Approval date: April 16, 2009
Revision date: 01/21/2010
July 18, 2011
May 15, 2013
February 18, 2014
June 16, 2014
July 17, 2014
September 29, 2014
XXXX XX/XX/2014
Escitalopram Oxalate Tablets Instructions
Please read the instructions carefully and use under the guidance of your physician.
Warnings
Antidepressants and suicidal ideation
Results of short-term clinical trials of depression (MDD) and other psychiatric disorders have shown that antidepressant medications increase the risk of suicidal thoughts and committing suicidal acts (suicidal ideation) in children, adolescents, and young adults (<24 years of age) compared to placebo. Any consideration of this or other antidepressant medications for use in children, adolescents, or young adults (<24 years of age) must weigh clinical need and risk. Short-term clinical trials have not shown an increased risk of suicidal ideation in patients older than 24 years of age using antidepressants compared with the placebo group; patients aged 65 years and older using antidepressants had a reduced risk of suicidal ideation compared with the placebo group. Depression and certain psychiatric disorders themselves, are associated with an increased risk of suicide and must be closely observed and reasonably monitored for worsening clinical symptoms, suicidal ideation, and abnormal changes in behavior after initiation of treatment with antidepressants in patients of all ages. Families and caregivers should be advised that they must closely observe and communicate with their physicians. This product is not approved for use in pediatric patients (see [Warnings], [Precautions] and [Pediatric Use]).
Drug Name]
Generic Name: Escitalopram Oxalate Tablets
English name: Escitalopram Oxalate Tablets
Hanyu Pinyin: Caosuan Aisixitaipulan Pian
Ingredients
Active ingredient: Escitalopram Oxalate
Chemical name: S (+)-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile oxalate
Chemical structure formula.
Molecular formula: C20H21FN2O-C2H2O4
Molecular weight: 414.43
Excipients: talc, microcrystalline cellulose, cross-linked sodium carboxymethylcellulose, cross-linked anhydrous silica gel, magnesium stearate, hydroxypropylmethylcellulose, polyethylene glycol 400, titanium dioxide
Properties
This product is white film-coated tablets.
Indications
Treatment of depression. Treatment of panic disorder with or without square phobia.
Specification
20 mg
Dosage and Administration
Dosage: Take orally, can be taken with food.
Dosage.
Depression
1 time daily. The usual dose is 10mg daily, and the maximum daily dose can be increased to 20mg depending on the individual response of the patient.
Antidepressant efficacy is usually obtained in 2 to 4 weeks. After remission of symptoms, treatment should be continued for at least 6 months to consolidate the efficacy.
Panic disorder with or without agoraphobia
1 dose per day. The recommended starting dose is 5 mg per day, increasing to 10 mg per day after one week, and the dose may be increased to a maximum of 20 mg per day depending on the individual response of the patient.
Optimal efficacy is achieved after approximately 3 months of treatment. The course of treatment usually lasts for several months.
Elderly patients (> 65 years)
It is recommended that treatment be initiated at half the usual starting dose (5 mg) as described above and that the maximum daily dose should not exceed 10 mg.
Children and adolescents (<18 years)
This product is not indicated for children and adolescents under 18 years of age.
People with reduced renal function
No dose adjustment is required for mild to moderate reduced renal function. Patients with severe reduced renal function (CLCR<30ml/min
) should be used with caution.
In patients with reduced hepatic function
The recommended starting dose is 5 mg daily for 2 weeks. The dose may be increased to 10 mg daily depending on the individual patient’s response, and special caution is advised in increasing the dose in patients with severely reduced hepatic function.
Cytochrome P450 2C19 (CYP2C19) slow metabolizers
For patients known to be CYP2C19 slow metabolizers, a starting dose of 5 mg daily is recommended for 2 weeks of treatment, which may be increased to 10 mg daily depending on the individual response of the patient.
Discontinuation
Abrupt discontinuation of the drug should be avoided. When it is necessary to discontinue treatment with this product, the dose should be gradually reduced over a period of at least 1 to 2 weeks to avoid discontinuation symptoms.
The safety of doses above 20mg per day has not been confirmed.
[Adverse reactions].
Adverse reactions occur mostly in the first 1-2 weeks of starting treatment, and the severity and incidence of adverse reactions decrease with continued treatment.
The known adverse reactions to selective 5-hydroxytryptamine reuptake inhibitor (SSRI) drugs that were reported in placebo-controlled clinical studies or post-marketing spontaneous reports of escitalopram, according to organ system classification and frequency, are listed in the following table.
Incidence rates were obtained from clinical trials; the incidence rates listed are not placebo-corrected. Incidence is defined as follows: very common (≥1/10), common (≥1/100 to <1/10), occasional (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), unknown (cannot be estimated from available data).
System Organ Classification Incidence Adverse Reactions Blood and lymphatic system disorders Unknown Thrombocytopenia Immune system disorders Rare Rapid onset allergic reactions Endocrine system disorders Unknown Abnormal secretion of antidiuretic hormone Metabolic and nutritional disorders Common Decreased appetite,.
Increased appetite, weight gain Occasionally weight loss Unknown hyponatremia, anorexia1 Psychiatric disorders Common anxiety, restlessness, abnormal dreams, decreased libido, lack of sexual pleasure (in women) Occasionally teeth grinding, agitation, hypersensitivity, panic attacks, confusional states Rare aggressive tendencies, loss of sense of self, fantasy Unknown mania, suicidal ideation, suicidal behavior2 Neurological disorders Common insomnia, drowsiness, dizziness , sensory abnormalities, tremor Occasionally taste disorder, sleep disorder, syncope Rare 5-hydroxytryptamine syndrome Unknown movement disorder, dyskinesia, spasticity
Difficulty sitting still/inability to sit still1 Eye disorders occasional pupil dilation, visual disturbances ear and vagus disorders occasional tinnitus Heart disorders occasional tachycardia rare bradycardia unknown ECG QT interval prolongation vascular disorders unknown upright hypotension respiratory, thoracic, and mediastinal disorders common sinusitis, yawning occasional rhinorrhea gastrointestinal disorders very common nausea common diarrhea, constipation, vomiting, dry mouth occasional Gastrointestinal bleeding (including rectal bleeding) Hepatobiliary system disorders unknown Hepatitis, abnormal liver function tests Skin and subcutaneous tissue disorders common Increased sweating occasional Hives, alopecia, rash, pruritus unknown Stasis, angioedema Musculoskeletal and connective tissue disorders common Arthralgia, myalgia Kidney and urinary system disorders unknown Urinary retention Reproductive system and breast disorders common Male: Ejaculatory disorders, erectile dysfunction Occasional female: irregular uterine bleeding, excessive menstruation unknown breast overflow
Male: abnormal penile erection Systemic diseases and administration site reactions common fatigue, fever occasional edema
Notes.
1. such events are reported in SSRI-like drug therapy.
2. Incidents of suicidal ideation and suicidal behavior have been reported early in treatment or discontinuation of treatment with this product.
Bone fractures
Epidemiological studies conducted primarily in patients aged 50 years and older have shown an increased risk of fracture in patients receiving SSRIs and TCAs (tricyclic antidepressants). The mechanisms contributing to this risk are unknown.
Prolonged QT interval
Prolonged QT intervals and ventricular arrhythmias, including tip-twist ventricular tachycardia, have been reported in post-marketing reports of QT interval prolongation, primarily in female patients, in patients with hypokalemia, or in patients with prolonged QT intervals with preexisting other cardiac conditions. In a double-blind placebo-controlled ECG study in healthy subjects, the change in QTc (Fridericia-corrected) from baseline was 4.3 ms and 10.7 ms in the 10 mg/day dose group and 30 mg/day dose group, respectively.
Discontinuation symptoms observed at SSRI treatment discontinuation
Discontinuation of this product, including discontinuation of SSRI/5hydroxytryptamine-norepinephrine reuptake inhibitors (SNRI) (especially abruptly) is often associated with discontinuation symptoms. Dizziness, sensory disturbances (including sensory abnormalities and electroconvulsive sensations), sleep disturbances (including insomnia and nightmares), agitation or anxiety, nausea and/or vomiting, tremor, confusion, sweating, headache, diarrhea, palpitations, mood swings, irritability, and visual disturbances are the most frequently reported reactions. Generally these events are mild or moderate and self-limiting, but in some patients may manifest severely or for a prolonged period of time. Therefore, it is recommended that the dose should be gradually reduced to discontinuation when treatment with this product is no longer required.
Contraindications
1. contraindicated in patients with hypersensitivity to the active ingredient or any of the excipients. 2.
2. Combination with non-selective, irreversible monoamine oxidase inhibitors (MAOI) is prohibited (see [WARNINGS] and [DRUG INTERACTIONS]).
3. Combination with linezolid is prohibited, see [Drug Interactions].
4. Combination with pimozide is prohibited, see [Drug Interactions].
5. This product is contraindicated in patients with known QT interval prolongation or congenital QT syndrome.
【Warning】.
Worsening of clinical symptoms and risk of suicide
Depression can lead to increased risk of suicidal thoughts, self-harm and suicide (suicide-related events) that will persist until significant improvement in the disease occurs. Improvement may not occur during the first few weeks of treatment or longer, so patients should be monitored closely until the disease improves. From clinical experience, the risk of suicide may increase in the early stages of recovery.
Other psychiatric disorders treated with this product can also lead to an increased risk of suicide-related events. In addition, these psychiatric disorders may be comorbid with depression. Therefore, when treating patients with other psychiatric disorders, they should be monitored as closely as when treating patients with depression.
Patients who have had a suicide-related event or major suicidal thoughts prior to treatment with this product are known to be at greater risk for suicidal thoughts or attempts and should be carefully monitored during treatment.
In a meta-analysis of antidepressant and placebo-controlled studies of adult patients with depressive disorders, it was shown that among patients younger than 25 years of age, patients treated with antidepressants were at an increased risk of suicidal behavior than patients treated with placebo. Patients should be monitored closely during antidepressant treatment, especially in patients at high risk or during the early stages of treatment and dose adjustment.
Patients and their caregivers should be reminded to closely monitor any clinical deterioration, suicidal behavior or thoughts, and abnormal behavioral changes and to seek immediate medical attention if these symptoms appear.
Antidepressants are not indicated for use in children and adolescents under the age of 18. In clinical trials in children and adolescents under 18 years of age, suicide-related behaviors (suicide attempts and suicidal ideation) and hostility (aggression, oppositional behavior, and irritability) were found to occur more frequently in the escitalopram group than in the placebo group.
2. Risk of prolonged QT interval
Escitalopram was found to cause dose-dependent QT interval prolongation, and cases of QT interval prolongation and ventricular arrhythmias including tip-turn ventricular tachycardia have been reported during the post-marketing period, primarily in female patients with hypokalemia, or with prior QT prolongation or other cardiac disease.
Caution should be exercised when administering the drug in patients with severe bradycardia or in patients who have recently developed acute myocardial infarction or decompensated heart failure, and ECG monitoring should be performed if the drug is necessary.
Electrolyte disturbances such as hypokalemia or hypomagnesemia can increase the risk of malignant arrhythmias and should be corrected prior to initiating treatment with this product.
If treating patients with stable heart disease, preexisting ECG results should be consulted prior to initiating therapy.
If arrhythmias occur during treatment with this product, treatment should be discontinued and an ECG should be performed.
3. Potential interactions with monoamine oxidase inhibitors (MAOI)
Serious, even fatal, adverse reactions have been reported with antidepressants in combination with MAOI. If an MAOI is combined with an SSRI drug, these adverse effects include hyperthermia, tonicity, myoclonus and instability of vital signs, and altered mental status (including extreme agitation that progresses to delirium and coma). Sometimes the case features resemble a malignant syndrome. Limited animal studies suggest that the combination of SSRI drugs and MAOI produces a synergistic effect of increased blood pressure and stimulation of abnormal behavioral arousal.
It is recommended that this product not be administered concomitantly with an MAOI and that it be administered only after at least 14 days of discontinuation of the MAOI. Similarly, MAOI should not be used until at least 7 days after discontinuation of this product.
4. 5-hydroxytryptamine syndrome
Caution should be exercised when this product is combined with 5-hydroxytryptaminergic drugs (e.g., sumatriptan or other traptans, tramadol, and tryptophan).
In rare cases, 5-hydroxytryptamine syndrome has been reported in patients on combined SSRI and 5-hydroxytryptaminergic drugs. A group of symptoms such as irritability, tremor, myoclonus, and hypothermia suggest possible development of the disorder. Combined SSRI and 5-hydroxytryptamine treatment should be discontinued immediately and symptomatic treatment should be initiated.
Precautions]
The following applies to all SSRI medications.
Discontinuation reactions observed when treatment is discontinued
Discontinuation reactions usually occur when treatment is discontinued, especially when the drug is stopped abruptly. In clinical trials, adverse events were observed at treatment discontinuation in approximately 25% of patients in the Benzedrine treatment group and 15% in the placebo group.
The risk of discontinuation reactions may depend on many factors: including the duration of treatment and the dose, the rate of dose reduction. Dizziness, sensory disturbances (including sensory abnormalities and electroconvulsive sensations), sleep disturbances (including insomnia and nightmares), agitation or anxiety, nausea and/or vomiting, tremor, confusion, sweating, headache, diarrhea, palpitations, emotional instability, irritability, and visual disturbances are the most commonly reported reactions. Usually, these symptoms are mild to moderate; however, in some patients, they may be severe.
Discontinuation reactions usually occur within the first few days after stopping treatment; however, a very few such reports have occurred in patients who have missed doses.
In general, these symptoms are self-limiting and usually resolve within 2 weeks, although in some individuals their duration may be prolonged (2 to 3 months or longer). Therefore, it is recommended that the dose of this product be tapered over a period of weeks or months, depending on the patient’s needs, when treatment is discontinued.
Abnormal bleeding
Subcutaneous bleeding times and/or bleeding abnormalities such as petechiae, purpura, gynecologic bleeding, gastrointestinal bleeding, and other skin or mucus bleeding have been reported with SSRI use. Caution is required in patients taking SSRIs, especially in combination with oral anticoagulants and medications known to affect platelet function (e.g., atypical antipsychotics, phenothiazines, most tricyclic antidepressants, aspirin, NSAIDs, ticlopidine, and dipyridamole) and in patients with a history of bleeding disorders.
Hyponatremia
Hyponatremia has been reported rarely with SSRI medications and may be caused by abnormal secretion of antidiuretic hormone (SIADH), which usually returns to normal by the time treatment is discontinued. Caution should be exercised in elderly patients, patients with cirrhosis, or patients at high risk of hyponatremia when combined with other drugs that may cause hyponatremia.
Sedentary inability/psychomotor agitation
SSRI/SNRI use has been associated with the development of sedentary inability, characterized by subjective unpleasant or disturbing agitation, the need for constant movement, and the inability to sit or stand quietly. This is most likely to occur within the first few weeks of treatment. In patients suffering from these symptoms, increasing the dose may be harmful.
Mania
SSRI medications should be used with caution in patients with a history of mania or mild hypomania. Patients with bipolar disorder may turn into manic episodes. This product should be discontinued in patients entering the manic phase of a seizure.
Seizures
This product should be discontinued if, during treatment, a patient develops seizures for the first time or if the frequency of seizures increases in patients with previously diagnosed epilepsy. It should be avoided in patients with unstable epilepsy and carefully monitored in patients whose epilepsy is already under control.
Diabetes mellitus
In patients with diabetes mellitus, treatment with an SSRI may alter glycemic control. Dose adjustments of insulin and/or oral hypoglycemic agents may be required.
ECT (electroconvulsive therapy)
There is limited clinical experience with concurrent administration of SSRI and ECT therapy; therefore, caution should be exercised.
St. John’s Wort
Adverse reactions may be more common during combined use of this product and herbal preparations containing St. John’s Wort (Hypericum perforatum). Therefore, this product and St. John’s wort preparations should not be taken together.
10. Psychiatric Disorders
This product may increase symptoms of psychiatric disorders in the treatment of patients with psychiatric disorders who have depressive episodes. It should be administered under medical supervision.
11. Ambivalent anxiety
Some patients with panic disorder may have increased symptoms of anxiety when starting treatment with antidepressants. This paradoxical response usually resolves within the first two weeks of starting treatment. It is recommended to use from a lower starting dose to reduce the likelihood of paradoxical anxiety effects.
12. Fertility
Data from animal studies suggest that some SSRIs may affect sperm quality.
Reports of human SSRI use indicate that the effects of some SSRIs on sperm quality are reversible. Effects on human fertility have not been observed.
13. Reversible, selective MAO-A inhibitors
This product is not recommended in combination with MAO-A inhibitors due to the risk of 5-hydroxytryptamine syndrome.
14. Effects on the ability to drive and operate machinery
This product has a mild or moderate effect on the ability to drive and use machinery.
Although this product has been shown not to affect intellectual functioning or psychomotor behavior, any psychotropic drug may reduce judgment and the ability to respond to emergency situations. Patients should be informed of these effects and warned that their ability to drive or operate machinery may be impaired.
15. Keep out of the reach of children.
Pregnant women and nursing mothers
Use in Pregnant Women
Clinical data on the use of this product in pregnant women are limited.
Animal studies have shown reproductive toxicity of this product. In a reproductive toxicology study in rats, fetal toxicity was observed (weight loss and slight delay in osteogenesis), but there was no effect on the development of the litter and no increase in the incidence of teratogenicity. This product is not recommended for use during pregnancy unless clearly indicated and after careful consideration of the risk/benefit ratio.
If a pregnant woman continues to use this product until the second trimester, the newborn should be monitored, especially in late gestation. Pregnant women who continue to use this product until the birth of the newborn or shortly before birth may experience withdrawal symptoms in the newborn.
Pregnant women using SSRI/SNRI drugs in late pregnancy may experience the following symptoms in their newborns: respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulties, vomiting, hypoglycemia, hypertonia, hypotonia, hyperreflexia, irritability, tremor, hypersensitivity, lethargy, persistent crying, drowsiness, difficulty sucking or falling asleep. It may be due to 5-hydroxytryptamine effects or withdrawal effects. SSRI medications should not be stopped abruptly in pregnant women. Most cases of neonatal complications occur immediately or soon (<24 hours) after delivery.
Epidemiological data suggest that the use of SSRI medications during pregnancy, especially late in pregnancy, may increase the risk of persistent pulmonary hypertension of the newborn (PPHN). About 5 cases were observed in 1000 pregnant women using SSRIs. In the general population, PPHN occurs in 1 to 2 cases per 1000 pregnant women.
Medication for breastfeeding women
Escitalopram can be secreted in breast milk and nursing women should not receive this product or discontinue breastfeeding during the administration of the drug. [For children].
Antidepressants are not suitable for use in children and adolescents under 18 years of age.
In clinical trials in children and adolescents under 18 years of age, suicide-related behaviors (suicide attempts and suicidal thoughts) and hostility (aggression, oppositional behavior and irritability) were found to occur more frequently in the drug administration group than in the placebo group.
[Geriatric Dosing].
For elderly patients over 65 years of age, it is recommended that treatment be started at half the usual starting dose (5 mg) as described above and that the maximum daily dose should not exceed 10 mg. see [Dosage].
Drug Interactions
Pharmacodynamic Interactions
Pharmacodynamically, cases of 5-hydroxytryptamine syndrome have been reported when citalopram is combined with morpholino and buspirone.
Contraindicated drug combinations
Non-selective, irreversible MAOI
Serious adverse reactions have been reported in patients treated with SSRIs in combination with non-selective, irreversible MAOIs and in patients who have recently discontinued SSRI therapy and started MAOI therapy. Some patients have developed 5-hydroxytryptamine syndrome.
It is contraindicated in combination with a non-selective, irreversible MAOI. Treatment with this product may be initiated at least 14 days after discontinuation of irreversible MAOI therapy. Treatment with a non-selective, irreversible MAOI may be initiated at least 7 days after discontinuation of treatment with this product.
Pimozide
Concomitant administration of a single 2 mg dose of pimozide to patients treated with this product at 40 mg/day for 11 days resulted in elevated area under the curve (AUC) and maximum blood concentrations of pimozide, even though this was not consistent throughout the study. The combination of pimozide and citalopram resulted in a prolongation of the QTc interval by approximately 10 ms. The combination of escitalopram and pimozide is contraindicated because of the interaction that can occur with lower doses of pimozide.
Reversible, non-selective MAO inhibitors (linezolid)
The antibiotic linezolid is a reversible, non-selective MAO inhibitor and is strictly contraindicated in patients already receiving this product. If a combination is clinically indicated, a minimal dose should be used and close clinical monitoring should be performed.
Cautious combination therapy is required
Reversible, selective MAO-A inhibitors (moclobemide)
Combination of this product with MAO-A inhibitors is not recommended due to the risk of 5-hydroxytryptamine syndrome. If combination therapy is indeed required, it should be started at the minimum recommended starting dose and intensive clinical monitoring is required.
Treatment with this product can be initiated at least 1 day after discontinuation of reversible MAOI therapy.
Silegiline
Caution should be exercised when combining with Slegiline [an irreversible monoamine oxidase B (MAO-B) inhibitor] because of the possible risk of 5-hydroxytryptamine syndrome.
5-Hydroxytryptamine Drugs
Combination with 5-hydroxytryptamine drugs (e.g., tramadol, sumatriptan, and other tretinoin drugs) may lead to 5-hydroxytryptamine syndrome.
Drugs that lower the seizure threshold
SSRI drugs can lower seizure thresholds and caution is recommended when combined with other drugs that can lower seizure thresholds, such as antidepressants (tricyclic ones, SSRIs), psychostimulants (phenothiazines, thiodiazepines, butylphenols), mefloquine, butylamphetamine, and tramadol.
Lithium salts, tryptophan
Synergistic effects have been reported with the combination of SSRI drugs and lithium salts or tryptophan, so caution should be exercised in combining SSRI drugs with these drugs.
St. John’s Wort
Combination of SSRI drugs and herbs containing St. John’s wort (Hypericum perforatum) may increase the incidence of adverse reactions.
Affects blood-clotting medications
When this product is combined with oral anticoagulants, the anticoagulant effect of such drugs may be altered. Patients receiving oral anticoagulant therapy should take special care to monitor the anticoagulant effect when starting or stopping treatment with this product.
Combination with non-steroidal anti-inflammatory drugs may increase the risk of bleeding.
Alcohol
There are no pharmacokinetic or pharmacodynamic interactions between this product and alcohol. However, as with other psychotropic drugs, combination with alcohol is not recommended.
Pharmacokinetic Interactions
Other drugs that affect the pharmacokinetics of this product
The metabolism of this product in vivo is primarily mediated by cytochrome CYP2C19. Cytochrome CYP3A4 and cytochrome CYP2D6 are also involved in its metabolism, but their effects are minor. The major metabolite of this product, desmethyl escitalopram oxalate, may also be partially catalyzed by CYP2D6.
Combined use of omeprazole (CYP2C19 enzyme inhibitor) results in a moderate increase (approximately 50%) in plasma concentrations of this product.
The combination of escitalopram with cimetidine (a moderately potent inhibitor of multiple enzymes) can moderately increase plasma concentrations of escitalopram (approximately 70%).
Therefore, the combination of CYP2C19 enzyme inhibitors (e.g., omeprazole, fluoxetine, fluvoxamine, lansoprazole, ticlopidine) and cimetidine should be used with caution when the upper therapeutic dose of this product is reached.
It may be necessary to reduce the dose of this product based on clinical judgment.
Effect of this product on the pharmacokinetics of other drugs
This product is an inhibitor of CYP2D6 and should be used with caution in combination with drugs that are primarily metabolized by CYP2D6, drugs with a narrow therapeutic index, such as flecainide, propafenone and metoprolol (when treating heart failure), or drugs that act on the central nervous system and are primarily metabolized by CYP2D6 (antidepressants such as norethindrone, chlorpromazine and nortriptyline or The antipsychotic drugs risperidone, methylpyridazine, and haloperidol). The dose should be adjusted when combined
Combination with desipramine or metoprolol may result in a more than twofold increase in plasma concentrations of both drugs (both CYP2D6 substrates).
In vitro studies have shown that this product may also cause mild inhibition of CYP2C19, and caution is advised when combining with drugs metabolized by CYP2C19.
Drug overdose]
Toxicity
Clinical data on overdose are very limited. Most of the reported cases are mild or asymptomatic. Deaths due to overdose have been reported rarely in isolated use, and most cases have been associated with combined overdoses of other drugs. No serious symptoms have been observed with single doses of 400 mg to 800 mg.
Symptoms
Symptoms reported with escitalopram overdose are mainly related to the following systems: central nervous system (ranging from vertigo, tremor and agitation to the rarely reported 5-hydroxytryptamine syndrome, spasticity and coma), gastrointestinal system (nausea/vomiting), cardiovascular system (hypotension, tachycardia, QT interval prolongation and arrhythmias) and electrolyte/fluid balance profile (hypokalemia, hyponatremia).
Treatment
There are no specific antidotes. It is critical to keep the airway open and ensure adequate oxygen uptake and respiratory function. Consider the use of gastric lavage and activated charcoal. Gastric lavage as soon as possible after oral medication. Monitoring of cardiac and vital signs and systemic supportive therapy is recommended.
[Clinical trials].
Depressive disorders
Three of four double-blind, placebo short-term (8-week) controlled trials have shown escitalopram to be effective in depressive disorders. At doses of 10 mg and 20 mg, the antidepressant effect was demonstrated two weeks after administration. After 8 weeks of treatment, the efficacy of this product was better in the 20 mg group than in the citalopram 40 mg group. The dose correlation was evident in severely depressed patients, with patients treated at 20 mg having better efficacy than the usual starting dose of 10 mg.
In a 24-week long-term double-blind trial, the efficacy of the 10-mg escitalopram and 20-mg citalopram groups was comparable, with half of the patients in the escitalopram group dropping out of the trial due to adverse effects. In the long-term trial for relapse prevention, escitalopram 10 or 20 mg/day was given for 8 weeks as open treatment, and 274 patients who responded to treatment were randomized to the same dose of escitalopram or placebo up to 36 weeks. In the 36-week study, patients treated with escitalopram developed relapses significantly later than in the placebo group.
Panic disorder
In a 10-week controlled trial for the treatment of panic disorder, the efficacy of escitalopram was evaluated by comparing the escitalopram 5-20 mg/day group with the placebo group and the citalopram 10-40 mg/day group. By assessing the frequency, severity, duration, and concomitant symptoms of panic attacks, it was shown that the escitalopram group had a statistically significant advantage over the placebo group in terms of efficacy. The effectiveness of citalopram compared to placebo was comparable in most of the effectiveness metrics. Most treatment-related adverse events (³5% of patients) were higher in the citalopram group than in the escitalopram group.
Social anxiety disorder
Three short-term (12-week) studies and one 6-month relapse prevention study showed that escitalopram was effective in patients with social anxiety disorder.
A 24-week long-term placebo-controlled trial confirmed the effectiveness of escitalopram at doses of 5 mg, 10 mg, and 20 mg.
The efficacy of 20 mg/day escitalopram for social anxiety disorder was statistically significantly superior to paroxetine 20 mg/day, escitalopram 5 mg/day and 10 mg/day. Transient discontinuation symptoms (lasting no longer than 2 weeks in all active treatment groups) were observed in all treatment groups and were more pronounced in the paroxetine group relative to the escitalopram group (p ≤ 0.05).
A pooled analysis including 670 escitalopram patients and 341 placebo patients showed efficiency rates of 58.1% and 40.2% (CGI-I score 1 or 2) and recovery rates of 24.8% and 12.9% (CGI-S score 1 or 2), respectively (P ≤ 0.001).
Generalized anxiety disorder
Results from 4 placebo-controlled trials all confirmed the effectiveness of escitalopram 10 mg and 20 mg/day, but not 5 mg/day.
A pooled analysis from 3 protocols of similar, 8-week clinical trials showed 47.5 % and 28.9 % efficacy (CGI-I score 1 or 2) and 37.1 % and 20.8 % recovery (CGI-S score 1 or 2) in 421 escitalopram-treated patients and 419 placebo patients, respectively (p ≤ 0.001). Sustained efficacy began to emerge from the first week.
In four 12-week controlled trials with paroxetine, escitalopram 10 mg/day was statistically significantly more effective than paroxetine 20 mg/day. Transient discontinuation symptoms were observed in both groups and were more pronounced in the paroxetine group relative to the escitalopram groups at doses of 5 mg, 10 mg and 20 mg/day (p ≤ 0.01).
In a 24- to 76-week randomized, ongoing trial of 373 patients who were effective on initial 12-week open treatment, the risk of relapse was significantly lower in patients treated with 20 mg/day escitalopram.
[Pharmacology and Toxicology].
Pharmacological effects
Escitalopram is a single dextro-optical isomer of the dicyclic hydrophthalide derivative racemic citalopram. The mechanism of antidepressant action of escitalopram may be related to the inhibition of 5-HT reuptake by neurons in the central nervous system, thus enhancing the function of central 5-hydroxytryptaminergic nerves. In vitro and animal tests have shown that escitalopram is a highly selective 5-HT reuptake inhibitor (SSRI) with a low effect on the reuptake of norepinephrine and dopamine. Escitalopram is at least 100-fold more active than leuprolide in 5-HT reuptake and inhibition of 5-HT neuronal metabolic rate. Long-term administration (up to 5 weeks) of escitalopram in a rat depression model did not show tolerance.
Escitalopram has no or only low affinity for 5-HT1-7 receptors, alpha receptors, beta receptors, D1-5 receptors, H1-3 receptors, M1-5 receptors, and benzodiazepine receptors. Escitalopram has no affinity for Na+, K+, Cl-, Ca2+ channels, or only low affinity.
Toxicological studies
Genotoxicity.
Two of the five test strains (TA98 and TA1537) in the Ames test for abbreviated citalopram showed positive results in the absence of metabolic activation. In the chromosomal aberration test of citalopram CHL, the results were positive with and without metabolic activation. Negative results were obtained in the positive mutation test (HPRT) in mouse lymphoma cells, the out-of-programme DNA synthesis test (UDS) in rat liver cells, the chromosomal aberration test in human lymphocytes, and the micronucleus test in mice.
Reproductive toxicity.
In the fertility test, oral administration of abbreviated citalopram 32, 48 and 72 mg/kg/day to rats showed reduced mating rate in all dose groups, reduced fertility at doses ≥32 mg/kg/day and prolonged pregnancy at a dose of 48 mg/kg/day. In the rat embryo-fetal development toxicity test, oral administration of escitalopram at 56, 112, 150 mg/kg/day and at medium and high doses (more than 56 times the maximum recommended human dose [MRHD] of 20 mg/day based on mg/m2) resulted in reduced fetal weight and delayed ossification, and maternal toxicity (abnormal clinical signs, reduced body weight gain, reduced food intake) was seen in all dose groups. Maternal toxicity (abnormal clinical signs, reduced body weight gain, reduced food intake) was observed in all dose groups, but no teratogenic effects were observed; the developmental no-effect dose was 56 mg/kg/day, which is approximately 28 times the MRHD. In pregnant rats given escitalopram 6, 12, 24 and 48 mg/kg/day perinatally, a slight increase in offspring mortality and growth retardation was observed in the highest dose group (equivalent to approximately 24 times the MRHD), and a slight maternal toxicity (abnormal clinical signs, reduced body weight gain, reduced food intake) was seen, and a slight increase in offspring mortality was observed in the 24 mg/kg/day dose group; the no-effect dose was The no-effect dose was 12 mg/kg/day, equivalent to approximately 6 times the MRHD.
In animal reproductive toxicity tests, adverse effects on embryo/fetus development and postnatal development were seen with abbreviated citalopram, including teratogenicity at higher than human therapeutic doses. In the rat embryo/fetus toxicity test, oral administration of abbreviated citalopram at 32, 56, and 112 mg/kg/day was associated with reduced embryo/fetus growth inhibition and survival, increased incidence of fetal malformations (including cardiovascular and skeletal defects), and maternal toxicity (abnormal clinical signs, reduced body weight gain) at high doses, with no developmental effects at 56 mg/kg/day. No significant embryo/fetal developmental toxicity was observed in rabbits given orally up to 16 mg/kg/day of abbreviated citalopram. In a perinatal toxicity test, oral administration of abbreviated citalopram at 4.8, 12.8, and 32 mg/kg/day to rats showed increased mortality and growth arrest of pups within 4 days of birth at a no-effect dose of 12.8 mg/kg/day in the high-dose group.
Carcinogenicity.
Negative citalopram was administered orally to NMRI/BOM mice and COBS WI rats for 18 and 24 months, respectively. No carcinogenicity was observed in mice at doses up to 240 mg/kg/day. An increased incidence of small bowel cancer was seen in rats at doses of 8 or 24 mg/kg/day. The relevance of this phenomenon to humans is unclear.
Pharmacokinetics]
Absorption
It is completely absorbed orally and is not affected by food (peak plasma concentration is reached in an average of 4 hours after multiple oral doses). Like citalopram, the absolute bioavailability of this product is about 80%.
Distribution
The apparent volume of distribution (Vd,b/F) after oral administration is about 12-26 L/kg. the plasma protein binding rate of this product and its metabolites is about 80%.
Metabolism
The product is metabolized in the liver mainly by demethylation and dimethylation. Both metabolites have pharmacological activity. In addition, the N group can be oxidized to produce N oxidation metabolites. The prodrug and metabolites can be partially excreted via glucuronidation. After multiple dosing, the mean plasma concentrations of the demethylated and dimethylated metabolites are 28% to 31% and <5% of the prodrug concentration, respectively. Demethylation of this product is primarily metabolized by the cytochrome P450 (CYP) 2C19 enzyme, with CYP3A4 and CYP2D6 also likely to play a partial role.
Elimination
The elimination half-life after multiple doses is approximately 30 hours, and the plasma clearance (CLoral) of the oral drug is approximately 0.6 L/min. The major metabolites of the drug have a longer half-life, and the product and its metabolites are eliminated primarily by the liver (metabolism) and the kidneys, and excreted primarily as metabolites in the urine.
The pharmacokinetics of this product are linear and steady-state plasma concentrations are reached after approximately one week, with a mean steady-state plasma concentration of 50 nmol/L (range: 20-125 nmol/L) for a daily dose of 10 mg.
Elderly Patients (> 65 years)
Drug elimination was slower in older patients compared to younger patients. The AUC was 50% higher in the elderly compared to younger healthy subjects.
Those with reduced liver function
In patients with mild and moderate hepatic impairment (Child-Pugh criteria A and B), the half-life of escitalopram was approximately twice that of patients with normal hepatic function and exposure was 60% higher.
Patients with reduced renal function
Prolonged half-life of citalopram and mildly elevated plasma drug concentrations (CLCR 10-53 ml/min) were observed in patients with reduced renal function. Plasma concentrations of metabolites have not been studied, but they may be elevated.
Polymorphisms
The plasma concentration of this product has been found to be twice as high in CYP2C19 slow metabolizers as in fast metabolizers, while there is no significant change in the plasma concentration of the drug in CYP2D6 slow metabolizers.
Storage
Store below 30℃.
Package
Aluminum-plastic plate packaging.
7 tablets/box; 14 tablets/box.
Expiration date
36 months
【Execution standard
JX20090196
Imported drug registration certificate
H20140121
Approval number for distribution
State Drug Certificate: J20140079
Manufacturer
Company name: H. Lundbeck A/S Denmark Ling North Pharmaceutical Factory
Production Address: Ottiliavej 9 DK-2500 Valby Denmark
[Dispense enterprise
Company name: Xi’an Janssen Pharmaceutical Co.
Address: No. 34 Wanshou North Road, Xi’an City, Shaanxi Province
Postal Code: 710043
Telephone number: 400 888 9988
Fax number: (029) 82576616
Website: http://www.xian-janssen.com.cn