CIPRALEX

Based on the mechanism of action of escitalopram and the potential for serotonin syndrome, caution is advised when Cipralex is co-administered with other drugs or agents that may affect the serotonergic neurotransmitter systems, such as tryptophan, triptans, serotonin reuptake inhibitors, lithium, tramadol, or St. John's Wort (see Warnings and Precautions, Serotonin Syndrome/Neuroleptic Malignant Syndrome (NMS)-Like Events). Concomitant use of Cipralex and MAO inhibitors (including linezolid, an antibiotic which is a reversible nonselective MAO inhibitor) is contraindicated (see Contraindications).

Cases of life-threatening serotonin syndrome have been reported during combined use of selective serotonin reuptake inhibitors (SSRIs)/serotonin norepinephrine reuptake inhibitors (SNRIs) and triptans. If concomitant treatment with Cipralex and a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see Warnings and Precautions, Serotonin Syndrome/Neuroleptic Malignant Syndrome (NMS)-Like Events).

Citalopram: Based on the results of broad in vitro and in vivo testing, racemic citalopram is neither the source nor the cause of any clinically important pharmacokinetic drug-drug interactions. In vitro enzyme inhibition data did not reveal an inhibitory effect of citalopram on CYP3A4, -1A2, -2D6, -2C9, -2C19 and -2E1. Accordingly, escitalopram would be expected to have little inhibitory effect on in vivo drug metabolism mediated by the cytochrome P-450 isozymes. In addition, pharmacokinetic interaction studies with racemic citalopram have also demonstrated no clinical important interactions with carbamazepine (CYP3A4 substrate), triazolam (CYP3A4 substrate), theophylline (CYP1A2 substrate), warfarin (CYP2C9 substrate), levomepromazine (CYP2D6 inhibitor).

Escitalopram: Using in vitro models of human liver microsomes, the biotransformation of escitalopram to its demethylated metabolites was shown to depend on three parallel pathways (CYP2C19, CYP3A4 with a smaller contribution from CYP2D6) (see Dosage and Administration, CYP2C19 Poor Metabolizers).

Studies also indicate that escitalopram is a very weak or negligible inhibitor of human hepatic isoenzyme CYP1A2, 2C9, 2C19, 2E1, and 3A4, and a weak inhibitor of 2D6. Although escitalopram has a low potential for clinically significant drug interactions, caution is recommended, when escitalopram is co-administered with drugs that are mainly metabolized by CYP2D6, and that have a narrow therapeutic index.

The possibility that the clearance of escitalopram will be decreased when administered with the following drugs in a multiple-dose regimen should be considered:

• potent inhibitors of CYP3A4 (eg. fluconazole, ketoconazole, itraconazole, erythromycin), or

  
  

• potent inhibitors of CYP2C19 (eg. omeprazole, esomeprazole, fluvoxamine, lansoprazole, ticlopidine). Caution should be exercised at the upper end of the dosage range of escitalopram when it is co-administered with CYP2C19 inhibitors.

  
  

In addition, a single-dose study of escitalopram co-administered with a multiple-dose regimen of cimetidine, a non-specific CYP inhibitor, led to significant changes in most of the pharmacokinetic parameters of escitalopram.

The overall metabolic pathways for escitalopram and citalopram are qualitatively similar and the interaction potential for escitalopram is expected to closely resemble that of citalopram. Thus, this allows for extrapolation to previous studies with citalopram.

In common with other SSRIs and newer antidepressants, pharmacodynamic interactions between escitalopram and the herbal remedy St-John's Wort may occur and may result in undesirable side effects.

Escitalopram is the active enantiomer of racemic citalopram. The pharmacokinetic studies described in the following sections, whether using escitalopram or racemic citalopram, were carried out in young healthy, mostly male volunteers. In addition, many of the studies utilized single doses of the specific concomitant medication, with multiple dosing of escitalopram or citalopram. Thus, data are not available in patients who would be receiving the concomitant drugs on an ongoing basis at therapeutic doses.

Combined use of escitalopram and MAO inhibitors is contraindicated due to the potential for serious reactions with features resembling serotonin syndrome or neuroleptic malignant syndrome (see Contraindications and Warnings and Precautions, Serotonin Syndrome/Neuroleptic Malignant Syndrome (NMS)-Like Events).

As escitalopram (Cipralex), is the active isomer of racemic citalopram (Celexa), the two drugs should not be taken together.

Various scientific publications have acknowledged that the main components in grapefruit juice may act as CYP3A4 inhibitors. Escitalopram is also metabolized by other isoenzymes not affected by grapefruit juice, namely CYP2C19 and CYP2D6. Although there is a theoretical possibility of pharmacokinetic drug interactions resulting from co-administration of escitalopram with grapefruit juice, the onset of an interaction is considered unlikely.

Interactions with laboratory test have not been established.

The interaction between escitalopram and alcohol has not been studied. Although racemic citalopram did not potentiate the cognitive and psychomotor effects of alcohol in volunteers, the concomitant use of alcohol in depressed patients taking escitalopram is not recommended.

Drug interactions have not been specifically studied between either escitalopram or racemic citalopram and other centrally acting drugs. Given the primary CNS effects of escitalopram, caution should be used as with other SSRIs when escitalopram is taken in combination with other centrally acting drugs.

It has been observed that poor metabolizers with respect to CYP2C19 have twice as high a plasma concentration of escitalopram as extensive metabolizers. (See Dosage and Administration, CYP2C19 Poor Metabolizers.) Although no significant change in exposure was observed in poor metabolizers with respect to CYP2D6, caution is recommended when escitalopram is co-administered with medicinal products that are mainly metabolizers by this enzyme, and that have a narrow therapeutic index.

See Potential Association with Behavioural and Emotional Changes, Including Self-harm under Warnings and Precautions.

Symptoms associated with the discontinuation or dosage reduction of escitalopram have been reported. Patients should be monitored for these and other symptoms when discontinuing treatment or during dosage reduction (see Warnings and Precautions and Adverse Reactions).

A gradual reduction in the dose over several weeks rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient's clinical response (see Warnings and Precautions and Adverse Reactions).

Dosages should be restricted to the lower end of the dose range in patients with mild to moderate hepatic insufficiency. Accordingly, an initial single oral dose of 5 mg daily is recommended. Subsequently, the dose may be increased based on the patient's response and clinical judgement. A daily dose of 10 mg is the recommended maximum dose for most patients with hepatic impairment. No information is available about the pharmacokinetics of escitalopram in patients with severe hepatic impairment (Child-Pugh Criteria C). Escitalopram should be used with additional caution in patients with severe hepatic impairment.

No dosage adjustment is necessary for patients with mild or moderate renal impairment. Since no information is available on the pharmacokinetic or pharmacodynamic effects of either escitalopram or racemic citalopram in patients with severely reduced renal function (creatinine clearance <30 mL/min), escitalopram should be used with caution in these patients.

During long-term therapy, the dosage should be maintained at the lowest effective level and patients should be periodically reassessed to determine the need to continue treatment.

Escitalopram should be administered as a single oral dose of 10 mg daily. Depending on individual patient response, an increase in the dose to a maximum of 20 mg daily should be considered. Where initial sensitivity to adverse events may be a concern, escitalopram could be started at 5 mg daily and titrated upwards as tolerated. During long-term therapy, the dosage should be maintained at the lowest effective level and patients should be periodically reassessed to determine the need to continue treatment.

In the event that a dose is missed, the patient should take the next dose when it is due.

At least 14 days should elapse between discontinuation of a MAOI and initiation of therapy with escitalopram. Similarly, at least 14 days should be allowed after stopping escitalopram before starting a MAOI (see Contraindications).

Escitalopram should be administered as a single oral dose of 10 mg daily. Depending on individual patient response, an increase in the dose to a maximum of 20 mg daily should be considered. Where initial sensitivity to adverse events may be a concern, escitalopram could be started at 5 mg daily and titrated upwards as tolerated.

Cipralex (escitalopram oxalate) is not indicated for use in children under 18 years of age (see Warnings and Precautions, Potential Association with Behavioural and Emotional Changes, Including Self-harm).

Escitalopram should be administered as a single oral dose of 10 mg daily. Depending on individual patient response, an increase in the dose to a maximum of 20 mg daily should be considered. Where initial sensitivity to adverse events may be a concern, escitalopram could be started at 5 mg daily and titrated upwards as tolerated. During long-term therapy, the dosage should be maintained at the lowest effective level and patients should be periodically reassessed to determine the need to continue treatment.

The metabolism of escitalopram is mainly mediated by CYP2C19. For patients who are known to be poor metabolizers with respect to CYP2C19, an initial dose of 5 mg daily is recommended. The dose may be increased based on the patient’s response and clinical judgement.

A longer half-life and decreased clearance have been demonstrated in the elderly, therefore lower doses and a lower maximum dose should be considered. It may be desirable to start at 5 mg daily and titrate upwards as needed and tolerated.

Post-marketing reports indicate that some neonates exposed to SSRIs such as Cipralex and other newer antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see Warnings and Precautions). When treating pregnant women with Cipralex during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering Cipralex in the third trimester.

Infrequent: accommodation disorder, blepharospasm, conjunctivitis, dry eye, eye pain, eye pruritus, mydriasis, photopsia, vision blurred. Rare: asthenopia, chromatopsia, eye haemorrhage, eye irritation, eye swelling, eyelid oedema, iritis, keratoconus, myopia, night blindness, retinal detachment, scotoma, vitreous detachment.

Rare: goiter, hyperthyroidism, thyroiditis.

Infrequent: animal bite, ankle fracture, arthropod bite, contusion, excoriation, fall, injury, intentional overdose, joint dislocation, joint injury, joint sprain, limb injury, mouth injury, procedural pain, road traffic accident, skin laceration, sunburn, thermal burn. Rare: arthropod sting, back injury, concussion, electric shock, eye injury, facial bones fracture, foot fracture, ligament injury, muscle rupture, neck injury, post-traumatic pain, radius fracture, rib fracture, sports injury, tooth injury, ulna fracture, whiplash injury.

From the short-term (8-week) placebo-controlled, phase III studies in patients suffering from MDD, the incidence of discontinuation was: 17.3% (124/715) on escitalopram, 15.7% (64/408) on citalopram and 16.4% (97/592) on placebo. Discontinuation due to adverse events was more common in the active treatment groups (5.9% in escitalopram and 5.4% in citalopram) than in the placebo group (2.2%).

The events that were associated with discontinuation of escitalopram in 1% or more of patients at a rate of at least twice that of placebo were: nausea (1.5% vs 0.2%) and ejaculation failure (1.8% vs 0.0% of male patients).

Among the 832 GAD patients who received escitalopram 10-20 mg/day in placebo-controlled trials, 7.8% discontinued treatment due to an adverse event, as compared to 3.2 % of 566 patients receiving placebo. Adverse events that were associated with the discontinuation of at least 1% of patients treated with escitalopram, and for which the rate was higher than the placebo rate, were: dizziness (1.2% vs. 0.2%), fatigue (1.1% vs. 0.2%) and nausea (1.8% vs. 0.2%).

During the first 12 weeks of treatment in the 24-week placebo controlled trial, discontinuation of treatment due to adverse events was reported for 9% and 11% of the 227 OCD patients who were treated with 10 mg/day or 20 mg/day escitalopram, respectively, compared to 5% of the 114 patients receiving placebo. All patients who discontinued treatment due to adverse events in the escitalopram groups did so in the first 12 weeks. Eight percent of patients receiving placebo discontinued treatment due to an adverse event during the 24-week period. Adverse events that were associated with discontinuation of at least 1% of patients treated with escitalopram, and for which the rate was higher than the placebo rate, were: nausea (1.8% vs. 0.0%), insomnia (1.8% vs. 0.9%), and erectile dysfunction (1.1% vs. 0.0%).

Infrequent: asthma, cough, dyspnoea, epistaxis, nasal congestion, postnasal drip, rhinitis allergic, rhinorrhoea, throat irritation, wheezing. Rare: allergic sinusitis, choking, dysphonia, nasal polyps, rhinitis perennial, throat tightness, trachoeal disorder.

In general, the safety profile was similar in the long-term (24-week) placebo-controlled phase of the trial in which patients who initially responded to 16 weeks of open label escitalopram treatment were randomized to treatment with escitalopram or placebo for up to 24 weeks. The following events (single or duplicate cases), which are not reported elsewhere, have been reported: abdominal pain lower, acute tonsillitis, blood pressure decreased, dental operation, depressive symptoms, dysarthria, dyspareunia, epicondylitis, facial pain, haematochezia, hordeolum, infrequent bowel movements, laceration, lacrimation increased, limb operation, negative thoughts, neuralgia, pain inflammation activated, subcutaneous abscess, tendon injury, wisdom teeth removal.

Rare: epidermal naevus, Gilbert’s syndrome.

Infrequent: acne, alopecia, dermatitis allergic, dermatitis contact, dry skin, eczema, increased tendency to bruise, rash, urticaria. Rare: cold sweat, dermal cyst, dermatitis, dermatitis acneiform, dermatitis atopic, hand dermatitis, ingrowing nail, photosensitivity reaction, rash maculo-papular, skin irritation, skin nodule, skin odor abnormal, skin warm.

In general, the adverse event profile that occurred among the patients who received escitalopram during the 24 weeks of the trial was similar to the profile observed in the first 12 weeks of the trial.

Infrequent: tooth extraction. Rare: colon polypectomy, gingival operation, scar excision.

Infrequent: arthritis, joint stiffness, muscle contracture, muscle spasms, muscle tightness, muscle twitching, muscular weakness, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal stiffness, osteoarthritis, pain in jaw. Rare: chest wall pain, costochondritis, exostosis, fibromyalgia, finger deformity, ganglion, intervertebral disc protrusion, musculoskeletal pain, plantar fasciitis, rheumatoid arthritis, sacroiliitis, sensation of heaviness, tendon disorder.

Infrequent: acute sinusitis, bronchitis acute, cystitis, ear infection, eye infection, folliculitis, fungal infection, gastrointestinal infection, laryngitis, lung infection, pelvic inflammatory disease (gs=Gender Specific), otitis media, pharyngitis, pharyngitis streptococcal, pneumonia, respiratory tract infection, skin infection, tooth abscess, tonsillitis, tooth infection, urinary tract infection, vaginal candidiasis (gs), viral infection, viral upper respiratory tract infection, vulvovaginal mycotic infection (gs). Rare: appendicitis, bronchitis viral, carbuncle, cellulitis, dental caries, erysipelas, furuncle, genitourinary chlamydia infection, gingival infection, impetigo, infection parasitic, mastitis, onychomycosis, otitis externa, peritonsillar abcess, pyelonephritis acute, rash pustular, salmonellosis, staphylococcal infection, streptococcal infection, tracheitis, vaginal infection, varicella, wound infection.

Patients treated with escitalopram in short-term controlled trials did not differ from placebo-treated patients with regards to clinically important change in body weight. In one 24-week randomized clinical trial in patients with Social Anxiety Disorder, 8.0% of patients treated with escitalopram and 3.2% of patients treated with placebo experienced weight gain of 7% or more.

Infrequent: flushing, haematoma, hypertension, hypotension, orthostatic hypotension, peripheral coldness, varicose vein. Rare: circulatory collapse, pallor, vein disorder.

Infrequent: blood glucose increased, blood pressure increased, body temperature increased, heart rate increased, weight decreased. Rare: arthroscopy, blood bilirubin increased, blood cholesterol increased, blood uric acid increased, blood urine present, electrocardiogram PR shortened, haemoglobin decreased, hepatic enzyme increased, pregnancy test positive (gs).

Infrequent: anaemia, lymphadenopathy. Rare: lymphadenitis.

Infrequent: agitation, apathy, bruxism, confusional state, crying, depersonalization, depressed mood, derealisation, disorientation, early morning awakening, emotional disorder, hallucination auditory, initial insomnia, libido increased, mental disorder, middle insomnia, mood swings, nervousness, obsessive-compulsive disorder, panic attack, suicidal ideation, suicide attempt, tension, thinking abnormal. Rare: aggression, emotional distress, euphoric mood, flat affect, generalized anxiety disorder, hallucination, hypomania, indifference, major depression, paranoia, psychomotor retardation, tic.

Infrequent: abdominal discomfort, abdominal distension, Crohn’s disease, dysphagia, enteritis, epigastric discomfort, food poisoning, frequent bowel movements, gastrointestinal pain, gastroesophageal reflux disease, gastritis, haemorrhoids, lip dry, rectal haemorrhage. Rare: anal fissure, colitis ulcerative, colonic polyp, eructation, gingival pain, haematemesis, haematochezia, ileitis, oral pain, pruritus ani, reflux gastritis, stomatitis, tongue black hairy, tongue disorder, tooth disorder, tooth erosion.

Adverse events that occurred in escitalopram-treated patients in the course of the short-term, placebo-controlled trials with an incidence greater than, or equal to, 10% were: headache and nausea. The incidence of headache was higher in the placebo group, which suggests that this is a non-specific symptom related to the underlying condition or treatment administration. The point prevalence of nausea increased during the first week (as expected with an SSRI) and then decreased to approach placebo levels by the end of the studies.

Infrequent: amenorrhoea (gs), epididymitis (gs), menstrual disorder (gs), menstruation irregular (gs), metrorrhagia (gs), orchitis noninfective (gs), painful erection (gs), pelvic pain, premenstrual syndrome (gs), postmenopausal haemorrhage (gs), sexual dysfunction, testicular pain (gs). Rare: breast discharge, breast pain, breast tenderness, genital pain, menopausal symptoms (gs), uterine spasm (gs), vaginal discharge (gs), vaginal haemorrhage (gs).

Untoward events associated with the exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. Reported adverse events were classified using the Medical Dictionary for Regulatory Activities, version 9.1.

The events listed below present treatment emergent adverse events reported during the clinical development program of escitalopram in depressed patients (n=896), which includes a long-term clinical trial, in GAD patients included in short-term (8-12 weeks) trials (n=832) and in one GAD long-term (24-76 weeks) trial (n=187); and in OCD patients included in a long-term (24 weeks with assessments at 12 weeks and 24 weeks) trial (n=227). Excluded from this list are those already listed in Table 1 (MDD), Table 4 (GAD) or Table 6 (OCD first 12 weeks of a 24 week trial).

It is important to emphasise that, although the events reported occurred during treatment with escitalopram, they were not necessarily caused by it. The events are categorized by body system and listed according to the following criteria: frequent: adverse events that occurred on one or more occasions in at least 1/100 patients; infrequent: adverse events that occurred in less than 1/100 patients but at least in 1/1000 patients; rare: adverse events that occurred in less than 1/1000 but at least in 1/10 000 patients.

Adverse events not listed above that have been reported to be temporally (but not necessarily causally) associated with escitalopram treatment since its market introduction include: aggression, alanine aminotransferase increased, amblyopia, amenorrhoea not otherwise specified (NOS), angioedema, anxiety aggravated, appetite decreased NOS, aspartate aminotransferase increased, atrial fibrillation, blood alkaline phosphatase NOS increased, blood cholesterol increased, blood glucose increased, blood pressure increased, burning sensation NOS, cardiac arrest, cerebrovascular accident, clonic convulsion, coma, completed suicide, confusional state, contusion, convulsions NOS, death NOS, delirium, diplopia, disorientation, drug level NOS increased, dysarthria, dysgeusia, dyskinesia, dysphasia, ecchymosis, electrocardiogram QT prolonged, emotional distress, epidermal necrolysis, epistaxis, erectile dysfunction NOS, extrapyramidal disorder, facial palsy, feeling abnormal, fluid retention, gait abnormal NOS, galactorrhoea, gastrointestinal haemorrhage, gingival bleeding, grand mal convulsion, haematemesis, hallucination visual, hepatitis NOS, hyperventilation, hypoglycaemia NOS, injury NOS, INR increased, irritability, leukocytosis, leukopenia NOS, liver function tests NOS abnormal, loss of consciousness, memory impairment, menometrorrhagia, muscle cramps, myocardial infarction, myocardial ischaemia, neuroleptic malignant syndrome, neurotransmitter level altered, night sweats, nightmare, orthostatic hypotension, pancreatitis NOS, panic attack, panic reaction, petit mal epilepsy, platelet count decreased, priapism, pulmonary embolism, pyrexia, renal failure acute, restlessness, rhabdomyolysis, rhinorrhoea, serotonin syndrome, SIADH, speech disorder, stomatitis, tardive dyskinesia, thrombocytopenia, torsades de pointes, trismus, urinary incontinence, vasovagal attack, ventricular tachycardia, vision blurred, visual disturbance NOS, weakness.

Infrequent: food craving. Rare: dehydration, gout, hypercholesterolaemia, hypermagnesaemia, hyperphagia, latent tetany.

Infrequent: breast neoplasm. Rare: benign breast neoplasm, lipoma, marrow hyperplasia, skin papilloma, uterine leiomyoma (gs).

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Rare: atrial fibrillation, atrial ventricular block first degree, bradycardia, extrasystoles, myocarditis, nodal rhythm, sinus bradycardia.

Infrequent: chest discomfort, chest pain, feeling abnormal, feeling jittery, influenza like illness, malaise, oedema, oedema peripheral, pain, respiratory sighs, sluggishness, thirst. Rare: early satiety, face oedema, feeling hot, hunger, local swelling, performance status decreased, sensation of blood flow.

Escitalopram and placebo groups in MDD and GAD patients were compared with respect to mean change from baseline in vital signs (pulse, systolic blood pressure, and diastolic blood pressure) and the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. The analyses did not reveal any clinically important changes in blood pressure associated with escitalopram treatment. In line with other SSRIs, including racemic citalopram, escitalopram causes statistically significant, but clinically unimportant decrease in heart rate. In MDD patients <60 years old, the mean decrease with escitalopram was approximately 2.3 bpm, while in patients ≥60 years old, the mean decrease was approximately 0.6 bpm.

Electrocardiograms from escitalopram and placebo groups in MDD and GAD patients were compared with respect to mean change from baseline in various ECG parameters and the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. Escitalopram was not associated with the development of clinically significant ECG abnormalities.

Infrequent: ear disorder, ear pain, tinnitus. Rare: cerumen impaction, deafness, Meniere’s disease, motion sickness, tympanic membrane perforation.

Infrequent: dysuria, haematuria, micturition urgency, urinary hesitation. Rare: bladder dilatation, bladder discomfort, chromaturia, nocturia, renal pain, urinary incontinence.

In general, the safety profile was similar in the long-term placebo-controlled study (24-76 weeks). The following events (single or duplicate cases), which are not listed in Table 4 and Table 5 or reported above in the short-term trials, have been reported: aneurysm, arteriosclerosis, dermatitis bullous, hypercholesterolaemia, hypocalcaemia, hypokalaemia, joint dislocation, migraine, nasal septum deviation, psoriasis, scoliosis, torticollis.

There have been reports of adverse reactions upon the discontinuation of SSRIs such as escitalopram (particularly when abrupt), including but not limited to the following: dizziness, abnormal dreams, sensory disturbances (including paraesthesias and electric shock sensations), agitation, anxiety, emotional indifference, impaired concentration, headache, migraine, tremor, nausea, vomiting and sweating or other symptoms which may be of clinical significance (see Warnings and Precautions and Dosage and Administration).

Patients should be monitored for these or any other symptoms. A gradual reduction in the dosage over several weeks, rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient's clinical response. These events are generally self-limiting. Symptoms associated with discontinuation have been reported for other selective serotonin reuptake inhibitors (see Warnings and Precautions and Dosage and Administration).

Infrequent: drug abuser. Rare: family stress, stress at work.

The treatment-emergent adverse event incidence profile of escitalopram in a longer term study in patients with major depressive disorder (MDD) consisting of a 36-week placebo-controlled relapse observation phase in responders of a preceding 8-week acute treatment phase was similar to that observed in short-term studies.

Infrequent: amnesia, balance disorder, burning sensation, carpal tunnel syndrome, coordination abnormal, dizziness postural, disturbance in attention, dysgeusia, hyperreflexia, hypersomnia, hypertonia, hypoaesthesia, memory impairment, muscle contractions involuntary, restless legs syndrome, sciatica, syncope, tension headache. Rare: dysaesthesia, dysphasia, facial paresis, facial spasm, head discomfort, hypogeusia, myoclonus, paralysis, psychomotor hyperactivity, sensory disturbance, sleep talking, syncope vasovagal.

Infrequent: pregnancy (gs).

Adverse events information for Cipralex (escitalopram oxalate) was collected from 715 patients with major depressive disorder (MDD) who were exposed to escitalopram and from 592 patients who were exposed to placebo in double-blind, placebo-controlled trials. During clinical trials, all treatment groups were comparable with respect to gender, age and race. The mean age of patients was 41 years (18 to 76 years). Of these patients, approximately 66% were females and 34% were males.

The adverse event information for Cipralex in patients with generalized anxiety disorder (GAD) was collected from 832 patients exposed to escitalopram and from 566 patients exposed to placebo in 8-12 week double-blind, placebo-controlled trials. A total of 187 patients exposed to escitalopram and 188 patients exposed to placebo in a 24 to 76 week double-blind phase of a placebo-controlled long-term trial were also included. The demographics of the clinical trial population in GAD were similar to the population of patients included in MDD clinical trials.

The adverse event information for Cipralex in patients with obsessive-compulsive disorder (OCD) was collected from two studies with double-blind, placebo-controlled treatment periods of up to 24 weeks. In the first study, a total of 227 patients were exposed to escitalopram and 114 patients were exposed to placebo in a 24-week double-blind, placebo-controlled, fixed-dose trial with assessments at weeks 12 and 24. In the second study, 322 patients who initially responded to 16 weeks of open-label escitalopram treatment were subsequently randomized to double-blind treatment with escitalopram (n=164) or placebo (n=158) for up to 24 weeks. In total, 391 patients were exposed to escitalopram and 272 patients were exposed to placebo in these two long-term studies. The mean age of patients with OCD included in the trials was approximately 36 to 38 years (ranging from 18 to 67 years). One trial included similar proportions of males and females and the other trial had a slightly higher proportion of females than males (57% females and 43% males).

Infrequent: anaphylactic reaction, house dust allergy, hypersensitivity, seasonal allergy. Rare: allergic oedema.

Although there was no evidence from clinical studies suggesting that use in geriatric population is associated with differences in safety and effectiveness, a greater sensitivity of some older individuals to effects of escitalopram cannot be ruled out. A brief discussion can be found in the appropriate sections (Action and Clinical Pharmacology, Pharmacokinetics; Warnings and Precautions and Dosage and Administration).

Escitalopram is not indicated for use in patients below the age of 18 (see Warnings and Precautions, General, Potential Association with Behavioural and Emotional Changes, Including Self-harm).

Cipralex (escitalopram oxalate) is indicated for the symptomatic relief of Major Depressive Disorder (MDD).

As with racemic citalopram, there is no specific antidote to escitalopram. Treatment is symptomatic and supportive. Establish and maintain an airway to ensure adequate ventilation and oxygenation. Gastric lavage and use of activated charcoal should be considered as soon as possible after oral ingestion. Cardiac and vital sign monitoring are recommended, along with general symptomatic and supportive measures.

Due to the large volume of distribution of escitalopram, forced diuresis, dialysis, haemoperfusion and exchange transfusion are unlikely to be of benefit.

In managing overdosage, the possibility of multiple drug involvement must be considered.

Each film-coated, white, oval, scored tablet, marked with “EL” on one side, contains: escitalopram 10 mg (as escitalopram oxalate). Nonmedicinal ingredients: colloidal silicon dioxide, croscarmellose sodium, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, talc and titanium dioxide (white E-171). Blister packages of 30. Bottles of 100.

Each film-coated, white, oval, scored tablet, marked with “EN” on one side, contains: escitalopram 20 mg (as escitalopram oxalate). Nonmedicinal ingredients: colloidal silicon dioxide, croscarmellose sodium, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, talc and titanium dioxide (white E-171). Blister packages of 30.

Neither escitalopram nor racemic citalopram has been systematically evaluated in diabetic patients; in the case of racemic citalopram, diabetes constituted an exclusion criterion. Rare events of hypoglycaemia were reported for racemic citalopram. Treatment with an SSRI in patients with diabetes may alter glycaemic control (hypoglycaemia and hyperglycaemia). Escitalopram should be used with caution in diabetic patients on insulin or oral hypoglycaemic drugs.

Recent analyses of placebo-controlled clinical trial safety databases from SSRIs and other newer antidepressants suggest that use of these drugs in patients under the age of 18 may be associated with behavioural and emotional changes, including an increased risk of suicidal ideation and behaviour over that of placebo.

In a study with healthy volunteers, racemic citalopram did not impair cognitive function or psychomotor performance. However, psychotropic medications may impair judgement, thinking or motor skills. Consequently, patients should be cautioned against driving a car or operating hazardous machinery until they are reasonably certain that escitalopram does not affect them adversely.

The following additional Precautions are listed alphabetically.

Post-marketing reports indicate that some neonates exposed to SSRIs such as escitalopram and other antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. When treating a pregnant woman with escitalopram during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see Warnings and Precautions, Special Populations, Pregnant Women and Nursing Women and Dosage and Administration).

Post-marketing reports indicate that some neonates exposed to SSRIs such as Cipralex and other antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnoea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycaemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and other newer antidepressants, or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see Warnings and Precautions, Serotonin Syndrome/Neuroleptic Malignant Syndrome (NMS)-Like Events). When treating a pregnant woman with Cipralex during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see Dosage and Administration).

The safety of escitalopram during human pregnancy and lactation has not been established. Therefore, escitalopram should not be used during pregnancy, unless the potential benefit to the patient outweighs the possible risk to the foetus.

Studies with escitalopram have not been performed in nursing mothers, but it is known that racemic citalopram is excreted in human milk and it is expected that escitalopram is also excreted into breast milk. Escitalopram should not be administered to nursing mothers unless the expected benefits to the patient outweigh the possible risk to the child.

When discontinuing treatment, patients should be monitored for symptoms that may be associated with discontinuation (e.g. dizziness, abnormal dreams, sensory disturbances [including paraesthesias and electric shock sensations], agitation, anxiety, emotional indifference, impaired concentration, headache, migraine, tremor, nausea, vomiting and sweating) or other symptoms that may be of clinical significance (see Adverse Reactions). A gradual reduction in the dosage over several weeks, rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient's clinical response (see Adverse Reactions and Dosage and Administration).

The safety and efficacy of the concurrent use of either escitalopram or racemic citalopram and ECT have not been studied.

Neither escitalopram nor racemic citalopram has been systematically evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were generally excluded from clinical trials during the drug's premarketing assessment. However, the electrocardiograms (ECG) of patients participating in clinical trials with escitalopram and racemic citalopram indicate that the medications were not associated with the development of clinically significant ECG abnormalities. In line with other SSRIs, including racemic citalopram, escitalopram causes statistically significant, but clinically unimportant decrease in heart rate. In patients <60 years old, the mean decrease with escitalopram was approximately 2.3 bpm, while in patients ≥60 years old, the mean decrease was approximately 0.6 bpm.

Based on a study conducted with escitalopram in patients with mild to moderate hepatic impairment, the half-life was approximately doubled and the exposure was increased by approximately two third, compared to subjects with normal liver function. Consequently, the use of escitalopram in hepatically impaired patients should be approached with caution and a lower dosage is recommended (see Dosage and Administration). No information is available about the pharmacokinetics of escitalopram in patients with severe hepatic impairment (Child-Pugh Criteria C). Escitalopram should be used with additional caution in patients with severe hepatic impairment.

In placebo-controlled trials of Cipralex (escitalopram oxalate) activation of mania/hypomania was reported in one patient of the n=715 treated with escitalopram and in none of the n=592 patients treated with placebo. Activation of mania/hypomania has also been reported in a small proportion of patients treated with racemic citalopram, and with other marketed antidepressants. As with other antidepressants, escitalopram should be used with caution in patients with a history of mania/hypomania.

Patients currently taking escitalopram should NOT be discontinued abruptly, due to risk of discontinuation symptoms. At the time that a medical decision is made to discontinue an SSRI or other newer antidepressant drug, a gradual reduction in the dose rather than an abrupt cessation is recommended.

Escitalopram is not indicated for use in patients below the age of 18 (see Warnings and Precautions, General, Potential Association with Behavioural and Emotional Changes, Including Self-harm ).

No information is available on the pharmacokinetic or pharmacodynamic effects of escitalopram on patients with renal impairment. Based on the information available for racemic citalopram, no dosage adjustment is needed in patients with mild to moderate renal impairment. Since no information is available on the pharmacokinetic or pharmacodynamic effects of either escitalopram or racemic citalopram in patients with severely reduced renal function (creatinine clearance <30 mL/min), escitalopram should be used with caution in these patients (see Dosage and Administration).

Approximately 5% of the 715 patients treated with escitalopram in clinical trials of depressive disorder were 60 years of age or over; elderly patients in these trials received daily doses between 10 and 20 mg. No overall significant differences in safety or effectiveness were observed between the elderly and younger subjects, but the number of elderly patients treated was insufficient to adequately assess for differential responses. Greater sensitivity of some older individuals to effects of escitalopram cannot be ruled out. In a multiple-dose pharmacokinetic study, the area under the curve (AUC) and half-life of escitalopram were increased by approximately 50% at steady-state in elderly subjects as compared to young subjects. Consequently, elderly patients should be administered lower doses and a lower maximum dose (see Action and Clinical Pharmacology, Pharmacokinetics and Dosage and Administration).

SSRIs and serotonin/norepinephrine reuptake inhibitors (SNRIs), including Cipralex, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. There have been reports of bleeding events ranging from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening haemorrhages, associated with treatment with SSRIs and SNRIs.

Caution is advised in patients taking SSRIs and SNRIs, particularly in concomitant use with drugs known to affect platelet function (e.g. atypical antipsychotics and phenothiazines, most tricyclic antidepressants, anticoagulants, platelet aggregation inhibitors, acetylsalicylic acid and NSAIDs), as well as in patients with a history of bleeding disorders or predisposing conditions (e.g., thrombocytopenia).

There are clinical trials and post-marketing reports with SSRIs and other newer antidepressants, in both pediatrics and adults, of severe agitation-type adverse events coupled with self-harm and harm to others. The agitation-type events include: akathisia, agitation, emotional lability, hostility, aggression, depersonalization. In some cases, the events occurred within several weeks of starting treatment.

Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behaviour is advised in patients of all ages. This includes monitoring for agitation-type emotional and behavioural changes.

As with other antidepressants, cases of hyponatraemia and SIADH (syndrome of inappropriate antidiuretic hormone secretion) have been reported with escitalopram and racemic citalopram as a rare adverse event. The majority of these occurrences have been in elderly individuals, some in patients taking diuretics or who were otherwise volume-depleted. Elderly female patients in particular seem to be a group at risk.

In one epidemiological case-control study on persistent pulmonary hypertension (PPHN) with n=377 infants with PPHN and n=836 matched control infants, PPHN was six times more common in babies whose mothers took an SSRI antidepressant after the 20th week of pregnancy compared to babies whose mothers did not take an antidepressant. The study was too small to determine relative risks among the specific SSRIs. This information is considered to be preliminary at this time. The absolute risk of PPHN in the general population is reported to be 1-2 per 1000.

Escitalopram has not been systematically evaluated in patients with a seizure disorder. These patients were excluded from the clinical studies. In clinical trials with escitalopram, convulsions have been reported very rarely (2 out of 3981 patients) in association with treatment with escitalopram. From post-marketing data, the reporting of seizures with escitalopram is comparable to that of other antidepressants. Like other antidepressants, escitalopram should be used with caution in patients with a history of seizure disorder.

The possibility of a suicide attempt is inherent in depression and may persist until remission occurs. Therefore, high-risk patients should be closely supervised throughout therapy with consideration to the possible need for hospitalization. In order to minimize the opportunity for overdosage, prescription for escitalopram should be written for the smallest quantity of drug consistent with good patient management.

Because of the well established comorbidity between depression and other psychiatric disorders, the same precautions observed when treating patients with depression should be observed when treating patients with other psychiatric disorders (see Warnings and Precautions, General, Potential Association with Behavioural and Emotional Changes, Including Self-harm).

On rare occasions serotonin syndrome or neuroleptic malignant syndrome-like events have occurred in association with treatment with SSRIs, including escitalopram, particularly when given in combination with other serotonergic and/or neuroleptic drugs. As these syndromes may result in potentially life-threatening conditions, treatment with Cipralex should be discontinued if such events (characterized by clusters of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma) occur and supportive symptomatic treatment should be initiated. Cipralex should not be used in combination with MAO inhibitors or serotonin-precursors (such as L-tryptophan, oxitriptan) and should be used with caution in combination with other serotonergic drugs (triptans, certain tricyclic antidepressants, lithium, tramadol, St. John’s Wort) due to the risk of serotonergic syndrome (see Contraindications and Drug Interactions, Serotonergic Drugs, Triptans (5HT1 agonists)).

In patients with mild to moderate hepatic impairment (Child-Pugh Criteria A and B), the half-life of escitalopram was approximately doubled (66 hours vs. 36 hours), and the exposure was about two-third higher than in subjects with normal liver function. Consequently, the doses in the lower end of the recommended range of escitalopram should be used for patients with hepatic dysfunction. No information is available about the pharmacokinetics of escitalopram in patients with severe hepatic impairment (Child-Pugh Criteria C). Escitalopram should be used with additional caution in patients with severe hepatic impairment (see Warnings and Precautions and Dosage and Administration).

Escitalopram pharmacokinetics in subjects older than 65 years of age was compared to younger subjects in a single/multiple-dose study (n=18 subjects ≥65). After a single dose, plasma escitalopram levels were similar in young and elderly subjects. At steady state in elderly subjects, escitalopram C_max, AUC and half-life values were increased by approximately 35, 50 and 50%, respectively, while the clearance values were decreased. In this population, lower doses and a lower maximum dose of escitalopram are recommended (see Warnings and Precautions and Dosage and Administration).

The single and multiple-dose pharmacokinetics of escitalopram are linear and dose-proportional in a dose range of 10 to 30 mg/day. Biotransformation of escitalopram is mainly hepatic with a mean terminal half-life of about 27-32 hours. With once daily dosing, steady-state plasma levels are achieved within approximately 1 week. At steady state, the plasma concentration of escitalopram in young healthy subjects was approximately 2.6 times that observed after a single dose.

The plasma clearance following oral administration is about 0,6 L/min with approximately 7% due to renal clearance. Escitalopram is metabolized in the liver to S-demethylcitalopram (S-DCT) and to S-didemethylcitalopram (S-DDCT). In humans, unchanged escitalopram is the predominant compound in plasma. After multiple-dose administration of escitalopram, the mean plasma concentrations of the metabolites S-DCT and S-DDCT are usually 28-31% and <5% of the parent compound concentration, respectively. Results from in vitro studies suggest that the metabolites (S-DCT and S-DDCT) do not contribute significantly to the clinical actions of escitalopram.

In vitro studies using human liver microsomes indicated that the biotransformation of escitalopram to its demethylated metabolites depends primarily on CYP2C19 and CYP3A4 with a smaller contribution from CYP2D6. The apparent hepatic clearance of drug amounts to approximately 90% of the administered dose. Following oral administration of escitalopram, the fraction of drug recovered as escitalopram and the metabolite S-DCT is about 8% and 10% respectively.

Following the administration of an oral dose (10 mg or 20 mg) of escitalopram to healthy volunteers, peak plasma levels occur at about 4 hours after dosing. Absorption of escitalopram is expected to be almost complete after oral administration and is not affected by food. After a single oral administration of escitalopram 10 mg, the apparent volume of distribution of (Vd,β,/F) is about 12 L/kg to 26 L/kg. The binding of escitalopram to human plasma proteins is independent of drug plasma levels and average 55 %.

No information is available about the pharmacokinetics of escitalopram in patients with reduced renal function. In n=7 patients with mild to moderate renal function impairment, oral clearance of racemic citalopram was reduced by 17% compared to normal subjects, with no clinically significant effect on the kinetics. No adjustment of dosage is recommended for such patients. At present no information is available about the pharmacokinetics of either escitalopram or racemic citalopram for the chronic treatment of patients with severely reduced renal function (creatinine clearance <30 mL/min) (see Warnings and Precautions and Dosage and Administration).

In a multiple dose study of escitalopram (10 mg/day for 3 weeks) in 18 male (9 elderly and 9 young) and 18 female (9 elderly and 9 young) subjects, there were no differences in the weight-adjusted values of the area under the curve (AUC), C_max, and half-life between the male and the female subjects. No adjustment in dosage is recommended on the basis of gender difference.