Approval date: 09/04/2007
Modification date: 01 December 2015
Date of revision: xx/xx/2018
Citalopram Hydrobromide Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Warnings
Antidepressants and suicidal ideation
Results of short-term clinical trials of depression (MDD) and other psychiatric disorders have shown that antidepressants increase the risk of suicidal ideation and committing suicidal acts (suicidal ideation) in children, adolescents, and young adults (<24 years of age) compared with placebo. Anyone considering the use of this or other antidepressants in children, adolescents, or young adults (<24 years of age) must weigh the clinical needs and risks. Short-term clinical trials have not shown an increased risk of suicidal ideation in adult patients older than 24 years of age using antidepressants compared with the placebo group; in adult patients aged 65 years and older using antidepressants, the risk of suicidal ideation was reduced compared with the placebo group. Depression and certain psychiatric disorders are inherently associated with an increased risk of suicide, and the worsening of clinical symptoms, suicidal ideation, and abnormal changes in behavior after initiation of antidepressant treatment in patients of all ages must be closely observed and reasonably monitored. Families and caregivers should be advised that patients must be closely observed and communicated with their physicians. This product is not approved for use in pediatric patients (see [Precautions] and [Pediatric Use]).
Drug Name]
Generic Name: Citalopram Hydrobromide Tablets
English name: Citalopram Hydrobromide Tablets
Hanyu Pinyin: Qingxiusuan Xitaipulan Pian
Ingredients
Active ingredient: Citalopram Hydrobromide
Chemical name: (±)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile hydrobromide
Chemical structure formula.
Molecular formula: C20H21FN2O -HBr
Molecular weight: 405.30
Properties
This product is a white film-coated tablet, which appears white or off-white after removing the coating.
Indications
Treatment of depression.
Specification
20 mg (based on C20H21FN2O).
Dosage and Administration
Adults
Take 20 mg once daily, at any time of the day, regardless of food intake. The dose may be increased to a maximum of 40 mg daily depending on the response of the individual patient.
Duration of treatment
The antidepressant effect usually starts after 2 to 4 weeks of dosing. Antidepressant treatment is symptomatic and therefore must be continued for an appropriately long period of time (usually up to 6 months after recovery) to prevent relapse. In patients with relapsing depression, maintenance therapy may need to be continued for many years to prevent relapse.
Elderly patients (> 65 years)
Geriatric patients should have their dose reduced to half the recommended dose, i.e., 10 to 20 mg daily. the recommended maximum dose is 20 mg daily.
Children and adolescents (<18 years)
This product is not intended for use in children and adolescents under 18 years of age.
People with renal impairment
In patients with mild to moderate renal impairment, no dose adjustment is required. Use with caution in patients with severe renal impairment (creatinine clearance less than 30 mL/min, see [Pharmacokinetics]).
Patients with hepatic impairment
For patients with mild to moderate hepatic impairment, an initial dose of 10 mg daily is recommended for the first two weeks of therapy. The maximum dose may be increased to 20 mg per day depending on individual patient response, and extra caution is required when making dose adjustments in patients with severe hepatic impairment.
Patients with weak CYP2C19 metabolism
For patients with known weak CYP2C19 metabolism, an initial dose of 10 mg per day is recommended for the first two weeks of treatment. Depending on individual patient response, the maximum dose may be increased to 20 mg per day.
Discontinuation
Abrupt discontinuation of this product should be avoided. When treatment with this product is discontinued, the dose should be tapered over at least 1 to 2 weeks in order to reduce the risk of discontinuation reactions. If intolerable symptoms develop after a dose reduction or after treatment has been discontinued, reinstatement of the previously prescribed dose may be considered. Subsequently, the physician may continue to reduce the dose, but should do so at a more gradual pace.
[Adverse Reactions].
Adverse reactions occur most frequently in the first 1-2 weeks of treatment and then gradually resolve. The following adverse reactions were observed to be dose-related: excessive sweating, dry mouth, insomnia, drowsiness, diarrhea, nausea, and fatigue. The following table shows the percentage of adverse drug reactions associated with SSRIs (selective 5-hydroxytryptamine reuptake inhibitor analogs) and/or citalopram hydrobromide observed in ≥ 1% of patients in double-blind placebo-controlled trials or post-marketing. Frequency definitions: very common (≥1/10); common (≥1/100, <1/10); occasional (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10000); unknown (cannot be estimated from available data).
System Organ Classification Frequency Adverse Reactions Blood and Lymphatic System Disorders Unknown Thrombocytopenia Immune System Disorders Occasional Hypersensitivity Reactions Very Rare Rapid Onset Allergic Reactions Endocrine System Disorders Rare Hypersecretion of Antidiuretic Hormone (Schwartz-Barty Syndrome/SIADH) Metabolic and Nutritional Disorders Common Decreased Appetite, Weight Loss, Increased Appetite Occasional Weight Gain Rare Hyponatremia Unknown Hypokalemia Psychiatric disorders very common agitation, nervous tension restlessness common decreased sexual desire, lack of sexual pleasure (in women), anxiety, blurred states of consciousness, emotional indifference, impaired concentration, dream abnormalities, memory impairment occasional aggression, depersonalization, hallucinations, mania, euphoria, increased sexual desire unknown panic attacks, teeth grinding disorder, fidgeting, suicidal ideation, suicidal behavior1 Neurological disorders very common drowsiness, insomnia, tremor, dizziness, headache common sensory abnormalities, sleep disorders, migraine, taste disorders, attention disorders occasional syncope, convulsions, extrapyramidal reactions rare convulsive seizures (grand mal seizures), movement disorders, psychomotor agitation/inability to sit still unknown 5-hydroxytryptamine syndrome, activity disorders eye organ disorders very common regulation abnormalities common visual abnormalities occasional pupil dilation ear and vagal disorders common tinnitus Cardiac disorders very common palpitations common tachycardia occasional bradycardia unknown ECG QT interval prolongation, ventricular arrhythmias (including tip-twist ventricular tachycardia) vascular and lymphatic disorders common hypotension, hypertension, postural hypotension rare hemorrhage respiratory, thoracic and mediastinal disorders common yawning, rhinitis, sinusitis occasional cough unknown epistaxis (rhinorrhea) gastrointestinal disorders very common Common dry mouth, nausea, constipation Common diarrhea, vomiting, dyspepsia, stomach pain, gastrointestinal gas Unknown gastrointestinal bleeding (including rectal bleeding) Hepatobiliary system disorders Rare hepatitis Unknown abnormal liver function tests Skin and subcutaneous tissue disorders Very common excessive sweating Common pruritus, rash Occasional urticaria, alopecia, purpura, photosensitivity Very rare angioneurotic edema Unknown petechiae Musculoskeletal and connective tissue disorders Common Myalgia, arthralgia renal and urinary disorders common dysuria occasional urinary retention genital and breast disorders common impotence, ejaculatory disorders, ejaculatory failure, dysmenorrhea occasional female: increased menstrual flow very rare breast overflow unknown female: irregular uterine bleeding
Males: abnormal penile erection Systemic diseases and various reactions at the site of administration very common malaise common fatigue, fever occasional edema, discomfort Note: 1 Suicidal ideation and suicidal behavior have been reported during citalopram hydrobromide treatment or early after treatment discontinuation.
Prolonged QT interval
Prolonged QT interval and ventricular arrhythmias including tip-twist ventricular tachycardia have been reported after the introduction of this product, primarily in female patients, patients with hypokalemia, or other cardiac patients with pre-existing QT interval prolongation.
Fractures
Epidemiological studies have shown an increased risk of fracture in patients receiving norepinephrine and selective 5-hydroxytryptamine reuptake inhibitor analogs (SSRIs) and tricyclic antidepressants (TCAs), primarily in patients aged 50 years and older. The mechanisms contributing to this risk are unknown.
Discontinuation symptoms observed at SSRI treatment discontinuation
Discontinuation of this drug (especially abrupt discontinuation) usually produces discontinuation symptoms. The most commonly reported reactions are: dizziness, sensory disturbances (including abnormal sensations), sleep disturbances (including insomnia and excessive dreaming), agitation or anxiety, nausea and/or vomiting, tremor, confusion, sweating, headache, diarrhea, palpitations, emotional instability, irritability, and visual disturbances. Typically, these adverse events are mild to moderate and self-limiting, and in some patients may manifest as severe and/or prolonged. Therefore, it is recommended that when the patient no longer requires treatment with this product, the drug should be discontinued gradually by tapering the dose.
[Contraindications
1. Contraindicated in patients with hypersensitivity to the active ingredient and/or any of the excipients in this product.
2. Combination with linezolid is prohibited unless blood pressure is closely observed and monitored.
3. Combination of citalopram with stavudine (at doses greater than 10 mg daily) is prohibited.
4. It is contraindicated in patients with known QT interval prolongation or congenital QT syndrome.
5. Combination with drugs known to prolong the QT interval is prohibited.
6. Combination with pimozide is prohibited.
7. This product is contraindicated in patients being treated with a monoamine oxidase inhibitor (MAOI) (patients with daily doses of selagiline exceeding 10 mg). This product should not be given during the 14-day period following discontinuation of an irreversible MAOI or during a specified time period following discontinuation of a RIMA as specified in the reversible MAOI (RIMA) formulary. An MAOI should not be given during the 7-day period after discontinuation of this product.
[Precautions].
Hyponatremia
Hyponatremia has rarely been reported with SSRIs and may be caused by abnormal secretion of antidiuretic hormone disorder (SIADH), which usually returns to normal when treatment is discontinued. Elderly female patients in particular are susceptible to this risk.
Suicide/suicidal ideation or clinical deterioration
Suicidal ideation, self-harm and suicide (suicide-related events) may occur as an inherent symptom of depression itself and will continue until significant improvement occurs as a result of treatment. Because improvement may occur in the first few weeks of treatment or in subsequent weeks, patients on antidepressants should be monitored closely until their illness improves. Clinical experience generally suggests that the risk of suicide may be increased during the early stages of recovery.
Other psychiatric events occurring with this product have also been associated with an increased risk of suicide-related events. In addition, psychiatric-like events may be comorbid with depression. The same precautions should be observed when treating other psychiatric disorders associated with depression as when treating patients with major depressive disorder.
Patients who have had a suicide-related event or serious suicidal ideation prior to treatment with this product are known to be at increased risk for suicidal ideation or suicide attempts and should be carefully monitored during treatment. A meta-analysis of antidepressant and placebo-controlled studies in adults with psychiatric disorders showed that among patients younger than 25 years of age, the risk of suicidal behavior was higher in patients treated with antidepressants than in those treated with placebo.
Patients, especially those at high risk, should be closely monitored during antidepressant treatment, especially in the early stages of treatment and during dose adjustment. Patients, families and caregivers should be reminded to closely monitor patients for any worsening of their condition, suicidal behavior or changes in ideation and abnormal behavior and to seek immediate medical attention if these symptoms occur.
Sedentary inability/psychomotor agitation
SSRI/SNRI use has been linked to the development of sedentary inability, which is characterized by subjective unpleasant or disturbing agitation, the need for constant movement, and the inability to sit still or remain standing. 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
Patients with bipolar disorder may turn to manic episodes. Patients who turn to manic episodes should discontinue the use of this product.
Seizures
Epilepsy is a potential risk when using antidepressants. Patients with seizures should discontinue use of this product. This product should be avoided in patients with unstable epilepsy and should be monitored closely in patients whose seizures have been controlled. If the frequency of seizures increases, this product should be discontinued.
Diabetes mellitus
Treatment with an SSRI may alter glycemic control in patients with diabetes mellitus. Dose adjustments of insulin and/or oral hypoglycemic agents may be required.
5-hydroxytryptamine syndrome
In rare cases, 5-hydroxytryptamine syndrome has been reported in patients using SSRIs. The presence of the following symptoms, such as agitation, tremor, myoclonus, and hypothermia, may indicate the development of the disorder when they occur simultaneously. Treatment with this product should be discontinued immediately and symptomatic treatment initiated.
5-HTergic drugs
Citalopram should not be used concomitantly with drugs that have 5-HTergic effects (e.g. sumatriptan or other tramadol-like drugs, tramadol, hydroxytryptophan and tryptophan).
Bleeding
Subcutaneous bleeding times and/or bleeding abnormalities, such as petechiae, gynecologic bleeding, gastrointestinal bleeding, and other skin or mucosal bleeding, have been reported with SSRI use. Caution is required in patients taking SSRIs (especially in combination with active substances known to affect platelet function or other active substances that may increase the risk of bleeding) and in patients with a history of bleeding disorders.
10. electroconvulsive therapy (ECT)
Clinical experience with concurrent administration of SSRI and ECT therapy is limited and should be approached with caution.
St. John’s Wort
Adverse reactions may be increased when this product is combined with herbal preparations containing St. John’s Wort (Onchocarpus). Therefore, concomitant administration of this product and St. John’s wort preparations should not be used.
Dose adjustment at the start of treatment
During the early treatment phase, patients may experience insomnia and agitation, which may be relieved by adjusting the dose administered.
Psychiatric disorders
Treatment of patients with psychiatric disorders with depressive episodes may exacerbate symptoms of psychiatric disorders.
Discontinuation reactions following treatment with SSRIs
Discontinuation reactions are more common after discontinuation of treatment, especially when discontinued abruptly. In a clinical study of citalopram for relapse prevention, 40% of patients who discontinued citalopram treatment experienced adverse events compared with 20% of patients who continued citalopram treatment.
The risk of discontinuation reactions may be influenced by several factors, including duration of treatment, treatment dose, and rate of dose reduction. The most commonly reported reactions were dizziness, sensory disturbances (including sensory confusion), sleep disorders (including insomnia and excessive dreaming), agitation, anxiety, nausea, vomiting, tremor, confusion, sweating, headache, diarrhea, palpitations, emotional instability, irritability, and visual disturbances. Usually these symptoms are mild to moderate in severity, but events of severe severity may be reported in some patients. These events usually occur within the first few days after discontinuation of treatment, and only rarely are such symptoms reported from subjects who inadvertently miss a dose.
Overall, these symptoms are transient and usually resolve completely within two weeks, but in some individual subjects, the time to recovery may be prolonged (2 to 3 months or longer). It is therefore recommended that the process of discontinuation of treatment should continue over several weeks or months and that the dose of citalopram should be gradually reduced according to the patient’s needs.
Risk of prolonged QT interval
Studies have found that this product can cause dose-dependent QT interval prolongation, and cases of QT interval prolongation and ventricular arrhythmias, including tip-turn ventricular tachycardia, have been reported post-marketing, primarily in female patients with hypokalemia or prior QT interval prolongation or other cardiac disease.
Caution should be exercised when administering the drug in patients with severe bradycardia or in patients with recent acute myocardial infarction or decompensated heart failure.
If treating patients with stable cardiac disease, the results of a pre-cardiac electrocardiogram (ECG) 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.
Closed-angle glaucoma
SSRIs (including citalopram) may have an effect on pupil size, resulting in pupil dilation. Such pupil dilatation effects may lead to narrowing of the eye angle, which may cause increased intraocular pressure and closed-angle glaucoma, especially in patients with a previous tendency to do so. Citalopram should therefore be used with caution in patients with closed-angle glaucoma or a history of glaucoma.
Fertility
Data from animal studies indicate that citalopram may affect sperm quality (see [Pharmacologic Toxicology]).
Reports of SSRI use in humans indicate that some SSRIs have reversible effects on sperm quality. No effect of this product on human fertility has been observed.
Excipients
The excipients of this product contain lactose monohydrate. It is contraindicated in patients with inherited galactose intolerance problems, specific forms of inherited lactase deficiency (Lapp lactase deficiency) or glucose-galactose malabsorption.
Effects on the ability to drive and operate machinery
This product has a mild or moderate effect on the ability to drive and operate machinery.
Psychotropic drugs can reduce judgment and the ability to respond to emergencies. Patients should be informed of these effects and warned that their ability to drive or operate machinery may be impaired.
Keep out of the reach of children.
Pregnant women and nursing mothers
Use during pregnancy
Published data on pregnant women (over 2500 exposure results) indicate that this product does not have any fetal/neonatal teratogenicity. However, this product should not be used during pregnancy except when clearly needed and only after weighing the risks/benefits.
No signs of fetal toxicity or teratogenic effects were observed in reproductive toxicity studies (Phases I, II, and III). However, in a rat study (not a replication study), teratogenic effects were observed at high doses that caused maternal toxicity. The potential risk in humans is not known.
The use of SSRIs in late pregnancy may result in neonates with neurobehavioral abnormalities and other symptoms.
Cases of withdrawal symptoms have been reported in neonates born to SSRI-treated mothers in late pregnancy.
The following symptoms may be seen in newborns following SSRI/SNRI use by mothers in late pregnancy: respiratory distress, cyanosis, asphyxia, convulsions, temperature instability, feeding difficulties, vomiting, hypoglycemia, hypertonia, hypotonia, hyperreflexia, tremor, shaking, irritability, sleepiness, persistent crying, lethargy, and sleep difficulties.
These symptoms may be due to 5-HTergic effects or withdrawal symptoms. In most cases, neonatal complications occur immediately or soon (<24 hours) after birth.
If citalopram is used continuously by the mother during the second trimester, the newborn should be observed. Abrupt discontinuation of the drug during pregnancy should be avoided.
Epidemiologic data suggest that SSRI use in pregnancy (especially in late pregnancy) may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). The observed risk is approximately 5 cases per 1000 pregnancies. In the general population, the risk of PPHN in newborns is approximately 1 to 2 cases per 1000 pregnancies.
Use during lactation
This product should not be used while breastfeeding. Citalopram is secreted into breast milk. It is estimated that approximately 5% of the mother’s daily dose (mg/kg) will be breastfed to the infant. No abnormalities have been observed in infants or only mild reactions have been observed. However, there is insufficient information to assess the risk of pediatric use.
Pediatric Dosage]
The safety and efficacy of the drug in pediatric and adolescent patients under 18 years of age have not been established.
Geriatric Use
The recommended maximum dose is 20 mg daily.
Drug Interactions
Pharmacodynamic Interactions
Contraindicated drug combinations
Monoamine oxidase inhibitors (MAOI)
Combination with MAOI (non-selective and selective MAO-A [morclobemide]) is prohibited and may result in serious adverse effects, including 5-hydroxytryptamine syndrome.
Several serious, even fatal, reactions have been reported in patients co-administered with a certain SSRI antidepressant and a certain monoamine oxidase inhibitor (MAOI, including the irreversible MAOI selegiline, the reversible MAOI linezolid, and morclobemide), as well as in patients who have recently discontinued SSRI therapy and started MAOI therapy.
Some cases present features similar to those of 5-hydroxytryptamine syndrome. Symptoms of active substance-MAOI interactions include
Hyperthermia, muscle tonicity, myoclonus, autonomic instability accompanied by possible sharp fluctuations in vital signs and altered mental status (including confusion, irritability and extreme agitation progressing to delirium and coma).
Drugs causing prolongation of the QT interval
Pharmacokinetic and pharmacodynamic studies between citalopram and other drugs that prolong the QT interval have not been performed. A superimposed effect between citalopram and these drugs cannot be excluded. Therefore, coadministration with drugs that prolong the QT interval such as class IA and III antiarrhythmics, antipsychotics (e.g. phenothiazine derivatives, pimozide, haloperidol), TCA, certain antimicrobials (e.g. sparfloxacin, moxifloxacin, erythromycin injection, pentazocine, antimalarial therapy especially halofantrine), certain antihistamines (astemizole, imipramine) should be prohibited. .
Pimozide
Co-administration of a single dose of 2 mg pimozide to subjects treated with abbreviated citalopram 40 mg/day for 11 days resulted in an increase in the area under the curve (AUC) and maximum blood concentration (Cmax) of pimozide (although this increase was inconsistent throughout the study). Co-administration of pimozide and citalopram resulted in a mean increase in the QTc interval of approximately 10 msec. Combined administration of citalopram and pimozide was prohibited due to the interaction observed at low dose pimozide levels.
Citalopram (selective MAO-B inhibitor)
Pharmacokinetic/pharmacodynamic interaction studies of citalopram 20 mg once daily in combination with sellegrin 10 mg once daily (a selective MAO-B inhibitor) have shown no clinically relevant interactions. Combination of citalopram with stavudine (at doses greater than 10 mg daily) is prohibited.
Drugs to be combined with caution
5-hydroxytryptamine-like drugs (5-HT)
Combination of 5-hydroxytryptamine mimetics may lead to 5-hydroxytryptamine syndrome.
Lithium or tryptophan
No pharmacodynamic interactions have been found in clinical studies of citalopram in combination with lithium salts. However, synergistic effects have been reported with SSRIs and lithium salts or tryptophan, so caution should be exercised when combining such drugs. Routine monitoring of lithium levels should continue as usual.
Combination with 5-hydroxytryptamine mimetics (e.g., tramadol, sumatriptan) may result in an increased risk of 5-HT-related adverse events. Concomitant use of citalopram and 5-HT agonists, e.g., sumatriptan and other tramadol analogs, is not recommended until more information is available.
St. John’s Wort
Dynamic interactions between SSRIs and the herb St. John’s Wort (onychomycetes) may occur, resulting in an increase in adverse reactions. Pharmacokinetic interactions have not been studied.
Drugs Affecting Blood Clotting
Caution is needed in patients being treated with concomitant anticoagulants, drugs that affect platelet function such as [non-steroidal anti-inflammatory drugs (NSAIDs)], acetylsalicylic acid, dipyridamole and ticlopidine or other drugs that may increase the risk of bleeding (e.g. atypical antipsychotics).
ECT (electroconvulsive therapy)
There are no clinical studies to determine the risks or benefits of combining electroconvulsive therapy (ECT) with citalopram.
Alcohol
No pharmacodynamic or pharmacokinetic interactions between citalopram and alcohol have been demonstrated. However, the combination of citalopram and alcohol is not recommended.
Drugs inducing hypokalemia/hypomagnesemia
Hypokalemia/hypomagnesemia can increase the risk of malignant arrhythmias, so caution is needed when combining drugs that can induce these disorders.
Drugs that lower seizure threshold
SSRIs may lower seizure thresholds. Caution should be exercised when combining other medications that lower seizure threshold [e.g., antidepressants (TCA, SSRI), tranquilizers (thapsigargyl and butylphenols), mefloquine, bupropion, and tramadol].
Pharmacokinetic interactions
Biotransformation of citalopram to desmethylcitalopram is mediated via the CYP2C19 (approximately 38%), CYP3A4 (approximately 31%), and CYP2D6 (approximately 31%) isozymes of cytochrome P450. Since the inhibition of one enzyme may be compensated by another, citalopram is metabolized through multiple CYPs, so the possibility of inhibition of citalopram biotransformation is small. Therefore, the potential for pharmacokinetic interactions from co-administration of citalopram with other drugs is very low.
Food
Absorption and other pharmacokinetic properties of citalopram have not been reported to be affected by food.
Other drugs affecting the pharmacokinetics of this product
The combination of ketoconazole (a potent inhibitor of CYP3A4) does not affect the pharmacokinetics of this product.
Pharmacokinetic interaction studies have shown that the combination of lithium salts does not affect the pharmacokinetics of this product.
Cimetidine (a potent inhibitor of CYP2D6, 3A4, and 1A2 enzymes) causes a moderate increase in mean steady-state blood levels of citalopram. Caution is required when citalopram is given in combination with cimetidine. Co-administration of escitalopram (the active enantiomer of citalopram) with omeprazole 30 mg once daily (CYP2C19 inhibitor) resulted in a moderate (approximately 50%) increase in plasma concentrations of escitalopram. Therefore, caution should be exercised when combining CYP2C19 inhibitors (e.g., omeprazole, escitalopram, fluvoxamine, lansoprazole, ticlopidine) or cimetidine. Dose adjustment may be required.
No pharmacokinetic interactions due to plasma protein binding are anticipated.
Effect of this product on the pharmacokinetics of other drugs
A pharmacokinetic and pharmacodynamic interaction study showed a twofold increase in the concentration of metoprolol when this product was combined with metoprolol (CYP2D6 enzyme substrate), but no statistically significant increase in blood pressure or heart rate effects of metoprolol in healthy subjects. Caution is recommended when combining metoprolol and citalopram, and dose adjustments may be necessary.
Citalopram is a weak inhibitor of CYP2D6. Caution is recommended when combining citalopram with drugs that are primarily metabolized by CYP2D6 and have a narrow therapeutic index (e.g., flecainide, propafenone, and metoprolol).
Caution should be exercised when citalopram is combined with antidepressants that are primarily metabolized by CYP2D6 (e.g., clomipramine, promethazine, nortriptyline, and amitriptyline) or antipsychotics (e.g., risperidone, thioridazine, and haloperidol). Dose adjustment may be required.
Citalopram and desmethylcitalopram have little to no inhibitory effect on CYP2C9, CYP2E1, and CYP3A4. Citalopram and desmethylcitalopram only weakly inhibit CYP1A2 and CYP2C19 compared to the marked inhibition of CYP1A2 and CYP2C19 by other SSRIs.
Levomepromazine, digoxin, carbamazepine
When citalopram was co-administered with substrates of CYP1A2 (clozapine and theophylline), CYP2C9 (warfarin), CYP2C19 (promethazine and mephentermine), CYP2D6 (spartine, promethazine, amitriptyline, risperidone) or CYP3A4 (warfarin, triazolam, carbamazepine and its metabolite carbamazepine epoxide), no or only clinically significant minor changes.
No pharmacokinetic interactions were observed between citalopram and levomepromazine or digoxin, suggesting that citalopram neither induces nor inhibits P-glycoprotein.
Desipramine, promethazine
In a pharmacokinetic study, although blood concentrations of desipramine (the major metabolite of promethazine) increased, it did not show any effect on blood concentrations of citalopram or promethazine. Elevated plasma concentrations of desipramine were observed when desipramine was co-administered with citalopram. The dose of desipramine may need to be reduced.
[Drug Overdose].
Toxicity
Clinical data on citalopram overdose are limited, and many cases involve combined overdose with other drugs/alcohol. Fatal overdoses with citalopram alone have been reported; however, the vast majority of fatal cases involve overdose with the combined drug.
Symptoms
The following symptoms have been observed in reported citalopram overdoses: convulsions, drowsiness, tachycardia, bradycardia (prolonged QT interval, prolonged QRS), hypotension, hypertension, cardiac arrest, bundle branch block, coma, nausea, vomiting, tremor, 5-hydroxytryptamine syndrome, agitation, dizziness, dilated pupils, tip-twisting ventricular tachycardia, mydriasis, sweating, cyanosis, hyperventilation and atrial and ventricular arrhythmias.
Treatment
There is no known specific antidote for citalopram. Symptomatic and supportive therapy should be given. The use of activated charcoal, osmotic laxatives (e.g., sodium sulfate), and gastric emptying should be considered. If the patient becomes unconscious, the patient should be extubated and ECG and vital signs should be monitored.
ECG monitoring is advisable in patients with congestive heart failure/slow arrhythmias, in patients who have used combination drugs that prolong the QT interval, or in patients with metabolic abnormalities (e.g., hepatic injury) who have overdosed on this product.
Pharmacology and Toxicology
Pharmacological effects
Citalopram is an antidepressant, a dicyclic hydrogenated phthalide derivative. The mechanism of antidepressant action of citalopram may be related to the inhibition of 5-HT reuptake by neurons in the central nervous system, thus enhancing the function of central 5-hydroxytryptamine nerves. In vitro tests and animal tests suggest that citalopram is a highly selective 5-HT reuptake inhibitor with less effect on the reuptake of norepinephrine and dopamine. The inhibition of 5-HT uptake was not tolerated in rats given citalopram for 14 days. Citalopram is racemic and its inhibitory effect on 5-HT reuptake is mainly exerted by its (S)-enantiomer.
Citalopram has no affinity or only low affinity for 5-HT1A, 5-HT2A, D1 receptors, D2 receptors, α1 receptors, α2 receptors, β receptors, H1 receptors, GABA receptors, M receptors, and benzodiazepine receptors.
Toxicological studies
Genotoxicity
In vitro bacterial revertant mutation assay (Ames test) was positive for two of the five strains (TA98 and TA1537) in the absence of metabolic activation, and the CHL chromosomal aberration assay was positive in the presence or absence of metabolic activation. The in vitro mouse lymphoma cell mutation test (HPRT), the in vitro/in vivo combined rat liver cell programmed DNA synthesis test, the in vitro human lymphocyte chromosomal aberration test, and the in vivo mouse micronucleus test were all negative.
Reproductive toxicity
In the fertility and early embryonic development toxicity assay, oral administration of citalopram 16/24 (male/female), 32, 48 and 72 mg/kg/day in rats showed reduced mating rates in all dose groups, with reduced fertility at doses ≥32 mg/kg/day [approximately 5 times the maximum recommended human dose (MRHD) of 60 mg/day at mg/m2 (same below)] and at doses of 48 mg/kg/day (approximately 8 times the MRHD), and prolonged pregnancy time.
Data from animal studies show that at doses well above human exposure, citalopram reduces fertility indices and pregnancy indices, decreased number of implantations and sperm abnormalities.
In embryo-fetal developmental toxicity tests, oral administration of citalopram at 32, 56, and 112 mg/kg/day to rats resulted in embryo/fetal growth inhibition, reduced fetal survival, increased fetal abnormalities (including cardiovascular and skeletal defects), and maternal toxicity at the highest dose (approximately 18 times the MRHD), with a no-effect dose of 56 mg/kg/day (approximately 9 times the MRHD). (approximately 9 times the MRHD). No adverse effects on embryo/fetus development were observed in rabbits given citalopram orally at doses up to 16 mg/kg/day (5 times the MRHD).
In perinatal toxicity tests, rats were given citalopram orally from late gestation to lactation at 4.8, 12.8, and 32 mg/kg/day, with increased offspring mortality and stalled offspring growth seen at the highest dose (approximately 5 times the MRHD) for 4 days after birth, with a no-effect dose of 12.8 mg/kg/day (approximately 2 times the MRHD). Similar effects on offspring mortality and growth were observed in rats given oral citalopram ≥24 mg/kg/day (approximately 4 times the MRHD) during gestation to early lactation, and no no-effect dose was determined in this assay.
Carcinogenicity
No carcinogenicity was observed in NMRI/BOM mice given citalopram orally for 18 consecutive months by adulteration at doses up to 240 mg/kg/day (equivalent to 20 times the MRHD).In COBS WI rats given citalopram orally for 24 consecutive months by adulteration at doses of 8 or 24 mg/kg/day (equivalent to 1.3 and 4 times the MRHD, respectively), an increased incidence of small bowel cancer was seen. increased incidence. The relevance of this phenomenon in humans is unclear.
Pharmacokinetics]
Absorption
Citalopram tablets are rapidly absorbed (mean Tmax approximately 3 hours), almost completely absorbed and unaffected by food intake. The oral bioavailability is about 80%.
Distribution
The apparent volume of distribution (Vd) is about 12-17 L/kg. plasma protein binding of citalopram and its major metabolites is less than 80%.
Metabolism
Citalopram is metabolized in the liver to the active desmethylcitalopram, desdimethylcitalopram, citalopram-N-oxide and inactive desaminopropionic acid derivatives. All active metabolites remain SSRI analogues, but are weaker than citalopram. The main presence in plasma is citalopram in its prodrug form. Usually, the concentrations of demethylcitalopram and desdimethylcitalopram are 30% to 50% and 5% to 10% of citalopram, respectively. Citalopram is converted to demethylcitalopram by CYP2C19 (about 38%), CYP3A4 (about 31%) and CYP2D6 (about 31%).
Elimination
The plasma elimination half-life (T½) of citalopram is approximately 1.5 days, and the total plasma clearance (Cls) is approximately 0.3-0.4 L/min for oral administration.Citalopram is predominantly (85%) excreted hepatically, with the remainder (15%) excreted renally, and 12%-23% of the daily dose of citalopram is excreted in its original form from excreted in the urine. The residual clearance was about 0.3 L/min in the liver and 0.05-0.08 L/min in the kidney.
Linearity
The pharmacokinetics of citalopram are linear, with steady-state plasma concentrations reached after approximately 1 to 2 weeks, with a mean steady-state plasma concentration of 300 nmol/L (range: 165 to 405 nmol/L) for a daily dose of 40 mg.
Elderly Patients (> 65 years)
Studies have demonstrated a prolonged half-life and decreased clearance in elderly patients due to a slowed metabolic rate.
Those with reduced hepatic function
Citalopram is metabolized at a slower rate in patients with hepatic impairment. Its half-life and mean steady-state concentration at a given dose is approximately twice that of patients with normal hepatic function.
In patients with reduced renal function
The metabolism of citalopram was slowed in patients with mild to moderate renal impairment after a single dose of 20 mg, but there was no serious effect on its pharmacokinetics. No data are available for patients with severely reduced renal function (clearance < 20 mL/min).
Polymorphism
In vivo studies have shown no clinically significant polymorphism in the metabolism of citalopram to the oxidation of spartine/isoquinuclidine (CYP 2D6). For CYP2C19, an initial dose of 10 mg should be considered as a precautionary measure for slow metabolizers.
Storage]
Keep sealed.
Package】 Aluminum-plastic package. 7 tablets/box; 14 tablets/box; 28 tablets/box.
Expiration date】 18 months
Execution Standard
Approval Number】 State Drug Administration H20041200
【Manufacturing enterprise】 【Effective date】
Company Name: Sichuan Keren Pharmaceutical Co.
Production Address: Ziyang Economic and Technological Development Zone, Anyue Industrial Park (Shiqiaopu Town, Anyue County)
Postal Code: 642350
Telephone number: 028-86130259
Fax number: 028-86139152
Web address: http://www.kelun.com