Antidepressant Citalopram hydrobromide is a highly selective and potent serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitor with minimal effects on the neuronal reuptake of norepinephrine (NE) and dopamine (DA). The ability of citalopram to potentiate serotonergic activity in the central nervous system via inhibition of the neuronal reuptake of serotonin is thought to be responsible for its antidepressant action. Tolerance to the inhibition of serotonin reuptake is not induced by long term (14 days) treatment of rats with citalopram. Citalopram has no or very low affinity for a series of receptors including serotonin 5-HT1A, 5-HT2, dopamine D1, and D2, a1-, a2-, b-adrenergic, histamine H1, muscarinic cholinergic, benzodiazepine, gamma aminobutyric acid (GABA) and opioid receptors. Celexa / Antidepressant Pharmacokinetics Absorption Following the administration of a single oral dose of citalopram (40 mg) to healthy male volunteers, peak blood levels occurred at about 4 hours (range 1 to 6 hours). The absolute bioavailability of citalopram was about 80% (range 52 to 93%) relative to an intravenous dose. Absorption was not affected by food. Distribution After intravenous infusion in healthy male volunteers the apparent volume of distribution (Vd)b was about 12 L/kg (range 9-17 L/kg), indicating a pronounced tissue distribution: (Vd)b oral was about 17 L/kg (range 14-17 L/kg). The binding of citalopram and its demethylated metabolites to human plasma proteins is about 80%. Steady-state The single- and multiple dose pharmacokinetics of citalopram are linear and dose proportional in a dose range of 10 to 60 mg/day. Steady-state plasma levels are achieved in patients in 1-2 weeks. At a daily dose of 40 mg, the average plasma concentration is about 83 ng/mL (n=114) with a range from 30 to 200 ng/mL. Citalopram does not accumulate during long term treatment. A clear relationship between citalopram plasma levels and therapeutic response or side effects has not been established. Metabolism Citalopram is metabolized in the liver to demethylcitalopram (DCT), didemethylcitalopram (DDCT), citalopram N-oxide and a deaninated propionic acid derivative. In vitro studies show that DCT, DDCT and citalopram-N-oxide also inhibit the neuronal reuptake of serotonin but are less selective and less potent than the parent compound and are of minor clinical importance. Unchanged citalopram is the predominant compound in plasma. In vitro studies indicated that the biotransformation of citalopram to its demethyl metabolites depends on both CYP2C19 and CYP3A4, with a small contribution from CYP2D6. Elimination The elimination half life of citalopram (t1/2b) is approximately 37 hours (range 30-42 hours) which allows recommendation of once-daily dosing. The systemic citalopram plasma clearance (Cl5) is 0.33 L/min. Citalopram is eliminated primarily via the liver (85%) and the remainder via the kidneys; approximately 12% (range 6-21%) of the daily dose is excreted in urine as unchanged citalopram. Special Populations: Elderly Patients Elderly patients (4 males and 7 females aged 73-90 years), received a 20 mg/day dose of citalopram for 3-4 weeks. In the elderly, steady state plasma levels were elevated (106 ng/mL), half-life prolonged (1.5-3.75 days) and clearance decreased (0.08-0.3 L/min). Elevation of citalopram plasma levels occurred at an earlier age in females than in males, In this population, lower doses and a lower maximum dose of citalopram are recommended (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). Reduced Hepatic Function The pharmacokinetics of citalopram were compared in patients with reduced hepatic function (3 female and 6 male patients aged 41-60 years) to those seen in 12 healthy male volunteers (aged 21-43 years), In patients with reduced hepatic function the half-life of citalopram was approximately doubled (83 hours versus 37 hours), steady state citalopram concentrations increased by 61% and oral clearance decreased by 37%. Consequently the use of citalopram in patients with reduced hepatic function should be approached with caution and lower maximal doses should be prescribed (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). Reduced Renal Function In patients with mild to moderate reduction of the renal function (4 females and 3 males, aged 30-55 years), citalopram was being eliminated more slowly than in 12 healthy male volunteers (aged 21-43 years), half-lives being 49 hours versus 37 hours. However, mild to moderate renal impairment had no major influence on the kinetics of citalopram. At present, no information is available for chronic treatment of patients with severely reduced renal function (creatinine clearance <20 mL/min). (See PRECAUTIONS.) Clinical Trials The efficacy of citalopram in the treatment of depression was established in five placebo-controlled studies in patients who met the DSM III or DSM-III-R criteria for major depression. Response to treatment was evaluated by the Hamilton Depression Rating Scale (HAMD) and/or the Montgomery Asberg Depression Rating Scale (MADRS) as well as the Clinical Global Impression (CGI) Severity Scale. On the HAMD and MADRS, total scores, selected single items, and percentage of responders (defined as patients whose HAMD/MADRS total score decreased by at least 50% versus baseline) were assessed. In a 6-week fixed dose, dose-response study, patients received citalopram at doses of 10, 20, 40, or 60 mg/day or placebo (n=129 to 131 per group). The 40 and 60 mg day doses were titrated, with patients reaching these designated doses within 4 and 8 days, respectively. The study showed that the 40 and 60 mg/day doses were significantly more effective than placebo, although the 60 mg/day dose was not more effective than the 40 mg/day dose. The lower doses did not show statistically significant superiority over placebo, except on the MADRS: on this scale the percent of responders was significantly higher in all the citalopram-treated groups than in the placebo-treated group. The second study was a 4-week flexible dose study in which 85% of the depressed patients met the criteria for melancholia. At entry, 89 and 91 patients were randomized to the citalopram and placebo groups, respectively. This was the only study in which more male than female patients participated (64% versus 36%). The initial dose of citalopram, 20 mg/day, could be titrated to the maximal tolerated dose or a maximum dose of 80 mg/day. Patients treated with citalopram showed significantly greater improvement than patients treated with placebo. At week 4, the average daily dose was 63 mg, with 52% of patients receiving the 80 mg/day dose. In a 6-week fixed-dose study, patients received citalopram, 20 or 40 mg/day, or placebo (n=64 to 70 per group). Patients treated with citalopram 40 mg/day, showed significantly greater improvement than placebo-treated patients. The difference between the lower dose of citalopram and placebo was not significant. In another 6-week fixed-dose study, patients received citalopram 20 or 40 mg/day or placebo (n=88 to 97 per group). Although citalopram-treated patients improved to a somewhat greater degree than the placebo-treated patients, the differences between drug and control groups did not reach statistical significance due to a high placebo response, i.e. substantial improvement in the placebo group. A 6-week, flexible dose study was conducted in elderly, depressed patients (the mean age of male and female patients was 75 and 77 years, respectively) to determine the antidepressant effect and safety of citalopram in this subpopulation. The number of patients who received citalopram and placebo was 98 and 51, respectively. The study allowed patients to enter with lower baseline HAMD scores than are usually acceptable (>=18 in clinical trials). However, only a small percentage of patients had HAMD scores of less than 18 at entry. The dose of citalopram was titrated from a starting dose of 10 mg day to a maximum dose of 30 mg day. Patients treated with citalopram showed significantly greater improvement than patients treated with placebo. The final dose of citalopram was 10, 20 and 30 mg/day in 5%, 51% and 44% of patients, respectively. The effectiveness of citalopram in preventing relapse was assessed in two long-term studies. Depressed patients who responded to citalopram 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 continue on citalopram or receive placebo. The number of patients who received citalopram and placebo was 257 and 116, respectively. In both studies, patients who continued on citalopram experienced significantly lower relapse rates over the subsequent 6 months compared to those receiving placebo. In the fixed-dose study, the relapse rates were similar at the 20 and 40 mg/day doses, namely 10% and 12%, respectively. Of the placebo-treated patients, 31% experienced relapse. In the flexible-dose study, the relapse rates were 14% and 24% in the citalopram- and placebo-treated patients, respectively. While the majority of patients (76%) were maintained on 20 or 40 mg/day of citalopram during most of the study, some patients received 60 mg/day, while a few patients were maintained on less than 20 mg/day. Indications and Clinical Use of Celexa / Antidepressant Citalopram hydrobromide is indicated for the symptomatic relief of depressive illness. The relapse rate was significantly lower in citalopram-treated patients than in placebo-treated patients in two placebo-controlled studies, that were conducted over a 24-week period in patients who responded to 6 or 8 weeks of acute treatment with citalopram (see CLINICAL TRIALS under ACTION AND CLINICAL PHARMACOLOGY.) Nevertheless, the physician who elects to use citalopram for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient. Celexa / Antidepressant Contraindications Citalopram hydrobromide is contraindicated in patients with known hypersensitivity to citalopram hydrobromide or the excipients of the drug product. Monoamine Oxidase Inhibitors In patients, receiving selective serotonin reuptake inhibitors (SSRIs) in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes, including extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued SSRI treatment and have been started on a MAOI. Some cases presented with features resembling serotonin syndrome. Therefore, it is recommended that citalopram should not be used in combination with a MAOI or within 14 days of discontinuing treatment with a MAOI. Similarly, at least 14 days should elapse after discontinuing citalopram treatment before starting a MAOI. Celexa / Antidepressant Precautions Suicide The possibility of a suicide attempt is inherent in depression and may persist until remission occurs. Therefore, high risk patients should be closely supervised throughout therapy with Citalopram hydrobromide and consideration should be given to the possible need for hospitalization. In order to minimize the opportunity for overdosage, prescription for citalopram should be written for the smallest quantity of drug consistent with good patient management. Activation of Mania/Hypomania In placebo-controlled trials with citalopram, some of which included patients with bipolar disorder, mania/hypomania was reported in 0.1% of 1027 patents treated with citalopram versus none of the 426 patients treated with placebo. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorders treated with other marketed antidepressants. If a patient enters a manic phase, citalopram should be discontinued. Seizures Citalopram has not been systematically evaluated in patients with a seizure disorder. These patients were excluded from clinical studies during the premarketing testing of citalopram. In clinical trials, seizures occurred in 0.25% of patients treated with citalopram and in 0.23% patients treated with placebo. Like other antidepressants, citalopram should be used with caution in patients with a history of seizure disorder. Serotonin Syndrome Rarely, the occurrence of serotonin syndrome has been reported in patients receiving SSRIs. A combination of symptoms, possibly including agitation, confusion, tremor, myoclonus and hyperthermia, may indicate the development of this condition. 5-HT1 Agonists There have been rare postmarketing reports describing patients with weakness, hyperreflexia and incoordination, following the concomitant use of a SSRI and the antimigraine drug sumatriptan, a 5-HT1 agonist. Such interaction should be considered if citalopram is to be used in combination with a 5-HT1 agonist. Hyponatremia Hyponatremia and SIADH (syndrome of inappropriate antidiuretic hormone secretion) have been reported with citalopram use as a rare adverse event. Pregnancy and Nursing Mothers The safety of citalopram during pregnancy and lactation has not been established. Therefore, citalopram should not be used during pregnancy, unless, in the opinion of the physician, the expected benefits to the patient markedly outweigh the possible hazards to the fetus. Citalopram is excreted in human milk. Citalopram should not be administered to nursing mothers unless, in the opinion of the treating physician, the expected benefits to the patient markedly outweigh the possible hazards to the child. Pediatric Use Safety and effectiveness in patients below the age of 18 have not been established. Geriatric Use In premarketing clinical trials, 800 elderly patients (>=65 years of age) have been treated with citalopram. Of these patients 298 were >=75 years old. In a pharmacokinetic study (n=11, age 73 to 90 years), clearance was substantially decreased and half-life prolonged (see PHARMACOKINETICS). In a 6-week placebo-controlled study, approximately equal numbers of patients received citalopram at 20 or 30 mg per day, as the final dose. In about 5% of patients, the final dose was 10 mg per day (see CLINICAL TRIALS). Consequently, elderly patients should be administered lower doses and a lower maximum dose (see DOSAGE AND ADMINISTRATION). Hepatic Impairment Citalopram clearance was significantly decreased and plasma concentrations, as well as elimination half-life significantly increased (see PHARMACOKINETICS). Consequently, the use of citalopram in hepatically impaired patients should be approached with caution and a lower maximum dosage is recommended (see DOSAGE AND ADMINISTRATION). Renal Impairment No dosage adjustment is needed in patients with mild to moderate renal impairment. To date, no information is available on the pharmacokinetic or pharmacodynamic effects of citalopram in patients with severely reduced renal function (creatinine clearance <20 mL/min). Use in Patients with Cardiac Disease Citalopram has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were generally excluded from clinical trials during the drugs premarketing assessment. However, the electrocardiograms of patients, who received citalopram in clinical trials, indicate that citalopram was not associated with the development of clinically significant ECG abnormalities. In clinical trials, citalopram caused small but statistically significant decreases in heart rate (see ECG under ADVERSE REACTIONS) Consequently, caution should be observed when citalopram is initiated in patients with pre-existing slow heart rate. Use in Diabetic Patients Citalopram has not been systematically evaluated in diabetic patients since diabetes constituted an exclusion criterion. Although 13 patients did receive insulin during the studies, this number is too small to determine whether citalopram affects the response to insulin. Rare events of hypoglycemia were reported. Citalopram should be used with caution in diabetic patients on insulin or other antidiabetic drugs. Interference with Cognitive and Motor Performance In studies in normal volunteers, citalopram in doses of 40 mg/day did not impair cognitive function or psychomotor performance. However, psychotropic medications may impair judgement, thinking or motor skills. Consequently, patients should be cautioned against driving a car or operating hazardous machinery until they are reasonably certain that citalopram does not affect them adversely. Electroconvulsive Therapy (ECT) The safety and efficacy of the concurrent use of citalopram and ECT have not been studied. Drug Interactions: Monoamine Oxidase Inhibitors (MAOI) For interactions between citalopram and MAOI, see CONTRAINDICATIONS. General The studies described in this section were carried out in young, healthy, mostly male volunteers. In addition, some of the studies, namely interactions with metoprolol, warfarin, digoxin, imipramine, and levomepromazine, utilized only single doses of these drugs, although citalopram was given repeatedly to attain steady state. Thus, data are not available in patients who would be receiving these drugs on an ongoing basis at therapeutic doses. Metoprolol Coadministration of citalopram (40 mg/day for 22 days) and the b-adrenergic backing agent metoprolol (single dose of 150 mg), resulted in a two-fold increase in the plasma levels of metoprolol. However, the effect of metoprolol on blood pressure and heart rate was not affected. Warfarin Administration of citalopram (40 mg day for 21 days), did not affect either the pharmacokinetics or the pharmacodynamics (prothrombin time) of a single, 1 mg dose of warfarin. Digoxin Administration of citalopram (40 mg/day for 21 days) did not affect the pharmacokinetics of digoxin (single dose of 1 mg), although the serum levels of citalopram were slightly lower in the presence of digoxin. Imipramine Coadministnation of citalopram (40 mg/day for 10 days) and the tricyclic antidepressant, imipramine (single dose of 100 mg), did not affect the pharmacokinetics of either drug. However, in the presence of citalopram, the concentration of desipramine, the metabolite of imipramine, increased by approximately 50% and its half-life was prolonged. The results indicate that citalopram does not interfere with the demethylation of imipramine to desipramine but does inhibit the metabolism of desipramine to its 2-hydroxy metabolite. Consequently, concomitant treatment with citalopram and imipramine/ desipramine should be undertaken with caution. Levomepromazme Coadministration of citalopram (40 mg/day for 10 days) and levomepromazine (single dose of 50 mg), did not affect the pharmacokinetics of either drug. Lithium Coadministration of citalopram (40 mg/day for 10 days) and lithium (30 mmol/day for 5 days), did not affect the pharmacokinetics of either drug. However, since lithium may increase serotonergic neurotransmission, concomitant treatment with these two drugs should be undertaken with caution. Cimetidine Citalopram 40 mg/day was administered for 29 days. During the last 8 days of treatment, cimetidine (400 mg bid) was added to the treatment regimen. In the presence of cimetidine, a potent inhibitor of hepatic cytochrome P450 enzymes, the Cmax and AUC of citalopram was increased by 39% and 41%, respectively. Thus, caution should be exercised at the upper end of the dose range of citalopram when it is used concomitantly with high doses of cimetidine. Carbamazepine Carbamazepine, titrated to 400 mg day, was given for 21 days alone and then in combination with citalopram (40 mg day) for an additional 14 days, citalopram did not affect the plasma levels of either carbamazepine, a CYP3A4 substrate, or its metabolite, carbamazepine-epoxide, However, since carbamazepine is a microsomal enzyme inducer, the possibility that carbamazepine may increase the clearance of citalopram should be considered if the two drugs are given concomitantly. Cytochrome P450 Isozymes Using in vitro models of human liver microsomes, the biotransformation of citalopram to its demethyl metabolites was shown to depend on both CYP2C19 and CYP3A4, with a small contribution from CYP2D6. Studies have also indicated that citalopram is a weak inhibitor of CYP2D6 and CYP2C19 and a weak or negligible inhibitor of CYP3A4 and CYP1A2. As data are not available from clinical pharmacokinetic studies, the possibility that the clearance of citalopram will be decreased when citalopram is administered with a potent inhibitor of CYP3A4 (e.g., ketoconazole, itraconazole, fluconazole or erythromycin), or a potent inhibitor of CYP2C19 (e.g., omeprazole), should be considered. Alcohol Although citalopram did not potentiate the cognitive and psychomotor effects of alcohol in volunteers, the concomitant use of alcohol and citalopram should be avoided. Other Drugs In clinical trials, citalopram has been given concomitantly with benzodiazepines (anxiolytics/hypnotics), analgesics (NSAIDs, nonNSAIDs), lithium, antihistamines, antihyperensives or other cardiovascular drugs. Celexa / Antidepressant Adverse Reactions During the premarketing clinical development, 3652 patients received Citalopram hydrobromide for the treatment of depression. Of these patients, 66% were females and 34% were males. The mean age of the patients was 50 years, with 70% being <60 years old (30% <40 years old, 40% 40 to 59 years old) and 30% being >=60 years old. Adverse Findings Observed in Short-Term, Placebo-Controlled Trials Adverse Reactions Associated with Discontinuation of Treatment From the short-term (4 to 6 weeks) placebo-controlled, Phase III clinical trials, 15.9% (163/1027) of the citalopram-treated patients discontinued treatment due to an adverse event. The discontinuation rate in the placebo-treated patients was 7.7% (33/426). The events associated with discontinuation of citalopram in 1% or more of patients at a rate of at least twice that of placebo, were as follows: Nausea (4.1% versus 0.0%), insomnia (2.4% versus 12%), somnolence (2.4% versus 1.2%), dizziness (2.3% versus 0.7%), vomiting (1.3% versus 0.0%), agitation (1.2% versus 0.0%), asthenia (11% versus 0.5%), and dry mouth (1.1% versus 0.2%). Incidence of Adverse Events in Placebo-controlled Studies 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 favors to the adverse event incidence rate in the population studied.
    
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