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citalopram hbr 20 mg tablet

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Uses

Citalopram hydrobromide is used in the treatment of major depressive disorder. In addition, citalopram has been used for the treatment of obsessive-compulsive disorder, panic disorder, social phobia (social anxiety disorder), alcohol dependence, premenstrual dysphoric disorder, premature ejaculation, eating disorders, diabetic neuropathy, and posttraumatic stress disorder.

Major Depressive Disorder

Citalopram hydrobromide is used in the treatment of major depressive disorder. A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks). According to DSM-IV criteria, a major depressive episode includes at least 5 of the following 9 symptoms (with at least one of the symptoms being either depressed mood or loss of interest or pleasure): depressed mood most of the day as indicated by subjective report (e.g., feels sad or empty) or observation made by others; markedly diminished interest or pleasure in all, or almost all, activities most of the day; significant weight loss (when not dieting) or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite; insomnia or hypersomnia; psychomotor agitation or retardation (observable by others, not merely subjective feelings of restlessness or being slowed down); fatigue or loss of energy; feelings of worthlessness or excessive or inappropriate guilt (not merely self-reproach or guilt about being sick); diminished ability to think or concentrate or indecisiveness (either by subjective account or as observed by others); and recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide attempt or specific plan for committing suicide.

Treatment of major depressive disorder generally consists of an acute phase (to induce remission), a continuation phase (to preserve remission), and a maintenance phase (to prevent recurrence). Various interventions (e.g., psychotherapy, antidepressant drug therapy, electroconvulsive therapy [ECT]) are used alone or in combination to treat major depressive episodes. Treatment should be individualized, and the most appropriate strategy for a particular patient is determined by clinical factors such as severity of depression (e.g., mild, moderate, severe), presence or absence of certain psychiatric features (e.g., suicide risk, catatonia, psychotic or atypical features, alcohol or substance abuse or dependence, panic or other anxiety disorder, cognitive dysfunction, dysthymia, personality disorder, seasonal affective disorder), and concurrent illness (e.g., asthma, cardiac disease, dementia, seizure disorder, glaucoma, hypertension). Demographic and psychosocial factors as well as patient preference also are used to determine the most effective treatment strategy.

While use of psychotherapy alone may be considered as an initial treatment strategy for patients with mild to moderate major depressive disorder (based on patient preference and presence of clinical features such as psychosocial stressors), combined use of antidepressant drug therapy and psychotherapy may be useful for initial treatment of patients with moderate to severe major depressive disorder with psychosocial issues, interpersonal problems, or a comorbid axis II disorder. In addition, combined use of antidepressant drug therapy and psychotherapy may be beneficial in patients who have a history of poor compliance or only partial response to adequate trials of either antidepressant drug therapy or psychotherapy alone.

Antidepressant drug therapy can be used alone for initial treatment of patients with mild major depressive disorder (if preferred by the patient) and usually is indicated alone or in combination with psychotherapy for initial treatment of patients with moderate to severe major depressive disorder (unless ECT is planned). ECT is not generally used for initial treatment of uncomplicated major depression, but is recommended as first-line treatment for severe major depressive disorder when it is coupled with psychotic features, catatonic stupor, severe suicidality, food refusal leading to nutritional compromise, or other situations when a rapid antidepressant response is required. ECT also is recommended for patients who have previously shown a positive response to or a preference for this treatment modality and can be considered for patients with moderate or severe depression who have not responded to or cannot receive antidepressant drug therapy. In certain situations involving depressed patients unresponsive to adequate trials of several individual antidepressant agents, adjunctive therapy with another agent (e.g., buspirone, lithium) or concomitant use of a second antidepressant agent (e.g., bupropion) has been used; however, such combination therapy is associated with an increased risk of adverse reactions, may require dosage adjustments, and (if not contraindicated) should be undertaken only after careful consideration of the relative risks and benefits.(See Drug Interactions: Serotonergic Drugs, Tricyclic and Other Antidepressants under Drug Interactions: Drugs Undergoing Hepatic Metabolism or Affecting Hepatic Microsomal Enzymes, and Drug Interactions: Lithium.)

The efficacy of citalopram for the management of major depression has been established in short-term (4-6 weeks' duration), placebo-controlled studies in outpatients 18-66 years of age who met DSM-III or -III-R criteria for major depressive disorder. In a 6-week study in which patients received fixed citalopram dosages of 10, 20, 40, or 60 mg daily, the drug was effective at dosages of 40 and 60 mg daily as measured by the Hamilton Depression Rating Scale (HAM-D) Total Score, the HAM-D Depressed Mood Item (Item 1), the Montgomery Asberg Depression Rating Scale, and the Clinical Global Impression (CGI) Severity Scale. This study showed no clear antidepressant effect of the 10 or 20 mg daily dosages, and the 60 mg daily dosage was not more effective than the 40 mg daily dosage.

In a 4-week, placebo-controlled study in depressed adult patients, of whom 85% met criteria for melancholia, those who were treated with citalopram (at an initial dosage of 20 mg daily, titrated to the maximum tolerated dosage or to a maximum daily dosage of 80 mg) showed greater improvement than patients receiving placebo on the HAM-D Total Score, HAM-D Item 1, and the CGI Severity score. In 3 additional placebo-controlled depression trials, the difference in response to treatment between patients receiving citalopram and patients receiving placebo was not statistically significant, possibly due at least in part to a high spontaneous response rate, a high placebo response rate, small sample size, or, in the case of one study, too low a dosage.

In 2 placebo-controlled studies, depressed adult patients who had responded to an initial 6- to 8-week course of citalopram (fixed dosage of 20 or 40 mg daily in one study and flexible dosages ranging from 20-60 mg daily in the second study) were randomized to continue receiving citalopram or placebo for up to 6 months. In both of these studies, patients receiving citalopram experienced substantially lower relapse rates over the subsequent 6 months compared with those receiving placebo. In the fixed-dose study, the decreased rate of depression relapse was similar in patients receiving 20 or 40 mg daily of citalopram. An analysis of these data for possible age-, gender-, and race-related effects on treatment outcome did not suggest any difference in antidepressant efficacy based on the age, gender, and race of the patient. In a placebo-controlled trial, citalopram also was shown to help prevent recurrences of depression in patients with recurrent major depression receiving the drug for up to 6-18 months.

While the optimum duration of citalopram therapy has not been established, many experts state that acute depressive episodes require several months or longer of sustained antidepressant therapy. In addition, some clinicians recommend that long-term antidepressant therapy be considered in certain patients at risk for recurrence of depressive episodes (such as those with highly recurrent unipolar depression). In placebo-controlled studies, citalopram has been shown to be effective for the long-term (e.g., up to 18 months) management of depression. In addition, the drug has been used in some patients for longer periods (e.g., up to 28 months) without apparent loss of clinical effect or increased toxicity. However, when citalopram is used for extended periods, the need for continued therapy should be reassessed periodically.(See Dosage and Administration: Dosage.)

The manufacturer states that efficacy of citalopram as an antidepressant in hospital settings has not been studied adequately to date; however, the drug has been shown to be effective in hospitalized patients with depression, including severe depression, in several studies.

As with other antidepressants, the possibility that citalopram may precipitate hypomanic or manic attacks in patients with bipolar or other major affective disorder should be considered. Citalopram is not approved for use in treating bipolar depression.

Considerations in Choosing an Antidepressant

A variety of antidepressant drugs are available for the treatment of major depressive disorder, including selective serotonin-reuptake inhibitors (SSRIs; e.g., citalopram, fluoxetine, paroxetine, sertraline), selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs; e.g., desvenlafaxine, duloxetine, venlafaxine), tricyclic antidepressants (e.g., amitriptyline, amoxapine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine), monoamine oxidase (MAO) inhibitors (e.g., phenelzine, tranylcypromine), and other antidepressants (e.g., bupropion, maprotiline, nefazodone, trazodone, vilazodone). Most clinical studies have shown that the antidepressant effect of usual dosages of citalopram in patients with depression is greater than that of placebo and comparable to that of usual dosages of tricyclic antidepressants (e.g., amitriptyline, imipramine, clomipramine), other SSRIs (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline), and other antidepressants (e.g., mirtazapine, venlafaxine). Escitalopram, the active S-enantiomer of citalopram, also is commercially available for the treatment of depression. Although there is some evidence that escitalopram may offer some clinical advantages compared with citalopram or other SSRIs (e.g., increased efficacy, more rapid onset of therapeutic effect, fewer adverse effects), additional studies are needed to confirm these initial findings. The onset of antidepressant action of citalopram appears to be comparable to that of tricyclic antidepressants and other SSRIs, although there is some evidence that the onset of action may occur slightly earlier with citalopram than with some other antidepressants, including sertraline. However, additional study is needed to confirm these findings.

In general, response rates in patients with major depression are similar for currently available antidepressants, and the choice of antidepressant agent for a given patient depends principally on other factors such as potential adverse effects, safety or tolerability of these adverse effects in the individual patient, psychiatric and medical history, patient or family history of response to specific therapies, patient preference, quantity and quality of available clinical data, cost, and relative acute overdose safety. No single antidepressant can be recommended as optimal for all patients because of substantial heterogeneity in individual responses and in the nature, likelihood, and severity of adverse effects. In addition, patients vary in the degree to which certain adverse effects and other inconveniences of drug therapy (e.g., cost, dietary restrictions) affect their preferences.

In the large-scale Sequenced Treatment Alternatives to Relieve Depression (STAR*D) effectiveness trial, patients with major depressive disorder who did not respond to or could not tolerate citalopram therapy were randomized to switch to extended-release (''sustained-release'') bupropion, sertraline, or extended-release venlafaxine as a second step of treatment (level 2). Remission rates as assessed by the 17-item Hamilton Rating Scale for Depression (HRSD-17) and the Quick Inventory of Depressive Symptomatology--Self Report (QIDS-SR-16) were approximately 21 and 26% for extended-release bupropion, 18 and 27% for sertraline, and 25 and 25% for extended-release venlafaxine therapy, respectively; response rates as assessed by the QIDS-SR-16 were 26, 27, and 28% for extended-release bupropion, sertraline, and extended-release venlafaxine therapy, respectively. These results suggest that after unsuccessful initial treatment of depressed patients with an SSRI, approximately 25% of patients will achieve remission after therapy is switched to another antidepressant, and either another SSRI (e.g., sertraline) or an agent from another class (e.g., bupropion, venlafaxine) may be reasonable alternative antidepressants in patients not responding to initial SSRI therapy.

Patient Tolerance Considerations

Because of differences in the adverse effect profile between selective serotonin-reuptake inhibitors and tricyclic antidepressants, particularly less frequent anticholinergic effects, cardiovascular effects, and/or weight gain with selective serotonin-reuptake inhibitors, these drugs may be preferred in patients in whom such effects are not tolerated or are of potential concern. The decreased incidence of anticholinergic effects associated with citalopram and other selective serotonin-reuptake inhibitors compared with tricyclic antidepressants is a potential advantage, since such effects may result in discontinuance of the drug early during therapy in unusually sensitive patients. In addition, some anticholinergic effects may become troublesome during long-term tricyclic antidepressant therapy (e.g., persistent dry mouth may result in tooth decay). Although selective serotonin-reuptake inhibitors share the same overall tolerability profile, certain patients may tolerate one drug in this class better than another. Antidepressants other than selective serotonin-reuptake inhibitors may be preferred in patients in whom certain adverse GI effects (e.g., nausea, anorexia), nervous system effects (e.g., anxiety, nervousness, insomnia), and/or weight loss are not tolerated or are of concern, since such effects appear to occur more frequently with citalopram and other drugs in this class.

Pediatric Considerations

The clinical presentation of depression in children and adolescents can differ from that in adults and generally varies with the age and developmental stages of the child. Younger children may exhibit behavioral problems such as social withdrawal, aggressive behavior, apathy, sleep disruption, and weight loss; adolescents may present with somatic complaints, self-esteem problems, rebelliousness, poor performance in school, or a pattern of engaging in risky or aggressive behavior.

Only limited data are available to date from controlled clinical studies evaluating various antidepressant agents in children and adolescents, and many of these studies have methodologic limitations (e.g., nonrandomized or uncontrolled, small sample size, short duration, nonspecific inclusion criteria). However, there is some evidence that the response to antidepressants in pediatric patients may differ from that seen in adults, and caution should be used in extrapolating data from adult studies when making treatment decisions for pediatric patients.

Results of several studies evaluating tricyclic antidepressants (e.g., amitriptyline, desipramine, imipramine, nortriptyline) in preadolescent and adolescent patients with major depression indicate a lack of overall efficacy in this age group. Based on the lack of efficacy data regarding use of tricyclic antidepressants and MAO inhibitors in pediatric patients and because of the potential for life-threatening adverse effects associated with the use of these drugs, many experts consider selective serotonin-reuptake inhibitors, including citalopram, the drugs of choice when antidepressant therapy is indicated for the treatment of major depressive disorder in children and adolescents. However, the US Food and Drug Administration (FDA) states that, while efficacy of fluoxetine has been established in pediatric patients, efficacy of other newer antidepressants (i.e., citalopram, desvenlafaxine, duloxetine, escitalopram, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, venlafaxine) was not conclusively established in clinical trials in pediatric patients with major depressive disorder. In addition, FDA now warns that antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder and other psychiatric disorders.(See Cautions: Pediatric Precautions.) FDA currently states that anyone considering using an antidepressant in a child or adolescent for any clinical use must balance the potential risk of therapy with the clinical need.(See Cautions: Precautions and Contraindications.)

Geriatric Considerations

The response to antidepressants in depressed geriatric patients without dementia is similar to that reported in younger adults, but depression in geriatric patients often is not recognized and is not treated. In geriatric patients with major depressive disorder, SSRIs appear to be as effective as tricyclic antidepressants but may cause fewer overall adverse effects than these other agents. Geriatric patients appear to be especially sensitive to anticholinergic (e.g., dry mouth, constipation, vision disturbance), cardiovascular, orthostatic hypotensive, and sedative effects of tricyclic antidepressants. The low incidence of anticholinergic effects associated with citalopram and other SSRIs compared with tricyclic antidepressants is a potential advantage in geriatric patients, since such effects (e.g., constipation, dry mouth, confusion, memory impairment) may be particularly troublesome in these patients. However, SSRI therapy may be associated with other troublesome adverse effects (e.g., nausea and vomiting, agitation and akathisia, parkinsonian adverse effects, sexual dysfunction, weight loss, and hyponatremia). Some clinicians state that SSRIs including citalopram may be preferred for treating depression in geriatric patients in whom the orthostatic hypotension associated with many antidepressants (e.g., tricyclics) potentially may result ininjuries (such as severe falls). However, despite the fewer cardiovascular and anticholinergic effects associated with SSRIs, these drugs did not show any advantage over tricyclic antidepressants with regard to hip fracture in a case-control study. In addition, there was little difference in the rates of falls between nursing home residents receiving SSRIs and those receiving tricyclic antidepressants in a retrospective study. Therefore, all geriatric patients receiving either type of antidepressant should be considered at increased risk of falls and appropriate measures should be taken. In addition, clinicians prescribing SSRIs in geriatric patients should be aware of the many possible drug interactions associated with these drugs, including those involving metabolism of the drugs through the cytochrome P-450 system.(See Drug Interactions.)

Patients with dementia of the Alzheimer's type (Alzheimer's disease, presenile or senile dementia) often present with depressive symptoms, such as depressed mood, appetite loss, insomnia, fatigue, irritability, and agitation. Most experts recommend that patients with dementia of the Alzheimer's type who present with clinically significant and persistent depressive symptoms be considered as candidates for pharmacotherapy even if they fail to meet the criteria for a major depressive syndrome. The goals of such therapy are to improve mood, functional status (e.g., cognition), and quality of life. Treatment of depression also may reduce other neuropsychiatric symptoms associated with depression in patients with dementia, including aggression, anxiety, apathy, and psychosis. Although patients may present with depressed mood alone, the possibility of more extensive depressive symptomatology should be considered. Therefore, patients should be evaluated and monitored carefully for indices of major depression, suicidal ideation, and neurovegetative signs since safety measures (e.g., hospitalization for suicidal ideations) and more vigorous and aggressive therapy (e.g., relatively high dosages, multiple drug trials) may be needed in some patients.

Although placebo-controlled trials of antidepressants in depressed patients with concurrent dementia have shown mixed results, the available evidence and experience with the use of antidepressants in patients with dementia of the Alzheimer's type and associated depressive manifestations indicate that depressive symptoms (including depressed mood alone and with neurovegetative changes) in such patients are responsive to antidepressant therapy. In some patients, cognitive deficits may partially or fully resolve during antidepressant therapy, but the extent of response will be limited to the degree of cognitive impairment that is directly related to depression. SSRIs such as citalopram, escitalopram, fluoxetine, paroxetine, or sertraline generally are considered first-line agents in the treatment of depressed patients with dementia since they usually are better tolerated than some other antidepressants (e.g., tricyclic antidepressants, monoamine oxidase inhibitors). Some possible alternative agents to SSRIs include bupropion, mirtazapine, and venlafaxine. Some geriatric patients with dementia and depression may be unable to tolerate the antidepressant dosages needed to achieve full remission. When a rapid antidepressant response is not critical, some experts therefore recommend a very gradual dosage titration to increase the likelihood that a therapeutic dosage of the SSRI or other antidepressant will be reached and tolerated. In a controlled study comparing citalopram and placebo in elderly patients with dementia, citalopram was found to improve depression as well as cognitive and emotional functioning more than placebo. In an open study in a limited number of patients with dementia and behavioral disturbances, citalopram was found to improve the behavioral complications associated with dementia.

Cardiovascular Considerations

Clinical studies of citalopram for the management of depression generally did not include individuals with cardiovascular disease (e.g., those with a recent history of myocardial infarction or unstable cardiovascular disease).

Citalopram causes dose-dependent QTc-interval prolongation, and torsades de pointes, ventricular tachycardia, and sudden death have been reported in postmarketing experience in patients receiving the drug. Patients with congenital long QT syndrome, uncompensated heart failure, bradyarrhythmias, recent acute myocardial infarction, or hypokalemia or hypomagnesemia or who are receiving other drugs that prolong the QT interval are at higher risk of developing torsades de pointes. (See Cautions: Cardiovascular Effects, Cautions: Precautions and Contraindications, and Drug Interactions: Drugs that Prolong the QT Interval.)

Sedative Considerations

Because citalopram and other selective serotonin-reuptake inhibitors generally are less sedating than some other antidepressants (e.g., tricyclics), some clinicians state that these drugs may be preferable in patients who do not require the sedative effects associated with many antidepressant agents or in patients who are prone to accidents; however, an antidepressant with more prominent sedative effects (e.g., trazodone) may be preferable in certain patients (e.g., those with insomnia).

Suicidal Risk Considerations

Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. However, there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidal thinking and behavior (suicidality) in certain patients during the early phases of treatment. FDA states that antidepressants increased the risk of suicidality in short-term studies in children, adolescents, and young adults (18-24 years of age) with major depressive disorder and other psychiatric disorders.(See Cautions: Pediatric Precautions.) An increased suicidality risk was not demonstrated with antidepressants compared with placebo in adults older than 24 years of age and a reduced risk was observed in adults 65 years of age or older. It currently is unknown whether the suicidality risk extends to longer-term antidepressant use (i.e., beyond several months); however, there is substantial evidence from placebo-controlled maintenance trials in adults with major depressive disorder that antidepressants can delay the recurrence of depression. Because the risk of suicidality in depressed patients may persist until substantial remission of depression occurs, appropriate monitoring and close observation of patients of all ages who are receiving antidepressant therapy are recommended.(See Cautions: Precautions and Contraindications.)

Other Considerations

Citalopram has been effective in patients with moderate to severe depression, endogenous depression, post-stroke depression and pathologic crying, and depression associated with chronic hepatitis C virus infection.

In an open study in a limited number of patients with bipolar depression (mainly bipolar I disorder), citalopram was effective and well tolerated when added to monotherapy or combined therapy with lithium, divalproex sodium, and/or carbamazepine. Controlled studies are needed to confirm these preliminary findings. The manufacturer states that citalopram is not approved for use in treating bipolar depression, and that the possibility that the drug may precipitate hypomanic or manic attacks in patients with bipolar or other major affective disorder should be considered. For detailed information on bipolar disorder, including its management, .

In patients with refractory depression, citalopram was more effective when given in combination with buspirone in one placebo-controlled study. However, combined citalopram and buspirone therapy was not found to be more effective than citalopram monotherapy in another placebo-controlled study. In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) level 2 trial, patients with major depressive disorder who did not respond to or could not tolerate citalopram therapy were randomized to receive either extended-release (''sustained-release'') bupropion or buspirone therapy in addition to citalopram. Although both extended-release bupropion and buspirone were found to produce similar remission rates, extended-release bupropion produced a greater reduction in the number and severity of symptoms and a lower rate of drug discontinuance than buspirone in this large-scale effectiveness trial. These results suggest that augmentation of SSRI therapy with extended-release bupropion may be useful in some patients with refractory depression. The addition of lithium to citalopram in depressed patients not responding to citalopram alone also has been found to be effective and well tolerated in a double-blind, placebo-controlled trial.(See Drug Interactions: Lithium.)

In a limited number of depressed patients not responding to citalopram alone, the addition of carbamazepine was effective and well tolerated in an open study. However, the possibility of serotonin syndrome and drug interactions should be considered pending further clinical experience with this combination.(See Drug Interactions: Serotonergic Drugs and Carbamazepine under Drug Interactions: Drugs Undergoing Hepatic Metabolism or Affecting Hepatic Microsomal Enzymes.)

Citalopram was found to improve personality disturbances (decrease in anxiety and aggression-related symptoms and increase in social desirability and socialization) in depressed patients in one study.

Obsessive-Compulsive Disorder

Citalopram has been used in the treatment of obsessive-compulsive disorder. In a large, double-blind, placebo-controlled trial evaluating citalopram (20, 40, or 60 mg daily for 12 weeks) in adults with obsessive-compulsive disorder, the drug was more effective than placebo as measured by Yale-Brown Obsessive-Compulsive Scale score changes at all 3 dosages. The highest response rate (65%) was observed in those who received 60 mg daily; this compared with 52 or 57% in those receiving 40 or 20 mg daily, respectively. An analysis of predictors of response to citalopram therapy from this trial suggested that patients with a longer duration of obsessive-compulsive disorder, more severe symptoms, or a history of previous selective serotonin-reuptake inhibitor therapy were less likely to respond to therapy with citalopram. In an open trial, 76% of patients with obsessive-compulsive disorder receiving citalopram therapy (usually 40 or 60 mg daily) for 24 weeks demonstrated improved symptoms associated with this condition. In another open study, citalopram (40 mg daily) was effective in a limited number of patients with refractory obsessive-compulsive disorder who had failed to respond to therapy with other selective serotonin-reuptake inhibitors. Clinical experience to date indicates that citalopram is well tolerated in patients with obsessive-compulsive disorder. Additional study is needed to determine the long-term efficacy of citalopram in the treatment of this condition.

For additional information on the use of selective serotonin-reuptake inhibitors in the treatment of obsessive-compulsive disorder, .

Panic Disorder

Citalopram has been used in the treatment of panic disorder with or without agoraphobia. In a randomized, single-blind study comparing citalopram and paroxetine in adults with panic disorder, both drugs were found to be effective and well tolerated, with 86% of the citalopram-treated patients and 84% of the paroxetine-treated patients responding well to 2 months of therapy. In a limited number of adults with panic disorder, citalopram therapy (20-60 mg daily) produced a full remission in 66% of the patients and improved symptomatology.

In a large, double-blind, placebo-controlled trial evaluating the efficacy and tolerability of long-term therapy (up to 1 year) with citalopram at 3 dosages (10-15 mg daily, 20-30 mg daily, 40-60 mg daily) or clomipramine in adult outpatients with panic disorder with or without agoraphobia, both drugs were more effective than placebo. Citalopram was more effective than placebo at all dosages studied, with a dosage of 20-30 mg daily being the most effective maintenance dosage in most patients.

For additional information on the use of selective serotonin-reuptake inhibitors in the treatment of panic disorder,

Social Phobia

Like some other selective serotonin-reuptake inhibitors, citalopram has been used in the treatment of social phobia (social anxiety disorder). However, additional evidence from well-designed studies is needed to more fully elucidate the role of the drug in this disorder.

In an open study in a limited number of patients with social phobia, 86% of patients responded to citalopram 40 mg daily after 12 weeks as rated by the Clinical Global Impressions (CGI) score and the Liebowitz Social Anxiety Scale (LSAS).

In an open, flexible-dose study in patients with social anxiety disorder with comorbid major depression, response rates after 12 weeks of citalopram therapy (mean dosage: 38 mg daily) were approximately 67 and 76% for social anxiety disorder and depression, respectively. However, the depression symptoms responded more rapidly and completely than the social anxiety symptoms after 12 weeks of citalopram therapy, suggesting that a longer duration of therapy may be necessary to fully assess the clinical efficacy of the drug in such patients.

In a randomized, open trial comparing citalopram and moclobemide (not commercially available in the US) in patients with social phobia, similar improvements in the CGI-improvement score and LSAS were noted with these drugs. Clinical experience to date suggests that citalopram generally is well tolerated in patients with social phobia. However, well controlled studies are needed to confirm the efficacy and safety and to determine the optimal dosage of citalopram in patients with this condition.

Alcohol Dependence

Like some other selective serotonin-reuptake inhibitors (fluoxetine, zimelidine [not commercially available in the US]), citalopram has been used in the management of alcohol dependence. In clinical studies, citalopram has been shown to reduce alcohol consumption in alcohol-dependent, nondepressed drinkers receiving short-term therapy with 40 mg of the drug daily. In clinical studies conducted to date with selective serotonin-reuptake inhibitors in alcoholic patients, considerable interindividual variability in response has been observed, with reduction in alcohol consumption ranging from 10 to more than 70%. Several factors, including gender, alcoholic subtype, presence or absence of depression, and extent of drinking, appear to affect the clinical efficacy of selective serotonin-reuptake inhibitors in the management of alcohol dependence. Additional study is required to fully determine the safety and efficacy of citalopram in the management of alcohol dependence.(See Pharmacology: Effects on Alcohol Intake and also see Drug Interactions: Alcohol.)

Premenstrual Dysphoric Disorder

Like some other selective serotonin-reuptake inhibitors (e.g., fluoxetine, paroxetine, sertraline), citalopram has been used in a limited number of women with premenstrual dysphoric disorder (previously late luteal phase dysphoric disorder). Clinical experience to date suggests that the onset of action of serotonin-reuptake inhibitors in women with premenstrual dysphoric disorder is more rapid than when used for other psychiatric conditions; therefore, administration only during the luteal phase of the menstrual cycle may potentially be effective in this condition.

In a placebo-controlled trial, intermittent administration of citalopram (10-30 mg daily during the luteal phase) for 3 menstrual cycles appeared to be more effective than continuous (10-30 mg daily throughout the menstrual cycle) or semi-intermittent administration (5 mg daily during the follicular phase and 10-30 mg daily during the luteal phase) of the drug and substantially more effective than placebo. Citalopram was well tolerated in all 3 regimens, and adverse effects generally were mild and transient. Additional controlled studies are needed to determine whether the efficacy of the drug is sustained during longer-term, maintenance therapy in women with this condition.

Premature Ejaculation

Like some other selective serotonin-reuptake inhibitors, citalopram has been used for the treatment of premature ejaculation. However, studies with citalopram to date have only involved a limited number of patients and there is some evidence that the drug may be less effective than certain other selective serotonin-reuptake inhibitors (e.g., paroxetine). In a double-blind study in men with premature ejaculation, citalopram 20 mg daily delayed ejaculation to a slight degree (1. 8-fold increase in intravaginal ejaculation latency time) compared with a marked increase (8. 9-fold increase) with paroxetine 20 mg daily following 6 weeks of therapy. These preliminary findings suggest that paroxetine may be more effective than citalopram in the treatment of premature ejaculation.

Eating Disorders

Citalopram has been used in a limited number of patients for the treatment of bulimia nervosa or anorexia nervosa. Although citalopram reportedly has been effective in some patients with these eating disorders, underweight patients with anorexia nervosa who received citalopram in conjunction with psychotherapy did worse (i.e., experienced greater weight loss) than those receiving psychotherapy alone in one open-label study. Because of limited evidence and experience to date, the role if any of citalopram in the management of eating disorders remains to be elucidated. For information on the use of selective serotonin-reuptake inhibitors in the treatment of eating disorders, .

Diabetic Neuropathy

Tricyclic antidepressants generally have been considered a mainstay of therapy for the treatment of diabetic neuropathy. However, because of potentially improved patient tolerability, therapy with selective serotonin-reuptake inhibitors or selective serotonin- and norepinephrine-reuptake inhibitors (e.g., duloxetine, venlafaxine) has been attempted as an alternative. In a double-blind, placebo-controlled trial, citalopram (40 mg daily) substantially reduced the symptoms associated with diabetic neuropathy (pain, paresthesia, and dysesthesia) in a limited number of patients and generally was well tolerated. When compared with earlier results obtained with imipramine in the management of this condition, selective serotonin-reuptake inhibitors such as citalopram, fluoxetine, paroxetine, and sertraline appear to be less effective but better tolerated overall. Additional study and experience are needed to elucidate the relative roles of selective serotonin-reuptake inhibitors versus tricyclic antidepressants, selective serotonin- and norepinephrine-reuptake inhibitors, anticonvulsants (e.g., pregabalin, gabapentin), and other forms of treatment in the management of this condition.

Posttraumatic Stress Disorder

Citalopram has been used in a limited number of adults with civilian- or combat-related posttraumatic stress disorder (PTSD). In an open study, patients treated with citalopram for 8 weeks showed marked improvement in PTSD manifestations (reexperiencing, hyperarousal, and avoidance) as well as in depression and anxiety. Well-designed, controlled studies are needed to confirm these preliminary findings.

For additional information on the use of selective serotonin-reuptake inhibitors in the treatment of PTSD, , and

Dosage and Administration

Administration

Citalopram hydrobromide is administered orally. Citalopram also has been administered by IV infusion, but a parenteral dosage form is not commercially available in the US.

Citalopram usually is administered once daily in the morning or evening. Since food does not substantially affect the absorption of citalopram, the drug may be administered without regard to meals.

Hypokalemia and hypomagnesemia, if present, should be corrected prior to initiation of citalopram therapy and electrolytes should be monitored periodically during therapy as needed.(See Cautions: Cardiovascular Effects and also see Cautions: Precautions and Contraindications.)

Dispensing and Administration Precautions

Because of similarity in spelling of Celexa (citalopram hydrobromide), Celebrex (celecoxib), and Cerebyx (fosphenytoin sodium), extra care should be exercised in ensuring the accuracy of prescriptions for these drugs.

Dosage

Dosage of citalopram hydrobromide is expressed in terms of citalopram.

Patients receiving citalopram should be monitored for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustment.(See Cautions: Precautions and Contraindications.)

The manufacturers state that at least 2 weeks must elapse between discontinuance of a monoamine oxidase (MAO) inhibitor intended to treat psychiatric disorders and initiation of citalopram therapy and that at least 2 weeks must elapse between discontinuance of citalopram and initiation of MAO inhibitor therapy intended to treat psychiatric disorders. For additional information on potentially serious drug interactions that may occur between citalopram and MAO inhibitors or other serotonergic agents, see Cautions: Precautions and Contraindications and also see Drug Interactions: Serotonergic Drugs.

Because withdrawal effects may occur with discontinuance of citalopram, other selective serotonin-reuptake inhibitors (SSRIs), and selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), abrupt discontinuance of these drugs should be avoided whenever possible. When citalopram therapy is discontinued, the dosage should be reduced gradually (e.g., over a period of several weeks) and the patient monitored for possible withdrawal symptoms. If intolerable symptoms occur following a dosage reduction or upon discontinuance of therapy, the drug may be reinstituted at the previously prescribed dosage. Subsequently, the clinician may continue decreasing the dosage, but at a more gradual rate. (See Cautions: Nervous System Effects and see Chronic Toxicity.)

Major Depressive Disorder

For the management of major depressive disorder in adults, the recommended initial dosage of citalopram is 20 mg once daily, with an increase to a maximum dosage of 40 mg once daily at an interval of not less than 1 week. Previously, the prescribing information for citalopram stated that certain patients may require a dosage of 60 mg daily. However, citalopram dosages above 40 mg once daily no longer are recommended because of the risk of QT-interval prolongation(see Cautions: Cardiovascular Effects and see also Cautions: Precautions and Contraindications) and because they provide no additional therapeutic benefit. A dose-response study did not show the 60-mg daily dosage to be more effective than the 40-mg daily dosage overall. Although antidepressant effects may be evident within 1 week in some patients, the full antidepressant effect of citalopram may not be observed for several weeks.

While the optimum duration of citalopram therapy has not been established, many experts state that acute depressive episodes require several months or longer of sustained antidepressant therapy. In addition, some clinicians recommend that long-term antidepressant therapy be considered in certain patients at risk for recurrence of depressive episodes (such as those with highly recurrent unipolar depression). Whether the dosage of citalopram required to induce remission is identical to the dosage needed to maintain and/or sustain euthymia is unknown. In placebo-controlled studies, the antidepressant efficacy of citalopram was maintained for up to 8 months in patients receiving 20-60 mg daily. In addition, the drug has been used in some patients for longer periods (e.g., up to 28 months) without apparent loss of clinical effect or increased toxicity.

If troublesome adverse effects occur during maintenance therapy, the manufacturer states that a decrease in dosage to 20 mg daily can be considered. If citalopram is used for extended periods, the need for continued therapy should be reassessed periodically.

Obsessive-Compulsive Disorder

For the management of obsessive-compulsive disorder in adults, citalopram usually has been given orally in an initial dosage of 20 mg daily and the dosage was then gradually increased according to clinical response. The usual maintenance dosage in adults has been 40 or 60 mg daily; however, citalopram dosages exceeding 40 mg daily no longer are recommended due to the risk of QT prolongation.

Panic Disorder

For the management of panic disorder in adults, the usual initial dosage of citalopram is 10 mg daily. After an interval of at least 1 week, the dosage may be gradually increased in increments of 10-20 mg up to a dosage of 20-40 mg daily, depending on individual patient response and tolerability. The usual maintenance dosage in adults has been 20-30 mg daily. Citalopram dosages exceeding 40 mg daily no longer are recommended due to the risk of QT prolongation.

Dosage in Geriatric Patients

Major Depressive Disorder

For the management of depression in geriatric patients over 60 years of age, the maximum recommended citalopram dosage is 20 mg once daily due to the risk of QT-interval prolongation.(See Cautions: Cardiovascular Effects.)

For the management of depressive symptoms associated with dementia of the Alzheimer's type in geriatric patients, some experts recommend a lower initial citalopram dosage of 5-10 mg once daily. The dosage may then be gradually increased at intervals of at least several weeks up to the maximum recommended dosage of 20 mg once daily.

Dosage in Hepatic and Renal Impairment

In depressed patients with hepatic impairment, the maximum recommended citalopram dosage is 20 mg once daily due to the risk of QT-interval prolongation. (See Cautions: Cardiovascular Effects and also see Pharmacokinetics: Elimination.)

Dosage adjustment is not necessary in depressed patients with mild to moderate renal impairment. Severe renal failure did not substantially affect the pharmacokinetics of citalopram in one study, suggesting that dosage adjustment also may be unnecessary in patients with severe renal impairment. However, the manufacturer recommends that the drug be used with caution in patients with severe renal impairment.(See Pharmacokinetics: Elimination.)

Dosage in Poor CYP2C19 Metabolizers or Patients Receiving CYP2C19 Inhibitors

For the management of major depressive disorder in patients who are poor metabolizers of the cytochrome P-450 (CYP) isoenzyme 2C19 and in patients receiving cimetidine or another CYP2C19 inhibitor, the maximum recommended dosage of citalopram is 20 mg once daily due to the risk of QT-interval prolongation. (See CYP2C19 Inhibitors under Drug Interactions: Drugs Undergoing Hepatic Metabolism or Affecting Hepatic Microsomal Enzymes and see also Pharmacokinetics: Elimination.)

Treatment of Pregnant Women during the Third Trimester

Some neonates exposed to citalopram and other SSRIs or SNRIs late in the third trimester of pregnancy have developed severe complications. When treating pregnant women with citalopram during the third trimester, the clinician should carefully consider the potential risks and benefits of therapy.(See Pregnancy under Cautions: Pregnancy, Fertility, and Lactation.)

Cautions

The adverse effect profile of citalopram is similar to that of other selective serotonin-reuptake inhibitors (SSRIs) (e.g., escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline). Because citalopram is a highly selective serotonin-reuptake inhibitor with little or no effect on other neurotransmitters, the incidence of some adverse effects commonly associated with tricyclic antidepressants, such as anticholinergic effects (e.g., dry mouth, constipation), certain cardiovascular effects (e.g., orthostatic hypotension), drowsiness, and weight gain, is lower in patients receiving citalopram. However, certain adverse GI (e.g., nausea, anorexia), nervous system (e.g., somnolence, anxiety, nervousness, insomnia), and sexual function effects appear to occur more frequently with citalopram and other SSRIs than with tricyclic antidepressants.

In controlled studies, the most common adverse effects occurring more frequently in patients receiving citalopram than in those receiving placebo included nervous system effects such as somnolence, insomnia, anxiety, agitation, fatigue, tremor, and yawning; GI effects such as nausea, dry mouth, diarrhea, dyspepsia, anorexia, vomiting, and abdominal pain; sweating; ejaculation dysfunction (principally ejaculation delay) and impotence in male patients, decreased libido, and dysmenorrhea; fever, arthralgia, and myalgia; and upper respiratory tract infection, rhinitis, and sinusitis.

The results of a fixed-dose clinical study in depressed patients suggest that somnolence, insomnia, increased sweating, fatigue, impotence, and yawning are dose-related adverse effects of citalopram.

In short-term, placebo-controlled trials (6 weeks or less), discontinuance of citalopram therapy was required in approximately 16% of depressed patients, principally because of adverse psychiatric (e.g., insomnia, somnolence, agitation), other nervous system (e.g., dizziness, asthenia), or GI (e.g., nausea, vomiting, dry mouth) effects.

Nervous System Effects

Somnolence and insomnia, which appear to be dose related, are the most common adverse nervous system effects of citalopram, occurring in approximately 18 and 15% of depressed patients, respectively, receiving the drug and in approximately 10 and 14% of those receiving placebo, respectively, in short-term controlled clinical trials. Insomnia or somnolence required discontinuance of therapy in about 3 or 2% of patients, respectively. However, because insomnia is a symptom also associated with depression, relief of insomnia and improvement in sleep patterns may occur when clinical improvement in depression becomes apparent during antidepressant therapy. Sleep disorders have been reported in at least 2% of citalopram-treated patients in clinical trials, although a causal relationship to the drug has not been established.

Fatigue, which appeared to be dose related, occurred in approximately 5% of patients receiving citalopram in short-term clinical studies. Asthenia has been reported in at least 2% of citalopram-treated patients in clinical trials and required discontinuance of therapy in about 1% of patients.

Tremor occurred in about 8%, anxiety in about 4%, and agitation in about 3% of patients receiving citalopram in short-term clinical studies; agitation resulted in discontinuance of therapy in about 1% of patients receiving the drug. Nervousness, headache, yawning, and dizziness have been reported in at least 2% of citalopram-treated patients in clinical trials. Yawning appeared to be dose related. Dizziness required discontinuance of therapy in 2% of patients.

Impaired concentration, amnesia, apathy, depression and aggravated depression, confusion, paresthesia, and migraine each have been reported in at least 1% of patients receiving citalopram; however, these adverse effects have not been definitely attributed to the drug.

Adverse nervous system effects reported in at least 0.1% of patients receiving citalopram include aggressive reaction, paroniria (disagreeable or terrifying dreams), depersonalization, hallucinations, euphoria, psychotic depression, delusion, paranoid reaction, emotional lability, panic reaction, psychosis, vertigo, neuralgia, abnormal gait, hyperkinesia, hypertonia, hypoesthesia, and ataxia; a causal relationship to the drug has not been clearly established.

Seizures occurred in 0.3% of patients receiving citalopram and in 0.5% of patients receiving placebo in clinical studies. A causal relationship to citalopram remains to be established in these cases.(See Cautions: Precautions and Contraindications.) Nonconvulsive status epilepticus also has been reported in a geriatric patient receiving citalopram for poststroke depression. In addition, involuntary muscle contractions have been reported in less than 1% of patients receiving the drug.

Activation of mania and hypomania have occurred in 0.2% of depressed patients receiving citalopram in placebo-controlled trials; some of these trials included patients with bipolar disorder. In an analysis of postmarketing clinical trials, manic episodes were reported in 0.62% of unipolar depressed patients.(See Cautions: Precautions and Contraindications.) Such reactions have been reported in patients receiving other antidepressant agents and may be caused by antidepressant-induced functional increases in catecholamine activity within the CNS, resulting in a ''switch'' from depressive to manic behavior. There is some evidence that patients with bipolar disorder may be more likely to experience antidepressant-induced hypomanic or manic reactions than patients without evidence of this disorder. In addition, limited evidence suggests that such reactions may occur more frequently in bipolar depressed patients receiving tricyclics and tetracyclics (e.g., maprotiline, mianserin [not commercially available in the US]) than in those receiving selective serotonin-reuptake inhibitors (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline). However, further studies are needed to confirm these findings.

Extrapyramidal reactions associated with citalopram, which are uncommon, appear to be a class effect of selective serotonin-reuptake inhibitors and dose related. Reactions occurring early during therapy with the drug may be secondary to preexisting parkinsonian syndrome and/or concomitant therapy. Although a causal relationship to citalopram has not been established, extrapyramidal symptoms reported in at least 0.1% of patients receiving the drug include tremor, hypokinesia, and dystonia. Choreoathetosis also has been reported rarely. Pending further clinical experience, some clinicians recommend that extrapyramidal reactions developing in patients receiving selective serotonin-reuptake inhibitors be managed by reducing the dosage or discontinuing the drug; if necessary, the symptoms appear to respond to the same treatment as antipsychotic-induced extrapyramidal reactions.

Adverse nervous system effects reported in less than 0.1% of patients receiving citalopram include abnormal coordination, hyperesthesia, melancholia, catatonic reaction, and stupor. Although a causal relationship to the drug has not been established, serotonin syndrome also has been reported in patients receiving citalopram, other selective serotonin-reuptake inhibitors (SSRIs), and selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs). (See Cautions: Precautions and Contraindications, Drug Interactions: Serotonergic Drugs, and see also Acute Toxicity.)

Withdrawal Reactions

Withdrawal symptoms, including dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures, have been reported upon discontinuance of citalopram, other SSRIs, and SNRIs, particularly when discontinuance of these drugs is abrupt. While these reactions are generally self-limiting, there have been reports of serious discontinuance symptoms. Therefore, patients should be monitored for such symptoms when discontinuing citalopram therapy. A gradual reduction in the dosage rather than abrupt cessation is recommended whenever possible.(See Dosage and Administration: Dosage.)

Withdrawal reactions have been reported rarely in citalopram-treated patients following discontinuance of the drug. Data from a controlled study evaluating citalopram in preventing depression relapse suggest that the symptoms associated with abrupt discontinuance of therapy generally are mild and transient. Overall clinical experience to date suggests that the risk of withdrawal effects may be somewhat lower with citalopram, fluoxetine, and sertraline compared with paroxetine. These differences may be due at least in part to the prolonged elimination half-lives of the parent drugs and/or their active metabolites. In addition, drug dependence has been reported in at least 0.1% of patients receiving citalopram, although a causal relationship to the drug remains to be established.(See Chronic Toxicity.)

Suicidality

Suicide and suicide attempts have been reported in less than 1% of depressed adults receiving citalopram. The US Food and Drug Administration (FDA) has determined that antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (18-24 years of age) with major depressive disorder and other psychiatric disorders. Patients, therefore, should be appropriately monitored and closely observed for clinical worsening, suicidality, and unusual changes in behavior, particularly during initiation of citalopram therapy (i.e., the first few months) and during periods of dosage adjustments.(See Cautions: Precautions and Contraindications, see Cautions: Pediatric Precautions, and see also Acute Toxicity.)

GI Effects

Like other selective serotonin-reuptake inhibitors (e.g., escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), citalopram therapy is associated with a relatively high incidence of GI disturbances, principally nausea, dry mouth, diarrhea, dyspepsia, anorexia, vomiting, and abdominal pain. The most frequent adverse GI effect associated with citalopram therapy is nausea, which occurred in about 21% of patients receiving the drug in controlled clinical trials. Nausea generally is mild to moderate in severity. In clinical trials, nausea required discontinuance of citalopram in about 4% of patients and was the most frequent adverse effect requiring discontinuance of the drug. While the mechanism(s) of citalopram-induced GI effects has not been fully elucidated, such effects appear to arise at least in part because of increased serotonergic activity in the GI tract (which may result in stimulation of small intestine motility and inhibition of gastric and large intestine motility) and possibly because of the drug's effect on central serotonergic type 3 (5-HT3) receptors.

Dry mouth occurred in about 20%, diarrhea in about 8%, and dyspepsia in about 5% of patients receiving citalopram in short-term controlled clinical trials. Other adverse GI effects associated with citalopram therapy include vomiting and anorexia, which both occurred in 4% of patients, and abdominal pain, which occurred in about 3% of patients receiving the drug in short-term controlled clinical trials. Vomiting and dry mouth each resulted in discontinuance of citalopram in about 1% of patients. Constipation was reported in at least 2% of citalopram-treated patients in clinical trials.

As with some other selective serotonin-reuptake inhibitors, bruxism (involuntary clenching or grinding of the teeth) has been reported in at least 0.1% of patients receiving citalopram. The cases of bruxism reported to date with citalopram and other serotonin-reuptake inhibitors suggest that bruxism may be dose dependent and that buspirone therapy may be helpful in relieving this symptom.

Although a causal relationship to citalopram has not been established, increased salivation and flatulence have been reported in at least 1% of patients receiving the drug. Gastritis, gastroenteritis, stomatitis, eructation, hemorrhoids, dysphagia, gingivitis, and esophagitis have been reported in at least 0.1% of patients receiving citalopram. However, a causal relationship to the drug has not been established for these effects.

Epidemiologic case-control and cohort design studies have suggested that selective serotonin-reuptake inhibitors may increase the risk of upper GI bleeding. Although the precise mechanism for this increased risk remains to be clearly established, serotonin release by platelets is known to play an important role in hemostasis, and selective serotonin-reuptake inhibitors decrease serotonin uptake from the blood by platelets thereby decreasing the amount of serotonin in platelets. In addition, concurrent use of aspirin or other nonsteroidal anti-inflammatory agents was found to substantially increase the risk of GI bleeding in patients receiving selective serotonin-reuptake inhibitors in 2 of these studies. Although these studies focused on upper GI bleeding, there is some evidence suggesting that bleeding at other sites may be similarly potentiated. Further clinical studies are needed to determine the clinical importance of these findings. (See Cautions: Hematologic Effects and see also Drug Interactions: Drugs Affecting Hemostasis.)

Colitis, gastric ulcer, duodenal ulcer, cholecystitis, cholelithiasis, gastroesophageal reflux, glossitis, diverticulitis, and rectal hemorrhage have been reported in less than 0.1% of patients receiving citalopram. However, these adverse effects have not been definitely attributed to the drug.

Dermatologic and Sensitivity Reactions

Increased sweating, which appears to be dose related, occurred in approximately 11% of patients receiving citalopram in short-term clinical studies. Rash and pruritus have been reported in at least 1% of patients receiving citalopram; however, these adverse effects have not been definitely attributed to the drug.

Photosensitivity reaction, urticaria, acne, skin discoloration, eczema, alopecia, dermatitis, dry skin, and psoriasis have been reported in less than 1% of patients receiving citalopram; however, these adverse effects have not been definitely attributed to the drug.

Hypertrichosis, decreased sweating, melanosis, keratitis, cellulitis, pruritus ani, hay fever, and facial edema have occurred in less than 0.1% of citalopram-treated patients, although a causal relationship to the drug has not been established. Allergic reactions, anaphylaxis, and angioedema also have been reported in patients receiving citalopram, although a causal relationship to the drug has not been established.

Severe adverse dermatologic effects such as erythema multiforme and epidermal necrolysis have occurred rarely in patients receiving citalopram. In addition, a case of extensive papular and purpuric erythema with keratinocytes, necrosis, and dermal leukocytoclastic vasculitis has been reported in a patient receiving citalopram; improvement occurred slowly following discontinuance of the drug.

Metabolic and Endocrine Effects

Weight loss and weight gain each occurred in at least 1% of patients receiving citalopram in controlled clinical trials; obesity has occurred rarely. Increased appetite also has been reported in at least 1% of patients receiving the drug, although a causal relationship has not been established. While clinically important weight loss may occur in some patients receiving citalopram, only minimal weight loss (averaging 0.5 kg) generally occurred in patients receiving the drug in controlled clinical trials. In addition, while decreased appetite was reported in about 4% of patients receiving citalopram in short-term clinical trials, the drug, unlike fluoxetine, does not appear to exhibit clinically important anorectic effects nor to produce clinically important long-term weight changes. In addition, short-term citalopram therapy did not produce substantial weight loss in severely obese individuals in one study.

Taste perversion has occurred in more than 1% of patients, and thirst and abnormal glucose tolerance have been reported in less than 1% of citalopram-treated patients, although a causal relationship to the drug has not been established. Taste loss has been reported rarely. Adverse metabolic and endocrine effects reported in less than 0.1% of patients receiving the drug include hypoglycemia, hypothyroidism, and goiter.

Ocular and Otic Effects

Vision abnormalities occurred in about 2% and abnormality of accommodation in at least 1% of patients receiving citalopram in short-term controlled clinical trials. Ocular dryness, conjunctivitis, and ocular pain have been reported in less than 1% of citalopram-treated patients, although a causal relationship to the drug has not been established. Mydriasis, photophobia, diplopia, ptosis, abnormal lacrimation, and cataract have been reported in less than 0.1% of patients receiving the drug; these adverse effects have not been definitely attributed to the drug. Angle-closure glaucoma (narrow-angle glaucoma) also has been reported in citalopram-treated patients.(See Cautions: Precautions and Contraindications.)

Tinnitus occurred in less than 1% of patients receiving citalopram; this adverse effect has not been definitely attributed to the drug.

Cardiovascular Effects

Citalopram does not exhibit clinically important anticholinergic activity, and current evidence suggests that the drug generally is less cardiotoxic than many older antidepressants (e.g., tricyclic antidepressants, monoamine oxidase inhibitors) at the usual recommended dosages.

No clinically important changes in vital signs (systolic and diastolic blood pressure and heart rate) were observed in patients receiving citalopram in controlled trials.

Citalopram causes dose-dependent prolongation of the corrected QT (QTc) interval, an ECG abnormality that has been associated with torsades de pointes, ventricular tachycardia, and sudden death, all of which have been reported in postmarketing experience in patients receiving the drug. In a study of the effects of citalopram on the QT interval, use of the drug was associated with a dose-dependent increase in the corrected QTc interval. In this placebo-controlled study, a change from baseline in QTcF (Fridericia's formula) greater than 60 msec occurred in 1.9% of patients receiving citalopram compared with 1.2% of patients receiving placebo. None of the patients receiving placebo had a post-dose QTcF greater than 500 msec compared with 0.5% of patients receiving citalopram. The incidence of tachycardic and bradycardic outliers was 0.5 and 0.9% in the citalopram group, respectively, and 0.4% in the placebo group. Individually corrected QTc (QTcNi) interval was evaluated in a randomized, double-blind, placebo- and active-controlled, crossover study in healthy individuals. In this study, the maximum mean differences from placebo were 8.5 and 18.5 msec for daily dosages of 20 and 60 mg of citalopram, respectively. Based on these results, the predicted QTcNi for citalopram 40 mg daily is 12.6 msec. ECG changes, including QT-interval prolongation, also have been reported in individuals receiving overdosages of the drug (more than 400-600 mg). (See Dosage and Administration: Dosage, Cautions: Precautions and Contraindications, and see also Acute Toxicity.)

Palpitation was reported in at least 2% of citalopram-treated patients in clinical trials, although a causal relationship to the drug remains to be established. A comparison of supine and standing vital signs in depressed patients receiving citalopram indicated that the drug generally does not produce orthostatic changes such as hypotension. Although postural hypotension and hypotension occurred in at least 1% of patients receiving citalopram in short-term controlled clinical trials, a causal relationship to the drug has not been established.

Tachycardia, hypertension, bradycardia, peripheral edema, syncope, angina pectoris, extrasystoles, cardiac failure, flushing and hot flushes, myocardial infarction, cerebrovascular accident, myocardial ischemia, transient ischemic attack, phlebitis, atrial fibrillation, ventricular arrhythmia, cardiac arrest, and bundle branch block have been reported in premarketing studies of citalopram or during postmarketing surveillance; these adverse effects have not been definitely attributed to the drug.

Musculoskeletal Effects

Arthralgia and myalgia each occurred in about 2% of patients receiving citalopram in short-term controlled clinical trials. In addition, back pain was reported in at least 2% of citalopram-treated patients in clinical trials, although a causal relationship to the drug remains to be established.

Arthritis, muscle weakness, leg cramps, and skeletal pain have been reported in at least 0.1% of citalopram-treated patients; these adverse effects have not been definitely attributed to the drug. Bursitis and osteoporosis have been reported in less than 0.1% of patients receiving citalopram, although a causal relationship has not been established.

Hematologic Effects

Purpura, anemia, leukocytosis, and leukopenia have been reported in at least 0.1% of patients receiving citalopram, although a causal relationship to the drug has not been established.

Adverse hematologic effects reported in less than 0.1% of patients receiving citalopram include pulmonary embolism, granulocytopenia, lymphocytosis, lymphopenia, hypochromic anemia, coagulation disorders, and gingival bleeding; however, a causal relationship to the drug has not been established. In addition, thrombocytopenia has been reported.

Bleeding complications (e.g., ecchymosis, purpura, menorrhagia, rectal bleeding) have been reported infrequently in patients receiving citalopram and other selective serotonin-reuptake inhibitors. Although the precise mechanism for these reactions has not been established, it has been suggested that impaired platelet aggregation and prolonged bleeding time may be due at least in part to inhibition of serotonin reuptake into platelets and/or that increased capillary fragility and vascular tone may contribute to these cases. (See Cautions: GI Effects and see also Drug Interactions: Drugs Affecting Hemostasis.)

Respiratory Effects

Respiratory disorders have been reported in patients receiving citalopram in short-term controlled clinical trials. Upper respiratory tract infections and rhinitis both have been reported in about 5% of citalopram-treated patients and sinusitis has occurred in about 3% of patients receiving the drug. Yawning and pharyngitis each occurred in about 2% of patients receiving citalopram. In addition, coughing has been reported in at least 1% of citalopram-treated patients.

Adverse respiratory effects reported in at least 0.1% of patients receiving citalopram in controlled trials include bronchitis, dyspnea, epistaxis, and pneumonia; however, a causal relationship to the drug remains to be established. Other adverse effects reported in less than 0.1% of citalopram-treated patients include asthma, laryngitis, bronchospasm, pneumonitis, and increased sputum; these adverse effects have not been definitely attributed to the drug.

Renal, Electrolyte, and Genitourinary Effects

Sexual Dysfunction

Like other selective serotonin-reuptake inhibitors, adverse effects on sexual function have been reported in both men and women receiving citalopram. Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they also may occur as the result of pharmacologic therapy. It is difficult to determine the true incidence and severity of adverse effects on sexual function during citalopram therapy, in part because patients and clinicians may be reluctant to discuss these effects. Therefore, incidence data reported in product labeling and earlier studies are most likely underestimates of the true incidence of adverse sexual effects. Recent reports indicate that up to 50% of patients receiving selective serotonin-reuptake inhibitors describe some form of sexual dysfunction during treatment and the actual incidence may be even higher.

Ejaculatory disturbances (principally ejaculatory delay) are the most common adverse urogenital effects associated with citalopram in males, occurring in about 6% of male patients receiving the drug compared with 1% of depressed patients receiving placebo in controlled clinical studies. However, the adverse effect of ejaculatory delay associated with serotonin-reuptake inhibitors has been used for therapeutic benefit in the treatment of premature ejaculation.(See Uses: Premature Ejaculation.) Results of some (but not all) studies in men and women suggest that paroxetine may be associated with a higher incidence of sexual dysfunction than some other currently available selective serotonin-reuptake inhibitors, including citalopram and sertraline. Since it is difficult to know the precise risk of sexual dysfunction associated with citalopram and other serotonin-reuptake inhibitors, clinicians should routinely inquire about such possible adverse effects in patients receiving these drugs.

Decreased libido was reported in about 4% of depressed male patients receiving citalopram in short-term placebo-controlled studies compared with less than 1% of patients receiving placebo. In these studies, impotence, which appears to be dose related, was reported in about 3% of male patients receiving citalopram compared with less than 1% of males receiving placebo. In female patients receiving citalopram in controlled clinical studies for the treatment of depression, decreased libido and anorgasmia were reported in about 1% of those receiving citalopram. Increased libido has been reported in up to 1% of patients receiving citalopram. Priapism also has been reported during postmarketing surveillance in male patients, and clitoral priapism has been reported in at least 3 female patients receiving the drug.

The long-term effects of selective serotonin-reuptake inhibitors on sexual function have not been fully determined to date. In a double-blind study evaluating 6 months of citalopram or sertraline therapy in depressed patients, sexual desire and overall sexual functioning (as measured on the UKU Side Effect Scale) substantially improved in women and sexual desire improved in men. In men, no change in orgasmic dysfunction, erectile dysfunction, or overall sexual functioning was reported after 6 months of therapy with citalopram or sertraline, although there was a trend toward worsening of ejaculatory dysfunction. However, in the subgroups of women and men reporting no sexual problems at baseline, approximately 12% of women reported decreased sexual desire and 14% reported orgasmic dysfunction after 6 months of citalopram therapy; the corresponding figures in the same subgroup of men were approximately 17 and 19%, respectively, and as many as 25% experienced ejaculatory dysfunction after 6 months. No substantial differences between citalopram and sertraline were reported in this study.

Management of sexual dysfunction caused by selective serotonin-reuptake inhibitor therapy includes waiting for tolerance to develop; using a lower dosage of the drug; using drug holidays; delaying administration of the drug until after coitus; or changing to another antidepressant. Although further study is needed, there is some evidence that adverse sexual effects of the selective serotonin-reuptake inhibitors may be reversed by concomitant use of certain drugs, including buspirone, 5-hydroxytryptamine-2 (5-HT2) receptor antagonists (e.g., nefazodone), 5-HT3 receptor inhibitors (e.g., granisetron), or α2-adrenergic receptor antagonists (e.g., yohimbine), selective phosphodiesterase (PDE) inhibitors (e.g., sildenafil), or dopamine receptor agonists (e.g., amantadine, dextroamphetamine, pemoline [no longer commercially available in the US], methylphenidate). In most patients, sexual dysfunction is fully reversed 1-3 days after discontinuance of the antidepressant.

Other Renal, Electrolyte, and Genitourinary Effects

Treatment with SSRIs, including citalopram, or selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs) may result in hyponatremia. In many cases, this hyponatremia appeared to be due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and was reversible when citalopram was discontinued. Cases with serum sodium concentrations lower than 110 mmol/L have been reported. Prolonged coma caused by hyponatremia has been reported in a patient with multiple sclerosis receiving citalopram therapy. Severe postoperative hyponatremia has been reported in an elderly female patient receiving the drug. Hyponatremia and SIADH usually develop an average of 2 weeks after initiating therapy (range: 3-120 days). Geriatric individuals and patients receiving diuretics or who are otherwise volume depleted may be at greater risk of developing hyponatremia during therapy with SSRIs or SNRIs. Discontinuance of citalopram should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Because geriatric patients may be at increased risk for hyponatremia associated with these drugs, clinicians prescribing citalopram in such patients should be aware of the possibility that such reactions may occur. In addition, periodic monitoring of serum sodium concentrations (particularly during the first several months) in geriatric patients receiving selective serotonin-reuptake inhibitors has been recommended by some clinicians.

Hypokalemia and dehydration have occurred in less than 0.1% of patients receiving citalopram; these adverse effects have not been definitely attributed to the drug.

Urinary disorders (e.g., micturition disorders) have been reported in at least 2% of patients receiving citalopram in short-term controlled trials. In addition, polyuria has been reported in at least 1% of patients receiving the drug. Although a definite causal relationship to citalopram has not been established, urinary frequency, urinary incontinence, urinary retention, and dysuria have been reported in at least 0.1% of patients receiving the drug. Other adverse urologic effects reported in less than 0.1% of citalopram-treated patients include hematuria, oliguria, pyelonephritis, renal calculus, and renal pain; these adverse effects have not been definitely attributed to the drug.

Dysmenorrhea has been reported in at least 3% of female patients receiving citalopram in short-term controlled trials. In addition, amenorrhea has been reported in at least 1% of patients receiving the drug. Galactorrhea, breast pain, breast enlargement, and vaginal hemorrhage have been reported in less than 1% of patients receiving citalopram, and spontaneous abortion has been reported rarely; however, these adverse effects have not been definitely attributed to the drug. Breast enlargement also has been reported in some women receiving chronic therapy with other selective serotonin-reuptake inhibitors. In one study, approximately 40% of patients receiving selective serotonin-reuptake inhibitors (e.g., fluoxetine, paroxetine, sertraline) or venlafaxine reported some degree of breast enlargement; most patients with breast enlargement also experienced weight gain. In addition, serum prolactin concentrations were increased in the women receiving other selective serotonin-reuptake inhibitors in this study. Gynecomastia has been reported rarely.

Hepatic Effects

Abnormal liver function test results, including elevations in serum hepatic enzyme concentrations, and increased serum alkaline phosphatase concentrations have been reported in at least 0.1% of patients receiving citalopram. Hepatitis, jaundice, and hyperbilirubinemia have been reported in less than 0.1% of patients receiving citalopram; however, these adverse effects have not been definitely attributed to the drug. Hepatic necrosis has also been reported during postmarketing surveillance in citalopram-treated patients.

Other Adverse Effects

Fever occurred in about 2% of patients receiving citalopram in short-term controlled clinical trials. Rigors, alcohol intolerance, lymphadenopathy, and influenza-like symptoms have been reported in less than 1% of patients receiving citalopram; however, these adverse effects have not been definitely attributed to the drug. Pancreatitis also has occurred in association with citalopram, although a causal relationship to the drug has not been clearly established.

Precautions and Contraindications

Worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior may occur in both adult and pediatric (see Cautions: Pediatric Precautions) patients with major depressive disorder or other psychiatric disorders, whether or not they are taking antidepressants. This risk may persist until clinically important remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. However, there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term, placebo-controlled studies of antidepressants (i.e., selective serotonin-reuptake inhibitors and other antidepressants) have shown an increased risk of suicidality in children, adolescents, and young adults (18-24 years of age) with major depressive disorder and other psychiatric disorders. An increased suicidality risk was not demonstrated with antidepressants compared with placebo in adults older than 24 years of age and a reduced risk was observed in adults 65 years of age or older. It currently is unknown whether the suicidality risk extends to longer-term use (i.e., beyond several months); however, there is substantial evidence from placebo-controlled maintenance trials in adults with major depressive disorder that antidepressants can delay the recurrence of depression.

The US Food and Drug Administration (FDA) recommends that all patients being treated with antidepressants for any indication be appropriately monitored and closely observed for clinical worsening, suicidality, and unusual changes in behavior, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, also should be advised to monitor patients on a daily basis for the emergence of agitation, irritability, or unusual changes in behavior as well as the emergence of suicidality, and to report such symptoms immediately to a health-care provider.

Although a causal relationship between the emergence of symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consequently, consideration should be given to changing the therapeutic regimen or discontinuing therapy in patients whose depression is persistently worse or in patients experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if such manifestations are severe, abrupt in onset, or were not part of the patient's presenting symptoms. If a decision is made to discontinue therapy, citalopram dosage should be tapered as rapidly as is feasible but with recognition of the risks of abrupt discontinuance.(See Dosage and Administration: Dosage.) FDA also recommends that the drugs be prescribed in the smallest quantity consistent with good patient management, in order to reduce the risk of overdosage.

Citalopram causes dose-dependent QTc-interval prolongation, an ECG abnormality that has been associated with torsades de pointes, ventricular tachycardia, and sudden death, all of which have been reported in postmarketing experience in patients receiving the drug. On August 24, 2011, the US Food and Drug Administration (FDA) notified healthcare professionals that citalopram should no longer be used at dosages exceeding 40 mg daily due to the risk of QT-interval prolongation and torsades de pointes; previously, the prescribing information for the drug stated that certain patients may require a dosage of 60 mg daily. On March 28, 2012, the FDA provided the following revised recommendations for citalopram use related to the potential risk of abnormal heart rhythms associated with higher dosages of the drug. The FDA advised that citalopram therapy is not recommended in patients with congenital long QT syndrome, bradycardia, hypokalemia or hypomagnesemia, recent acute myocardial infarction, or uncompensated heart failure. The FDA also stated that citalopram should not be used in patients receiving other drugs known to prolong the QTc interval. Such drugs include class IA (e.g., quinidine, procainamide) or class III (e.g., amiodarone, sotalol) antiarrhythmic agents, certain antipsychotic agents (e.g., chlorpromazine, thioridazine), some anti-infective agents (e.g., gatifloxacin, moxifloxacin), and other drugs (e.g., pentamidine, levomethadyl acetate, methadone). In addition, the maximum dosage of citalopram should be limited to 20 mg once daily in patients who are poor metabolizers of the cytochrome P-450 (CYP) isoenzyme 2C19; patients receiving cimetidine or another CYP2C19 inhibitor; patients with hepatic impairment; and in patients older than 60 years of age; higher citalopram exposures in such patients increase the risk of QT-interval prolongation and torsades de pointes. Furthermore, electrolyte and/or ECG monitoring is recommended in certain situations. Patients being considered for citalopram therapy who are at risk for clinically important electrolyte disturbances should have baseline measurements of serum potassium and magnesium concentrations with subsequent periodic monitoring. Because hypokalemia and/or hypomagnesemia may increase the risk of QTc-interval prolongation and arrhythmias, hypokalemia and hypomagnesemia should be corrected prior to citalopram administration and serum concentrations of these electrolytes should be periodically monitored. In addition, ECG monitoring is recommended in patients for whom citalopram use is not recommended but nevertheless considered essential, including those with the above-mentioned cardiovascular conditions (e.g., congenital long QT syndrome, bradycardia, recent acute myocardial infarction, uncompensated heart failure) and those concurrently receiving other drugs that may prolong the QTc interval. Citalopram should be discontinued in any patient who has persistent QTc measurements exceeding 500 msec. Patients receiving citalopram should be informed of the possible symptoms of QT-interval prolongation and torsades de pointes (e.g., chest pain, irregular heartbeat, shortness of breath, dizziness or fainting) and advised to seek immediate medical attention should such symptoms occur. If a citalopram-treated patient experiences such symptoms, further evaluation should be initiated, including cardiac monitoring.

It is generally believed (though not established in controlled trials) that treating a major depressive episode with an antidepressant alone may increase the likelihood of precipitating a mixed or manic episode in patients at risk for bipolar disorder. Therefore, patients should be adequately screened for bipolar disorder prior to initiating treatment with an antidepressant; such screening should include a detailed psychiatric history (e.g., family history of suicide, bipolar disorder, and depression).

Potentially life-threatening serotonin syndrome has been reported with SSRIs, including citalopram, and selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs) when used alone, but particularly with concurrent use of other serotonergic drugs (including serotonin [5-hydroxytryptamine; 5-HT] type 1 receptor agonists [''triptans''], tricyclic antidepressants, buspirone, fentanyl, lithium, tramadol, tryptophan, and St. John's wort [Hypericum perforatum]) and with drugs that impair the metabolism of serotonin (particularly monoamine oxidase [MAO] inhibitors, both those used to treat psychiatric disorders and others, such as linezolid and methylene blue). Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or GI symptoms (e.g., nausea, vomiting, diarrhea). Patients receiving citalopram should be monitored for the development of serotonin syndrome.

Concomitant use of citalopram and MAO inhibitors intended to treat psychiatric disorders is contraindicated. Citalopram also should not be initiated in patients who are being treated with other MAO inhibitors such as linezolid or IV methylene blue. In patients who require more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered. Citalopram may be started 24 hours after the last dose of linezolid or IV methylene blue.

If concurrent therapy with citalopram and other serotonergic drugs is clinically warranted, the patient should be made aware of the potential increased risk for serotonin syndrome, particularly during initiation of therapy or when dosage is increased. If manifestations of serotonin syndrome occur, treatment with citalopram and any concurrently administered serotonergic agents should be discontinued immediately and supportive and symptomatic treatment should be initiated.(See Drug Interactions: Serotonergic Drugs.) For further information on serotonin syndrome, including manifestations and treatment,

The pupillary dilation (mydriasis) that occurs following the use of many antidepressant agents, including citalopram, may trigger an acute attack of angle-closure glaucoma (narrow-angle glaucoma) in patients with anatomically narrow angles who do not have a patent iridectomy. Possible symptoms of angle-closure glaucoma include eye pain, vision changes, and swelling or redness in or around the eye. Preexisting glaucoma is almost always open-angle glaucoma since angle-closure glaucoma can be treated definitively with iridectomy when diagnosed; open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients should be advised that citalopram can cause mild pupillary dilation, which can lead to an episode of angle-closure glaucoma in susceptible individuals. In addition, patients may wish to be examined to determine whether they are susceptible to angle-closure glaucoma and have a prophylactic procedure (e.g., iridectomy) if they are susceptible.

Citalopram should be used with caution and a lower maximum dosage (20 mg once daily) is recommended in patients with hepatic impairment, since decreased clearance and increased plasma concentrations of the drug may occur in such patients.(See Dosage and Administration: Dosage in Hepatic and Renal Impairment and see also Pharmacokinetics: Elimination.)

Because citalopram is extensively metabolized, excretion of unchanged drug in urine is a minor route of elimination. Severe renal failure did not markedly affect the pharmacokinetics of citalopram in one study, suggesting that dosage adjustment may not be necessary in patients with severe renal impairment. However, until long-term citalopram therapy has been more fully evaluated in such patients, citalopram should be used with caution in patients with severe renal impairment.(See Dosage and Administration: Dosage in Hepatic and Renal Impairment and see also Pharmacokinetics: Elimination.)

Because of the potential for adverse drug interactions, patients receiving citalopram should be advised to notify their clinician if they are taking or plan to take nonprescription (over-the-counter) or prescription medications. Although citalopram has not been shown to potentiate the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while receiving the drug.

Citalopram generally is less sedating than many other currently available antidepressants and does not appear to produce substantial impairment of cognitive or psychomotor function nor to potentiate psychomotor impairment induced by other CNS depressants (e.g., alcohol). However, patients should be cautioned that citalopram may impair their ability to perform activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle) and to avoid such activities until they gain experience with the drug's effects.

Patients receiving citalopram should be advised that while they may notice improvement within 1-4 weeks after starting therapy, they should continue therapy with the drug as directed by their clinician.

Although anticonvulsant effects have been observed in animal studies with citalopram, the drug has not been systematically evaluated in patients with a seizure disorder. In addition, patients with seizure disorders were excluded from premarketing clinical trials with the drug. In clinical studies of citalopram, seizures occurred in 0.3% of patients receiving citalopram and in 0.5% of patients receiving placebo; a causal relationship to the drug remains to be established. However, as with other antidepressants, citalopram should be initiated and used with caution in patients with a history of seizures.

Activation of mania and hypomania have occurred in patients receiving therapeutic dosages of citalopram. The drug should be used with caution in patients with a history of mania.(See Cautions: Nervous System Effects.)

Treatment with SSRIs, including citalopram, or SNRIs may result in hyponatremia. In many cases, this hyponatremia appears to be due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and was reversible when the SSRI or SNRI was discontinued. Geriatric individuals and patients receiving diuretics or who are otherwise volume depleted may be at greater risk of developing hyponatremia during therapy with SSRIs or SNRIs. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls; more severe and/or acute cases have been associated with hallucinations, syncope, seizures, coma, respiratory arrest, and death. Discontinuance of citalopram should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.(See Cautions: Renal, Electrolyte, and Genitourinary Effects and see also see Cautions: Geriatric Precautions.)

Because of similarity in spelling of Celexa (citalopram hydrobromide), Celebrex (celecoxib), and Cerebyx (fosphenytoin sodium), extra care should be exercised in ensuring the accuracy of prescriptions for these drugs.

Use of citalopram is contraindicated in patients who are currently receiving or have recently (i.e., within 2 weeks) received therapy with an MAO inhibitor intended to treat psychiatric disorders because of an increased risk of serotonin syndrome. Conversely, use of an MAO inhibitor intended to treat psychiatric disorders is contraindicated within 2 weeks of citalopram discontinuance.(See Drug Interactions: Serotonergic Drugs.)

Initiation of citalopram therapy in patients receiving MAO inhibitors such as linezolid or IV methylene blue also is contraindicated because of an increased risk of serotonin syndrome.(See Drug Interactions: Serotonergic Drugs.)

Concurrent use of citalopram in patients receiving pimozide is contraindicated.(See Drug Interactions: Pimozide.)

Citalopram is contraindicated in patients who are hypersensitive to the drug, escitalopram, or any ingredient in the formulation.

Pediatric Precautions

Safety and efficacy of citalopram in pediatric patients have not been established. Two placebo-controlled trials involving 407 children and adolescents with major depressive disorder have been conducted with citalopram; the results of these trials were not sufficient to support a claim of efficacy for use of the drug in pediatric patients with this condition.(See Pediatric Considerations under Uses: Major Depressive Disorder.)

Decreased appetite and weight loss have been observed in patients receiving SSRIs. Therefore, regular monitoring of weight and growth should be performed in children and adolescents receiving citalopram therapy.

FDA warns that antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder and other psychiatric disorders. The risk of suicidality for these drugs was identified in a pooled analysis of data from a total of 24 short-term (4-16 weeks), placebo-controlled studies of 9 antidepressants (i.e., citalopram, bupropion, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, venlafaxine) in over 4400 children and adolescents with major depressive disorder, obsessive-compulsive disorder (OCD), or other psychiatric disorders. The analysis revealed a greater risk of adverse events representing suicidal behavior or thinking (suicidality) during the first few months of treatment in pediatric patients receiving antidepressants than in those receiving placebo. However, a more recent meta-analysis of 27 placebo-controlled trials of 9 antidepressants (SSRIs and others) in patients younger than 19 years of age with major depressive disorder, OCD, or non-OCD anxiety disorders suggests that the benefits of antidepressant therapy in treating these conditions may outweigh the risks of suicidal behavior or suicidal ideation. No suicides occurred in these pediatric trials.

The risk of suicidality in the FDA's pooled analysis differed across the different psychiatric indications, with the highest incidence observed in the major depressive disorder studies. In addition, although there was considerable variation in risk among the antidepressants, a tendency toward an increase in suicidality risk in younger patients was found for almost all drugs studied. It currently is unknown whether the suicidality risk in pediatric patients extends to longer-term use (i.e., beyond several months).

As a result of this analysis and public discussion of the issue, FDA has directed manufacturers of all antidepressants to add a boxed warning to the labeling of their products to alert clinicians of this suicidality risk in children and adolescents and to recommend appropriate monitoring and close observation of patients receiving these agents.(See Cautions: Precautions and Contraindications.) The drugs that are the focus of the revised labeling are all drugs included in the general class of antidepressants, including those that have not been studied in controlled clinical trials in pediatric patients, since the available data are not adequate to exclude any single antidepressant from an increased risk. In addition to the boxed warning and other information in professional labeling on antidepressants, FDA currently recommends that a patient medication guide explaining the risks associated with the drugs be provided to the patient each time the drugs are dispensed. Caregivers of pediatric patients whose depression is persistently worse or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality during antidepressant therapy should consult their clinician regarding the best course of action (e.g., whether the therapeutic regimen should be changed or the drug discontinued).Patients should not discontinue use of selective serotonin-reuptake inhibitors without first consulting their clinician; it is very important that the drugs not be abruptly discontinued, as withdrawal effects may occur.(See Dosage and Administration: Dosage.)

Anyone considering the use of citalopram in a child or adolescent for any clinical use must balance the potential risk of therapy with the clinical need.

Geriatric Precautions

While safety and efficacy of citalopram in geriatric patients have not been established specifically, approximately 31% of patients receiving the drug for depression in clinical trials were 60 years of age or older, approximately 23% were 65 years of age or older, and approximately 10% were 75 years of age or older.

Although no overall differences in the efficacy or adverse effect profile of citalopram were observed between geriatric and younger patients and other clinical experience revealed no evidence of age-related differences in response, pharmacokinetic studies in healthy geriatric individuals and depressed patients 60 years of age or older have revealed higher areas under the plasma concentration-time curve (AUC) values and longer elimination half-lives compared with those in younger individuals.(See Pharmacokinetics: Absorption and Elimination.) Therefore, the manufacturer and some clinicians recommend a maximum citalopram dosage of 20 mg once daily for geriatric patients older than 60 years of age with major depressive disorder.(See Dosage and Administration: Dosage in Geriatric Patients.)

In pooled data analyses, a reduced risk of suicidality was observed in adults 65 years of age or older with antidepressant therapy compared with placebo.(See Cautions: Precautions and Contraindications.)

Limited evidence suggests that geriatric patients also may be more likely than younger patients to develop citalopram-induced hyponatremia and transient syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Therefore, clinicians prescribing citalopram in geriatric patients should be aware of the possibility that such reactions may occur. In addition, periodic monitoring (especially during the first several months) of serum sodium concentrations in geriatric patients receiving selective serotonin-reuptake inhibitors has been recommended by some clinicians.

In a double-blind, multicenter trial, citalopram (20 or 40 mg daily) was found to be as effective as and better tolerated than amitriptyline in depressed geriatric patients. In a small study comparing citalopram and nortriptyline in depressed geriatric patients, citalopram was found to be somewhat less effective but better tolerated than nortriptyline.

In a controlled study comparing citalopram and placebo in elderly patients with dementia, citalopram (20-30 mg daily) was found to improve depression as well as cognitive and emotional functioning more than placebo. In an open study in a limited number of patients with dementia and behavioral disturbances, citalopram was found to improve the behavioral complications associated with dementia.

As with other psychotropic drugs, geriatric patients receiving antidepressants appear to have an increased risk of hip fracture. Despite the decreased incidence of cardiovascular and anticholinergic effects associated with selective serotonin-reuptake inhibitors, these drugs did not show any advantage over tricyclic antidepressants with regard to hip fracture in a case-control study. In addition, there was little difference in the rates of falls between nursing home residents receiving selective serotonin-reuptake inhibitors and those receiving tricyclic antidepressants in a retrospective study. Therefore, all geriatric individuals receiving either type of antidepressant should be considered at increased risk of falls, and appropriate measures should be taken.

Mutagenicity and Carcinogenicity

Citalopram was mutagenic in the in vitro bacterial reverse mutation assay (Ames test) in 2 out of 5 bacterial strains (Salmonella TA98 and TA1537) in the absence of metabolic activation. In the in vitro Chinese hamster lung cell assay for chromosomal aberrations, citalopram was clastogenic in the presence and absence of metabolic activation. The drug was not mutagenic in the in vitro mammalian forward gene mutation assay (HPRT) in mouse lymphoma cells or in a coupled in vitro/in vivo unscheduled DNA synthesis (UDS) assay in rat liver. Citalopram was not found to be clastogenic in the in vitro chromosomal aberration assay in human lymphocytes or in 2 in vivo mouse micronucleus assays.

Studies to determine the carcinogenic potential of citalopram were performed in mice receiving oral dosages of up to 240 mg/kg daily for 18 months and in rats receiving 8 or 24 mg/kg daily for 24 months. These dosages were approximately 20 times the maximum recommended human daily dosage of 60 mg on a surface area (mg/m) basis in mice and approximately 1.3 and 4 times the maximum recommended human daily dosage on a mg/m basis in rats, respectively. No evidence of carcinogenicity was found in the mice. In rats receiving 8 or 24 mg/kg daily of citalopram, an increased incidence of small intestine carcinoma was reported. The manufacturer states that a no-effect dosage for this finding was not established; the relevance of this finding to humans is not known.

Pregnancy, Fertility, and Lactation

Pregnancy

Some neonates exposed to citalopram and other selective serotonin-reuptake inhibitors (SSRIs) or selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs) late in the third trimester of pregnancy have developed complications that have sometimes been severe and required prolonged hospitalization, respiratory support, enteral nutrition, and other forms of supportive care in special-care nurseries. Such complications can arise immediately upon delivery and usually last several days or up to 2-4 weeks. Clinical findings reported to date in the neonates have included respiratory distress, cyanosis, apnea, seizures, temperature instability or fever, feeding difficulty, dehydration, excessive weight loss, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, lethargy, reduced or lack of reaction to pain stimuli, and constant crying. These clinical features appear to be consistent with either a direct toxic effect of the SSRI or SNRI or, possibly, a drug withdrawal syndrome. It should be noted that, in some cases, the clinical picture was consistent with serotonin syndrome (see Drug Interactions: Serotonergic Drugs).

Infants exposed to SSRIs in late pregnancy may have an increased risk of persistent pulmonary hypertension of the newborn (PPHN). PPHN is a rare heart and lung condition occurring in an estimated 1-2 infants per 1000 live births in the general population; it occurs when a neonate does not adapt to breathing outside the womb. Some experts have suggested that respiratory distress in neonates exposed to SSRIs may occur along a spectrum of seriousness in association with maternal use of SSRIs, with PPHN among the most serious consequences. Neonates with PPHN may require intensive care support, including mechanical ventilation; in severe cases, multiple organ damage, including brain damage, and even death may occur. Although several epidemiologic studies have suggested an increased risk of PPHN with SSRI use during pregnancy, other studies did not demonstrate a statistically significant association. Thus, the FDA states that it is currently unclear whether use of SSRIs, including citalopram, during pregnancy can cause PPHN and recommends that clinicians not alter their current clinical practice of treating depression during pregnancy.

Clinicians should consider that in a prospective longitudinal study of 201 women with a history of recurrent major depression who were euthymic in the context of antidepressant therapy at the beginning of pregnancy, women who discontinued their antidepressant medication (SSRIs, tricyclic antidepressants, or others) during pregnancy were found to be substantially more likely to have a relapse of depression than were women who continued to receive their antidepressant therapy while pregnant. When treating a pregnant woman with citalopram, the clinician should carefully consider the potential risks of taking an SSRI along with the established benefits of treating depression with an antidepressant; this decision can only be made on a case-by-case basis. (See Dosage and Administration: Treatment of Pregnant Women during the Third Trimester.)

For additional information on the management of depression in women prior to conception and during pregnancy, including treatment algorithms, the FDA advises clinicians to consult the joint American Psychiatric Association and American College of Obstetricians and Gynecologists guidelines (at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3103063/pdf/nihms293836.pdf).

Most epidemiologic studies of pregnancy outcome following first-trimester exposure to SSRIs, including citalopram, conducted to date have not revealed evidence of an

Drug Interactions

Drugs that Prolong the QT Interval

Citalopram use is not recommended in patients concurrently receiving other drugs known to prolong the QTc interval, including class IA (e.g., quinidine, procainamide) or class III (e.g., amiodarone, sotalol) antiarrhythmic agents, certain antipsychotic agents (e.g., chlorpromazine, thioridazine), some anti-infective agents (e.g., gatifloxacin, moxifloxacin), and other drugs (e.g., pentamidine, levomethadyl acetate, methadone). However, if citalopram therapy is considered essential in such patients, ECG monitoring is recommended.(See Cautions: Cardiovascular Effects and see Drug Interactions: Pimozide.)

Serotonergic Drugs

Use of selective serotonin-reuptake inhibitors (SSRIs) such as citalopram concurrently or in close succession with other drugs that affect serotonergic neurotransmission may result in potentially life-threatening serotonin syndrome. Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or GI symptoms (e.g., nausea, vomiting, diarrhea). The precise mechanism of serotonin syndrome is not fully understood; however, it appears to result from excessive serotonergic activity in the CNS, probably mediated by activation of serotonin 5-HT1A receptors. The possible involvement of dopamine and 5-HT2 receptors also has been suggested, although their roles remain unclear.

Serotonin syndrome most commonly occurs when 2 or more drugs that affect serotonergic neurotransmission are administered either concurrently or in close succession. Serotonergic agents include those that increase serotonin synthesis (e.g., the serotonin precursor tryptophan), stimulate synaptic serotonin release (e.g., some amphetamines, dexfenfluramine [no longer commercially available in the US], fenfluramine [no longer commercially available in the US]), inhibit the reuptake of serotonin after release (e.g., SSRIs, selective serotonin- and norepinephrine-reuptake inhibitors [SNRIs], tricyclic antidepressants, trazodone, dextromethorphan, meperidine, tramadol), decrease the metabolism of serotonin (e.g., monoamine oxidase [MAO] inhibitors), have direct serotonin postsynaptic receptor activity (e.g., buspirone), or nonspecifically induce increases in serotonergic neuronal activity (e.g., lithium salts). Selective agonists of serotonin (5-hydroxytryptamine; 5-HT) type 1 (5-HT1) receptors (''triptans'') and dihydroergotamine, agents with serotonergic activity used in the management of migraine headache, and St. John's wort (Hypericum perforatum) also have been implicated in cases of serotonin syndrome.

The combination of SSRIs and MAO inhibitors may result in serotonin syndrome. Such reactions also have been reported in patients receiving SSRIs concomitantly with tryptophan, lithium, dextromethorphan, sumatriptan, or dihydroergotamine. In rare cases, serotonin syndrome reportedly has occurred in patients receiving the recommended dosage of a single serotonergic agent (e.g., clomipramine) or during accidental overdosage (e.g., sertraline intoxication in a child). Some other drugs that have been implicated in precipitating symptoms suggestive of serotonin syndrome include buspirone, bromocriptine, dextropropoxyphene, linezolid, methylene blue, methylenedioxymethamphetamine (MDMA; ''ecstasy''), selegiline (a selective MAO-B inhibitor), and sibutramine (an SNRI used for the management of obesity [no longer commercially available in the US]). Other drugs that have been associated with the syndrome but for which less convincing data are available include carbamazepine, fentanyl, and pentazocine.

Clinicians should be aware of the potential for serious, possibly fatal reactions associated with serotonin syndrome in patients receiving 2 or more drugs that affect serotonergic neurotransmission, even if no such interactions with the specific drugs have been reported to date in the medical literature. Such patients should be monitored for the emergence of serotonin syndrome. Serotonin syndrome may be more likely to occur when initiating therapy, increasing the dosage, or following the addition of another serotonergic drug. Some clinicians state that patients who have experienced serotonin syndrome may be at higher risk for recurrence of the syndrome upon reinitiation of serotonergic drugs. Pending further experience in such cases, some clinicians recommend that therapy with serotonergic agents be limited following recovery. If concomitant use of citalopram and other serotonergic drugs is clinically warranted, patients should be advised of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases. If manifestations of serotonin syndrome occur, treatment with citalopram and any concurrently administered serotonergic agents should be discontinued immediately and supportive and symptomatic treatment should be initiated.

For further information on serotonin syndrome, including manifestations and treatment,

Monoamine Oxidase Inhibitors

Concomitant use of citalopram and MAO inhibitors, both those used to treat psychiatric disorders and others such as linezolid and methylene blue, is associated with a risk of potentially life-threatening serotonin syndrome. Such reactions also have been reported in patients who recently have discontinued an SSRI and have initiated therapy with an MAO inhibitor.

Because of the potential risk of serotonin syndrome, concomitant use of citalopram and MAO inhibitors intended to treat psychiatric disorders is contraindicated. At least 2 weeks should elapse between discontinuance of MAO inhibitors intended to treat psychiatric disorders and initiation of citalopram therapy and vice versa.

Linezolid

Linezolid, an anti-infective agent that is a nonselective and reversible MAO inhibitor, has been associated with drug interactions resulting in serotonin syndrome, including some associated with SSRIs. Because of this potential risk, linezolid generally should not be used in patients receiving citalopram. However, certain life-threatening or urgent situations may necessitate immediate linezolid treatment in a patient receiving a serotonergic drug, including citalopram. In such emergency situations, the availability of acceptable alternative anti-infectives should be considered and the benefits of linezolid should be weighed against the risk of serotonin syndrome. If linezolid is indicated in such emergency situations, citalopram must be immediately discontinued and the patient monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last linezolid dose, whichever comes first. Treatment with citalopram may be resumed 24 hours after the last linezolid dose.

If nonemergency use of linezolid is being planned for a patient receiving citalopram, citalopram should be withheld for at least 2 weeks prior to initiating linezolid.

Initiation of citalopram in a patient receiving linezolid is contraindicated; when necessary, citalopram may be started 24 hours after the last linezolid dose.

Methylene Blue

Methylene blue, a potent and reversible inhibitor of MAO-A, has been associated with drug interactions resulting in serotonin syndrome, including some associated with SSRIs. All of the reports of serotonin syndrome with methylene blue that provided information on the route of administration involved IV administration of doses of 1-8 mg/kg (e.g., when used as a diagnostic [visualizing] dye during parathyroid surgery); none of the reports to date involved administration of methylene blue by other routes (such as oral tablets or by local tissue injection) or at lower doses. Because of this potential risk, methylene blue generally should not be used in patients receiving citalopram. However, certain life-threatening or urgent situations may necessitate immediate IV methylene blue administration in a patient receiving a serotonergic drug, including citalopram. In such emergency situations, the availability of acceptable alternatives to methylene blue should be considered and the benefits of IV methylene blue should be weighed against the risk of serotonin syndrome. If methylene blue is indicated in such emergency situations, citalopram must be immediately discontinued and the patient monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last methylene blue dose, whichever comes first. Treatment with citalopram may be resumed 24 hours after the last methylene blue dose.

If nonemergency use of methylene blue is being planned for a patient receiving citalopram, citalopram should be withheld for at least 2 weeks prior to initiating methylene blue treatment.

Initiation of citalopram in a patient receiving IV methylene blue is contraindicated; when necessary, citalopram may be started 24 hours after the last IV methylene blue dose.

Moclobemide

Moclobemide (not commercially available in the US), a selective and reversible MAO-A inhibitor, has been associated with serotonin syndrome, and such reactions have been fatal in several cases in which the drug was given in combination with citalopram or with clomipramine. Pending further experience with such combinations, some clinicians recommend that concurrent therapy with moclobemide and a selective serotonin-reuptake inhibitor be used only with extreme caution and serotonin-reuptake inhibitors should have been discontinued for some time (depending on the elimination half-lives of the drug and its active metabolites) before initiating moclobemide therapy.

Selegiline

Selegiline, a selective MAO-B inhibitor used in the management of parkinsonian syndrome, has been reported to cause serotonin syndrome when given concurrently with selective serotonin-reuptake inhibitors (e.g., fluoxetine, paroxetine, sertraline). Although selegiline is a selective MAO-B inhibitor at therapeutic dosages, the drug appears to lose its selectivity for the MAO-B enzyme at higher dosages (e.g., those exceeding 10 mg/kg), thereby increasing the risk of serotonin syndrome in patients receiving higher dosages of the drug either alone or in combination with other serotonergic agents.

In a double-blind, placebo-controlled study in healthy individuals receiving citalopram and selegiline concurrently, no clinically important differences in vital signs or in the frequency of adverse events between the study groups were reported. In addition, no evidence of a clinically relevant pharmacokinetic interaction between the 2 drugs was found. Pending further accumulation of data, the manufacturer of selegiline recommends avoiding concurrent selegiline and selective serotonin-reuptake inhibitor therapy. In addition, the manufacturer of selegiline recommends that at least 2 weeks elapse between discontinuance of selegiline and initiation of selective serotonin-reuptake inhibitor therapy.

Isoniazid

Isoniazid, an antituberculosis agent, appears to have some MAO-inhibiting activity. In addition, iproniazid (not commercially available in the US), another antituberculosis agent structurally related to isoniazid that also possesses MAO-inhibiting activity, reportedly has resulted in serotonin syndrome in at least 2 patients when given in combination with meperidine. Pending further experience, clinicians should be aware of the potential for serotonin syndrome when isoniazid is given in conjunction with selective serotonin-reuptake inhibitor therapy (such as citalopram) or other serotonergic agents.

Tryptophan

An interaction between paroxetine (another SSRI) and tryptophan (a serotonin precursor) has been reported during concurrent use. Adverse reactions reported to date during combined therapy with these drugs resemble serotonin syndrome and have consisted principally of headache, nausea, sweating, and dizziness. If concomitant use of citalopram and tryptophan is clinically warranted, patients should be advised of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome manifestations occur, treatment with citalopram, tryptophan, and any other concurrently administered serotonergic agents should be discontinued immediately and supportive and symptomatic treatment should be initiated.(See Cautions: Precautions and Contraindications.)

5-HT1 Receptor Agonists (''Triptans'')

Weakness, hyperreflexia, and incoordination have been reported rarely during postmarketing surveillance in patients receiving sumatriptan concomitantly with an SSRI (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline); these reactions resembled serotonin syndrome. Oral or subcutaneous sumatriptan and SSRIs were used concomitantly in some clinical studies without unusual adverse effects. However, an increase in the frequency of migraine attacks and a decrease in the effectiveness of sumatriptan in relieving migraine headache have been reported in a patient receiving subcutaneous injections of sumatriptan intermittently while undergoing fluoxetine therapy.

Clinicians prescribing triptans, SSRIs, and SNRIs should consider that triptans often are used intermittently and that either the triptan, SSRI, or SNRI may be prescribed by a different clinician. Clinicians also should weigh the potential risk of serotonin syndrome with the expected benefit of using a triptan concurrently with SSRI or SNRI therapy. If concomitant treatment with a triptan and citalopram is clinically warranted, patients should be advised of the increased risk of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome manifestations occur, treatment with citalopram, the triptan, and any other concurrently administered serotonergic agents should be discontinued immediately and supportive and symptomatic treatment should be initiated.(See Cautions: Precautions and Contraindications.)

Other Selective Serotonin-reuptake Inhibitors and Selective Serotonin- and Norepinephrine-reuptake Inhibitors

Concomitant use of citalopram and other SSRIs or SNRIs potentially may result in serotonin syndrome. If concomitant use of citalopram and other SSRIs or SNRIs is clinically warranted, patients should be advised of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome manifestations occur, treatment with citalopram, the other SSRI or SNRI, and any other concurrently administered serotonergic agents should be discontinued immediately and supportive and symptomatic treatment should be initiated.(See Cautions: Precautions and Contraindications.)

Clinical experience regarding the optimal timing of switching from other SSRIs to citalopram therapy is limited. Therefore, care and prudent medical judgment should be exercised when switching from other SSRIs to citalopram, particularly from long-acting agents (e.g., fluoxetine). Because some adverse reactions resembling serotonin syndrome have developed when fluoxetine therapy has been abruptly discontinued and therapy with another SSRI (sertraline) was initiated immediately afterward, a washout period may be advisable when transferring a patient from fluoxetine to another SSRI. However, the appropriate duration of the washout period when switching from other SSRIs to citalopram has not been clearly established. Pending further experience in patients being transferred from therapy with another SSRI to citalopram and as the clinical situation permits, it generally is recommended that the previous antidepressant be discontinued according to the recommended guidelines for the specific SSRI prior to initiation of citalopram therapy.

Drugs Undergoing Hepatic Metabolism or Affecting Hepatic Microsomal Enzymes

In vitro enzyme inhibition data did not reveal an inhibitory effect of citalopram on cytochrome P-450 (CYP) isoenzyme 3A4, 2C9, or 2E1 but did suggest that it is a weak inhibitor of 1A2, 2D6, and 2C19. Citalopram would be expected to have little inhibitory effect on in vivo metabolism mediated by these isoenzymes. However, in vivo data to address this question are very limited.

In vitro studies have indicated that CYP3A4 and CYP2C19 are the principal isoenzymes involved in the metabolism of citalopram. Therefore, it is expected that potent inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, macrolide antibiotics) and potent inhibitors of CYP2C19 (e.g., omeprazole) might decrease the clearance of citalopram. However, concurrent administration of citalopram and ketoconazole, a potent inhibitor of CYP3A4, did not substantially affect the pharmacokinetics of citalopram.(See Ketoconazole under Drug Interactions: Drugs Undergoing Hepatic Metabolism or Affecting Hepatic Microsomal Enzymes.)

Steady-state plasma citalopram concentrations were not substantially different in healthy individuals with poor or extensive CYP2D6 metabolizer phenotypes following multiple-dose administration of citalopram, suggesting that coadministration of citalopram with a drug that inhibits CYP2D6 is unlikely to have clinically important effects on citalopram metabolism.

Carbamazepine

Concurrent administration of citalopram (40 mg daily for 14 days) and carbamazepine (titrated up to 400 mg daily for a total of 35 days) in healthy individuals did not significantly affect the pharmacokinetics of carbamazepine, a CYP3A4 substrate. Trough plasma citalopram concentrations were unaffected in this study, which suggests that the initiation of citalopram therapy in patients stabilized on carbamazepine should not produce clinically important changes in plasma carbamazepine concentrations. However, in an open study in depressed patients, the addition of carbamazepine to citalopram therapy resulted in a decrease in the plasma concentrations of escitalopram, the active enantiomer with the 1-(S) absolute configuration. In addition, 2 cases of increased plasma citalopram concentrations and altered antidepressant response have been reported when carbamazepine was discontinued. Because of the enzyme-inducing properties of carbamazepine, the possibility that carbamazepine might increase the clearance of citalopram should be considered if the 2 drugs are administered concomitantly or if carbamazepine therapy is initiated or discontinued in a patient receiving citalopram.

CYP2C19 Inhibitors

Cimetidine is known to inhibit many CYP oxidative enzymes, including CYP2C19, and can affect the pharmacokinetics of citalopram. In a study in which oral citalopram (40 mg daily) was given for 3 weeks, the area under the plasma concentration-time curve (AUC) and peak plasma concentrations of citalopram were increased by approximately 43 and 39%, respectively, during concomitant use of oral cimetidine (400 mg daily) for the final 8 days. The possible effects of citalopram on the pharmacokinetics of cimetidine have not been studied.

Because of the potential risk of QT-interval prolongation and torsades de pointes, the maximum recommended dosage of citalopram is 20 mg once daily in patients concomitantly receiving citalopram and cimetidine or other CYP2C19 inhibitors.

Ketoconazole

In a randomized, double-blind study, concurrent administration of single doses of citalopram (40 mg) and ketoconazole (200 mg), a potent inhibitor of CYP3A4, in healthy individuals decreased the peak plasma ketoconazole concentrations and AUC by 21 and 10%, respectively. The pharmacokinetics of citalopram and demethylcitalopram were not substantially affected during concomitant administration of these two drugs in this study. Therefore, citalopram dosage adjustment is unlikely to be necessary in patients receiving ketoconazole concurrently.

Triazolam

Concurrent administration of citalopram (titrated to 40 mg daily for 28 days) and a single dose of triazolam (0.25 mg), a CYP3A4 substrate, in healthy individuals did not substantially affect the pharmacokinetics of either drug. However, triazolam appeared to be absorbed slightly more quickly during citalopram coadministration.

Tricyclic and Other Antidepressants

The extent to which selective serotonin-reuptake inhibitor interactions with tricyclic antidepressants may pose clinical problems depends on the degree of inhibition and the pharmacokinetics of the serotonin-reuptake inhibitor involved. In vitro studies suggest that citalopram is a relatively weak inhibitor of CYP2D6 and CYP2C19. In one study in healthy adults receiving citalopram (40 mg once daily for 10 days), concurrent administration of a single 100-mg dose of imipramine hydrochloride, a CYP2D6 and CYP2C19 substrate, did not substantially affect the plasma concentrations of either citalopram or imipramine. However, the plasma concentration of the principal imipramine metabolite, desipramine, increased by approximately 50%; the clinical importance of this change is not known. The manufacturer of citalopram recommends that caution be exercised during concurrent use of tricyclic antidepressants with citalopram.

In addition, concomitant use of citalopram and tricyclic antidepressants potentially may result in serotonin syndrome. If concomitant use of citalopram and a tricyclic antidepressant is clinically warranted, patients should be advised of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome manifestations occur, treatment with citalopram, the tricyclic antidepressant, and any concurrently administered serotonergic agents should be discontinued immediately and supportive and symptomatic treatment should be initiated. (See Cautions: Precautions and Contraindications and also see Drug Interactions: Serotonergic Drugs.)

Clinical experience regarding the optimal timing of switching from other antidepressants to citalopram therapy is limited. Therefore, care and prudent medical judgment should be exercised when switching from other antidepressants to citalopram. Pending further experience in patients being transferred from therapy with another antidepressant to citalopram and as the clinical situation permits, it generally is recommended that the previous antidepressant be discontinued according to the recommended guidelines for the specific antidepressant prior to initiation of citalopram therapy.

Alcohol

Citalopram has not been shown to potentiate the impairment of mental and motor skills caused by alcohol. However, the drug's ability to reduce alcohol consumption in animals and humans suggests that there may be a serotonergically mediated, pharmacodynamic interaction between citalopram and alcohol within the CNS.(See Pharmacology: Effects on Alcohol Intake, and also see Uses: Alcohol Dependence.) The manufacturer recommends that patients be advised to avoid alcohol while receiving citalopram.

Lithium

The manufacturer states that coadministration of lithium and citalopram did not substantially affect the pharmacokinetics of either drug in healthy individuals. In a placebo-controlled trial in depressed patients refractory to citalopram therapy alone, there also was no evidence of a pharmacokinetic interaction when lithium therapy (800 mg daily) was added; the combination was found to be well tolerated. However, pending further accumulation of data, the manufacturer of citalopram recommends that plasma lithium concentrations be monitored in patients receiving citalopram concurrently and that the lithium dosage be adjusted accordingly. Lithium also may enhance the serotonergic effects of citalopram, potentially resulting in serotonin syndrome. Caution should be exercised in patients receiving these two drugs concomitantly.(See Drug Interactions: Serotonergic Drugs.)

Drugs Affecting Hemostasis

Warfarin

The administration of a single, 25-mg dose of warfarin, a CYP3A4 substrate, in healthy individuals receiving citalopram 40 mg daily for 15 days did not affect the pharmacokinetics of warfarin. However, the prothrombin time increased by an average of 5% compared with baseline. The clinical importance, if any, of these findings is not known.

Other Drugs that Interfere with Hemostasis

Epidemiologic case-control and cohort design studies that have demonstrated an association between selective serotonin-reuptake inhibitor therapy and an increased risk of upper GI bleeding also have shown that concurrent use of aspirin or other nonsteroidal anti-inflammatory agents substantially increases the risk of GI bleeding. Although these studies focused on upper GI bleeding, there is some evidence suggesting that bleeding at other sites may be similarly potentiated. The precise mechanism for this increased risk remains to be clearly established; however, serotonin release by platelets is known to play an important role in hemostasis, and selective serotonin-reuptake inhibitors decrease serotonin uptake from the blood by platelets, thereby decreasing the amount of serotonin in platelets. Patients receiving citalopram should be cautioned about the concomitant use of drugs that interfere with hemostasis, including aspirin and other nonsteroidal anti-inflammatory agents.

Pimozide

In a controlled study, concurrent administration of a single 2-mg dose of pimozide in individuals receiving citalopram (40 mg once daily for 11 days) was associated with mean increases in the QTc interval of approximately 10 msec compared with pimozide given alone. Citalopram did not substantially affect the mean AUC or peak plasma concentrations of pimozide. The mechanism for this potential pharmacodynamic interaction is not known. In addition, concomitant use of citalopram and pimozide rarely may result in potentially serious, sometimes fatal serotonin syndrome.

The manufacturers of citalopram hydrobromide state that concurrent administration of citalopram and pimozide is contraindicated.

Other CNS-active Agents

The manufacturers state that, given the primary CNS effects of citalopram, caution should be used when it is given concurrently with other centrally acting drugs.

Digoxin

In healthy adults who received citalopram (40 mg daily for 3 weeks), the concurrent administration of a single, 1-mg dose of digoxin did not significantly affect the pharmacokinetics of citalopram or digoxin. Concurrent administration of the 2 drugs was well tolerated, with no serious adverse events and no clinically important ECG changes reported. These data suggest that concomitantly administered citalopram is unlikely to substantially affect serum digoxin concentrations in patients who are receiving chronic digoxin therapy.

Diuretics

Concomitant use of citalopram and diuretics may increase the risk of hyponatremia.(See Other Renal, Electrolyte, and Genitourinary Effects under Cautions: Renal, Electrolyte, and Genitourinary Effects.)

Electroconvulsive Therapy

The manufacturer states that there are no clinical studies on the concurrent use of citalopram and electroconvulsive therapy (ECT). In a limited number of depressed women given either citalopram 20 mg or placebo before their third and fourth ECT sessions, no adverse effects were reported after citalopram administration and the length of the electrically induced seizures and neurohormonal responses did not substantially differ between the 2 groups. However, additional studies are needed to confirm the safety and efficacy of ECT in patients receiving citalopram.

Metoprolol

Administration of citalopram 40 mg daily for 22 days resulted in a twofold increase in the plasma concentrations of metoprolol in one study. Increased plasma concentrations of metoprolol have been associated with decreased cardioselectivity. Concurrent administration of citalopram and metoprolol had no clinically important effects on blood pressure or heart rate.

Theophylline

In an open, multiple-dose study, concurrent administration of citalopram (40 mg daily) for 21 days and theophylline (single, 300-mg dose), a CYP1A2 substrate, in healthy individuals did not substantially affect the pharmacokinetics of theophylline. Therefore, some clinicians state that dosage adjustment of theophylline may not be necessary in patients receiving citalopram concurrently. The effect of theophylline on the pharmacokinetics of citalopram was not evaluated.

Cyclosporine

Limited evidence suggests that citalopram does not substantially affect the pharmacokinetics of cyclosporine; further study is needed to confirm these preliminary findings.

Pharmacokinetics

In all human studies described in the Pharmacokinetics section, citalopram was administered as the hydrobromide salt; dosages and concentrations are expressed in terms of citalopram.

A concentration of 1 nmol/L of citalopram is approximately equivalent to 0.32 ng/mL.

Absorption

Like other selective serotonin-reuptake inhibitors, citalopram is a highly lipophilic compound that appears to be rapidly and well absorbed from the GI tract following oral administration. Following a single 40-mg oral dose of citalopram as a tablet, the manufacturer states that peak plasma concentrations averaging approximately 44 ng/mL occur at about 4 hours.

The absolute bioavailability of citalopram is approximately 80% relative to an IV dose. The oral tablets and solution of citalopram reportedly are bioequivalent. Food does not substantially affect the absorption of citalopram.

The single- and multiple-dose pharmacokinetics of citalopram are linear and dose-proportional in a dosage range of 10-60 mg daily. With once-daily dosing, steady-state plasma concentrations are achieved within approximately 1 week. In one study, the steady-state plasma concentrations ranged from about 30-230 ng/mL in depressed patients receiving dosages of 30-60 mg daily and agreed well with predicted values. The mean plasma concentration was approximately 80 ng/mL at the usual dosage of 40 mg daily. At steady state, the extent of accumulation of citalopram in plasma, based on the half-life, is expected to be about 2.5 times higher than the plasma concentrations observed after a single dose of the drug.

In depressed patients receiving 20-60 mg daily of citalopram, steady-state plasma concentrations of racemic citalopram and demethylcitalopram, a principal metabolite, ranged from 9-200 ng/mL and 10-105 ng/mL, respectively. When using a stereoselective analysis method, plasma concentrations ranged from 9-106 ng/mL for escitalopram (S-citalopram), 20-186 ng/mL for R-citalopram, 4-38 ng/mL for S-demethylcitalopram, and 3-75 ng/mL for R-demethylcitalopram in depressed patients receiving citalopram therapy (20-80 mg daily). The mean ratio between R-citalopram and escitalopram was 0.56 (range: 0.32-0.97).

The effect of age on the pharmacokinetics of citalopram has not been fully elucidated. Studies in healthy individuals and depressed patients 60 years of age or older have found higher areas under the plasma concentration-time curves (AUC) and longer elimination half-lives compared with those in younger individuals.(See Pharmacokinetics: Elimination.) In healthy individuals 60 years of age or older, the AUC of citalopram was increased by an average of approximately 30% in a single-dose study and by an average of approximately 23% in a multiple-dose study. Steady-state plasma citalopram concentrations were up to 4 times higher in geriatric patients receiving 20 mg of the drug once daily in one multiple-dose study than expected based on data in younger patients and healthy individuals.(See Dosage and Administration: Dosage in Geriatric Patients and see Cautions: Geriatric Precautions.)

The effect of gender on the pharmacokinetics of citalopram has not been fully elucidated to date. The manufacturer states that in 3 pharmacokinetic studies, the AUC of citalopram in women was 1.5-2 times higher than that found in men; however, this difference was not observed in 5 other pharmacokinetic studies performed with the drug. In clinical studies, no differences in steady-state plasma citalopram concentrations were observed between men and women. In addition, there were no gender differences in the pharmacokinetics of the principal metabolites of citalopram, demethylcitalopram and didemethylcitalopram. Therefore, the manufacturer states that no adjustment of citalopram dosage on the basis of gender is necessary.

The onset of antidepressant activity following oral administration of citalopram hydrobromide usually occurs within 1-4 weeks.

As with other selective serotonin-reuptake inhibitors, the relationship between plasma citalopram concentrations and the therapeutic and/or toxic effects of the drug has not been clearly established. Since citalopram is administered as a racemic mixture with the pharmacologic effect of the drug associated mainly with escitalopram, the S-enantiomer, it may be important to take the stereoselective metabolism of the drug into account when evaluating the relationship between the clinical effect of the drug and plasma concentrations of citalopram.

Distribution

Distribution of citalopram and its metabolites into human body tissues and fluids has not been fully characterized. However, limited pharmacokinetic data suggest that the drug, which is highly lipophilic, is widely distributed in body tissues.

The volume of distribution of citalopram is approximately 12 L/kg. The drug crosses the blood-brain barrier in humans and animals.

The binding of citalopram, demethylcitalopram, and didemethylcitalopram to human plasma proteins in vitro is about 80%.

Citalopram and demethylcitalopram are distributed into milk and also cross the placenta. In a study involving 7 lactating women who received median oral citalopram doses of 0.36 mg/kg daily for the treatment of depression, mean milk-to-plasma AUC values of 1.8 were calculated for both citalopram and demethylcitalopram. Depending on the method of calculation, mean infant exposure was estimated to be 3.2 or 3.7% for citalopram and 1.2 or 1.4% for demethylcitalopram in this study. In 9 lactating women receiving 20-40 mg daily of citalopram in another study, maternal milk-to-plasma ratios of the drug ranged from approximately 2-3; however, plasma citalopram concentrations in the neonates were found to be very low or below the limit of detection. In a lactating woman receiving 40 mg daily of citalopram, concentrations of the drug in milk and serum were about 205 ng/mL and 99 ng/mL, respectively, and the drug concentration in the infant's serum was about 13 ng/mL. In another lactating woman receiving 20 mg daily of citalopram, peak milk concentrations of the drug occurred 3-9 hours following maternal drug intake; the milk-to-serum concentration ratio was approximately 3 for both citalopram and demethylcitalopram. Accordingly, the infant received approximately 5% of the mother's dose when adjusted for weight.(See Cautions: Pregnancy, Fertility, and Lactation.)

Elimination

The elimination half-life of citalopram averages approximately 35 hours in adults with normal renal and hepatic function.

The exact metabolic fate of citalopram has not been fully elucidated; however, metabolism of citalopram is mainly hepatic and involves N-demethylation. Citalopram is metabolized to demethylcitalopram, didemethylcitalopram, citalopram-N-oxide, and a deaminated propionic acid derivative. In vitro studies have indicated that cytochrome P-450 (CYP) 3A4 and 2C19 isoenzymes are the principal enzymes involved in the N-demethylation of citalopram to demethylcitalopram and that demethylcitalopram is further N-demethylated to didemethylcitalopram by CYP2D6. Because citalopram is metabolized by multiple enzyme systems, inhibition of a single enzyme is unlikely to appreciably decrease the clearance of citalopram. Unlike some other selective serotonin-reuptake inhibitors, the demethylated metabolites of citalopram, demethylcitalopram and didemethylcitalopram, are substantially less active than the parent compound as inhibitors of serotonin reuptake. Thus, citalopram's metabolites are unlikely to contribute to the antidepressant and other clinical actions of the drug.

In humans, unchanged citalopram is the predominant compound in plasma. At steady state, the concentrations of demethylcitalopram and didemethylcitalopram in plasma are approximately one-half and one-tenth, respectively, that of the parent drug. Following IV (parenteral dosage form not commercially available in the US) administration of citalopram, the fraction of drug recovered in urine as citalopram and demethylcitalopram was about 10 and 5%, respectively.

Following oral administration of a single, radiolabeled dose of citalopram in healthy individuals, approximately 75% of the dose was excreted in urine and approximately 10% was eliminated in feces within 17 days. An analysis of the urinary composition showed that besides the known metabolites of citalopram, 3 glucuronides were present. The relative amounts of citalopram, demethylcitalopram, didemethylcitalopram, and the N-oxide metabolite present in urine collected for 7 days were 26, 19, 9, and 7%, respectively, with glucuronidated metabolites accounting for the remainder.

Following IV administration, the mean systemic clearance of citalopram is approximately 330 mL/minute, with approximately 20% of that due to renal clearance.

The effect of age on the elimination of citalopram has not been fully elucidated. Studies in healthy geriatric individuals and depressed geriatric patients have found higher AUC values and longer elimination half-lives compared with younger individuals.(See Pharmacokinetics: Absorption.) In healthy individuals 60 years of age or older, the elimination half-life of citalopram was increased by 50% in a single-dose study and by 30% in a multiple-dose study. It has been suggested that these differences in pharmacokinetic parameters may reflect declining liver and kidney function. In addition, the stereoselective metabolism of the enantiomers for citalopram and demethylcitalopram in older individuals appears to differ from that reported in younger patients, suggesting possible age-associated changes in CYP2C19 activities.(See Dosage and Administration: Dosage in Geriatric Patients and see Cautions: Geriatric Precautions.)

Because citalopram is extensively metabolized in the liver, hepatic impairment can affect the elimination of the drug. Following oral administration, the clearance of citalopram in patients with impaired hepatic function was reduced by 37% and the elimination half-life was increased twofold compared with that in healthy individuals. Therefore, the manufacturer recommends that in depressed patients with hepatic impairment, the maximum recommended dosage of citalopram is 20 mg once daily due to the risk of QT-interval prolongation.(See Dosage and Administration: Dosage in Hepatic and Renal Impairment and see Cautions: Precautions and Contraindications.)

In poor metabolizers of CYP2C19, steady-state peak concentrations and AUC values of citalopram increased by 68 and 107%, respectively. Therefore, the manufacturer recommends that in poor metabolizers of CYP2C19, the maximum recommended dosage of citalopram is 20 mg once daily due to the risk of QT-interval prolongation.(See Dosage and Administration: Dosage in Poor CYP2C19 Metabolizers or Patients Receiving CYP2C19 Inhibitors and see Cautions: Precautions and Contraindications.) Steady-state plasma citalopram concentrations were not substantially different in healthy individuals with poor or extensive CYP2D6 metabolizer phenotypes following multiple-dose administration of the drug.

The effect of renal impairment on the pharmacokinetics of citalopram has not been fully evaluated to date. In patients with moderate renal impairment, the renal clearance of citalopram and its 2 principal metabolites was reduced and the elimination half-life of citalopram was slightly prolonged to an average of about 50 hours. In a study comparing the pharmacokinetics of citalopram in a limited number of patients with severe renal failure undergoing hemodialysis and in healthy individuals, no substantial differences were found between the 2 groups in any of the pharmacokinetic parameters, with the exception of the renal clearance of citalopram, which was significantly lower in the renal failure group than in the control group (1.7 mL/minute versus 66 mL/minute). Therefore, moderate to severe renal failure does not appear to markedly affect the pharmacokinetics of citalopram suggesting that dosage adjustment in such patients may not be necessary. Additional studies evaluating long-term citalopram therapy in patients with severe renal impairment are necessary to confirm these findings.(See Dosage and Administration: Dosage in Hepatic and Renal Impairment.)

Limited data indicate that citalopram and demethylcitalopram are not appreciably removed by hemodialysis. In a limited number of patients, hemodialysis cleared only about 1% of an oral dose of citalopram as the parent drug and 1% as demethylcitalopram. Because of the large volume of distribution of citalopram, hemodialysis, peritoneal dialysis, forced diuresis, hemoperfusion, and/or exchange transfusion also are unlikely to be effective in removing substantial amounts of citalopram from the body.

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