studied. the efficacy of citalopram in maintaining an antidepressant response for up to 24 weeks following 6 to 8 weeks of acute treatment was demonstrated in two placebo-controlled trials (see clinical pharmacology). nevertheless, the physician who elects to use citalopram for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

ajor depressive disorder (mdd) and other psychiatric disorders. short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. the pooled analyses of placebo-controlled trials in children and adolescents with mdd, obsessive compulsive disorder (ocd), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. the pooled analyses of placebo-controlled trials in adults with mdd or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. there was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. there were differences in absolute risk of suicidality across the different indications, with the highest incidence in mdd. the risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. these risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in table 1. table 1 age range drug-placebo difference in number of cases of suicidality per 1000 patients treated increases compared to placebo <18 14 additional cases 18-24 5 additional cases decreases compared to placebo 25-64 1 fewer case ≥65 6 fewer cases no suicides occurred in any of the pediatric trials. there were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. it 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 depression that the use of antidepressants can delay the recurrence of depression. all patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. the following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. although a causal link between the emergence of such symptoms 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. consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. if the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see precautions and dosage and administration—discontinuation of treatment with citalopram, for a description of the risks of discontinuation of citalopram). families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. such monitoring should include daily observation by families and caregivers. prescriptions for citalopram should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. qt-prolongation and torsade de pointes citalopram causes dose-dependent qtc prolongation, an ecg abnormality that has been associated with torsade de pointes (tdp), ventricular tachycardia, and sudden death, all of which have been observed in postmarketing reports for citalopram. individually corrected qtc (qtcni) interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg) controlled cross-over, escalating multiple-dose study in 119 healthy subjects. the maximum mean (upper bound of the 95% one-sided confidence interval) difference from placebo were 8.5 (10.8) and 18.5 (21.0) msec for 20 mg and 60 mg citalopram, respectively. based on the established exposure-response relationship, the predicted qtcni change from placebo (upper bound of the 95% one-sided confidence interval) under the cmax for the dose of 40 mg is 12.6 (14.3) msec. because of the risk of qtc prolongation at higher citalopram doses, it is recommended that citalopram should not be given at doses above 40 mg/day. it is recommended that citalopram should not be used in patients with congenital long qt syndrome, bradycardia, hypokalemia or hypomagnesemia, recent acute myocardial infarction, or uncompensated heart failure. citalopram should also not be used in patients who are taking other drugs that prolong the qtc interval. such drugs include class 1a (e.g., quinidine, procainamide) or class iii (e.g., amiodarone, sotalol) antiarrhythmic medications, antipsychotic medications (e.g., chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the qtc interval (e.g., pentamidine, levomethadyl acetate, methadone). the citalopram dose should be limited in certain populations. the maximum dose should be limited to 20 mg/day in patients who are cyp2c19 poor metabolizers or those patients who may be taking concomitant cimetidine or another cyp2c19 inhibitor, since higher citalopram exposures would be expected. the maximum dose should also be limited to 20 mg/day in patients with hepatic impairment and in patients who are greater than 60 years of age because of expected higher exposures. electrolyte and/or ecg monitoring is recommended in certain circumstances. patients being considered for citalopram treatment who are at risk for significant electrolyte disturbances should have baseline serum potassium and magnesium measurements with periodic monitoring. hypokalemia (and/or hypomagnesemia) may increase the risk of qtc prolongation and arrhythmia, and should be corrected prior to initiation of treatment and periodically monitored. ecg monitoring is recommended in patients for whom citalopram use is not recommended (see above), but, nevertheless, considered essential. these include those patients with the cardiac conditions noted above, and those taking other drugs that may prolong the qtc interval. citalopram should be discontinued in patients who are found to have persistent qtc measurements >500 ms. if patients taking citalopram experience symptoms that could indicate the occurrence of cardiac arrhythmias, e.g., dizziness, palpitations, or syncope, the prescriber should initiate further evaluation, including cardiac monitoring. screening patients for bipolar disorder: a major depressive episode may be the initial presentation of bipolar disorder. it is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. whether any of the symptoms described above represent such a conversion is unknown. however, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. it should be noted that citalopram is not approved for use in treating bipolar depression. serotonin syndrome the development of a potentially life-threatening serotonin syndrome has been reported with snris and ssris, including citalopram, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, trytophan, buspirone, and st. john's wort) and with drugs that impair metabolism of serotonin (in particular, maois, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and 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 gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). patients should be monitored for the emergence of serotonin syndrome. the concomitant use of citalopram with maois intended to treat psychiatric disorders is contraindicated. citalopram should also not be started in a patient who is being treated with maois such as linezolid or intravenous methylene blue. all reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. no reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. there may be circumstances when it is necessary to initiate treatment with an maoi such as linezolid or intravenous methylene blue in a patient taking citalopram. citalopram should be discontinued before initiating treatment with the maoi (see contraindications and dosage and administration). if concomitant use of citalopram with other serotonergic drugs including, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, trytophan and st. john's wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome particularly during treatment initiation and dose increases. treatment with citalopram and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. angle-closure glaucoma the pupillary dilation that occurs following use of many antidepressant drugs including citalopram may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

eatment of pregnant women during the third trimester neonates exposed to citalopram and other ssris or snris, late in the third trimester, have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see precautions). when treating pregnant women with citalopram during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. maintenance treatment it is generally agreed that acute episodes of depression require several months or longer of sustained pharmacologic therapy. systematic evaluation of citalopram in two studies has shown that its antidepressant efficacy is maintained for periods of up to 24 weeks following 6 or 8 weeks of initial treatment (32 weeks total). in one study, patients were assigned randomly to placebo or to the same dose of citalopram (20-60 mg/day) during maintenance treatment as they had received during the acute stabilization phase, while in the other study, patients were assigned randomly to continuation of citalopram 20 or 40 mg/day, or placebo, for maintenance treatment. in the latter study, the rates of relapse to depression were similar for the two dose groups (see clinical trials under clinical pharmacology). based on these limited data, it is not known whether the dose of citalopram needed to maintain euthymia is identical to the dose needed to induce remission. if adverse reactions are bothersome, a decrease in dose to 20 mg/day can be considered. discontinuation of treatment with citalopram symptoms associated with discontinuation of citalopram and other ssris and snris have been reported (see precautions). patients should be monitored for these symptoms when discontinuing treatment. a gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. if intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. subsequently, the physician may continue decreasing the dose but at a more gradual rate. switching a patient to or from a monoamine oxidase inhibitor (maoi) intended to treat psychiatric disorders at least 14 days should elapse between discontinuation of an maoi intended to treat psychiatric disorders and initiation of therapy with citalopram. conversely, at least 14 days should be allowed after stopping citalopram before starting an maoi intended to treat psyachiatric disorders (see contraindications). use of citalopram with other maois, such as linezolid or methylene blue do not start citalopram in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. in a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see contraindications). in some cases, a patient already receiving citalopram therapy may require urgent treatment with linezolid or intravenous methylene blue. if acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, citalopram should be stopped promptly, and linezolid or intravenous methylene blue can be administered. the patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. therapy with citalopram may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see warnings). the risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with citalopram is unclear. the clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see warnings).

quiry and recorded by clinical investigators using terminology of their own choosing. consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a smaller number of standardized event categories. in the tables and tabulations that follow, standard world health organization (who) terminology has been used to classify reported adverse events. the stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. an event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. adverse findings observed in short-term, placebo-controlled trials adverse events associated with discontinuation of treatment among 1063 depressed patients who received citalopram at doses ranging from 10 to 80 mg/day in placebo-controlled trials of up to 6 weeks in duration, 16% discontinued treatment due to an adverse event, as compared to 8% of 446 patients receiving placebo. the adverse events associated with discontinuation and considered drug-related (i.e., associated with discontinuation in at least 1% of citalopram-treated patients at a rate at least twice that of placebo) are shown in table 2. it should be noted that one patient can report more than one reason for discontinuation and be counted more than once in this table. table 2 adverse events associated with discontinuation of treatment in short-term, placebo- controlled, depression trials percentage of patients discontinuing due to adverse event citalopram placebo (n=1063) (n=446) body system/adverse event general asthenia 1% <1% gastrointestinal disorders nausea 4% 0% dry mouth 1% <1% vomiting 1% 0% central and peripheral nervous system disorders dizziness 2% <1% psychiatric disorders insomnia 3% 1% somnolence 2% 1% agitation 1% <1% adverse events occurring at an incidence of 2% or more among citalopram -treated patients table 3 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred among 1063 depressed patients who received citalopram at doses ranging from 10 to 80 mg/day in placebo-controlled trials of up to 6 weeks in duration. events included are those occurring in 2% or more of patients treated with citalopram and for which the incidence in patients treated with citalopram was greater than the incidence in placebo-treated patients. the prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. the cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied. the only commonly observed adverse event that occurred in citalopram patients with an incidence of 5% or greater and at least twice the incidence in placebo patients was ejaculation disorder (primarily ejaculatory delay) in male patients (see table 3). table 3 * events reported by at least 2% of patients treated with citalopram are reported, except for the following events which had an incidence on placebo ≥ citalopram: headache, asthenia, dizziness, constipation, palpitation, vision abnormal, sleep disorder, nervousness, pharyngitis, micturition disorder, back pain. 1 denominator used was for females only (n=638 citalopram; n=252 placebo). 2 primarily ejaculatory delay. 3 denominator used was for males only (n=425 citalopram; n=194 placebo). treatment-emergent adverse events: incidence in placebo-controlled clinical trials* (percentage of patients reporting event) body system/adverse event citalopram hbr placebo (n=1063) (n=446) autonomic nervous system disorders dry mouth 20% 14% sweating increased 11% 9% central & peripheral nervous system disorders tremor 8% 6% gastrointestinal disorders nausea 21% 14% diarrhea 8% 5% dyspepsia 5% 4% vomiting 4% 3% abdominal pain 3% 2% general fatigue 5% 3% fever 2% <1% musculoskeletal system disorders arthralgia 2% 1% myalgia 2% 1% psychiatric disorders somnolence 18% 10% insomnia 15% 14% anxiety 4% 3% anorexia 4% 2% agitation 3% 1% dysmenorrhea1 3% 2% libido decreased 2% <1% yawning 2% <1% respiratory system disorders upper respiratory tract infection 5% 4% rhinitis 5% 3% sinusitis 3% <1% urogenital ejaculation disorder2,3 6% 1% impotence3 3% <1% dose dependency of adverse events the potential relationship between the dose of citalopram administered and the incidence of adverse events was examined in a fixed-dose study in depressed patients receiving placebo or citalopram 10, 20, 40, and 60 mg. jonckheere's trend test revealed a positive dose response (p<0.05) for the following adverse events: fatigue, impotence, insomnia, sweating increased, somnolence, and yawning. male and female sexual dysfunction with ssris although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. in particular, some evidence suggests that ssris can cause such untoward sexual experiences. reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling, are likely to underestimate their actual incidence. the table below displays the incidence of sexual side effects reported by at least 2% of patients taking citalopram in a pool of placebo-controlled clinical trials in patients with depression. treatment citalopram placebo (425 males) (194 males) abnormal ejaculation 6.1% 1% (mostly ejaculatory delay) (males only) (males only) libido decreased 3.8% <1% (males only) (males only) impotence 2.8% <1% (males only) (males only) in female depressed patients receiving citalopram, the reported incidence of decreased libido and anorgasmia was 1.3% (n=638 females) and 1.1% (n=252 females), respectively. there are no adequately designed studies examining sexual dysfunction with citalopram treatment. priapism has been reported with all ssris. while it is difficult to know the precise risk of sexual dysfunction associated with the use of ssris, physicians should routinely inquire about such possible side effects. vital sign changes citalopram and placebo groups were compared with respect to (1) mean change from baseline in vital signs (pulse, systolic blood pressure, and diastolic blood pressure) and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. these analyses did not reveal any clinically important changes in vital signs associated with citalopram treatment. in addition, a comparison of supine and standing vital sign measures for citalopram and placebo treatments indicated that citalopram treatment is not associated with orthostatic changes. weight changes patients treated with citalopram in controlled trials experienced a weight loss of about 0.5 kg compared to no change for placebo patients. laboratory changes citalopram and placebo groups were compared with respect to (1) mean change from baseline in various serum chemistry, hematology, and urinalysis variables, and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. these analyses revealed no clinically important changes in laboratory test parameters associated with citalopram treatment. ecg changes in a thorough qt study, citalopram was found to be associated with a dose-dependent increase in the qtc interval (see warnings - qt-prolongation and torsade de pointes). electrocardiograms from citalopram (n=802) and placebo (n=241) groups were compared with respect to outliers defined as subjects with qtc changes over 60 msec from baseline or absolute values over 500 msec post-dose, and subjects with heart rate increases to over 100 bpm or decreases to less than 50 bpm with a 25% change from baseline (tachycardic or bradycardic outliers, respectively). in the citalopram group 1.9% of the patients had a change from baseline in qtcf >60 msec compared to 1.2% of the patients in the placebo group. none of the patients in the placebo group had a post-dose qtcf >500 msec compared to 0.5% of the patients in the citalopram group. the incidence of tachycardic outliers was 0.5% in the citalopram group and 0.4% in the placebo group. the incidence of bradycardic outliers was 0.9% in the citalopram group and 0.4% in the placebo group. other events observed during the premarketing evaluation of citalopram hbr following is a list of who terms that reflect treatment-emergent adverse events, as defined in the introduction to the adverse reactions section, reported by patients treated with citalopram at multiple doses in a range of 10 to 80 mg/day during any phase of a trial within the premarketing database of 4422 patients. all reported events are included except those already listed in table 3 or elsewhere in labeling, those events for which a drug cause was remote, those event terms which were so general as to be uninformative, and those occurring in only one patient. it is important to emphasize that, although the events reported occurred during treatment with citalopram, they were not necessarily caused by it. events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in less than 1/100 patients but at least 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. cardiovascular - frequent: tachycardia, postural hypotension, hypotension. infrequent: hypertension, bradycardia, edema (extremities), angina pectoris, extrasystoles, cardiac failure, flushing, myocardial infarction, cerebrovascular accident, myocardial ischemia. rare: transient ischemic attack, phlebitis, atrial fibrillation, cardiac arrest, bundle branch block. central and peripheral nervous system disorders - frequent: paresthesia, migraine. infrequent: hyperkinesia, vertigo, hypertonia, extrapyramidal disorder, leg cramps, involuntary muscle contractions, hypokinesia, neuralgia, dystonia, abnormal gait, hypesthesia, ataxia. rare: abnormal coordination, hyperesthesia, ptosis, stupor. endocrine disorders - rare: hypothyroidism, goiter, gynecomastia. gastrointestinal disorders - frequent: saliva increased, flatulence. infrequent: gastritis, gastroenteritis, stomatitis, eructation, hemorrhoids, dysphagia, teeth grinding, gingivitis, esophagitis. rare: colitis, gastric ulcer, cholecystitis, cholelithiasis, duodenal ulcer, gastroesophageal reflux, glossitis, jaundice, diverticulitis, rectal hemorrhage, hiccups. general - infrequent: hot flushes, rigors, alcohol intolerance, syncope, influenza-like symptoms. rare: hayfever. hemic and lymphatic disorders - infrequent: purpura, anemia, epistaxis, leukocytosis, leucopenia, lymphadenopathy. rare: pulmonary embolism, granulocytopenia, lymphocytosis, lymphopenia, hypochromic anemia, coagulation disorder, gingival bleeding. metabolic and nutritional disorders - frequent: decreased weight, increased weight. infrequent: increased hepatic enzymes, thirst, dry eyes, increased alkaline phosphatase, abnormal glucose tolerance. rare: bilirubinemia, hypokalemia, obesity, hypoglycemia, hepatitis, dehydration. musculoskeletal system disorders - infrequent: arthritis, muscle weakness, skeletal pain. rare: bursitis, osteoporosis. psychiatric disorders - frequent: impaired concentration, amnesia, apathy, depression, increased appetite, aggravated depression, suicide attempt, confusion. infrequent: increased libido, aggressive reaction, paroniria, drug dependence, depersonalization, hallucination, euphoria, psychotic depression, delusion, paranoid reaction, emotional lability, panic reaction, psychosis. rare: catatonic reaction, melancholia. reproductive disorders/female* - frequent: amenorrhea. infrequent: galactorrhea, breast pain, breast enlargement, vaginal hemorrhage. *% based on female subjects only: 2955 respiratory system disorders - frequent: coughing. infrequent: bronchitis, dyspnea, pneumonia. rare: asthma, laryngitis, bronchospasm, pneumonitis, sputum increased. skin and appendages disorders - frequent: rash, pruritus. infrequent: photosensitivity reaction, urticaria, acne, skin discoloration, eczema, alopecia, dermatitis, skin dry, psoriasis. rare: hypertrichosis, decreased sweating, melanosis, keratitis, cellulitis, pruritus ani. special senses - frequent: accommodation abnormal, taste perversion. infrequent: tinnitus, conjunctivitis, eye pain. rare: mydriasis, photophobia, diplopia, abnormal lacrimation, cataract, taste loss. urinary system disorders - frequent: polyuria. infrequent: micturition frequency, urinary incontinence, urinary retention, dysuria. rare: facial edema, hematuria, oliguria, pyelonephritis, renal calculus, renal pain. other events observed during the postmarketing evaluation of citalopram hbr it is estimated that over 30 million patients have been treated with citalopram since market introduction. although no causal relationship to citalopram treatment has been found, the following adverse events have been reported to be temporally associated with citalopram treatment, and have not been described elsewhere in labeling: acute renal failure, akathisia, allergic reaction, anaphylaxis, angioedema, angle-closure glaucoma, choreoathetosis, chest pain, delirium, dyskinesia, ecchymosis, epidermal necrolysis, erythema multiforme, gastrointestinal hemorrhage, glaucoma, grand mal convulsions, hemolytic anemia, hepatic necrosis, myoclonus, nystagmus, pancreatitis, priapism, prolactinemia, prothrombin decreased, qt prolonged, rhabdomyolysis, spontaneous abortion, thrombocytopenia, thrombosis, ventricular arrhythmia, torsades de pointes, and withdrawal syndrome.

receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of other psychotropic drugs. pharmacokinetics the single- and multiple-dose pharmacokinetics of citalopram are linear and dose-proportional in a dose range of 10-60 mg/day. biotransformation of citalopram is mainly hepatic, with a mean terminal half-life of about 35 hours. with once daily dosing, steady state plasma concentrations are achieved within approximately one week. at steady state, the extent of accumulation of citalopram in plasma, based on the half-life, is expected to be 2.5 times the plasma concentrations observed after a single dose. absorption and distribution following a single oral dose (40 mg tablet) of citalopram, peak blood levels occur at about 4 hours. the absolute bioavailability of citalopram was about 80% relative to an intravenous dose, and absorption is not affected by food. the volume of distribution of citalopram is about 12 l/kg and the binding of citalopram (ct), demethylcitalopram (dct) and didemethylcitalopram (ddct) to human plasma proteins is about 80%. metabolism and elimination following intravenous administrations of citalopram, the fraction of drug recovered in the urine as citalopram and dct was about 10% and 5%, respectively. the systemic clearance of citalopram was 330 ml/min, with approximately 20% of that due to renal clearance. citalopram is metabolized to demethylcitalopram (dct), didemethylcitalopram (ddct), citalopram-n-oxide, and a deaminated propionic acid derivative. in humans, unchanged citalopram is the predominant compound in plasma. at steady state, the concentrations of citalopram's metabolites, dct and ddct, in plasma are approximately one-half and one-tenth, respectively, that of the parent drug. in vitro studies show that citalopram is at least 8 times more potent than its metabolites in the inhibition of serotonin reuptake, suggesting that the metabolites evaluated do not likely contribute significantly to the antidepressant actions of citalopram. in vitro studies using human liver microsomes indicated that cyp3a4 and cyp2c19 are the primary isozymes involved in the n-demethylation of citalopram. population subgroups age - citalopram pharmacokinetics in subjects ≥ 60 years of age were compared to younger subjects in two normal volunteer studies. in a single-dose study, citalopram auc and half-life were increased in the subjects ≥ 60 years old by 30% and 50%, respectively, whereas in a multiple-dose study they were increased by 23% and 30%, respectively. 20 mg/day is the maximum recommended dose for patients who are greater than 60 years of age (see warnings and dosage and administration), due to the risk of qt prolongation. gender - in three pharmacokinetic studies (total n=32), citalopram auc in women was one and a half to two times that in men. this difference was not observed in five other pharmacokinetic studies (total n=114). in clinical studies, no differences in steady state serum citalopram levels were seen between men (n=237) and women (n=388). there were no gender differences in the pharmacokinetics of dct and ddct. no adjustment of dosage on the basis of gender is recommended. reduced hepatic function - citalopram oral clearance was reduced by 37% and half-life was doubled in patients with reduced hepatic function compared to normal subjects. 20 mg/day is the maximum recommended dose for hepatically impaired patients (see warnings and dosage and administration), due to the risk of qt prolongation. cyp2c19 poor metabolizers – in cyp2c19 poor metabolizers, citalopram steady state cmax and auc was increased by 68% and 107%, respectively. citalopram 20 mg/day is the maximum recommended dose in cyp2c19 poor metabolizers due to the risk of qt prolongation (see warnings and dosage and administration). cyp2d6 poor metabolizers - citalopram steady state levels were not significantly different in poor metabolizers and extensive metabolizers of cyp2d6 reduced renal function - in patients with mild to moderate renal function impairment, oral clearance of citalopram was reduced by 17% compared to normal subjects. no adjustment of dosage for such patients is recommended. no information is available about the pharmacokinetics of citalopram in patients with severely reduced renal function (creatinine clearance < 20 ml/min). drug-drug interactions in vitro enzyme inhibition data did not reveal an inhibitory effect of citalopram on cyp3a4, -2c9, or -2e1, but did suggest that it is a weak inhibitor of cyp1a2, -2d6, and -2c19. citalopram would be expected to have little inhibitory effect on in vivo metabolism mediated by these enzymes. however, in vivo data to address this question are limited. cyp3a4 and cyp 2c19 inhibitors: since cyp3a4 and cyp 2c19 are the primary enzymes involved in the metabolism of citalopram, it is expected that potent inhibitors of cyp3a4 (e.g., ketoconazole, itraconazole, and macrolide antibiotics) and potent inhibitors of cyp2c19 (e.g., omeprazole) might decrease the clearance of citalopram. however, coadministration of citalopram and the potent cyp3a4 inhibitor ketoconazole did not significantly affect the pharmacokinetics of citalopram. citalopram 20 mg/day is the maximum recommended dose in patients taking concomitant cimetidine or another cyp2c19 inhibitor, because of the risk of qt prolongation (see warnings and dosage and administration). cyp2d6 inhibitors: coadministration of a drug that inhibit cyp2d6 with citalopram is unlikely to have clinically significant effects on citalopram metabolism, based on study results in cyp2d6 poor metabolizers. clinical efficacy trials the efficacy of citalopram as a treatment for depression was established in two placebo-controlled studies (of 4 to 6 weeks in duration) in adult outpatients (ages 18-66) meeting dsm-iii or dsm-iii-r criteria for major depression. study 1, a 6-week trial in which patients received fixed citalopram doses of 10, 20, 40, and 60 mg/day, showed that citalopram at doses of 40 and 60 mg/day was effective as measured by the hamilton depression rating scale (hamd) total score, the hamd depressed mood item (item 1), the montgomery asberg depression rating scale, and the clinical global impression (cgi) severity scale. this study showed no clear effect of the 10 and 20 mg/day doses, and the 60 mg/day dose was not more effective than the 40 mg/day dose. in study 2, a 4-week, placebo-controlled trial in depressed patients, of whom 85% met criteria for melancholia, the initial dose was 20 mg/day, followed by titration to the maximum tolerated dose or a maximum dose of 80 mg/day. patients treated with citalopram showed significantly greater improvement than placebo patients on the hamd total score, hamd item 1, and the cgi severity score. in three 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 to high spontaneous response rate, smaller sample size, or, in the case of one study, too low a dose. in two long-term studies, depressed patients who had responded to citalopram hbr during an initial 6 or 8 weeks of acute treatment (fixed doses of 20 or 40 mg/day in one study and flexible doses of 20-60 mg/day in the second study) were randomized to continuation of citalopram or to placebo. in both studies, patients receiving continued citalopram treatment experienced significantly lower relapse rates over the subsequent 6 months compared to those receiving placebo. in the fixed-dose study, the decreased rate of depression relapse was similar in patients receiving 20 or 40 mg/day of citalopram. analyses of the relationship between treatment outcome and age, gender, and race did not suggest any differential responsiveness on the basis of these patient characteristics. comparison of clinical trial results highly variable results have been seen in the clinical development of all antidepressant drugs. furthermore, in those circumstances when the drugs have not been studied in the same controlled clinical trial(s), comparisons among the results of studies evaluating the effectiveness of different antidepressant drug products are inherently unreliable. because conditions of testing (e.g., patient samples, investigators, doses of the treatments administered and compared, outcome measures, etc.) vary among trials, it is virtually impossible to distinguish a difference in drug effect from a difference due to one of the confounding factors just enumerated.

shaped, biconvex film coated tablets with '4|0' debossed ('4' on left side and '0' on right side of the break line) on one side and '1011' on the other side. store at 20°-25°c (68°-77°f); excursions permitted to 15°-30°c (59°-86°f) [see usp controlled room temperature].