Toxicity
Clinical data on escitalopram overdose are limited and many cases involve concomitant overdoses of other drugs. In the majority of cases mild or no symptoms have been reported. Fatal cases of escitalopram overdose have rarely been reported with escitalopram alone; the majority of cases have involved overdose with concomitant medications. Doses between 400 and 800 mg of escitalopram alone have been taken without any severe symptoms.
Symptoms
Symptoms seen in reported overdose of escitalopram include symptoms mainly related to the central nervous system (ranging from dizziness, tremor, and agitation to rare cases of serotonin syndrome, convulsion, and coma), the gastrointestinal system (nausea/vomiting), and the cardiovascular system (hypotension, tachycardia, QT interval prolongation, and arrhythmia) and electrolyte/fluid balance conditions (hypokalaemia, hyponatraemia).
Management
There is no specific antidote. Establish and maintain an airway, ensure adequate oxygenation and respiratory function. Gastric lavage and the use of activated charcoal should 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.
ECG monitoring is advised 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.
Not applicable.
Adverse reactions are most frequent during the first or second week of treatment and usually decrease in intensity and frequency with continued treatment.
Tabulated list of adverse reactions
Adverse reactions known for SSRIs and also reported for escitalopram in either placebo-controlled clinical studies or as spontaneous post-marketing events are listed below by system organ class and frequency.
Frequencies are taken from clinical studies; they are not placebo-corrected. Frequencies are defined as: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000), very rare (<1/10,000), or not known (cannot be estimated from the available data).
| System organ class | Frequency | Undesirable Effect |
| Blood and lymphatic system disorders | Not known | Thrombocytopenia |
| Immune system disorders | Rare | Anaphylactic reaction |
| Endocrine disorders | Not known | Inappropriate ADH secretion |
| Metabolism and nutrition disorders | Common | Decreased appetite, increased appetite, weight increased |
| Uncommon | Weight decreased | |
| Not known | Hyponatraemia, anorexia1 | |
| Psychiatric disorders | Common | Anxiety, restlessness, abnormal dreams libido decreased Female: anorgasmia |
| Uncommon | Bruxism, agitation, nervousness, panic attack, confusional state | |
| Rare | Aggression, depersonalisation, hallucination | |
| Not known | Mania, suicidal ideation, suicidal behaviour2 | |
| Nervous system disorders | Very common | Headache |
| Common | Insomnia, somnolence, dizziness, paraesthesia, tremor | |
| Uncommon | Taste disturbance, sleep disorder, syncope | |
| Rare | Serotonin syndrome | |
| Not known | Dyskinesia, movement disorder, convulsion, psychomotor restlessness/akathisia1 | |
| Eye disorders | Uncommon | Mydriasis, visual disturbance |
| Ear and labyrinth disorders | Uncommon | Tinnitus |
| Cardiac disorders | Uncommon | Tachycardia |
| Rare | Bradycardia | |
| Not known | Electrocardiogram QT prolonged Ventricular arrhythmia including torsade de pointes | |
| Vascular disorders | Not known | Orthostatic hypotension |
| Respiratory, thoracic and mediastinal disorders | Common | Sinusitis, yawning |
| Uncommon | Epistaxis | |
| Gastrointestinal disorders | Very common | Nausea |
| Common | Diarrhoea, constipation, vomiting, dry mouth | |
| Uncommon | Gastrointestinal haemorrhages (including rectal haemorrhage) | |
| Hepatobiliary disorders | Not known | Hepatitis, liver function test abnormal |
| Skin and subcutaneous tissue disorders | Common | Sweating increased |
| Uncommon | Urticaria, alopecia, rash, pruritus | |
| Not known | Ecchymosis, angioedemas | |
| Musculoskeletal and connective tissue disorders | Common | Arthralgia, myalgia |
| Renal and urinary disorders | Not known | Urinary retention |
| Reproductive system and breast disorders | Common | Male: ejaculation disorder, impotence |
| Uncommon | Female: metrorrhagia, menorrhagia | |
| Not known | Galactorrhoea Male: priapism | |
| General disorders and administration site conditions | Common | Fatigue, pyrexia |
| Uncommon | Oedema |
1 These events have been reported for the therapeutic class of SSRIs.
2 Cases of suicidal ideation and suicidal behaviours have been reported during escitalopram therapy or early after treatment discontinuation.
QT interval prolongation
4, 4.5, 4.9 and 5.1).Class effects
Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRIs and TCAs. The mechanism leading to this risk is unknown.
Discontinuation symptoms seen when stopping treatment
Discontinuation of SSRIs/SNRIs (particularly when abrupt) commonly leads to discontinuation 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 escitalopram treatment is no longer required, gradual discontinuation by dose tapering should be carried out.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard
No complete conventional battery of preclinical studies was performed with escitalopram since the bridging toxicokinetic and toxicological studies conducted in rats with escitalopram and citalopram showed a similar profile. Therefore, all the citalopram information can be extrapolated to escitalopram.
In comparative toxicological studies in rats, escitalopram and citalopram caused cardiac toxicity, including congestive heart failure, after treatment for some weeks, when using dosages that caused general toxicity. The cardiotoxicity seemed to correlate with peak plasma concentrations rather than to systemic exposures (AUC). Peak plasma concentrations at no-effect-level were in excess (8-fold) of those achieved in clinical use, while AUC for escitalopram was only 3- to 4-fold higher than the exposure achieved in clinical use. For citalopram AUC values for the S-enantiomer were 6- to 7-fold higher than exposure achieved in clinical use. The findings are probably related to an exaggerated influence on biogenic amines i.e. secondary to the primary pharmacological effects, resulting in haemodynamic effects (reduction in coronary flow) and ischaemia. However, the exact mechanism of cardiotoxicity in rats is not clear. Clinical experience with citalopram, and the clinical trial experience with escitalopram, do not indicate that these findings have a clinical correlate.
Increased content of phospholipids has been observed in some tissues e.g. lung, epididymides and liver after treatment for longer periods with escitalopram and citalopram in rats. Findings in the epididymides and liver were seen at exposures similar to that in man. The effect is reversible after treatment cessation. Accumulation of phospholipids (phospholipidosis) in animals has been observed in connection with many cationic amphiphilic medicines. It is not known if this phenomenon has any significant relevance for man.
In the developmental toxicity study in the rat embryotoxic effects (reduced foetal weight and reversible delay of ossification) were observed at exposures in terms of AUC in excess of the exposure achieved during clinical use. No increased frequency of malformations was noted. A pre- and postnatal study showed reduced survival during the lactation period at exposures in terms of AUC in excess of the exposure achieved during clinical use.
Animal data have shown that citalopram induces a reduction of fertility index and pregnancy index, reduction in implantation number and abnormal sperm at exposure well in excess of human exposure. No animal data related to this aspect are available for escitalopram.
Pharmacotherapeutic group: antidepressants, selective serotonin reuptake inhibitors
ATC-code: N 06 AB 10
Mechanism of action
Escitalopram is a selective inhibitor of serotonin (5-HT) re-uptake with high affinity for the primary binding site. It also binds to an allosteric site on the serotonin transporter, with a 1000 fold lower affinity.
Escitalopram has no or low affinity for a number of receptors including 5-HT1A, 5-HT2, DA D1 and D2 receptors, α1-, α2-, β-adrenoceptors, histamine H1, muscarine cholinergic, benzodiazepine, and opioid receptors.
The inhibition of 5-HT re-uptake is the only likely mechanism of action explaining the pharmacological and clinical effects of escitalopram.
Pharmacodynamic effects
4, 4.5, 4.8 and 4.9).Clinical efficacy
Major depressive episodes
Escitalopram has been found to be effective in the acute treatment of major depressive episodes in three out of four double-blind, placebo controlled short-term (8-week) studies. In a long-term relapse prevention study, 274 patients who had responded during an initial 8-week open label treatment phase with escitalopram 10 or 20 mg/day, were randomised to continuation with escitalopram at the same dose, or to placebo, for up to 36 weeks. In this study, patients receiving continued escitalopram experienced a significantly longer time to relapse over the subsequent 36 weeks compared to those receiving placebo.
Social anxiety disorder
Escitalopram was effective in both three short-term (12- week) studies and in responders in a 6-month relapse prevention study in social anxiety disorder. In a 24-week dose-finding study, efficacy of 5, 10 and 20 mg escitalopram has been demonstrated.
Generalised anxiety disorder
Escitalopram in doses of 10 and 20 mg/day was effective in four out of four placebo-controlled studies.
In pooled data from three studies with similar design comprising 421 escitalopram-treated patients and 419 placebo-treated patients there were 47.5% and 28.9% responders respectively and 37.1% and 20.8% remitters. Sustained effect was seen from week 1.
Maintenance of efficacy of escitalopram 20mg/day was demonstrated in a 24 to 76 week, randomised, maintenance of efficacy study in 373 patients who had responded during the initial 12-week open-label treatment.
Obsessive-compulsive disorder
In a randomised, double-blind, clinical study, 20 mg/day escitalopram separated from placebo on the Y-BOCS total score after 12 weeks. After 24 weeks, both 10 and 20 mg/day escitalopram were superior as compared to placebo.
Prevention of relapse was demonstrated for 10 and 20 mg/day escitalopram in patients who responded to escitalopram in a 16-week open-label period and who entered a 24-week, randomised, double-blind, placebo controlled period.
Absorption
Absorption is almost complete and independent of food intake. (Mean time to maximum concentration (mean Tmax) is 4 hours after multiple dosing).
As with racemic citalopram, the absolute bioavailability of escitalopram is expected to be about 80%.
Distribution
The apparent volume of distribution (Vd,β/F) after oral administration is about 12 to 26 L/kg. The plasma protein binding is below 80% for escitalopram and its main metabolites.
Biotransformation
Escitalopram is metabolised in the liver to the demethylated and didemethylated metabolites. Both of these are pharmacologically active. Alternatively, the nitrogen may be oxidised to form the N-oxide metabolite. Both parent substance and metabolites are partly excreted as glucuronides. After multiple dosing the mean concentrations of the demethyl and didemethyl metabolites are usually 28-31% and <5%, respectively, of the escitalopram concentration. Biotransformation of escitalopram to the demethylated metabolite is mediated primarily by CYP2C19. Some contribution by the enzymes CYP3A4 and CYP2D6 is possible.
Elimination
The elimination half-life (t½ β) after multiple dosing is about 30 hours and the oral plasma clearance (Cloral) is about 0.6 L/min. The major metabolites have a significantly longer half-life. Escitalopram and major metabolites are assumed to be eliminated by both the hepatic (metabolic) and the renal routes, with the major part of the dose excreted as metabolites in the urine.
Linearity
There is linear pharmacokinetics. Steady-state plasma levels are achieved in about 1 week. Average steady-state concentrations of 50 nmol/L (range 20 to 125 nmol/L) are achieved at a daily dose of 10 mg.
Elderly patients (> 65 years)
Escitalopram appears to be eliminated more slowly in elderly patients compared to younger patients. Systemic exposure (AUC) is about 50 % higher in elderly compared to young healthy volunteers.
Reduced hepatic function
In patients with mild or moderate hepatic impairment (Child-Pugh Criteria A and B), the half-life of escitalopram was about twice as long and the exposure was about 60% higher than in subjects with normal liver function.
Reduced renal function
With racemic citalopram, a longer half-life and a minor increase in exposure have been observed in patients with reduced kidney function (CLcr 10-53 ml/min). Plasma concentrations of the metabolites have not been studied, but they may be elevated.
Polymorphism
It has been observed that poor metabolisers with respect to CYP2C19 have twice as high a plasma concentration of escitalopram as extensive metabolisers. No significant change in exposure was observed in poor metabolisers with respect to CYP2D6.
No special requirements.
