Citalopram Hydrobromide: Package Insert and Label Information (Page 4 of 5)

11 DESCRIPTION

Citalopram tablets, USP contain citalopram, a selective serotonin reuptake inhibitor (SSRI). Citalopram hydrobromide is a racemic bicyclic phthalane structure and is designated (±)-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3­dihydroisobenzofuran-5-carbonitrile hydrobromide with the following structural formula:

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The molecular formula is C 20 H 22 BrFN 2 O and its molecular weight is 405.35.

Citalopram hydrobromide, USP occurs as a fine, white to off-white powder. Citalopram hydrobromide is sparingly soluble in water and soluble in ethanol.

Citalopram, USP 10 mg tablets are film-coated, round shaped tablets containing citalopram hydrobromide in strengths equivalent to 10 mg citalopram base. Citalopram hydrobromide, USP 20 mg and 40 mg tablets are film-coated, oval shaped, scored tablets containing citalopram hydrobromide, in strengths equivalent to 20 mg or 40 mg citalopram base. The tablets also contain the following inactive ingredients: copovidone, croscarmellose sodium, ferric oxide red, ferric oxide yellow, glycerin, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, starch, and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action of citalopram is unclear, but is presumed to be related to potentiation of serotonergic activity in the central nervous system (CNS) resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT).

12.2 Pharmacodynamics

In vitro and in vivo studies in animals suggest that citalopram is a selective serotonin reuptake inhibitor (SSRI) with minimal effects on norepinephrine (NE) and dopamine (DA) neuronal reuptake.

Citalopram has no or very low affinity for 5-HT 1A , 5-HT 2A , dopamine D 1 and D 2 , α 1 -, α 2 -, and β-adrenergic, histamine H 1 , gamma aminobutyric acid (GABA), muscarinic cholinergic, and benzodiazepine receptors.

Cardiac Electrophysiology

Individually corrected QT c (QT c Ni) 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 (1.5 times the maxium recommended dosage) 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 C max for the dose of 40 mg is 12.6 (14.3) msec [see Warnings and Precautions ( 5.2)] .

12.3 Pharmacokinetics

The single- and multiple-dose pharmacokinetics of citalopram are linear and dose-proportional in a dose range of 10 to 40 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
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.

Distribution
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%.

Elimination

Metabolism
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.

Excretion
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.

Specific Populations

Geriatric Patients
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 [see Dosage and Administration ( 2.3), Warnings and Precautions ( 5.2), Use in Specific Populations ( 8.5)] .

Male and Female Patients
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.

Patients with Hepatic Impairment
Citalopram oral clearance was reduced by 37% and half-life was doubled in patients with reduced hepatic function compared to normal subjects [see Dosage and Administration ( 2.3), Warnings and Precautions ( 5.2), Use in Specific Populations ( 8.6)] .

Patients with Renal Impairment
In patients with mild to moderate renal 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 severe renal impairment (creatinine clearance < 20 mL/min).

CYP2C19 poor metabolizers
In CYP2C19 poor metabolizers, citalopram steady state C max and AUC was increased by 68% and 107%, respectively [see Dosage and Administration ( 2.3),Warnings and Precautions ( 5.2)] .

CYP2D6 poor metabolizers
Citalopram steady state levels were not significantly different in poor metabolizers and extensive metabolizers of CYP2D6.

Drug Interaction Studies
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 CYP2C19 Inhibitors
Since CYP3A4 and CYP2C19 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 inhibitors of CYP2C19 (e.g., omeprazole, cimetidine) might decrease the clearance of citalopram. However, coadministration of citalopram and the potent CYP3A4 inhibitor ketoconazole did not significantly affect the pharmacokinetics of citalopram. 20 mg/day is the maximum recommended citalopram dose in patients taking concomitant cimetidine or another CYP2C19 inhibitor, because of the risk of QT prolongation [see Dosage and Administration ( 2.2), Warnings and Precautions ( 5.2)] .

Cimetidine
In subjects who had received 21 days of 40 mg/day citalopram, combined administration of 400 mg twice a day cimetidine for 8 days resulted in an increase in citalopram AUC and C max of 43% and 39%, respectively [see Dosage and Administration ( 4),Warnings and Precautions ( 5.2), Drug Interactions ( 7)] .

CYP2D6 Inhibitors
Coadministration of a drug that inhibits CYP2D6 with citalopram is unlikely to have clinically significant effects on citalopram metabolism, based on the study results in CYP2D6 poor metabolizers.

Digoxin
In subjects who had received 21 days of 40 mg/day citalopram, combined administration of citalopram and digoxin (single dose of 1 mg) did not significantly affect the pharmacokinetics of either citalopram or digoxin.

Lithium
Coadministration of citalopram (40 mg/day for 10 days) and lithium (30 mmol/day for 5 days) had no significant effect on the pharmacokinetics of citalopram or lithium.

Pimozide
In a controlled study, a single dose of pimozide 2 mg co-administered with citalopram 40 mg given once daily for 11 days was associated with a mean increase in QTc values of approximately 10 msec compared to pimozide given alone.
Citalopram did not alter the mean AUC or C max of pimozide. The mechanism of this pharmacodynamic interaction is not known [see Contraindications ( 4), Warnings and Precautions ( 5.2)] .

Theophylline
Combined administration of citalopram (40 mg/day for 21 days) and the CYP1A2 substrate theophylline (single dose of 300 mg) did not affect the pharmacokinetics of theophylline. The effect of theophylline on the pharmacokinetics of citalopram was not evaluated.

Warfarin
Administration of 40 mg/day citalopram for 21 days did not affect the pharmacokinetics of warfarin, a CYP3A4 substrate. Prothrombin time was increased by 5%, the clinical significance of which is unknown.

Carbamazepine
Combined administration of citalopram (40 mg/day for 14 days) and carbamazepine (titrated to 400 mg/day for 35 days) did not significantly affect the pharmacokinetics of carbamazepine, a CYP3A4 substrate. Although trough citalopram plasma levels were unaffected, given the enzyme-inducing properties of carbamazepine, the possibility that carbamazepine might increase the clearance of citalopram should be considered if the two drugs are coadministered.

Triazolam
Combined administration of citalopram (titrated to 40 mg/day for 28 days) and the CYP3A4 substrate triazolam (single dose of 0.25 mg) did not significantly affect the pharmacokinetics of either citalopram or triazolam.

Ketoconazole
Combined administration of citalopram (40 mg) and ketoconazole (200 mg) decreased the C max and AUC of ketoconazole by 21% and 10%, respectively, and did not significantly affect the pharmacokinetics of citalopram.

Metoprolol
Administration of 40 mg/day citalopram for 22 days resulted in a two-fold increase in the plasma levels of the beta­ adrenergic blocker metoprolol. Increased metoprolol plasma levels have been associated with decreased cardioselectivity. Coadministration of citalopram and metoprolol had no clinically significant effects on blood pressure or heart rate.

Imipramine and Other Tricyclic Antidepressants (TCAs)
In vitro studies suggest that citalopram is a relatively weak inhibitor of CYP2D6. Coadministration of citalopram (40 mg/day for 10 days) with the TCA imipramine (single dose of 100 mg), a substrate for CYP2D6, did not significantly affect the plasma concentrations of imipramine or citalopram. However, the concentration of the imipramine metabolite desipramine was increased by approximately 50%. The clinical significance of the desipramine change is unknown.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Citalopram increased the incidence of small intestine carcinoma in rats treated for 24 months at doses of 8 and 24 mg/kg/day in the diet, which are approximately 2 and 6 times the Maximum Recommended Human Dose (MRHD) of 40 mg, respectively, based on mg/m 2 body surface area. A no-effect level (NOEL) for this finding was not established.

Citalopram did not increase the incidence of tumors in mice treated for 18 months at doses up 240 mg/kg/day in the diet, which is approximately 30 times the MRDH of 40 mg based on mg/m 2 body surface area.

Mutagenesis

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 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.

Impairment of Fertility

Citalopram was administered orally to female and male rats at doses of 32, 48, and 72 mg/kg/day prior to and throughout mating and continuing to gestation. These doses are approximately 8, 12, and 17 times the MRHD of 40 mg based on mg/m 2 body surface area. Mating and fertility were decreased at doses ≥ 32 mg/kg/day, which is approximately 8 times the MRHD. Gestation duration was increased at 48 mg/kg/day, which is approximately 12 times the MRHD.

13.2 Animal Toxicology and/or Pharmacology

Retinal Changes in Rats

Pathologic changes (degeneration/atrophy) were observed in the retinas of albino rats in the 2-year 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, which is approximately 19 times the MRHD of 40 mg based on mg/m 2 body surface area. Similar findings were not present in rats treated for two years at the dose of 24 mg/kg/day, 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, which are approximately 6, 29, and 17 times the MRHD, respectively, based on mg/m 2 body surface area.

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.

14 CLINICAL STUDIES

The efficacy of citalopram as a treatment for major depressive disorder was established in two placebo-controlled studies (of 4 to 6 weeks duration) in adult outpatients (ages 18 to 66) meeting DSM-III or DSM-III-R criteria for major depressive disorder (MDD) (Studies 1 and 2).

Study 1, a 6-week trial in which patients received fixed citalopram doses of 10 mg, 20 mg, 40 mg, and 60 mg daily, showed that citalopram 40 daily and 60 mg daily (1.5 times the maximum recommended daily dosage) was effective as measured by the Hamilton Depression Rating Scale (HAMD) total score, the primary efficacy endpoint. The HAMD-17 is a 17-item, clinician-rated scale used to assess severity of depressive symptoms. Scores on the HAMD-17 range from 0 to 52, with higher scores indicating more severe depression. This study showed no clear effect of the 10 mg and 20 mg daily doses, and the 60 mg daily dose was not more effective than the 40 mg daily dose. Due to the risk of QTc prolongation and ventricular arrhythmias, the maximum recommended dosage of citalopram is 40 mg once daily.

In study 2, a 4-week, placebo-controlled trial in patients with MDD, the initial dose was 20 mg daily, followed by titration to the maximum tolerated dose or a maximum dose of 80 mg daily (2 times the maximum recommended daily dosage). Patients treated with citalopram showed statistically significantly greater improvement than placebo patients on the HAMD total score, the primary efficacy endpoint. In three additional placebo-controlled trials in patients with MDD, the difference in response to treatment between patients receiving citalopram and patients receiving placebo was not statistically significant.

In two long-term studies, patients with MDD who had responded to citalopram during an initial 6 or 8 weeks of acute treatment were randomized to continuation of citalopram or placebo. In one study, patients received fixed doses of citalopram 20 mg or 40 mg daily and in the second study, patients received flexible doses of citalopram 20 mg daily to 60 mg daily (1.5 times the maximum recommended daily dosage). In both studies, patients receiving continued citalopram treatment experienced statistically 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 mg or 40 mg daily of citalopram. Due to the risk of QTc prolongation and ventricular arrhythmias, the maximum recommended dosage of citalopram is 40 mg once daily.

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.

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