Celexa

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 i.v. dose. Absorption was not affected by food.

Distribution: After i.v. infusion in healthy male volunteers, the apparent volume of distribution (V_d)β was about 12 L/kg (range 9 to 17 L/kg), indicating a pronounced tissue distribution; (V_d)β oral was about 17 L/kg (range 14 to 21 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 to 2 weeks. At a daily dose of 40 mg, the average plasma concentration is about 83 ng/mL (n=114) with a range from 30 to 200 ng/mL. Citalopram does not accumulate during long-term treatment. A clear relationship between citalopram plasma levels and therapeutic response or side effects has not been established.

Metabolism: Citalopram is metabolized in the liver to demethylcitalopram (DCT), didemethylcitalopram (DDCT), citalopram-N-oxide, and a deaminated propionic acid derivative. In vitro studies show that DCT, DDCT and citalopram-N-oxide also inhibit the neuronal reuptake of serotonin but are less selective and less potent than the parent compound and are of minor clinical importance. Unchanged citalopram is the predominant compound in plasma. In vitro studies indicated that the biotransformation of citalopram to its demethyl metabolites depends on both CYP 2C19 and CYP 3A4, with a small contribution from CYP 2D6.

Elimination: The elimination half-life of citalopram (t_½β) is approximately 37 hours (range: 30 to 42 hours) which allows recommendation of once-daily dosing. The systemic citalopram plasma clearance (Cl_S) is 0.33 L/min. Citalopram is eliminated primarily via the liver (85%) and the remainder via the kidneys; approximately 12% (range 6 to 21%) of the daily dose is excreted in urine as unchanged citalopram.

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

Reduced Hepatic Function: The pharmacokinetics of citalopram were compared in patients with reduced hepatic function (3 female and 6 male patients aged 41 to 60 years) to those seen in 12 healthy male volunteers (aged 21 to 43 years). In patients with reduced hepatic function the half-life of citalopram was approximately doubled (83 hours vs 37 hours), steady-state citalopram concentrations increased by 61% and oral clearance decreased by 37%. Consequently the use of citalopram in patients with reduced hepatic function should be approached with caution and lower maximal doses should be prescribed (see Precautions and Dosage).

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

The efficacy of citalopram in the treatment of depression was established in 5 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% vs 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 vs 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 2 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 to 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.

MAOIs: For interactions between citalopram and MAOIs, 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 β-adrenergic blocking agent metoprolol (single dose of 150 mg), resulted in a 2-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, 25 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: Coadministration 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.

Levomepromazine: 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 2 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 b.i.d.) was added to the treatment regimen. In the presence of cimetidine, a potent inhibitor of hepatic cytochrome P450 enzymes, the C_max 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 CYP 3A4 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.

Pimozide: In a double-blind crossover study in healthy young adults, a single dose of pimozide 2 mg co-administered with racemic citalopram 40 mg given once daily for 11 days was associated with a mean increase in QTc values at Tmax of approximately 12 ms compared to pimozide when given with placebo. The mechanism of this apparent pharmacodynamic interaction is not known.

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 CYP 2C19 and CYP 3A4, with a small contribution from CYP 2D6. Studies have also indicated that citalopram is a weak inhibitor of CYP 2D6 and CYP 2C19 and a weak or negligible inhibitor of CYP 3A4 and CYP 1A2. One in vitro study using human liver microsomes has shown that ketoconazole and omeprazole reduced the rate of formation of the demethylcitalopram metabolite of citalopram to 45-60% and 75-85% of control, respectively. As data are not available from multi-dose pharmacokinetic studies, the possibility that the clearance of citalopram will be decreased when citalopram is administered with a potent inhibitor of CYP 3A4 (e.g., ketoconazole, itraconazole, fluconazole or erythromycin), or a potent inhibitor of CYP 2C19 (e.g., omeprazole), should be considered.

Various scientific publications have acknowledged that the main components in grapefruit juice may act as a CYP3A4 inhibitor. Citalopram is also metabolized by other isoenzymes not affected by grapefruit juice, namely CYP2C19 and CYP2D6. Although there is a theoretical possibility of pharmacokinetic drug interactions resulting from co-administration of citalopram with grapefruit juice, the onset of an interaction is considered unlikely.

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

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 Pharmacology, Pharmacokinetics). In a 6-week placebo-controlled study, approximately equal numbers of patients received citalopram at 20 or 30 mg/day, as the final dose. In about 5% of patients, the final dose was 10 mg/day (see Pharmacology, Clinical Trials). Consequently, elderly patients should be administered lower doses and a lower maximum dose (see Dosage).

Hepatic Impairment: In subjects with hepatic impairment, citalopram clearance was significantly decreased and plasma concentrations, as well as elimination half-life significantly increased (see Pharmacology, Pharmacokinetics). Consequently, the use of citalopram in hepatically impaired patients should be approached with caution and a lower maximum dosage is recommended (see Dosage).

Renal Impairment: No dosage adjustment is needed in patients with mild to moderate renal impairment. Since, no information is available on the pharmacokinetic or pharmacodynamic effects of citalopram in patients with severely reduced renal function (creatinine clearance <20 mL/min), citalopram should be used with caution in these patients.

Patients with Cardiac Disease: Citalopram has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were generally excluded from clinical trials during the drug's premarketing assessment. 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 Adverse Effects, ECG). Consequently, caution should be observed when citalopram is initiated in patients with pre-existing slow heart rate.

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.

Bleeding Disorders: There have been reports of cutaneous bleeding abnormalities such as ecchymosis and purpura with SSRIs. Caution is advised in patients taking SSRIs, particularly in concomitant use with drugs known to affect platelet function (e.g., atypical antipsychotics and phenothiazines, most tricyclic antidepressants, ASA, and NSAIDs) as well as in patients with a history of bleeding disorders.

See Pregnancy. 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.

Safety and effectiveness in patients below the age of 18 have not been established.

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.

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

Each film-coated, white, oval, scored tablet, marked “C” and “R” symmetrically around the score, contains: citalopram 40 mg (as citalopram HBr). Nonmedicinal ingredients: copolyvidone, cornstarch, croscarmellose sodium, glycerin, lactose monohydrate, magnesium stearate, methylhydroxypropyl cellulose, microcrystalline cellulose, polyethylene glycol 400 and titanium dioxide. Blister packages of 30.

Store in a dry place at room temperature between 15 and 30°C.

Each film-coated, white, oval, scored tablet, marked “C” and “N” symmetrically around the score, contains: citalopram 20 mg (as citalopram HBr). Nonmedicinal ingredients: copolyvidone, cornstarch, croscarmellose sodium, glycerin, lactose monohydrate, magnesium stearate, methylhydroxypropyl cellulose, microcrystalline cellulose, polyethylene glycol 400 and titanium dioxide. Blister packages of 30. Bottles of 100 and 250.

Rare: goiter, gynecomastia, hypothyroidism.

Adverse events which have been reported to be temporally (but not necessarily causally) associated with citalopram treatment in at least 3 patients since its market introduction include: abnormal hepatic function, acute renal failure, aggravated condition, aggravated migraine, akathisia, anaphylaxis, angioedema, asthma, choreoathetosis, convulsions NOS, decreased drug level, decreased prothrombin time, delirium, dyskinesia, ecchymosis, eosinophilia, epidermal necrolysis, erythema multiforme, gastrointestinal hemorrhage, gynecological problems, hemolytic anemia, hepatitis, hypersensitivity NOS, hyperprolactinemia, hypomania, hyponatremia, increased drug level, increased prothrombin time, menometrorrhagia, myoclonic jerks, neuroleptic malignant syndrome, neuropathy, nystagmus, pancreatitis, pancytopenia, purpura NOS, rhabdomyolysis, serotonin syndrome, SIADH, spontaneous abortion/fetal death, suicide ideation, thrombocytopenia, vasodilatation, ventricular arrhythmia, torsades de pointes, withdrawal syndrome.

Rare: rheumatoid arthritis.

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

Frequent: abnormal accommodation. Infrequent: conjunctivitis, earache, eye pain, mydriasis, taste perversion, tinnitus. Rare: eye abnormality, keratitis, photophobia.

Infrequent: arthralgia, arthritis, arthrosis, dystonia, muscle weakness, myalgia. Rare: bone disorder, bursitis, osteoporosis, tendon disorder.

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

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

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

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

Infrequent: penis disorder, prostatic disorder, testis disorder.

The following events had an incidence on placebo ≥ citalopram: asthenia, back pain, headache, dizziness, constipation, palpitation, insomnia, abnormal vision.

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

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

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

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

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

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

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

Adverse Reactions following Discontinuation of Treatment (or Dose Reduction): There have been reports of adverse reactions upon the discontinuation of citalopram (particularly when abrupt), including but not limited to the following: dizziness, abnormal dreams, sensory disturbances (including paresthesias and electric shock sensations), agitation, anxiety, emotional indifference, impaired concentration, headache, migraine, tremor, nausea, vomiting and sweating or other symptoms which may be of clinical significance (see Precautions and Dosage).

Patients should be monitored for these or any other symptoms. A gradual reduction in the dosage over several weeks, rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient's clinical response. These events are generally self-limiting. Symptoms associated with discontinuation have been reported for other selective serotonin reuptake inhibitors (see Precautions and Dosage).

Additional Adverse Events Observed During the Premarketing Evaluation of Citalopram: The events listed below include all adverse events that were reported in the overall development program of citalopram (n=3652). All reported events are included except those already listed in Table 1 and those events which occurred in only one patient. It is important to emphasize that, although the events reported occurred during treatment with citalopram, they were not necessarily caused by it. The events are enumerated using the following criteria: frequent: adverse events that occurred on one or more occasions in at least 1/100 patients; infrequent: adverse events that occurred in less than 1/100 patients but at least in 1/1000 patients; rare: adverse events that occurred in fewer than 1/1000 patients.

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

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

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

Rare: breast neoplasm malignant female.

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

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

Infrequent: cholecystitis, cholelithiasis, increased gamma-GT, increased ALT. Rare: bilirubinemia, increased AST, jaundice.

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

Frequent: Influenza-like symptoms, non-pathological trauma, pain. Infrequent: alcohol intolerance, allergic reaction, allergy, chest pain, edema, hot flushes, leg pain, malaise, rigors, syncope. Rare: peripheral edema, sudden death, traumatic injury.

Citalopram has a wide margin of safety in overdose. Cases of overdoses involved the ingestion of citalopram either alone or in combination with other drugs and/or alcohol. Cases of overdoses of citalopram ranging from 180 mg to 2000 mg have been reported during the premarketing clinical development. All patients recovered. One patient, ingesting over 1500 mg citalopram, had reversible ECG abnormalities, the most important of which was prolongation of QTc.

Citalopram is given to patients at potential risk of suicide and reports of attempted suicide have been received after its market introduction. Post-marketing reports of drug overdoses involving citalopram have included fatalities with citalopram alone as well as non-fatal overdoses of up to 5200 mg. In many cases, details regarding the precise dose of citalopram or combination with other drugs and/or alcohol are often lacking. Although most patients recovered without sequelae, fatalities have been reported at doses of citalopram up to 3920 mg.

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

Symptoms most often accompanying citalopram overdose included dizziness, sweating, nausea, vomiting, tremor, and somnolence. In more rare cases, observed symptoms included confusion, loss of consciousness, convulsions, coma, sinus tachycardia, cyanosis, hyperventilation and rhabdomyolysis.

Establish and maintain an airway to ensure adequate ventilation and oxygenation. Gastric lavage and use of activated charcoal should be considered. Cardiac and vital sign monitoring are recommended, along with general symptomatic and supportive measures. There are no specific antidotes for citalopram.

Due to the large volume of distribution of citalopram, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. In managing overdosage, the possibility of multiple drug involvement must be considered.

A single oral dose of 20 mg/day is the recommended dose for most elderly patients. Some patients may respond to a 10 mg/day dose (see Pharmacology, Clinical Trials). The dose may be titrated to a maximum of 40 mg/day if needed and tolerated. As with other SSRIs, caution should be exercised in treating elderly female patients who may be more susceptible to adverse events such as hyponatremia and SIADH (syndrome of inappropriate antidiuretic hormone secretion) (see Precautions).

Hepatic Impairment: Patients with reduced hepatic function should receive dosages of no more than 30 mg/day.

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

Maintenance Treatment: Evaluation of citalopram in 2 placebo- controlled studies has shown that its antidepressant efficacy was maintained for periods of up to 24 weeks, following 6 or 8  weeks of initial treatment (total of 32 weeks) (see Pharmacology, Clinical Trials). In the flexible dose study, the great majority of patients were receiving 20 or 40 mg/day doses both at 12 and 24 weeks. During maintenance therapy, the dosage should be kept at the lowest effective level and patients should be periodically reassessed to determine the need for continued treatment.

Switching Patients To or From a Monoamine Oxidase Inhibitor (MAOI): At least 14 days should elapse between discontinuation of a MAOI and initiation of therapy with citalopram. Similarly, at least 14 days should be allowed after stopping citalopram before starting a MAOI (see Contraindications).

Discontinuation of Citalopram Treatment: Symptoms associated with the discontinuation or dosage reduction of citalopram have been reported. Patients should be monitored for these and other symptoms when discontinuing treatment or during dosage reduction (see Precautions and Adverse Effects).

A gradual reduction in the dose over several weeks rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient's clinical response (see Precautions and Adverse Effects ).

Children: See Warnings, Potential Association with Behavioral and Emotional Changes, Including Self-Harm.