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Citalopram
Brand name (Celexa)
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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.
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.
Citalopram hydrobromide 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. In clinical trials, with overdoses of citalopram ranging from 180 mg to 2000 mg, all patients recovered. One patient, ingesting over 1500 mg citalopram,
had reversible ECG abnormalities, the most important of which was prolongation of QTc.
Of the cases reported postmarketing, six were fatal. The doses of citalopram in these patients ranged from 840 mg to 1960 mg. All but one of these patients had concomitant drugs and/or alcohol. Serum levels of citalopram in patients who ingested 2000 mg, 4000 mg and 5200 mg of the drug were 2900 ng/mL, 3800 ng/mL and 10,040 ng/mL
citalopram, respectively. All these patients recovered. Three 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.
General
Citalopram hydrobromide should be administered once daily, in the morning or evening, with or without food.
Adults
Citalopram should be administered as a single oral dose of 20 mg/day. In patients who do not respond adequately, an increase of dosage to 40 mg/day should be considered. Certain patients may require 60 mg/day. However, in a dose response study, the 60 mg/day dose did not demonstrate an advantage regarding effectiveness over the 40 mg/day
dose. Dose increases should usually occur in increments of 20 mg, at intervals of no less than one week.
Elderly Patients
A single oral dose of 20 mg/day is the recommended dose for most elderly patients. Some patients may respond to a 10 mg/day dose (see CLINICAL TRIALS under ACTION AND CLINICAL PHARMACOLOGY). The dose may be titrated to a maximum of 40 mg/day if needed and tolerated.
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 two placebo-controlled studies has shown that its antidepressant efficacy was maintained for periods of up to 24 weeks, following 6 or 8 weeks of initial treatment (total of 32 weeks) (See CLINICAL TRIALS under ACTION AND CLINICAL PHARMACOLOGY). 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.
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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 Back to top of page
Since some patients may experience discontinuation symptoms when citalopram is stopped abruptly, the dose of citalopram should be tapered off over 1 to 2 weeks.
Pharmaceutical Information
| DRUG SUBSTANCE |
|
| Common Name:
| Citalopram hydrobromide |
| Code Name:
| Lu 10-171-B |
| Chemical Name:
| (RS)-1-[3-(dimethylamino)propyl]-1-(p-flurophenyl)-5-phthalancarbonitrile, hydrobromide |
| Structural Formula:
|  |
| Molecular Formulas:
| C20H22BrFN2O |
| Molecular Weight:
| 405.35 |
| Description:
| White to off-white, crystalline having no more than a slight odour. |
| Melting Point:
| 185°-188°C |
| pH:
| 5.5-6.5 (0.5% w/v in water) |
| pKa:
| 9.5 (microtitration) |
| Solubility:
| Water (sparingly soluble)
Ethanol (soluble)
Chloroform (freely soluble)
Diethylether (very slightly soluble)
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| Partition Coefficient:
| Log P (octanol/phosphate buffer pH 7.4) - 1.57 |
Composition:
Citalopram tablets contain citalopram hydrobromide corresponding to 20 mg or 40 mg citalopram, and the following non- medicinal ingredients: corn starch,lactose monohydrate, microcrystalline cellulose, copolyvidone, glycerin, croscarmellose sodium, magnesium stearate, methylhydroxypropyl cellulose, polyethylene glycol 400, and titanium
dioxide.
Stability and Storage:
Citalopram tablets should be stored in a dry place at room temperature between 15° and 30°C.
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