Citalopram: Package Insert and Label Information (Page 5 of 7)

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 tablets, 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 (2), 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 tablets, combined administration of citalopram tablets and digoxin (single dose of 1 mg) did not significantly affect the pharmacokinetics of either citalopram or digoxin.

Lithium

Coadministration of citalopram tablets (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 tablets (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 tablets 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 tablets (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 tablets (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 tablets (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 tablets 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 tablets 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 tablets (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/m² 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/m² 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/m² 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/m² 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/m² 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 tablets as a treatment for major depressive disorder was established in two placebo-controlled studies (of 4 to 6 weeks duration) in adult outpatients (ages 18-66) 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 tablets doses of 10 mg, 20 mg, 40 mg, and 60 mg daily, showed that citalopram tablets 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 tablets 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 tablets 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 tablets and patients receiving placebo was not statistically significant.

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

16 HOW SUPPLIED/STORAGE AND HANDLING

Citalopram Tablets, USP are available containing citalopram hydrobromide, USP equivalent to 10 mg, 20 mg or 40 mg citalopram.

The 10 mg tablets are orange, film-coated, round, unscored tablets debossed with MX31 on one side of the tablet and plain on the other side. They are available as follows:

NDC 0378-6231-01
bottles of 100 tablets

NDC 0378-6231-05
bottles of 500 tablets

The 20 mg tablets are pink, film-coated, round, scored tablets debossed with MX32 on one side of the tablet and a score line on the other side. They are available as follows:

NDC 0378-6232-01
bottles of 100 tablets

NDC 0378-6232-05
bottles of 500 tablets

The 40 mg tablets are white, film-coated, round, scored tablets debossed with MX33 on one side of the tablet and a score line on the other side. They are available as follows:

NDC 0378-6233-01
bottles of 100 tablets

NDC 0378-6233-05bottles of 500 tablets

Storage and Handling: Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

PHARMACIST: Dispense a Medication Guide with each prescription.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Suicidal Thoughts and Behaviors: Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dosage is adjusted up or down, and instruct them to report such symptoms to the healthcare provider [see Boxed Warning, Warnings and Precautions (5.1)].

QT Prolongation and Torsade de Pointes: Advise patients to consult their health care provider immediately if they feel faint, lose consciousness, or have heart palpitations. Instruct patients to inform their health care provider that they are taking citalopram tablets before taking any new medications [see Warnings and Precautions (5.2), Drug Interactions (7)].

Serotonin Syndrome: Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of citalopram tablets with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, St. John’s Wort, and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid). Instruct patients to contact their health care provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome [see Warnings and Precautions (5.3), Drug Interactions (7)].

Increased Risk of Bleeding: Inform patients about the concomitant use of citalopram tablets with aspirin, NSAIDs, other antiplatelet drugs, warfarin, or other anticoagulants because the combined use has been associated with an increased risk of bleeding. Advise patients to inform their health care providers if they are taking or planning to take any prescription or over-the-counter medications that increase the risk of bleeding [see Warnings and Precautions (5.4)].

Activation of Mania or Hypomania: Advise patients and their caregivers to observe for signs of activation of mania/hypomania and instruct them to report such symptoms to the healthcare provider [see Warnings and Precautions (5.5)].

Discontinuation Syndrome: Advise patients not to abruptly discontinue citalopram tablets and to discuss any tapering regimen with their healthcare provider. Inform patients that adverse reactions can occur when citalopram tablets are discontinued [see Warnings and Precautions (5.6)].

Sexual Dysfunction: Advise patients that use of citalopram tablets may cause symptoms of sexual dysfunction in both male and female patients. Inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider [see Warnings and Precautions (5.10)].

Pregnancy:

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Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with citalopram tablets [see Use in Specific Populations (8.1)].

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Advise patients that citalopram tablets use late in pregnancy may lead to an increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, tube feeding, and/or persistent pulmonary hypertension of the newborn (PPHN) [see Use in Specific Populations (8.1)].

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Advise women that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to citalopram during pregnancy [see Use in Specific Populations (8.1)].

Lactation: Advise breastfeeding women to monitor infants for excess sedation, restlessness, agitation, poor feeding and poor weight gain and to seek medical care if they notice these signs [see Use in Specific Populations (8.2)].