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General: Potential Association with Behavioral and Emotional Changes, Including Self-Harm: Pediatrics: Placebo-Controlled Clinical Trial Data: Recent analyses of placebo-controlled clinical trial safety databases from SSRIs and other newer anti-depressants suggest that use of these drugs in patients under the age of 18 may be associated with behavioral and emotional changes, including an increased risk of suicidal ideation and behavior over that of placebo.
The small denominators in the clinical trial database, as well as the variability in placebo rates preclude reliable conclusions on the relative safety profiles among these drugs.
Adults and Pediatrics: Additional data: There are clinical trial and post-marketing reports with SSRIs and other newer anti-depressants, in both pediatrics and adults, of severe agitation-type adverse events coupled with self-harm and harm to others. The agitation-type events include: akathisia, agitation, disinhibition, emotional lability, hostility, aggression and depersonalization. In some cases, the events occurred within several weeks of starting treatment.
Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behavior is advised in patients of all ages. This includes monitoring for agitation-type emotional and behavioral changes.
An FDA meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients aged 18 to 24 years with psychiatric disorders showed an increased risk of suicidal behaviours with antidepressants compared to placebo.
Discontinuation Symptoms: Patients currently taking citalopram should NOT be discontinued abruptly, due to risk of discontinuation symptoms. At the time that a medical decision is made to discontinue an SSRI or other newer antidepressant drug, a gradual reduction in the dose rather than an abrupt cessation is recommended.
Discontinuation of Treatment with Citalopram: Symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt (see Clinical Trial Adverse Drug Reactions: Adverse Reactions following Discontinuation of Treatment (or Dose Reduction) under Adverse Reactions).
When discontinuing treatment, patients should be monitored for symptoms which may be associated with discontinuation. The risk of discontinuation symptoms may be dependent on several factors, including the duration and dose of therapy and the rate of dose reduction. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor and headache are the most commonly reported reactions.
Generally, these symptoms are mild to moderate; however, in some patients they may be severe in intensity. They usually occur within the first few days of discontinuing treatment, but there have been very rare 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 (2-3 months or more).
It is therefore advised that citalopram should be gradually tapered over a period of several weeks or months when discontinuing treatment, according to the patient's needs (see Recommended Dose and Dosage Adjustment: Discontinuation of pms-CITALOPRAM Treatment under Dosage & Administration).
If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient's clinical response (see Recommended Dose and Dosage Adjustment: Discontinuation of pms-CITALOPRAM Treatment under Dosage & Administration and Clinical Trial Adverse Drug Reactions: Adverse Reactions following Discontinuation of Treatment (or Dose Reduction) under Adverse Reactions).
Citalopram Treatment during Pregnancy - Effects on Newborns: In animal reproduction studies, citalopram has been shown to have adverse effects on embryo/fetal and postnatal development, including teratogenic effects, when administered at doses greater than human therapeutic doses (see Pharmacology: Toxicology: Reproduction Toxicity under Actions). There are no adequate and well-controlled studies in pregnant women; therefore, citalopram should be used during pregnancy only if the potential benefit to the patient justifies the potential risk to the fetus.
Post-marketing reports indicate that some neonates exposed to SSRIs and other antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. When treating a pregnant woman with citalopram during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see Recommended Dose and Dosage Adjustment: Treatment of Pregnant Women under Dosage & Administration; Pregnant Women: Complications following late third trimester exposure to SSRIs under Use in Pregnancy & Lactation; Nursing Women under Use in Pregnancy & Lactation).
Interference with Cognitive and Motor Performance: In studies in normal volunteers, citalopram hydrobromide in doses of 40 mg/day did not impair cognitive function or psychomotor performance. However, psychotropic medications may impair judgement, thinking or motor skills. Consequently, patients should be cautioned against driving a car or operating hazardous machinery until they are reasonably certain that pms-CITALOPRAM does not affect them adversely.
Bone Fracture Risk: Epidemiological studies show an increased risk of bone fractures following exposure to some antidepressants, including SSRIs/SNRIs. The risks appear to be greater at the initial stages of treatment, but significant increased risks were also observed at later stages of treatment. The possibility of fracture should be considered in the care of patients treated with pms-CITALOPRAM. Elderly patients and patients with important risk factors for bone fractures should be advised of possible adverse events which increase the risk of falls, such as dizziness and orthostatic hypotension, especially at the early stages of treatment but also soon after withdrawal. Preliminary data from observational studies show association of SSRIs/SNRIs and low bone mineral density in older men and women. Until further information becomes available, a possible effect on bone mineral density with long term treatment with SSRIs/SNRIs, including citalopram hydrobromide, cannot be excluded, and may be a potential concern for patients with osteoporosis or major risk factors for bone fractures.
Carcinogenesis and Mutagenesis: For animal data, see Pharmacology: Toxicology: Mutagenic Potential and Carcinogenicity under Actions.
Cardiovascular: Patients with Cardiac Disease: Citalopram has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were generally excluded from clinical trials during the drug's premarketing assessment.
In clinical trials, citalopram hydrobromide caused small but statistically significant decreases in heart rate (see Clinical Trial Adverse Drug Reactions: ECG under Adverse Reactions). Consequently, caution should be observed when citalopram is initiated in patients with pre-existing slow heart rate.
QT Prolongation and Torsades de Pointes: Citalopram hydrobromide can cause a dose-dependent increase in the QT interval (see Dosage & Administration; Overdosage; QT Prolongation under Contraindications; Post-Market Adverse Drug Reactions under Adverse Reactions; Interactions).
Events of torsade de pointes, ventricular fibrillation, cardiac arrest, and sudden death have been reported during post-marketing use of citalopram hydrobromide. Torsade de pointes is a polymorphic ventricular tachyarrhythmia. Generally, the risk of torsade de pointes increases with the magnitude of QT/QTc prolongation produced by the drug. Torsade de pointes may be asymptomatic or experienced by the patient as dizziness, palpitations, syncope, or seizures. If sustained, torsade de pointes can progress to ventricular fibrillation and sudden cardiac death.
A randomized, double-blind, placebo- and positive-controlled, crossover study was performed in healthy subjects (N=119) to examine the effects of citalopram 20 mg/day and 60 mg/day on ECG intervals (individually corrected QTcNi interval) when administered according to an escalating multiple dose regimen (9 days at 20 mg/day, 4 days at 40 mg/day, 9 days at 60 mg/day). The maximum mean (upper bound of the 95% one-sided confidence interval) differences from placebo were 8.5 (10.8) and 18.5 (21.0) msec for 20 mg and 60 mg citalopram, respectively. The effects of the 40 mg/day dose were not studied, but are predicted to be approximately 13 ms (estimate value on QTcNI).
Citalopram hydrobromide should not be dosed above 40 mg/day.
In patients who are CYP2C19 poor metabolizers or patients taking concomitant cimetidine or another CYP2C19 inhibitor, citalopram hydrobromide should not be dosed over 20 mg/day.
Hypokalemia and hypomagnesemia should be corrected prior to initiation of treatment and periodically monitored.
ECG monitoring is recommended in patients with risk factors for torsades de pointes, such as congestive heart failure, recent myocardial infarction, bradyarrhythmias, or patients on concomitant medications that prolong the QT interval or in patients with altered metabolism. e.g. liver impairment.
Endocrine and Metabolism: Diabetic Patients: Citalopram hydrobromide has not been systematically evaluated in diabetic patients since diabetes constituted an exclusion criterion. Although 13 patients did receive insulin during the studies, this number is too small to determine whether citalopram hydrobromide affects the response to insulin. Rare events of hypoglycemia were reported. Treatment with an SSRI in patients with diabetes may alter glycaemic control (hypoglycaemia and hyperglycaemia). pms-CITALOPRAM should be used with caution in diabetic patients on insulin or other antidiabetic drugs.
Hematologic: Abnormal Bleeding: SSRIs and SNRIs, including citalopram hydrobromide, may increase the risk of bleeding events by causing abnormal platelet aggregation. Concomitant use of acetylsalicylic acid (ASA), nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin and other anticoagulants may add to the risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening haemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of pms-CITALOPRAM and NSAIDs, ASA, or other drugs that affect coagulation (see Interactions).
Caution is advised in patients with a history of bleeding disorder or predisposing conditions (e.g. thrombocytopenia).
Hepatic/Biliary/Pancreatic: Hepatic Impairment: In subjects with hepatic impairment, citalopram hydrobromide clearance was significantly decreased and plasma concentrations, as well as elimination half-life significantly increased (see Pharmacology: Pharmacokinetics: Special Populations and Conditions: Hepatic Insufficiency under Actions). Consequently, the use of pms-CITALOPRAM in hepatically impaired patients should be approached with caution and a lower maximum dosage is recommended (see Recommended Dose and Dosage Adjustment: Hepatic Impairment under Dosage & Administration).
Neurologic: Seizures: Citalopram hydrobromide has not been systematically evaluated in patients with a seizure disorder. These patients were excluded from clinical studies during the premarketing testing of citalopram hydrobromide. In clinical trials, seizures occurred in 0.25% of patients treated with citalopram hydrobromide and in 0.23% patients treated with placebo. Like other antidepressants, pms-CITALOPRAM should be used with caution in patients with a history of seizure disorder. The drug should be discontinued in any patient who develops seizures.
Serotonin Syndrome/Neuroleptic Malignant Syndrome (NMS)-Like Events: On rare occasions serotonin syndrome or neuroleptic malignant syndrome-like events have occurred in association with treatment with SSRIs, including citalopram, particularly when given in combination with other serotonergic and/or neuroleptic drugs. As these syndromes may result in potentially life-threatening conditions, treatment with pms-CITALOPRAM should be discontinued if such events (characterized by clusters of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma) occur and supportive symptomatic treatment should be initiated. pms-CITALOPRAM should not be used in combination with MAO inhibitors or serotonin-precursors (such as L-tryptophan, oxitriptan) and should be used with caution in combination with other serotonergic drugs (triptans, certain tricyclic antidepressants, lithium, tramadol, St. John's Wort) due to the risk of serotonergic syndrome (see Monoamine Oxidase Inhibitors under Contraindications and Overview: Serotonergic Drugs and Triptans (5HT1 agonists) under Interactions).
Ophthalmologic: Angle-Closure Glaucoma: As with other antidepressants, pms-CITALOPRAM can cause mydriasis, which may trigger an angle-closure attack in a patient with anatomically narrow ocular angles. Healthcare providers should inform patients to seek immediate medical assistance if they experience eye pain, changes in vision or swelling or redness in or around the eye.
Psychiatric: Suicide: Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery. Therefore, high risk patients should be closely supervised throughout therapy with citalopram hydrobromide and consideration should be given to the possible need for hospitalization. In order to minimize the opportunity for overdosage, prescription for citalopram hydrobromide should be written for the smallest quantity of drug consistent with good patient management.
Other psychiatric conditions for which citalopram is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.
Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment, are at greater risk of suicidal thoughts or suicide attempts and should receive careful monitoring during treatment. In addition, there is a possibility of an increased risk of suicidal behaviour in young adults.
Patients (and caregivers of patients) should be alerted about the need to monitor for the emergence of such events and to seek medical advice immediately if these symptoms present. (See General: Potential Association with Behavioral and Emotional Changes, Including Self-Harm as previously mentioned.)
Activation of Mania/Hypomania: In placebo-controlled trials with citalopram hydrobromide, some of which included patients with bipolar disorder, mania/hypomania was reported in 0.1% of 1027 patients treated with citalopram hydrobromide versus none of the 426 patients treated with placebo. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorders treated with other marketed antidepressants. If a patient enters a manic phase, pms-CITALOPRAM should be discontinued.
As with all drugs effective in the treatment of depression, pms-CITALOPRAM should be used with caution in patients with a history of mania. A major depressive episode may be the initial presentation of bipolar disorder. Patients with bipolar disorder may be at an increased risk of experiencing manic episodes when treated with antidepressants alone. Therefore, the decision to initiate symptomatic treatment of depression should only be made after patients have been adequately assessed to determine if they are at risk for bipolar disorder.
Electroconvulsive Therapy (ECT): The safety and efficacy of the concurrent use of citalopram hydrobromide and ECT have not been studied and therefore, caution is advisable.
Renal: Hyponatremia: Hyponatremia and SIADH (syndrome of inappropriate antidiuretic hormone secretion) have been reported as a rare adverse event with use of citalopram hydrobromide, as with other SSRIs. The majority of these occurrences have been in elderly individuals, some in patients taking diuretics or who were otherwise volume-depleted. Elderly female patients in particular seem to be a group at risk.
Renal Impairment: No dosage adjustment is needed in patients with mild to moderate renal impairment. Since, no information is available on the pharmacokinetic or pharmacodynamic effects of citalopram hydrobromide in patients with severely reduced renal function (creatinine clearance < 30 mL/min), pms-CITALOPRAM should be used with caution in these patients.
Male Fertility: Animal data have shown that citalopram may affect sperm quality (see Pharmacology: Toxicology: Fertility under Actions). Human case reports with some SSRIs have shown that an effect on sperm quality is reversible. Impact on human fertility has not been observed.
Use in Children: pms-CITALOPRAM is not indicated for use in patients below the age of 18 years (see General: Potential Association with Behavioral and Emotional Changes, Including Self-Harm as previously mentioned).
Use in Elderly: Elderly patients should be administered lower doses and a lower maximum dose (see Recommended Dose and Dosage Adjustment: Geriatrics (≥ 65 years of age) under Dosage & Administration). In premarketing clinical trials, 800 elderly patients (≥65 years of age) have been treated with citalopram hydrobromide. Of these patients 298 were ≥75 years old. In a pharmacokinetic study (N=11, age 73 to 90 years), clearance was substantially decreased and half-life prolonged. In a multiple-dose pharmacokinetic study, the area under the curve (AUC) and half-life of S-citalopram were increased by approximately 50% at steady-state in elderly subjects as compared to young subjects. (See Pharmacology: Pharmacokinetics: Special Populations and Conditions: Geriatrics under Actions.) In a 6-week placebo-controlled study, approximately equal numbers of patients received citalopram hydrobromide at 20 or 30 mg per day, as the final dose. In about 5% of patients, the final dose was 10 mg per day (see Pharmacology: Pharmacodynamics: Clinical Trials under Actions).
