Abbott-Citalopram: Indications, Dosage, Precautions, Adverse Effects
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Abbott-Citalopram - Product Information

Manufacture: Abbott
Country: Canada
Condition: Anxiety and Stress, Depression, Postpartum Depression
Class: Selective serotonin reuptake inhibitors
Form: Tablets
Ingredients: Cornstarch, lactose monohydrate, microcrystalline cellulose, copovidone, glycerin, croscarmellose sodium, magnesium stearate, hypromellose, polyethylene glycol 400, and titanium dioxide, ferric oxide red and ferric oxide yellow.

Summary Product Information

Route of
Administration
Dosage Form / Strength All Non-medicinal Ingredients
oral tablet 10 mg, 20 mg and 40 mg cornstarch, lactose monohydrate, microcrystalline cellulose, copovidone, glycerin, croscarmellose sodium, magnesium stearate, hypromellose, polyethylene glycol 400, and titanium dioxide. Ferric oxide red and ferric oxide yellow are included as colouring agents.

Indications and Clinical Use

Adults

Abbott-Citalopram (citalopram hydrobromide) is indicated for:

  • the symptomatic relief of depressive illness

The relapse rate was significantly lower in citalopram-treated patients than in placebo-treated patients in two placebo-controlled studies that were conducted over a 24-week period in patients who responded to 6 or 8 weeks of acute treatment with citalopram (see CLINICAL TRIALS). Nevertheless, the physician who elects to use Abbott-Citalopram for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Geriatrics (≥ 65 Years of Age)

Elderly patients should be administered lower doses and a lower maximum dose (see DOSAGE AND ADMINISTRATION, Geriatrics and WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics).

Pediatrics (<18 Years of Age)

Abbott-Citalopram is not indicated for use in patients below the age of 18 (see WARNINGS AND PRECAUTIONS, General, Potential Association with Behavioral and Emotional Changes, Including Self-Harm).

Contraindications

Patients who are hypersensitive to citalopram hydrobromide or to any ingredient in the formulation or component of the container. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING.

Monoamine Oxidase Inhibitors

Cases of serious reactions have been reported in patients receiving selective serotonin reuptake inhibitors (SSRIs) in combination with a monoamine oxidase inhibitor (MAOI) or the reversible MAOI (RIMA), moclobemide, and in patients who have recently discontinued an SSRI and have been started on a MAOI (see DRUG INTERACTIONS). With the co-administration of an SSRI with MAOI, there have been reports of serious, sometimes fatal reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible fluctuations of vital signs, and mental status changes, including extreme agitation progressing to delirium and coma. Some cases presented with features resembling serotonin syndrome.

Therefore, citalopram should not be used in combination with a MAOI or within 14 days of discontinuing treatment with a MAOI, (including linezolid, an antibiotic which is a reversible non-selective MAO inhibitor and methylene blue, which is a MAOI). Similarly, at least 14 days should elapse after discontinuing citalopram treatment before starting a MAOI.

Pimozide

Abbott-Citalopram (citalopram hydrobromide) should not be used in combination with the antipsychotic drug pimozide, as results from a controlled study indicate that concomitant use is associated with an increased risk of QTc prolongation compared to pimozide alone. This apparent pharmacodynamic interaction occurred in the absence of a clinically significant pharmacokinetic interaction; the mechanism is unknown (see DRUG INTERACTIONS).

Qt Prolongation

Abbott-Citalopram is contraindicated in patients with known QT interval prolongation or with congenital long QT syndrome. (see WARNINGS AND PRECAUTIONS, Cardiovascular/QT Prolongation; ADVERSE REACTIONS, Post-Market Adverse Reactions; DRUG INTERACTIONS; DOSAGE AND ADMINISTRATION, OVERDOSAGE).

Warnings and Precautions

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 antidepressants 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
  • 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

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 ADVERSE REACTIONS, Adverse Reactions following Discontinuation of Treatment (or Dose Reduction)).

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 DOSAGE AND ADMINISTRATION, Discontinuation of Citalopram Treatment).

If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient’s clinical response (see ADVERSE REACTIONS, Adverse Reactions following Discontinuation of Treatment (or Dose Reduction) and DOSAGE AND ADMINISTRATION, Discontinuation of Citalopram Treatment).

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 TOXICOLOGY, Reproduction Toxicity). 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 WARNINGS AND PRECAUTIONS, Special Populations, Pregnant and Nursing Women; and DOSAGE AND ADMINISTRATION).

Interference With Cognitive and Motor Performance

In studies in normal volunteers, citalopram 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 Abbott-Citalopram (citalopram hydrobromide) does not affect them adversely.

Bone Fracture Risk

Epidemiological studies show an increased risk of bone fractures in patients receiving SSRIs and TCAs. The mechanism leading to this risk is unknown. 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 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 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, including citalopram, cannot be excluded, and may be a potential concern for patients with osteoporosis or major risk factors for bone fractures.

The following additional PRECAUTIONS are listed alphabetically.

Carcinogenesis and Mutagenesis

For animal data, see Part II: TOXICOLOGY section.

Cardiovascular

Patients With Cardiac Disease

Abbott-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 caused small but statistically significant decreases in heart rate (see ADVERSE REACTIONS, ECG). Consequently, caution should be observed when citalopram is initiated in patients with pre-existing slow heart rate.

Qt Prolongation and Torsades de Pointes

Abbott-Citalopram can cause a dose-dependent increase in the QT interval (see CONTRAINDICATIONS; ADVERSE REACTIONS, Post-Market Adverse Reactions; DRUG INTERACTIONS; DOSAGE AND ADMINISTRATION; OVERDOSAGE).

Events of torsade de pointes, ventricular fibrillation, cardiac arrest, and sudden death have been reported during post-marketing use of Citalopram. 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).

  • Abbott-Citalopram should not be dosed above 40 mg/day.
  • In patients who are CYP2C19 poor metabolizers or patients taking concomitant cimetidine or another CYP2C19 inhibitor, Abbott-Citalopram should not be dosed over 20 mg/day.
  • Hypokalemia and hypomagnesemia should be corrected prior to initiation of treatment and periodically
  • 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

Endocrine and Metabolism

Diabetic Patients

Abbott-Citalopram 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 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). Abbott-Citalopram should be used with caution in diabetic patients on insulin or other antidiabetic drugs.

Hematologic

Abnormal Bleeding

SSRIs and serotonin/norepinephrine reuptake inhibitors (SNRIs), including Abbott-Citalopram, 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 this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. 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 Abbott-Citalopram and NSAIDs, ASA, or other drugs that affect coagulation (see DRUG 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 clearance was significantly decreased and plasma concentrations, as well as elimination half-life significantly increased (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populations, Hepatic Impairment). Consequently, the use of Abbott-Citalopram in hepatically impaired patients should be approached with caution and a lower maximum dosage is recommended (see DOSAGE AND ADMINISTRATION, Recommended Dose and Dose Adjustments, Hepatic Impairment).

Neurologic

Seizures

Abbott-Citalopram has not been systematically evaluated in patients with a seizure disorder. These patients were excluded from clinical studies during the premarketing testing of Citalopram. In clinical trials, seizures occurred in 0.25% of patients treated with citalopram and in 0.23% patients treated with placebo. Like other antidepressants, Abbott-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 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. Abbott-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 CONTRAINDICATIONS and DRUG INTERACTIONS, Serotonergic Drugs, Triptans).

Ophtalmologic Glaucoma

As with other SSRIs/SNRIs, Abbott-Citalopram can cause mydriasis and should be used with caution in patients with raised intraocular pressure or those with narrow-angle glaucoma.

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 Abbott-Citalopram and consideration should be given to the possible need for hospitalization. In order to minimize the opportunity for overdosage, prescription for Abbott-Citalopram 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 behavior 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 WARNINGS AND PRECAUTIONS: Potential Association with Behavioral and Emotional Changes, Including Self-Harm).

Activation of Mania/Hypomania

In placebo-controlled trials with citalopram, some of which included patients with bipolar disorder, mania/hypomania was reported in 0.1% of 1027 patients treated with citalopram 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, Abbott-Citalopram should be discontinued.

As with all drugs effective in the treatment of depression, Abbott-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 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, 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 in patients with severely reduced renal function (creatinine clearance < 30 mL/min), Abbott- Citalopram should be used with caution in these patients.

Special Populations

Male Fertility

Animal data have shown that citalopram may affect sperm quality (see TOXICOLOGY, Fertility). Human case reports with some SSRIs have shown that an effect on sperm quality is reversible. Impact on human fertility has not been observed.

Pregnant Women

The safety of Abbott-Citalopram during pregnancy has not been established. Therefore, Abbott- Citalopram should not be used during pregnancy, unless, in the opinion of the physician, the expected benefits to the patient markedly outweigh the possible risk to the fetus.

Complications Following Late Third Trimester Exposure to SSRIs

Post-marketing reports indicate that some neonates exposed to SSRIs such as citalopram and other antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and other newer anti-depressants, or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS AND PRECAUTIONS, Neurologic, Serotonin Syndrome). When treating a pregnant woman with Abbott-Citalopram during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION, Recommended Dose and Dose Adjustments, Treatment of Pregnant Women).

Risk of PPHN and Exposure to SSRIs (Including Citalopram)

Epidemiological studies on persistent pulmonary hypertension of the newborn (PPHN) have shown that the use of SSRIs (including citalopram) in pregnancy, particularly use in late pregnancy, was associated with an increased risk of PPHN. PPHN occurs in 1-2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy (Odds Ratio 6.1, 95% CI 2.2-16.8). A study using data from the Swedish Medical Birth Register for 831,324 infants born in 1997-2005 found an increased risk of PPHN of approximately 2-fold associated with patient-reported maternal use of SSRIs in the first trimester of pregnancy (Risk Ratio 2.4, 95% CI 1.2-4.3), and an increased risk of PPHN of approximately 4-fold associated with a combination of patient-reported maternal use of SSRIs in the first trimester and an antenatal SSRI prescription in later pregnancy (Risk Ratio 3.6, 95% CI 1.2-8.3).

Nursing Women

The safety of Abbott-Citalopram during lactation has not been established. Citalopram is excreted in human milk. Abbott-Citalopram should not be administered to nursing mothers unless, in the opinion of the treating physician, the expected benefits to the patient markedly outweigh the possible risks to the child; in which case the infant should be closely monitored.

Pediatrics (<18 Years of Age)

Abbott-Citalopram is not indicated for use in patients below the age of 18 years (see WARNINGS AND PRECAUTIONS, Potential Association with Behavioural and Emotional Changes, Including Self Harm).

Geriatrics (≥65 Years of Age)

Elderly patients should be administered lower doses and a lower maximum dose (see DOSAGE AND ADMINISTRATION, Recommended Dose and Dose Adjustments, Geriatrics). In premarketing clinical trials, 800 elderly patients (≥65 years of age) have been treated with citalopram. 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 ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populations and Conditions, Geriatrics). In a 6-week placebo-controlled study, approximately equal numbers of patients received citalopram 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 CLINICAL TRIALS).

Adverse Reactions

Adverse Drug Reaction Overview

During the premarketing clinical development, 3652 patients received citalopram for the treatment of depression. Of these patients, 66% were females and 34% were males. The mean age of the patients was 50 years, with 70% being <60 years old (30% <40 years old, 40% 40 to 59 years old) and 30% being ≥60 years old. Adverse events observed with citalopram are in general mild and transient. They usually attenuate during the first one or two weeks of treatment.

Clinical Trial Adverse Drug Reactions

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

Adverse Findings Observed in Short-Term, Placebo-Controlled Trials

Adverse Reactions Leading to Discontinuation of Treatment

From the short-term (4 to 6 weeks) placebo-controlled, Phase III clinical trials, 15.9% (163/1027) of the citalopram-treated patients discontinued treatment due to an adverse event. The discontinuation rate in the placebo-treated patients was 7.7% (33/426).

The events associated with discontinuation of citalopram in 1% or more of patients at a rate of at least twice that of placebo, were as follows: nausea (4.1% vs. 0.0%), insomnia (2.4% vs. 1.2%), somnolence (2.4% vs. 1.2%), dizziness (2.3% vs. 0.7%), vomiting (1.3% vs. 0.0%), agitation (1.2% vs. 0.0%), asthenia (1.1% vs. 0.5%), and dry mouth (1.1% vs. 0.2%).

Incidence of Adverse Events in Placebo-Controlled Studies

Table 1 enumerates the incidence of treatment emergent adverse events that occurred in 1027 depressed patients who received citalopram at doses ranging from 10 to 80 mg/day in placebo-controlled trials of up to 6 weeks in duration. Events included are those occurring in 2% or more of patients treated with citalopram, and for which the incidence in patients treated with citalopram was greater than the incidence in placebo-treated patients. Reported adverse events were classified using the standard World Health Organization (WHO)-based dictionary terminology.

The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied.

Table 1: Treatment-emergent adverse events* incidence in placebo-controlled clinical trials
Body System /Adverse Event Percentage of Patients Reporting
Citalopram
(N=1027)
Placebo
(N=426)
Body as a Whole    
 Fatigue 5.2 3.1
 Fever1 2.4 0.2
Autonomic Nervous System    
 Dry mouth1 19.4 12.2
 Sweating increased 10.5 8.0
Central and Peripheral Nervous System
 Tremor
8.4 6.3
Gastrointestinal System    
 Nausea1 20.6 13.4
 Diarrhea 8.1 5.4
 Dyspepsia 4.3 3.5
 Vomiting 3.9 2.6
 Abdominal pain 3.1 2.1
Psychiatric    
 Somnolence1 17.3 9.9
 Anorexia1 4.2 1.6
 Nervousness 3.6 3.5
 Anxiety 3.3 2.1
 Agitation1 2.4 0.7
 Libido decreased1 2.2 0.2
 Yawning1 2.1 0
Reproductive, Female 2
 Dysmenorrhea (<50 years)
2.7 1.6
Reproductive, Male3    
 Ejaculation disorder1 6.2 1.1
 Impotence3 3.2 0.6
Respiratory System    
 Upper respir. tract infection 5.1 4.7
 Rhinitis 4.9 3.3
 Pharyngitis 3.4 2.8
 Sinusitis1 2.4 0.2
Urinary System
 Micturition disorder
2.3 2.1

*Events included are those occurring in 2% or more of patients treated with citalopram, and for which the incidence in patients treated with citalopram was greater than the incidence in placebo-treated patients.

1Statistically significantly higher incidence in the citalopram group (p<0.05).

2Denominator used was for females only (N=623 for citalopram; N=245 for Placebo).

3Denominator used was for males only (N=404 for citalopram; N=181 for Placebo)

The following events had a higher incidence in the placebo group compared to the citalopram group: asthenia, back pain, headache, dizziness, constipation, palpitation, insomnia, abnormal vision.

Most Frequent Adverse Events

Adverse events that occurred in citalopram-treated patients in the course of the short-term, placebo-controlled trials with an incidence greater than, or equal to, 10% were: nausea, dry mouth, somnolence, and increased sweating (Table 1).

Dose Dependency of Adverse Events

The potential relationship between the dose of citalopram and the incidence of an adverse event was examined in a fixed dose short-term, placebo-controlled study in which patients received citalopram at doses of 10, 20, 40 or 60 mg per day. The incidence of diarrhea, dry mouth, fatigue, insomnia, increased sweating, nausea and somnolence was dose-related.

Male and Female Sexual Dysfunction with SSRIs

While sexual dysfunction is often part of depression and other psychiatric disorders, there is increasing evidence that treatment with SSRIs may induce sexual side effects. This is a difficult area to study because patients may not spontaneously report symptoms of this nature, and therefore, it is thought that sexual side effects with SSRIs may be underestimated.

In placebo-controlled, short-term clinical trials, the reported incidence of decreased libido, ejaculation disorders (primarily ejaculation delay and ejaculation failure), and impotence in male depressed patients receiving citalopram (N=404) was 3.7%, 6.2%, and 3.2%, respectively. In female depressed patients receiving citalopram (N=623), the reported incidence of decreased libido and anorgasmia was 1.3% and 1.1%, respectively. The reported incidence of each of these adverse events was ≤1% among male and female depressed patients receiving placebo.

Weight Changes

Patients treated with citalopram in controlled trials experienced a weight loss of about 0.5 kg compared to no change for placebo patients.

ECG

Retrospective analyses of electrocardiograms in citalopram-treated (N=779 <60 years and N=313 ≥60 years) and placebo-treated (N=74 <60 years and N=43 ≥60 years) patients indicated that citalopram decreases heart rate. In patients <60 years old, the mean decrease was approximately 5 bpm, while in patients ≥60 years old, mean decreases ranged between 5 to 10 bpm. Following the initial drop, heart rate remained decreased but stable over prolonged periods of time (up to one year in over 100 younger and over 50 elderly patients). The effect was reversible within approximately a week after stopping treatment.

In the 6-week, fixed dose, dose-response study, the mean decreases in heart rate ranged between 2-6 bpm in the 20-60 mg/day dose range, but the effect did not seem to be dose-related and was independent of gender. In placebo-treated patients heart rates remained unaffected. The differences in heart rates between Citalopram - and placebo-treated patients were statistically significant.

ECG parameters, including QT interval, remained unaffected.

Adverse Reactions Following Discontinuation of Treatment (or Dose Reduction)

There have been reports of adverse reactions upon the discontinuation of citalopram (particularly when abrupt), including but not limited to the following: dizziness, abnormal dreams, sensory disturbances (including paresthesias and electric shock sensations), agitation or anxiety, emotional indifference, impaired concentration, headache, migraine, tremor, nausea and/or vomiting, sleep disturbances (including insomnia and intense dreams), confusion, diarrhoea, palpitations, irritability, visual disturbances and sweating or other symptoms which may be of clinical significance (see WARNINGS AND PRECAUTIONS: Discontinuation Symptoms and DOSAGE AND ADMINISTRATION, Recommended Dose and Dose Adjustments, Discontinuation of Citalopram Treatment).

Patients should be monitored for these or any other symptoms. A gradual reduction in the dosage over a period of at least one to two weeks, rather than abrupt cessation is recommended to reduce the risk of withdrawal reactions. Generally these events are mild to moderate and are self- limiting, however, in some patients they may be severe and/or prolonged. It is therefore advised that when citalopram treatment is no longer required, gradual discontinuation by dose tapering should be carried out. 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. Symptoms associated with discontinuation have been reported for other selective serotonin reuptake inhibitors (see WARNINGS AND PRECAUTIONS: Discontinuation Symptoms and DOSAGE AND ADMINISTRATION, Recommended Dose and Dose Adjustments, Discontinuation of Citalopram Treatment).

Additional Adverse Events Observed During the Premarketing Evaluation of Citalopram

The events listed below include all adverse events that were reported in the overall development program of citalopram (N=3652). All reported events are included except those already listed in Table 1 and those events which occurred in only one patient. It is important to emphasize that, although the events reported occurred during treatment with citalopram, they were not necessarily caused by it. The events are enumerated using the following criteria:

  • frequent: adverse events that occurred on one or more occasions in at least 1/100 patients
  • infrequent: adverse events that occurred in less than 1/100 patients but at least in 1/1000 patients
  • rare: adverse events that occurred in fewer than 1/1000

Body as a Whole - General Disorders: Frequent: influenza-like symptoms, non-pathological trauma, pain. Infrequent: alcohol intolerance, allergic reaction, allergy, chest pain, edema, hot flushes, leg pain, malaise, rigors, syncope. Rare: peripheral edema, sudden death, traumatic injury.

Cardiovascular Disorders: Frequent: postural hypotension, tachycardia. Infrequent: angina pectoris, arrhythmia, bradycardia, cardiac failure, cerebrovascular disorders, edema dependent, extrasystoles, flushing, hypertension, hypotension, myocardial infarction, myocardial ischemia, peripheral ischemia. Rare: aggravated hypertension, bundle branch block, cardiac arrest, coronary artery disorder, ECG abnormal, heart disorder, phlebitis, supraventricular extrasystoles.

Central and Peripheral Nervous System Disorders: Frequent: migraine, paraesthesia. Infrequent: abnormal gait, ataxia, convulsions, dysphonia, dystonia, extrapyramidal disorder, hyperkinesia, hypertonia, hypoesthesia, hypokinesia, involuntary muscle contractions, leg cramps, neuralgia, speech disorder, vertigo. Rare: abnormal coordination, convulsions grand mal, hyperesthesia, ptosis, sensory disturbance, stupor.

Collagen Disorders: Rare: rheumatoid arthritis.

Endocrine Disorders: Rare: goiter, gynecomastia, hypothyroidism.

Gastrointestinal System Disorders: Frequent: flatulence. Infrequent: colitis, dental abscess, dysphagia, eructation, gastritis, gastroenteritis, gastrointestinal disorder (not specified), hemorrhoids, increased saliva, teeth grinding, toothache. Rare: appendicitis, esophagitis, gastric ulcer, gastroesophageal reflux, gingivitis, stomatitis, tooth disorder, ulcerative stomatitis.

Hematopoietic and Lymphatic Disorders: Infrequent: anemia, epistaxis, leukocytosis, purpura. Rare: coagulation disorder, gingival bleeding, granulocytopenia, hematoma, leukopenia, lymphadenopathy, lymphocytosis, pulmonary embolism.

Liver and Biliary System Disorders: Infrequent: cholecystitis, cholelithiasis, increased gamma- GT, increased ALT. Rare: bilirubinemia, increased AST, jaundice.

Metabolic and Nutritional Disorders: Frequent: appetite decreased, weight decrease, weight increase. Infrequent: leg edema, xerophthalmia. Rare: dehydration, edema, hypoglycemia, hypokalemia, increased alkaline phosphatase, obesity, thirst.

Musculo-Skeletal System Disorders: Infrequent: arthralgia, arthritis, arthrosis, dystonia, muscle weakness, myalgia. Rare: bone disorder, bursitis, osteoporosis, tendon disorder.

Neoplasm: Rare: breast neoplasm malignant female.

Psychiatric Disorders: Frequent: abnormal dreaming, aggravated depression, amnesia, apathy, confusion, depression, impaired concentration, increased appetite, sleep disorder, suicide attempt. Infrequent: abnormal thinking, aggressive reaction, delusion, depersonalization, drug abuse, drug dependence, emotional lability, euphoria, hallucination, increased libido, manic reaction, neurosis, paranoid reaction, paroniria, psychosis, psychotic depression. Rare: catatonic reaction, hysteria, personality disorder.

Reproductive Disorders, Female: Frequent: Abnormal orgasm Infrequent: amenorrhea, breast pain, lactation nonpuerperal, menorrhagia, menstrual disorder, premenstrual syndrome, salpingitis, unintended pregnancy, vaginal dryness, vaginitis. Rare: breast enlargement, vaginal hemorrhage.

Reproductive Disorders, Male: Infrequent: penis disorder, prostatic disorder, testis disorder.

Resistance Mechanism Disorders: Infrequent: abscess, fungal infection, herpes simplex infection, otitis media, viral infection. Rare: bacterial infection, moniliasis, sepsis.

Respiratory System Disorders: Infrequent: bronchitis, coughing, dyspnea, pneumonia. Rare: asthma, bronchospasm, increased sputum, laryngitis, pneumonitis, respiratory disorder.

Skin and Appendage Disorders: Frequent: pruritus, rash. Infrequent: acne, alopecia, dermatitis, dry skin, eczema, photosensitivity reaction, psoriasis, rash erythematous, rash maculo-papular, skin discoloration, urticaria. Rare: cellulitis, decreased sweating, hypertrichosis, melanosis, pruritus ani.

Special Senses, Vision, Hearing and Vestibular Disorders: Frequent: abnormal accommodation. Infrequent: conjunctivitis, earache, eye pain, mydriasis, taste perversion, tinnitus. Rare: eye abnormality, keratitis, photophobia.

Urinary System Disorders: Frequent: polyuria. Infrequent: abnormal urine, cystitis, hematuria, micturition frequency, urinary incontinence, urinary retention, urinary tract infection. Rare: dysuria, facial edema, oliguria, renal calculus, renal pain.

Post-Market Adverse Drug Reactions

During the 22 year of post marketing experience, it is estimated that more than 138 million patients have been treated with citalopram, which corresponds to more than 34 million patient- years of treatment.

The following adverse events have been identified during post-approval use of citalopram. These events are reported voluntarily from a population of uncertain size, and it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Table 2 – Spontaneous Adverse Events
System Organ Class Adverse Event
Blood and lymphatic disorders Eosinophilia, hemolytic anemia, Pancytopenia, Thrombocytopenia,
Immune system disorders Anaphylactic reaction, Hypersensitivity
Endocrine disorders Hyperprolactinemia , Inappropriate ADH secretion
Metabolism and nutrition disorders Hyponatremia, hypokalaemia
Psychiatric disorders Abnormal orgasm (female), Bruxism , Confusional state, Delirium, Hypomania, Panic attack, Restlessness, Withdrawal syndrome, abnormal dreams
Nervous system disorders Akathisia, Choreoathetosis, Dyskinesia, Extrapyramidal disorder , Movement disorder, Myoclonus, Neuroleptic malignant syndrome, Neuropathy, Nystagmus, Serotonin syndrome, Syncope, dizziness, disturbance in attention, taste disturbance
Eye disorders Visual disturbance
Cardiac disorders Torsade de pointes, Ventricular arrhythmia, cardiac arrest, cardio-respiratory arrest, electrocardiogram QT interval prolonged, long QT syndrome, ventricular fibrillation, ventricular tachycardia, sudden death
Vascular disorders Orthostatic hypotension, Vasodilatation
Gastrointestinal disorders Gastrointestinal haemorrhage (including rectal haemorrhage), Pancreatitis, constipation
Hepatobiliary disorders Hepatitis, Liver function test abnormal
Skin and subcutaneous tissue disorders Angioedemas, Ecchymosis, Epidermal necrolysis, Erythema multiforme, Stevens-Johnson syndrome, photosensitivity
Musculoskeletal and connective tissue disorders Rhabdomyolysis
Renal and urinary disorders Acute renal failure
Reproductive system and breast disorders Female: menometrorrhagia, Male: Priapism, Galactorrhoea
General disorders and administration site conditions Fatigue, Condition aggravated, pyrexia
Investigations Decreased drug level, Decreased prothrombin time, Increased drug level, Increased prothrombin time
Pregnancy, puerperium and perinatal conditions Spontaneous abortion/fetal death

Drug Interactions

Serious Drug Interactions

  • Monoamine Oxidase Inhibitors: see CONTRAINDICATIONS.
  • Pimozide: see CONTRAINDICATIONS.

Overview

Alcohol

Although citalopram did not potentiate the cognitive and psychomotor effects of alcohol in volunteers, the concomitant use of alcohol and Abbott-Citalopram (citalopram hydrobromide) should be avoided.

Cimetidine

Citalopram should not be dosed above 20 mg/day in patients receiving cimetidine.

CNS Drugs

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

Cytochrome P450 Isozymes

Using in vitro models of human liver microsomes, the biotransformation of citalopram to its demethyl metabolites was shown to depend on both CYP2C19 and CYP3A4, with a small contribution from CYP2D6. Studies have also indicated that citalopram is a weak inhibitor of CYP2D6 and CYP2C19 and a weak or negligible inhibitor of CYP3A4, CYP1A2, CYP2C9 and CYP2E1. Although citalopram has a low potential for clinically significant drug interactions, caution is recommended, when citalopram is co-administered with drugs that are mainly metabolized by CYP2D6, and that have a narrow therapeutic index.

One in vitro study using human liver microsomes has shown that ketoconazole and omeprazole reduced the rate of formation of the demethylcitalopram metabolite of citalopram to 45-60% and 75-85% of control, respectively. As data are not available from multi-dose pharmacokinetic studies, the possibility that the clearance of citalopram will be decreased when citalopram is administered with a potent inhibitor of CYP3A4 (e.g., ketoconazole, itraconazole, fluconazole or erythromycin), or a potent inhibitor of CYP2C19 (e.g., omeprazole, esomeprazole, fluvoxamine, lansoprazole, ticlopidine), should be considered.

Abbott-Citalopram 20 mg/day is the maximum recommended dose for patients taking concomitant CYP2C19 inhibitors because of the risk of QT prolongation.

In addition, a single-dose study of escitalopram co-administered with a multiple-dose regimen of cimetidine, a non-specific CYP inhibitor, led to significant changes in most of the pharmacokinetic parameters of escitalopram.The overall metabolic pathways for escitalopram and citalopram are qualitatively similar and the interaction potential for escitalopram is expected to closely resemble that of citalopram. Thus, this allows for extrapolation to previous studies with escitalopram.

Various scientific publications have acknowledged that the main components in grapefruit juice may act as a CYP3A4 inhibitor. Citalopram is also metabolized by other isoenzymes not affected by grapefruit juice, namely CYP2C19 and CYP2D6.

Drug Affecting Platelet Function (e.g. NSAIDs, ASA and Other Anticoagulants)

Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID, ASA or other anticoagulants may potentiate the risk of bleeding.

Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are co-administered with warfarin. Patients receiving warfarin therapy should be carefully monitored when Abbott-Citalopram is initiated or discontinued. (see WARNINGS AND PRECAUTIONS, Hematologic, Abnormal Bleeding.)

Drugs That Prolong the QT Interval

ECG monitoring is recommended if Abbott-Citalopram is administered with concomitant medications that have demonstrated prolongation of the QT interval. (See CONTRAINDICATIONS; WARNINGS AND PRECAUTIONS; ADVERSE REACTIONS/POST-MARKET ADVERSE DRUG REACTIONS; DRUG INTERACTIONS/OVERVIEW/Cytochrome P450 Isozymes and Cimetidine; DOSAGE AND ADMINISTRATION)

Drugs known to prolong the QT/QTc

The concomitant use of citalopram with another drug known to prolong the QT/QTc interval should be carefully considered to determine that the therapeutic benefit outweighs the potential risk. Drugs that have been associated with QT/QTc interval prolongation and/or torsade de pointes include, but are not limited to, the examples in the following list.

Chemical/pharmacological classes are listed if some, although not necessarily all, class members have been implicated in QT/QTc prolongation and/or torsade de pointes:

  • class IA antiarrhythmics (e.g., procainamide, disopyramide);
  • class III antiarrhythmics (e.g., amiodarone, sotalol, ibutilide);
  • class IC antiarrhythmics (e.g., propafenone);
  • antipsychotics (e.g., chlorpromazine, pimozide, haloperidol, droperidol, ziprasidone);
  • antidepressants (e.g., fluoxetine, venlafaxine, tricyclic/tetracyclic antidepressants (e.g.,amitriptyline, imipramine, maprotiline);
  • opioids (e.g., methadone);
  • macrolide antibiotics and analogues (e.g., erythromycin, clarithromycin, telithromycin, tacrolimus);
  • quinolone antibiotics (e.g., moxifloxacin, levofloxacin, ciprofloxacin);
  • antimalarials (e.g., quinine, chloroquine);
  • azole antifungals (e.g., ketoconazole, fluconazole, voriconazole);
  • domperidone; 5- hydroxytryptamine (5-HT)3 receptor antagonists (e.g., ondansetron);
  • tyrosine kinase inhibitors (e.g., sunitinib, nilotinib, lapatinib);
  • histone deacetylase inhibitors (e.g., vorinostat);
  • beta-2 adrenoceptor agonists (e.g., salmeterol, formoterol).

The use of citalopram should be carefully considered with drugs that can disrupt electrolyte levels (see WARNINGS AND PRECAUTIONS), including, but not limited to, the following:

  • loop, thiazide, and related diuretics;
  • laxatives and enemas;
  • amphotericin B;
  • high dose corticosteroids.

Monoamine Oxidase Inhibitors

In patients receiving SSRIs in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes, including extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued SSRI treatment and have been started on a MAOI. Some cases presented with features resembling serotonin syndrome or neuroleptic malignant syndrome. Citalopram should not be used in combination with a MAOI, (including linezolid, an antibiotic which is a reversible non-selective MAO inhibitor) and methylene blue, which is a MAOIs) or within 14 days of discontinuing treatment with a MAOI. Similarly, at least 14 days should elapse after discontinuing Citalopram treatment before starting a MAOI (see CONTRAINDICATIONS).

Serotonergic Drugs

Based on the mechanism of action of citalopram and the potential for serotonin syndrome, caution is advised when Abbott-Citalopram is coadministered with other drugs or agents that may affect the serotonergic neurotransmitter systems, such as tryptophan, triptans, serotonin reuptake inhibitors, lithium, or St. John's Wort, fentanyl and its analogues, dextromethorphan, tramadol, tapentadol, meperidine, methadone and pentazocine. (see WARNINGS AND PRECAUTIONS: Serotonin Syndrome/Neuroleptic Malignant Syndrome (NMS)-like events). Concomitant use of Abbott-Citalopram and MAO inhibitors (including linezolid and methylene blue), is contraindicated (see CONTRAINDICATIONS).

Triptans (5HT1 Agonists)

Cases of life-threatening serotonin syndrome have been reported during combined use of selective serotonin reuptake inhibitors (SSRIs)/serotonin norepinephrine reuptake inhibitors (SNRIs) and triptans. If concomitant treatment with Abbott-Citalopram and a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS AND PRECAUTIONS: Serotonin Syndrome/Neuroleptic Malignant Syndrome (NMS)-like events).

Racemic Citalopram

Citalopram is a racemic mixture of R-citalopram and S-citalopram, the later being the active isomer. As escitalopram, is the active isomer of racemic citalopram, the two drugs should not be taken together.

Other Drugs

No pharmacodynamic interactions have been noted in clinical trials where citalopram has been given concomitantly with benzodiazepines (anxiolytics/hypnotics), analgesics (NSAIDs, non- NSAIDs), antihistamines, antihypertensives or other cardiovascular drugs. Pharmacokinetic interactions between citalopram and these drugs were not specifically studied.

Drug-Drug Interactions

Where studies are described in this section, they were carried out in young, healthy, mostly male volunteers. In addition, some of the studies, namely interactions with metoprolol, warfarin, digoxin, imipramine, and levomepromazine, utilized only single doses of these drugs, although citalopram was given repeatedly to attain steady state. Thus, data are not available in patients who would be receiving these drugs on an ongoing basis at therapeutic doses.

Potential Drug-Drug
Interactions with:
Effect Clinical Recommendations
Carbamazepine Carbamazepine, titrated to 400 mg/day, was given for 21 days alone and then in combination with Citalopram (40 mg/day) for an additional 14 days. Citalopram did not affect the plasma levels of either carbamazepine, a CYP3A4 substrate, or its metabolite carbamazepine-epoxide. Since carbamazepine is a microsomal enzyme inducer, the possibility that carbamazepine may increase the clearance of Abbott-Citalopram should be considered if the two drugs are given concomitantly.
Cimetidine Citalopram 40 mg/day was administered for 29 days. During the last 8 days of treatment, cimetidine (400 mg bid) was added to the treatment regimen. In the presence of cimetidine, a potent inhibitor of hepatic cytochrome P450 enzymes (CYP2D6, 3A4 and 1A2 inhibitor), the Cmax and AUC of Citalopram was increased by 39% and 41%, respectively. Caution should be exercised at the upper end of the dose range of citalopram when it is used concomitantly with high doses of cimetidine.

Abbott-Citalopram 20 mg/day is the maximum recommended dose when taken with cimetidine.
Cipralex Escitalopram is the active isomer of racemic citalopram. The two drugs should not be taken together.
Digoxin Administration of citalopram (40 mg/day for 21 days) did not affect the pharmacokinetics of digoxin (single dose of 1 mg), although the serum levels of citalopram were slightly lower in the presence of digoxin.  
Imipramine/ Desipramine Co administration of citalopram (40 mg/day for 10 days) and the tricyclic antidepressant, imipramine (single dose of 100 mg), did not affect the pharmacokinetics of either drug. However, in the presence of citalopram, the concentration of desipramine, the metabolite of imipramine, increased by approximately 50% and its half-life was prolonged. The results indicate that citalopram does not interfere with the demethylation of imipramine to desipramine but does inhibit the metabolism of desipramine to its 2- hydroxy metabolite.
Both imipramine and desipramine are substrate for CYP2D6.
The clinical significance of this finding is unknown.
Concomitant treatment with citalopram and imipramine/desipramine should be undertaken with caution.
Ketoconazole Combined administration of citalopram (40 mg single dose) and the potent CYP3A4 inhibitor ketoconazole (200 mg single dose) decreased the Cmax of ketoconazole by 21% and did not affect the pharmacokinetics of citalopram.  
Levomepromazine Co administration of citalopram (40 mg/day for 10 days) and levomepromazine (single dose of 50 mg), a CYP2D6 inhibitor, did not affect the pharmacokinetics of either drug.  
Lithium Co administration of citalopram (40 mg/day for 10 days) and lithium (30 mmol/day for 5 days), did not affect the pharmacokinetics of either drug. Since lithium may increase serotonergic neurotransmission, concomitant treatment with these two drugs should be undertaken with caution.
Metoprolol Co administration of citalopram (40 mg/day for 22 days) and the β-adrenergic blocking agent metoprolol (single dose of 150 mg), resulted in a twofold increase in the plasma levels of metoprolol. However, the effect of metoprolol, a CYP2D6 substrate, on blood pressure and heart rate was not affected.  
Omeprazole CYP2C19 inhibitor Co-administration of omeprazole (30 mg once daily for 6 days), a CYP2C19 inhibitor, with escitalopram (single dose of 20 mg on day 5) resulted in an increase in escitalopram AUC and Cmax of approximately 50% and 10%, respectively.

Citalopram 20 mg/day is the maximum recommended dose for patients taking concomitant CYP2C19 inhibitors because of the risk of QT prolongation.
Pimozide In a double-blind crossover study in healthy young adults, a single dose of the anti- psychotic drug, pimozide 2 mg co- administered with citalopram 40 mg given once daily for 11 days was associated with a mean increase in QTc values at Tmax of approximately 12 msec compared to pimozide when given with placebo. This apparent pharmacodynamic interaction occurred in the absence of a clinically significant pharmacokinetic interaction; the mechanism is unknown. Concomitant use of citalopram and pimozide is contraindicated (see CONTRAINDICATIONS).
Ritonavir Substrate for CYP3A4. Combined administration of a single dose of ritonavir (600 mg), a CYP3A4 substrate and a potent inhibitor of CYP3A4, and escitalopram (20 mg) did not affect the pharmacokinetics of either ritonavir or escitalopram.
Theophylline Co-administration of citalopram (40 mg/day for 21 days) with the CYP1A2 substrate theophylline (single dose of 300 mg) did not affect the pharmacokinetics of theophylline.  
Triazolam Combined administration of citalopram (titrated to 40 mg/day for 28 days) and the CYP3A4 substrate triazolam (single dose of 0.25 mg) did not significantly affect the pharmacokinetics of either drug.  
Warfarin Administration of citalopram (40 mg/day for 21 days), did not affect either the pharmacokinetics or the pharmacodynamics (prothrombin time) of a single, 25 mg dose of warfarin, a CYP3A4 and CYP2C9 substrate.  

Drug-Food Interactions

Although there is a theoretical possibility of pharmacokinetic drug product interactions resulting from co administration of citalopram with grapefruit juice, the onset of an interaction is considered unlikely (see CYTOCHROME P450 ISOZYMES).

Drug-Herb Interactions

St-John’s Wort: In common with other SSRIs, pharmacodynamic interactions between citalopram and the herbal remedy St-John’s Wort may occur and may result in undesirable effects.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

Dosage and Administration

Dosing Considerations

  • Abbott-Citalopram (citalopram hydrobromide) is not indicated for use in children under 18 years of age (see WARNINGS AND PRECAUTIONS, Potential Association with Behavioral and Emotional Changes, Including Self-Harm).
  • General: Abbott-Citalopram should be administered once daily, in the morning or evening, with or without

Recommended Dose and Dosage Adjustment

Adults

Abbott-Citalopram should be administered as a single oral dose of 20 mg/day. In patients who do not respond adequately, an increase of dosage to a maximum of 40 mg/day should be considered. Dose increases should usually occur at intervals of no less than one week.

Treatment of Pregnant Women

The safety of Abbott-Citalopram during pregnancy has not been established. Therefore, Abbott- Citalopram should not be used during pregnancy, unless, in the opinion of the physician, the expected benefits to the patient markedly outweigh the possible risk to the fetus.

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

Geriatrics (≥ 65 Years of Age)

A longer half-life and decreased clearance have been demonstrated in the elderly, therefore lower doses and a lower maximum dose should be considered. It may be desirable to start at 10 mg daily and titrate upwards as needed and tolerated. A single oral dose of 20 mg/day is the recommended dose for most elderly patients. Some patients may respond to a 10 mg/day dose (see CLINICAL TRIALS). The dose may be titrated to a maximum of 20 mg/day if needed and tolerated. As with other SSRIs, caution should be exercised in treating elderly female patients who may be more susceptible to adverse events such as hyponatremia and SIADH (syndrome of inappropriate antidiuretic hormone secretion) (see WARNINGS AND PRECAUTIONS, Renal, Hyponatremia).

Hepatic Impairment

Dosages should be restricted to the lower end of the dose range in patients with mild to moderate hepatic insufficiency. Accordingly, an initial single oral dose of 10 mg daily is recommended.

Subsequently, the dose may be increased based on the patient’s response and clinical judgement. Patients with reduced hepatic function should receive dosages of no more than 20 mg/day (see WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic). Citalopram should be used with additional caution in patients with severe hepatic impairment.

Renal Impairment

No dosage adjustment is necessary for patients with mild to moderate renal impairment. Since there is no information available on the pharmacokinetic or pharmacodynamic effects of citalopram in patients with severe renal impairment, Abbott-Citalopram should be used with caution in these patients.

CYP2C19 Poor Metabolisers An initial dose of 10 mg daily during the first two weeks of treatment is recommended for patients who are known to be poor metabolisers of CYP2C19. The dose may be increased to a maximum of 20 mg daily depending on individual patient response (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).

Maintenance Treatment

Evaluation of citalopram in two placebo-controlled studies has shown that its antidepressant efficacy was maintained for periods of up to 24 weeks, following 6 or 8 weeks of initial treatment (total of 32 weeks) (See CLINICAL TRIALS). In the flexible dose study, the great majority of patients were receiving 20 or 40 mg/day doses both at 12 and 24 weeks. During maintenance therapy, the dosage should be kept at the lowest effective level and patients should be periodically reassessed to determine the need for continued treatment.

Switching Patients To or From a MAOI

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

Discontinuation of Citalopram Treatment

Symptoms associated with the discontinuation or dosage reduction of citalopram have been reported. Patients should be monitored for these and other symptoms when discontinuing treatment or during dosage reduction (see WARNINGS AND PRECAUTIONS, Discontinuation Symptoms and ADVERSE REACTIONS).

A gradual reduction in the dose over a period of at least one to two weeks rather than abrupt cessation is recommended to reduce the risk of withdrawal reactions. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient’s clinical response (see WARNINGS AND PRECAUTIONS, Dependence/Tolerance, Withdrawal Symptoms Seen on Discontinuation of SSRI and ADVERSE REACTIONS, Adverse Reactions following Discontinuation of Treatment (or Dose Reduction)).

Missed Dose

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

Overdosage

For management of a suspected drug overdose, contact your regional Poison Control Centre immediately.

In clinical trials with racemic citalopram, there were no reports of fatal citalopram overdoses of up to 2000 mg. All patients recovered. Events of torsade de pointes have been reported during overdose with Citalopram during post-market use (see CONTRAINDICATIONS; WARNINGS AND PRECAUTIONS, Cardiovascular; ADVERSE REACTIONS/Post Market Adverse Drug Reactions, DRUG INTERACTIONS; DOSAGE AND ADMINISTRATION). When specified, these overdoses were in the range of 800-1000 mg.

Comprehensive clinical data on citalopram overdose are limited and many cases involve concomitant overdoses of other drugs and/or alcohol. Fatal cases of citalopram overdose have been reported with citalopram alone; however, the majority of fatal cases have involved overdose with concomitant medications. Post-marketing reports of drug overdoses involving citalopram have included fatalities with citalopram alone as well as nonfatal overdoses of up to 5200 mg.

Although most patients recovered without sequelae, 3 fatalities with known overdoses of racemic citalopram alone have been reported in the literature (doses of 2800 mg, 2880 mg, and

3920 mg).

Fatal cases of serotonin syndrome have been reported in patients who took overdoses of moclobemide (Manerix) and Citalopram (see WARNINGS AND PRECAUTIONS: Neurologic, Serotonin Syndrome). The plasma concentrations of moclobemide were between 16 and 90 mg/L (therapeutic range: 1 to 3 mg/L) and those of Citalopram between 0.3 and 1.7 mg (therapeutic concentration: 0.3 mg/L). This indicates that a relatively low dose of Citalopram, given with an overdose of moclobemide represents a serious risk for the patient.

The following symptoms have been seen in reported overdose of citalopram: agitation, atrial and ventricular arrhythmia, bradycardia, bundle branch block, cardiac arrest, confusion, convulsion, coma, cyanosis, dizziness, ECG changes, hyperventilation, hypotension, hypertension, loss of consciousness, mydriasis, nausea, QRS prolongation, QT prolongation, rhabdomyolysis, seizure, serotonin syndrome, somnolence, stupor, sweating, tachycardia, torsade de pointes, tremor, and vomiting.

Management of Overdose

Establish and maintain an airway to ensure adequate ventilation and oxygenation. Gastric lavage and use of activated charcoal should be considered. Gastric lavage should be carried out as soon as possible after oral ingestion. Cardiac and vital sign monitoring are recommended, along with general symptomatic and supportive measures. There are no specific antidotes for Citalopram.

ECG monitoring is advisable in case of overdose.

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

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

Action and Clinical Pharmacology

Mechanism of Action

Citalopram is a highly selective and potent serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor with minimal effects on the neuronal reuptake of norepinephrine (NE) and dopamine (DA). The ability of citalopram to potentiate serotonergic activity in the central nervous system via inhibition of the neuronal reuptake of serotonin is thought to be responsible for its antidepressant action. Tolerance to the inhibition of serotonin reuptake is not induced by long- term (14 days) treatment of rats with citalopram.

Pharmacodynamics

Citalopram has no or very low affinity for a series of receptors including serotonin 5-HT1A, 5- HT2, dopamine D1 and D2, α1-, α2-, β-adrenergic, histamine H1, muscarinic cholinergic, benzodiazepine, gamma aminobutyric acid (GABA) and opioid receptors.

Pharmacokinetics

Absorption

Following the administration of a single oral dose of citalopram (40 mg) to healthy male volunteers, peak blood levels occurred at about 4 hours (range 1 to 6 hours). The absolute bioavailability of citalopram was about 80% (range 52 to 93%) relative to an intravenous dose. Absorption was not affected by food.

Distribution

After intravenous infusion in healthy male volunteers, the apparent volume of distribution (Vd)β was about 12 L/kg (range 9-17 L/kg), indicating a pronounced tissue distribution; (Vd)β oral was about 17 L/kg (range 14-21 L/kg). The binding of citalopram and its demethylated metabolites to human plasma proteins is about 80%.

The single- and multiple-dose pharmacokinetics of citalopram are linear and dose-proportional in a dose range of 10 to 60 mg/day. Steady-state plasma levels are achieved in patients in 1-2 weeks. At a daily dose of 40 mg, the average plasma concentration is about 83 ng/mL (n=114) with a range from 30 to 200 ng/mL. Citalopram does not accumulate during long-term treatment. A clear relationship between citalopram plasma levels and therapeutic response or side effects has not been established.

Metabolism

Citalopram is metabolized in the liver to demethylcitalopram (DCT), didemethylcitalopram (DDCT), citalopram-N-oxide, and a deaminated propionic acid derivative. In vitro studies show that DCT, DDCT and citalopram-N-oxide also inhibit the neuronal reuptake of serotonin but are less selective and less potent than the parent compound and are of minor clinical importance. Unchanged citalopram is the predominant compound in plasma.

In vitro studies indicated that the biotransformation of citalopram to its demethyl metabolites depends on both CYP2C19 and CYP3A4, with a small contribution from CYP2D6. An initial dose of 10 mg is recommended for known poor metabolisers of CYP2C19 (see DOSAGE AND ADMINISTRATION).

Elimination

The elimination half-life of citalopram (t½β) is approximately 37 hours (range: 30 - 42 hours) which allows recommendation of once-daily dosing. The systemic citalopram plasma clearance (ClS) is 0.33 L/min. Citalopram is eliminated primarily via the liver (85%) and the remainder via the kidneys; approximately 12% (range 6-21%) of the daily dose is excreted in urine as unchanged citalopram.

Special Populations and Conditions

Geriatrics

Elderly patients (4 males and 7 females aged 73 - 90 years), received a 20 mg/day dose of citalopram for 3-4 weeks. In the elderly, steady state plasma levels were elevated (106 ng/mL), half-life prolonged (1.5 - 3.75 days) and clearance decreased (0.08 - 0.3 L/min).

Elevation of citalopram plasma levels occurred at an earlier age in females than in males. In this population, lower doses and a lower maximum dose of citalopram are recommended (see WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics and DOSAGE AND ADMINISTRATION, Recommended Dose and Dose Adjustments, Geriatrics).

Hepatic Insufficiency

The pharmacokinetics of citalopram were compared in patients with reduced hepatic function (3 female and 6 male patients aged 41 - 60 years) to those seen in 12 healthy male volunteers (aged 21 - 43 years). In patients with reduced hepatic function the half-life of citalopram was approximately doubled (83 hours vs. 37 hours), steady state citalopram concentrations increased by 61% and oral clearance decreased by 37%.

Consequently, the use of citalopram in patients with reduced hepatic function should be approached with caution and lower maximal doses should be prescribed (see WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic and DOSAGE AND ADMINISTRATION, Recommended Dose and Dose Adjustments, Hepatic Insufficiency).

Renal Insufficiency

In patients with mild to moderate reduction of the renal function (4 female and 3 male patients aged 30-55 years), citalopram was being eliminated more slowly than in 12 healthy male volunteers (aged 21-43 years); half-lives being 49 hours vs. 37 hours. However, mild to moderate renal impairment had no major influence on the kinetics of citalopram. At present, no information is available for chronic treatment of patients with severely reduced renal function (creatinine clearance <20 mL/min).

Storage and Stability

Abbott-Citalopram (citalopram hydrobromide) should be stored in a dry place at room temperature between 15° and 30°C.

Dosage Forms, Composition and Packaging

Abbott-Citalopram contains citalopram hydrobromide corresponding to 10 mg, 20 mg, or 40 mg citalopram, and the following non-medicinal ingredients: cornstarch, lactose monohydrate, microcrystalline cellulose, copovidone, glycerin, croscarmellose sodium, magnesium stearate, hypromellose, polyethylene glycol 400, and titanium dioxide. Ferric oxide red and ferric oxide yellow are included as colouring agents.

Abbott-Citalopram is available as film-coated, tablets.

10 mg tablets: Each round, tan coloured, biconvex, film-coated tablet, marked “10” on one side contains 10 mg citalopram (as citalopram hydrobromide). Bottles of 100 tablets.
20 mg tablets: Each oval, tan coloured, scored, biconvex, film-coated tablet, marked “20”, symmetrically around the score on one side and “1010” on the other side contains 20 mg citalopram (as citalopram hydrobromide). Bottles of 100 and 500 tablets.
40 mg tablets: Each oval, tan coloured, scored, biconvex, film-coated tablet, marked “40”, symmetrically around the score on one side and “1011” on the other side contains 40 mg citalopram (as citalopram hydrobromide). Bottles of 100 and 500 tablets.