Source: Health Products Regulatory Authority (ZA) Revision Year: 2019 Publisher: CIPLA MEDPRO (PTY) LTD., Building 9, Parc du Cap, Mispel Street, Bellville, 7530
The use of LEXAMIL is contraindicated in the following circumstances:
Safety and efficacy in children younger than 18 years have not been established (see “CONTRAINDICATIONS”). In clinical trials in major depressive disorder, there were increased reports of hostility and suicide-related adverse events such as suicidal ideation and self-harm.
Patients should be closely monitored during the first few weeks or more of therapy as improvement may not occur during this period. The possibility of a suicide attempt which is inherent in depression, may persist until significant therapeutic effect has been established.
Both adults and children diagnosed with major depressive disorder may experience worsening of their depression and/or emergence of suicidal ideation and behaviour, whether or not they are receiving treatment with antidepressant medicine. Suicide risk may persist until significant remission occurs. However, it has not been established that antidepressant medicine plays a causal role in inducing such behaviour. Patients who are receiving treatment with LEXAMIL should be closely monitored for clinical worsening of their symptoms and suicidality, especially at the start of a course of therapy or at any time dosages are altered (including both increases and decreases).
Due to the possibility of co-morbid psychiatric and non-psychiatric disorders occurring in conjunction with major depressive disorder, the same precautions taken when treating patients with major depressive disorders should be observed when treating patients with other psychiatric and non-psychiatric disorders.
Patients who have received treatments with antidepressants for major depressive disorder as well as for other indications (both psychiatric and non-psychiatric), reported the following symptoms: anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia, hypomania and mania. Although a causal link between the use of antidepressants and the emergence of suicidal impulses has not been demonstrated, consideration should be given to changing the therapeutic regimen, including possibly discontinuing LEXAMIL, in patients for whom such symptoms are severe, abrupt in onset, or in whom such symptoms did not form part of the patient’s presenting complaints.
If the decision is made to discontinue treatment, administration of LEXAMIL should be tapered (see “DOSAGE AND DIRECTIONS FOR USE”).
Usage of LEXAMIL should be discontinued in any patient entering a manic phase. In patients with a history of mania/hypomania, LEXAMIL should be used with caution.
Some patients who suffer from panic disorder may experience increased anxiety symptoms after initiation of treatment with antidepressants, including LEXAMIL. With continued treatment this paradoxical reaction usually subsides within 2 weeks. The likelihood of a paradoxical anxiogenic effect may be reduced with the use of low starting doses.
LEXAMIL administration should be discontinued in any patient who develops seizures for the first time. Patients with controlled epilepsy should be carefully monitored, but use of LEXAMIL should be avoided in patients with unstable epilepsy. Should a patient develop an increase in seizure frequency, the administration of LEXAMIL should be discontinued.
Treatment with LEXAMIL may alter glycaemic control in diabetics. This may possibly be due to an improvement of depressive symptoms. It may be necessary to adjust insulin and/or oral hypoglycaemic medicine dosages.
Cutaneous bleeding abnormalities, including ecchymoses and purpura, have been reported with the use of LEXAMIL. Caution is advised in patients who are receiving treatment with LEXAMIL, especially in instances where there is concomitant administration of medicines known to affect platelet function [such as atypical antipsychotics and phenothiazines, most tricyclic antidepressants, aspirin and non-steroidal anti-inflammatory drugs (NSAIDS)], as well as in patients with a history of bleeding disorders (see “INTERACTIONS”).
Caution is advised inpatients who require concomitant ECT while taking LEXAMIL because of limited published clinical experience.
Co-administration of LEXAMIL with MAO inhibitors can lead to serotonin syndrome. Co-administration with other antidepressants with serotonergic properties, as well as other serotonergic medicines (e.g. tramadol, sumatriptan) may result in an enhancement of serotonin associated effects, e.g. the serotonin syndrome (see “INTERACTIONS”). A combination of symptoms (agitation, tremor, myoclonus and hyperthermia) may indicate the development of serotonin syndrome. LEXAMIL and the serotonergic medicine should be discontinued immediately if these symptoms occur and symptomatic treatment initiated.
Escitalopram, as found in LEXAMIL, has been found to cause a dose-dependent prolongation of the QT interval. Cases of QT interval 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 (see “CONTRAINDICATIONS”, “INTERACTIONS” and “SIDE-EFFECTS”).
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 life-threatening dysrhythmias and should be corrected before treatment with LEXAMIL 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 LEXAMIL, the treatment should be withdrawn and an ECG should be performed.
The use of SSRIs, such as LEXAMIL, 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 during the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental (see “SIDE-EFFECTS”) and it may be necessary to review the use of LEXAMIL.
Hyponatraemia, probably due to inappropriate antidiuretic hormone secretion (SIADH), has been reported with the use of SSRIs and generally resolves on discontinuation of therapy. Caution should be exercised in patients at risk, such as the elderly, or patients with cirrhosis, or if LEXAMIL is used in combination with other medications which may cause hyponatraemia.
Concomitant use of LEXAMIL and herbal remedies containing St. John’s Wort (Hypericum perforatum) may result in an increased incidence of adverse reactions (see “INTERACTIONS”).
Due to limited clinical experience, caution is advised in patients with coronary heart disease.
Epidemiology studies conducted mainly in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRIs, including LEXAMIL, and TCAs (tricyclic antidepressants). The mechanism leading to this risk is unknown.
SSRIs including escitalopram, as in LEXAMIL, may have an effect on pupil size resulting in mydriasis. This mydriatic effect has the potential to narrow the eye angle resulting in increased intraocular pressure and angle-closure glaucoma, especially in patients pre-disposed. LEXAMIL should therefore be used with caution in patients with angle-closure glaucoma or history of glaucoma.
Discontinuation symptoms when stopping treatment are common, particularly if discontinuation is abrupt (see “SIDE-EFFECTS”). The risk of discontinuation symptoms may be dependent on several factors, including the duration and dose of therapy and the rate of dose reduction. They usually occur within the first few days of discontinuing treatment, but there have been 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 to 3 months or more). It is therefore advised, when discontinuing treatment, that LEXAMIL should be gradually tapered over a period of several weeks or months, according to the patient’s needs (see “DOSAGE AND DIRECTIONS FOR USE”).
LEXAMIL has a low potential for causing clinically significant medicine interactions. The biotransformation of escitalopram to its demethylated metabolites depends on three parallel pathways, namely cytochrome P450 (CYP) 2C19, 3A4 and 2D6). Escitalopram, as in LEXAMIL, inhibits iso-enzymes CYP1A2, 2C9, 2C19, 2E1 and 3A very weakly, while it inhibits 2D6 weakly.
Co-administration of a single dose of ritonavir (CYP3A4 inhibitor) does not change the pharmacokinetics of single doses of LEXAMIL.
The pharmacokinetics of racemic citalopram is not affected by the co-administration of ketoconazole (a potent CYP3A4 inhibitor).
When cimetidine (potent CYP2D6, 3A4 and 1A2 inhibitor) is administered in conjunction with citalopram, the plasma concentrations of the racemate is increased (AUC by 43 % and Cmax by 39 %). Caution is therefore advised at the upper end of the dose range of LEXAMIL when used concomitantly with high doses of cimetidine.
Co-administration of escitalopram, as in LEXAMIL, with omeprazole 30 mg once daily (a CYP2C19 inhibitor) resulted in moderate (approximately 50 %) increases in the plasma concentrations of escitalopram.
Thus, caution should be exercised when LEXAMIL is used concomitantly with CYP2C19 inhibitors (e.g. omeprazole, esomeprazole, fluvoxamine, lansoprazole, ticlopidine). A reduction in the dose of LEXAMIL may be necessary based on monitoring of side-effects during concomitant treatment.
Co-administration of LEXAMIL with MAO inhibitors may give rise to the development of serotonin syndrome. When LEXAMIL is co-administered with other serotonergic medicines (such as tramadol and sumatriptan), including antidepressants with serotonergic properties, it may cause an enhancement of serotonin associated effects, e.g. the serotonin syndrome (see “WARNINGS AND SPECIAL PRECAUTIONS”).
The antibiotic linezolid is a reversible non-selective MAO inhibitor and should not be given to patients treated with LEXAMIL (see ʺCONTRAINDICATIONSʺ).
Reports have indicated that concomitant use of LEXAMIL and lithium or tryptophan may lead to enhanced effects. Co-administration of LEXAMIL with these medicines should therefore be undertaken with caution.
Concomitant use of LEXAMIL and herbal remedies containing St. John’s Wort (Hypericum perforatum) may result in an increased incidence of adverse reactions.
SSRIs, including LEXAMIL, can lower the seizure threshold. Caution is advised when concomitantly using other medicines capable of lowering the seizure threshold [e.g. antidepressants (tricyclics, SSRIs), neuroleptics (phenothiazines, thioxanthenes and butyrophenones), mefloquine, bupropion and tramadol].
When LEXAMIL is co-administered with a single dose of desipramine (a CYP2D6 substrate) it leads to a twofold increase in plasma levels of desipramine. Co- administration of LEXAMIL and desipramine should therefore be undertaken with caution. A similar increase in plasma levels of desipramine, following administration of imipramine, is seen when administered concomitantly with racemic citalopram.
When LEXAMIL is co-administered with a single dose of metoprolol 100 mg (a CYP2D6 substrate) it results in a twofold increase in the Cmax and a 52 % increase in the AUC of metoprolol. Despite this, the combination did not produce clinically significant effects on blood pressure and heart rate.
The AUC of selegiline is increased by 29 % following co-administration with racemic citalopram. The combination with selegiline (irreversible MAO B inhibitor) is contraindicated due to the risk of developing serotonin syndrome (see “CONTRAINDICATIONS”).
Pharmacokinetic and pharmacodynamic studies of escitalopram, as contained in LEXAMIL, combined with other medicines that prolong the QT interval have not been performed. An additive effect of LEXAMIL and these medicines cannot be excluded.
Co-administration of a single dose of pimozide 2 mg to patients treated with racemic citalopram 40 mg per day for 11 days caused an increase in AUC and C max of pimozide. The co-administration of pimozide and citalopram resulted in a mean increase in the QTc interval of approximately 10 msec.
Therefore, co-administration of LEXAMIL with medicines that prolong the QT interval, such as Class IA and III antidysrhythmics, antipsychotics (e.g. phenothiazine derivatives, pimozide, haloperidol), tricyclic antidepressants, certain antimicrobial medicines (e.g. sparfloxacin, moxifloxacin, erythromycin, pentamidine, antimalarial treatment particularly halofantrine), certain antihistamines (e.g. mizolastine), is contraindicated (see “CONTRAINDICATIONS” and “WARNINGS AND SPECIAL PRECAUTIONS”).
Results from pharmacokinetic interaction studies with racemic citalopram did not show any clinically significant interactions with carbamazepine (CYP3A4 substrate), triazolam (CYP3A4 substrate), theophylline (CYP1A2 substrate) (single dose), warfarin (CYP3A4 and CYP2C9 substrate), levomepromazine (CYP2D6 inhibitor), and digoxin. There was a slight increase in prothrombin time following administration of a single dose of 25 mg warfarin. The International Normalised Ratio (INR) needs to be carefully monitored in patients who require treatment with a combination of LEXAMIL and warfarin.
Altered anticoagulant effects may occur when LEXAMIL is combined with oral anticoagulants. Patients receiving oral anticoagulant therapy should receive careful coagulation monitoring when LEXAMIL is started or stopped. Concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs) may increase bleeding-tendency (see “WARNINGS AND SPECIAL PRECAUTIONS”).
No pharmacodynamic or pharmacokinetic interactions are expected between escitalopram, as in LEXAMIL, and alcohol. However, as with other psychotropic medicines, the combination with alcohol is not advisable
The use of LEXAMIL during pregnancy and lactation is not recommended as safety and efficacy have not been established.
Neonates should be observed if maternal use of LEXAMIL continues into the later stages of pregnancy, particularly in the third trimester. Abrupt discontinuation should be avoided during pregnancy.
The following symptoms may occur in the neonate after maternal SSRI/SNRI, including LEXAMIL, use in later stages of pregnancy: respiratory distress, cyanosis, apnoea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycaemia, hypertonia, hypotonia, hyperreflexia, tremor, jitteriness, irritability, lethargy, constant crying, somnolence and difficulty sleeping. These symptoms could be due to either serotonergic effects or discontinuation symptoms. In a majority of instances the complications begin immediately or soon (<24 hours) after delivery.
Epidemiological data have suggested that the use of SSRIs, such as LEXAMIL, in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN).
Use of LEXAMIL is not associated with impairment of intellectual function or psychomotor performance. However, patients who suffer from depression and who require treatment may have an impaired ability to drive or operate machinery and should therefore be warned of the potential risk. Patients should be advised to avoid such tasks if so affected.
Adverse reactions following administration of LEXAMIL are most frequently observed during the first one or two weeks of treatment. Adverse events may decrease in intensity and frequency with continued treatment.
After prolonged administration, abrupt discontinuation of LEXAMIL may cause withdrawal symptoms in some patients.
Frequency unknown: Thrombocytopenia.
Less frequent: Anaphylactic reactions.
Frequency unknown: Inappropriate ADH secretion.
Frequent: Decreased appetite, increased appetite, weight increased.
Less frequent: Weight decreased.
Frequency unknown: Hyponatraemia, anorexia.
Frequent: Anxiety, restlessness, abnormal dreams, decreased libido (males and females), anorgasmia (females).
Less frequent: Bruxism, agitation, nervousness, panic attack, confusional state, aggression, depersonalisation, hallucinations.
Frequency unknown: Mania, suicidal ideation, suicidal behaviour.
Frequent: Headache, insomnia, somnolence, dizziness, paraesthesia, tremor.
Less frequent: Serotonin syndrome (typically characterised by a rapid onset of changes in mental state, with confusion, mania, agitation, hyperactivity, shivering, fever, tremor, ocular movements, myoclonus, hyperreflexia, and incoordination), sleep disorder, taste disturbances, syncope.
Frequency unknown: Dyskinesia, movement disorder, convulsion, psychomotor restlessness / akathisia (see “WARNINGS AND SPECIAL PRECAUTIONS”).
Less frequent: Mydriasis, visual disturbances.
Less frequent: Tinnitus.
Less frequent: Tachycardia, bradycardia.
Frequency unknown: Electrocardiogram QT prolonged, ventricular dysrhythmia including torsade de pointes.
Frequency unknown: Orthostatic hypotension.
Frequent: Sinusitis, yawning.
Less frequent: Epistaxis.
Frequent: Nausea, diarrhoea, constipation, vomiting, dry mouth.
Less frequent: Gastrointestinal haemorrhages (including rectal haemorrhage).
Frequency unknown: Hepatitis, abnormal liver function tests.
Frequent: Increased sweating.
Less frequent: Urticaria, alopecia, rash, pruritus.
Frequency unknown: Ecchymosis, angioedema.
Frequent: Arthralgia, myalgia.
Frequency unknown: Urinary retention.
Frequent: Ejaculation disorder, impotence (males).
Less frequent: Metrorrhagia, menorrhagia.
Frequency unknown: Galactorrhoea, priapism.
Frequent: Fatigue, pyrexia.
Less frequent: Oedema.
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