma concentrations of the racemate (43% increase in AUC, 39% increase in C_max). Thus, caution should be exercised at the upper end of the dose range of EMERDYNE when used concomitantly with high doses of cimetidine.

Monoamine Oxidase Inhibitors (MAOI’s), Sumatriptan and Tramadol

Co-administration with MAO inhibitors may cause serotonin syndrome.

Co-administration with other serotonergic medicines (e.g. tramadol, sumatriptan) as well as other antidepressants with serotonergic properties may lead to an enhancement of serotonin associated effects, e.g. the serotonin syndrome.

Lithium and Tryptophan

There have been reports of enhanced effects when escitalopram has been given with lithium or tryptophan and therefore concomitant use of EMERDYNE with these medicines should be undertaken with caution.

Desipramine

Co-administration with a single dose of desipramine (a CYP2D6 substrate) resulted in a two-fold increase in plasma levels of desipramine. Therefore, caution is advised when EMERDYNE and desipramine are co-administered. A similar increase in plasma levels of desipramine, after administration of imipramine, was seen when given together with racemic citalopram.

Metoprolol

Co-administration with a single dose of metoprolol 100 mg (a CYP2D6 substrate) resulted in a two-fold increase in the C_max and a 52% increase of the AUC of metoprolol. However, the combination had no clinically significant effects on blood pressure and heart rate.

Selegiline

Racemic citalopram increases the AUC of selegiline by 29%.

QT interval prolongation

Pharmacokinetic and pharmacodynamic studies of EMERDYNE combined with other medicinal products that prolong the QT interval have not been performed. An additive effect of escitalopram and these medicinal products cannot be excluded. Therefore, co-administration of EMERDYNE with medicinal products that prolong the QT interval, such as Class 1A and III antidysrhythmics (e.g. amiodarone, quinidine), antipsychotics (e.g. phenothiazine derivatives, pimozide, haloperidol), tricyclic antidepressants (e.g. desipramine, imipramine), certain antimicrobial agents (e.g. moxifloxacin, erythromycin IV, pentamidine, anti-malarial treatment particularly halofentrine), certain antihistamines (e.g. mizolastine) and anti-retrovirals (e.g. ritonavir, saquinavir, lopinavir), is contra-indicated.

Other

Pharmacokinetic interaction studies with racemic citalopram have demonstrated no clinically important interactions with carbamazepine (CYP3A4 substrate), triazolam (CYP3A4 substrate), theophylline (CYP1A2 substrate) (single dose), warfarin (CYP3A4 and CYP2C9 substrate), levomepromazine (CYP2D6 inhibitor), lithium and digoxin. However, prothrombin time was slightly increased after a single dose of 25 mg warfarin.

The International Normalised Ratio (INR) needs to be carefully monitored in patients on the combination.

The safety of EMERDYNE in pregnant and lactating women has not been established.

Patients who are depressed and require treatment may have an impaired ability to drive or operate machinery. Furthermore, EMERDYNE can induce fatigue, dizziness, drowsiness and impair vision. The treating doctor should routinely evaluate the ability of patients on EMERDYNE to continue driving or operating complex machines.

Summary of the reported safety profile

Adverse reactions observed with EMERDYNE are most frequent during the first one or two weeks of treatment and may decrease in intensity and frequency with continued treatment. After prolonged administration, abrupt cessation of EMERDYNE may produce withdrawal reactions in some patients.

Table 1. Tabulated summary of adverse events:

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

Cases of QT-prolongation have been reported during the post-marketing period, predominantly in patients with pre-existing cardiac disease.

QT-prolongation may lead to ventricular dysrhythmia and torsade de pointes.

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

After prolonged administration, abrupt cessation of EMERDYNE may produce withdrawal reactions in some patients.

The following symptoms, hostility, suicidal ideation and self-harm, have been reported in children being treated with antidepressants

Post-marketing experience

There has been evidence of an association between antidepressants [particularly selective serotonin reuptake inhibitors (SSRIs) and serotonin non-selective reuptake inhibitors (SNRIs)] and post-partum haemorrhage (PPH). Observational data indicate an increased risk (less than 2-fold) of postpartum haemorrhage PPH following SSRI/SNRI exposure within the month prior to birth. Healthcare professionals should be aware of the potential risk of PPH while making treatment decisions for prescribing SSRI/SNRI towards the end of pregnancy.

Patients should be advised to inform their doctors before taking SSRI/SNRI if they have history of bleeding disorders, such as von Willebrand disease (VWD) or haemophilia or if they are pregnant.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reactions & Quality Problem Reporting Form”, found online under SAHPRA’s publications: https://sahpra.org.za/wpcontent/uploads/2020/01/6.04_ARF1_v5.1_27Jan2020.pdf

Not applicable.