Source: FDA, National Drug Code (US) Revision Year: 2019
The mechanism of action of citalopram HBr as an antidepressant is presumed to be linked to potentiation of serotonergic activity in the central nervous system (CNS) resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT). In vitro and in vivo studies in animals suggest that citalopram is a highly selective serotonin reuptake inhibitor (SSRI) with minimal effects on norepinephrine (NE) and dopamine (DA) neuronal reuptake. Tolerance to the inhibition of 5-HT uptake is not induced by long-term (14-day) treatment of rats with citalopram. Citalopram is a racemic mixture (50/50), and the inhibition of 5-HT reuptake by citalopram is primarily due to the (S)-enantiomer.
Citalopram has no or very low affinity for 5-HT1A, 5-HT2A, dopamine D1 and D2, α1, α2, and βadrenergic, histamine H1, gamma aminobutyric acid (GABA), muscarinic cholinergic, and benzodiazepine receptors. Antagonism of muscarinic, histaminergic, and adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of other psychotropic drugs.
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.
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%.
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.
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.
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.
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.
In CYP2C19 poor metabolizers, citalopram steady state Cmax and AUC was increased by 68% and 107%, respectively. Celexa 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).
Citalopram steady state levels were not significantly different in poor metabolizers and extensive metabolizers of CYP2D6.
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).
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. Celexa 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 inhibits CYP2D6 with Celexa is unlikely to have clinically significant effects on citalopram metabolism, based on the study results in CYP2D6 poor metabolizers.
The efficacy of Celexa 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 DSMIII-R criteria for major depression. Study 1, a 6-week trial in which patients received fixed
Celexa doses of 10, 20, 40, and 60 mg/day, showed that Celexa 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 Celexa 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 Celexa 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 Celexa 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 2060 mg/day in the second study) were randomized to continuation of Celexa or to placebo. In both studies, patients receiving continued Celexa 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 Celexa.
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.
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.
Citalopram was administered in the diet to NMRI/BOM strain mice and COBS WI strain rats for 18 and 24 months, respectively. There was no evidence for carcinogenicity of citalopram in mice receiving up to 240 mg/kg/day, which is equivalent to 20 times the maximum recommended human daily dose (MRHD) of 60 mg on a surface area (mg/m²) basis. There was an increased incidence of small intestine carcinoma in rats receiving 8 or 24 mg/kg/day, doses which are approximately 1.3 and 4 times the MRHD, respectively, on a mg/m² basis. A no-effect dose for this finding was not established. The relevance of these findings to humans is unknown.
Citalopram was mutagenic in the in vitro bacterial reverse mutation assay (Ames test) in 2 of 5 bacterial strains (Salmonella TA98 and TA1537) in the absence of metabolic activation. It was clastogenic in the in vitro Chinese hamster lung cell assay for chromosomal aberrations in the presence and absence of metabolic activation. Citalopram was not mutagenic in the in vitro mammalian forward gene mutation assay (HPRT) in mouse lymphoma cells or in a coupled in vitro/in vivo unscheduled DNA synthesis (UDS) assay in rat liver. It was not clastogenic in the in vitro chromosomal aberration assay in human lymphocytes or in two in vivo mouse micronucleus assays.
When citalopram was administered orally to 16 male and 24 female rats prior to and throughout mating and gestation at doses of 32, 48, and 72 mg/kg/day, mating was decreased at all doses, and fertility was decreased at doses ≥32 mg/kg/day, approximately 5 times the MRHD of 60 mg/day on a body surface area (mg/m²) basis. Gestation duration was increased at 48 mg/kg/day, approximately 8 times the MRHD.
Pathologic changes (degeneration/atrophy) were observed in the retinas of albino rats in the 2year carcinogenicity study with citalopram. There was an increase in both incidence and severity of retinal pathology in both male and female rats receiving 80 mg/kg/day (13 times the maximum recommended daily human dose of 60 mg on a mg/m² basis). Similar findings were not present in rats receiving 24 mg/kg/day for two years, in mice treated for 18 months at doses up to 240 mg/kg/day, or in dogs treated for one year at doses up to 20 mg/kg/day (4, 20, and 10 times, respectively, the maximum recommended daily human dose on a mg/m² basis).
Additional studies to investigate the mechanism for this pathology have not been performed, and the potential significance of this effect in humans has not been established.
In a one-year toxicology study, 5 of 10 beagle dogs receiving oral doses of 8 mg/kg/day (4 times the maximum recommended daily human dose of 60 mg on a mg/m² basis) died suddenly between weeks 17 and 31 following initiation of treatment. Although appropriate data from that study are not available to directly compare plasma levels of citalopram (CT) and its metabolites, demethylcitalopram (DCT) and didemethylcitalopram (DDCT), to levels that have been achieved in humans, pharmacokinetic data indicate that the relative dog-to-human exposure was greater for the metabolites than for citalopram. Sudden deaths were not observed in rats at doses up to 120 mg/kg/day, which produced plasma levels of CT, DCT, and DDCT similar to those observed in dogs at doses of 8 mg/kg/day. A subsequent intravenous dosing study demonstrated that in beagle dogs, DDCT caused QT prolongation, a known risk factor for the observed outcome in dogs. This effect occurred in dogs at doses producing peak DDCT plasma levels of 810 to 3250 nM (39-155 times the mean steady state DDCT plasma level measured at the maximum recommended human daily dose of 60 mg). In dogs, peak DDCT plasma concentrations are approximately equal to peak CT plasma concentrations, whereas in humans, steady state DDCT plasma concentrations are less than 10% of steady state CT plasma concentrations. Assays of DDCT plasma concentrations in 2020 citalopram-treated individuals demonstrated that DDCT levels rarely exceeded 70 nM; the highest measured level of DDCT in human overdose was 138 nM. While DDCT is ordinarily present in humans at lower levels than in dogs, it is unknown whether there are individuals who may achieve higher DDCT levels. The possibility that DCT, a principal metabolite in humans, may prolong the QT interval in dogs has not been directly examined because DCT is rapidly converted to DDCT in that species.
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