escitalopram 15 mg Capsule, 30-count — NDC 52427-795-30 (Billing 52427-0795-30)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action The mechanism of antidepressant action of escitalopram, the S-enantiomer of racemic citalopram, 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).

12.2Pharmacodynamics In vitro and in vivo studies in animals suggest that escitalopram is a highly selective serotonin reuptake inhibitor (SSRI) with minimal effects on norepinephrine and dopamine neuronal reuptake. Escitalopram is at least 100-fold more potent than the R-enantiomer with respect to inhibition of 5-HT reuptake and inhibition of 5-HT neuronal firing rate. Tolerance to a model of antidepressant effect in rats was not induced by long-term (up to 5 weeks) treatment with escitalopram.

Escitalopram has no or very low affinity for serotonergic (5-HT 1-7 ) or other receptors including alpha- and beta-adrenergic, dopamine (D 1-5 ), histamine (H 1-3 ), muscarinic (M 1-5 ), and benzodiazepine receptors. Escitalopram also does not bind to, or has low affinity for, various ion channels including Na + , K + , Cl - , and Ca ++ channels. Antagonism of muscarinic, histaminergic, and adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular side effects of other psychotropic drugs.

In vitro studies show that escitalopram is at least 7 and 27 times more potent than S-demethylcitalopram (S-DCT) and S-didemethylcitalopram (S-DDCT), respectively, in the inhibition of serotonin reuptake, suggesting that the metabolites of escitalopram do not contribute significantly to the antidepressant actions of escitalopram. S-DCT and S-DDCT also have no or very low affinity for serotonergic (5-HT 1-7 ) or other receptors including alpha- and beta-adrenergic, dopamine (D 1-5 ), histamine (H 1-3 ), muscarinic (M 1-5 ), and benzodiazepine receptors.

S-DCT and S-DDCT also do not bind to various ion channels including Na + , K + , Cl - , and Ca ++ channels. Alcohol Escitalopram did not potentiate the cognitive and motor effects of alcohol in a clinical trial [see Drug Interactions ( 7 )] . Cardiac Electrophysiology QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg) controlled cross-over, escalating multiple dose study in 113 healthy subjects.

The maximum mean (95% upper confidence bound) difference from the placebo arm were 4.5 (6.4) and 10.7 (12.7) msec for 10 mg and 30 mg (1.5 times the maximum recommend dose) escitalopram given once daily, respectively. Based on the established exposure-response relationship, the predicted QTcF change from placebo arm (95% confidence interval) under the C max for the dose of 20 mg is 6.6 (7.9) msec. Escitalopram 30 mg given once daily resulted in mean C max of 1.7-fold higher than the mean C max for the maximum recommended dose of another escitalopram product at steady state (20 mg).

The exposure under the 30 mg dose is similar to the steady state concentrations expected in CYP2C19 poor metabolizers following a dose of 20 mg.

12.3Pharmacokinetics The single- and multiple-dose pharmacokinetics of escitalopram are linear and dose-proportional in a dose range of 10 to 30 mg/day. With once-daily dosing, steady state plasma concentrations are achieved within approximately one week. At steady state, the extent of accumulation of escitalopram in plasma in young healthy subjects was 2.2-2.5 times the plasma concentrations observed after a single dose.

Absorption The absolute bioavailability of citalopram is about 80% relative to an intravenous dose. Effect of Food Following the administration of a single oral dose of 15 mg Escitalopram Capsules to healthy volunteers, peak blood plasma levels occur at about (T max median) 4.5 hours under fasting condition and 5.0 hours under fed condition. Absorption of escitalopram is not affected by food.

Distribution The binding of escitalopram to human plasma proteins is… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action The mechanism of antidepressant action of escitalopram, the S-enantiomer of racemic citalopram, 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).

12.3Pharmacokinetics The single- and multiple-dose pharmacokinetics of escitalopram are linear and dose-proportional in a dose range of 10 to 30 mg/day. With once-daily dosing, steady state plasma concentrations are achieved within approximately one week. At steady state, the extent of accumulation of escitalopram in plasma in young healthy subjects was 2.2-2.5 times the plasma concentrations observed after a single dose.

Absorption The absolute bioavailability of citalopram is about 80% relative to an intravenous dose. Effect of Food Following the administration of a single oral dose of 15 mg Escitalopram Capsules to healthy volunteers, peak blood plasma levels occur at about (T max median) 4.5 hours under fasting condition and 5.0 hours under fed condition. Absorption of escitalopram is not affected by food.

Distribution The binding of escitalopram to human plasma proteins is approximately 56%. The volume of distribution of citalopram is about 12 L/kg. Data specific on escitalopram are unavailable.

Elimination Biotransformation of escitalopram is mainly hepatic, with a mean terminal half-life of about 27-32 hours. The oral clearance of escitalopram is 600 mL/min, with approximately 7% of that due to renal clearance. Metabolism Escitalopram is metabolized to S-demethylcitalopram (S-DCT) and S-didemethylcitalopram (S-DDCT).

In humans, unchanged escitalopram is the predominant compound in plasma. At steady state, the concentration of the escitalopram metabolite S-DCT in plasma is approximately one-third that of escitalopram. The level of S-DDCT was not detectable in most subjects.

In vitro studies using human liver microsomes indicated that CYP3A4 and CYP2C19 are the primary isozymes involved in the N-demethylation of escitalopram. Excretion Following oral administrations of escitalopram, the fraction of drug recovered in the urine as escitalopram and S-DCT is about 8% and 10%, respectively. Specific Populations Pediatric Patients Pediatric patients 12 to 17 years of age: In a single dose study of 10 mg escitalopram, AUC of escitalopram decreased by 19%, and C max increased by 26% in healthy pediatric subjects 12 to 17 years of age compared to adults.

Following multiple dosing of 40 mg/day citalopram, escitalopram elimination half-life, steady-state C max and AUC were similar in pediatric patients 12 to 17 years of age with MDD compared to adults [see Use in Specific Populations ( 8.4 )] . Additional pediatric use information is approved for AbbVie Inc.’s LEXAPRO (escitalopram) tablets and LEXAPRO (escitalopram) oral solution. However, due to AbbVie Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

Geriatric Patients Escitalopram pharmacokinetics in subjects ≥ 65 years of age were compared to adults in a single-dose and a multiple-dose study. Escitalopram AUC and half-life were increased by approximately 50% in geriatric subjects, and C max was unchanged [see Use in Specific Populations ( 8.5 )] . Male and Female Patients Based on data from single- and multiple-dose studies measuring escitalopram in geriatric, young adults, and adolescents, no dosage adjustment on the basis of gender is needed.

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 Use in Specific Populations ( 8.6 )] . Patients with Renal Impairment In patients with mild to moderate renal function impairment, oral clearance of citalopram was reduced by 17% compared to normal subjects. No information is available about the pharmacokinetics of escitalopram in patients with severely reduced renal function (creatinine clearance < 20 mL/min).

Drug Interaction Studies In vitro enzyme inhibition data did not reveal an inhibitory effect of escitalopram on CYP3A4, -1A2, -2C9, -2C19, and -2E1. Based on in vitro data, escitalopram would be expected to have little inhibitory effect on in vivo metabolism med… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics In vitro and in vivo studies in animals suggest that escitalopram is a highly selective serotonin reuptake inhibitor (SSRI) with minimal effects on norepinephrine and dopamine neuronal reuptake. Escitalopram is at least 100-fold more potent than the R-enantiomer with respect to inhibition of 5-HT reuptake and inhibition of 5-HT neuronal firing rate. Tolerance to a model of antidepressant effect in rats was not induced by long-term (up to 5 weeks) treatment with escitalopram.

Escitalopram has no or very low affinity for serotonergic (5-HT 1-7 ) or other receptors including alpha- and beta-adrenergic, dopamine (D 1-5 ), histamine (H 1-3 ), muscarinic (M 1-5 ), and benzodiazepine receptors. Escitalopram also does not bind to, or has low affinity for, various ion channels including Na + , K + , Cl - , and Ca ++ channels. Antagonism of muscarinic, histaminergic, and adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular side effects of other psychotropic drugs.

In vitro studies show that escitalopram is at least 7 and 27 times more potent than S-demethylcitalopram (S-DCT) and S-didemethylcitalopram (S-DDCT), respectively, in the inhibition of serotonin reuptake, suggesting that the metabolites of escitalopram do not contribute significantly to the antidepressant actions of escitalopram. S-DCT and S-DDCT also have no or very low affinity for serotonergic (5-HT 1-7 ) or other receptors including alpha- and beta-adrenergic, dopamine (D 1-5 ), histamine (H 1-3 ), muscarinic (M 1-5 ), and benzodiazepine receptors.

S-DCT and S-DDCT also do not bind to various ion channels including Na + , K + , Cl - , and Ca ++ channels. Alcohol Escitalopram did not potentiate the cognitive and motor effects of alcohol in a clinical trial [see Drug Interactions ( 7 )] . Cardiac Electrophysiology QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg) controlled cross-over, escalating multiple dose study in 113 healthy subjects.

The maximum mean (95% upper confidence bound) difference from the placebo arm were 4.5 (6.4) and 10.7 (12.7) msec for 10 mg and 30 mg (1.5 times the maximum recommend dose) escitalopram given once daily, respectively. Based on the established exposure-response relationship, the predicted QTcF change from placebo arm (95% confidence interval) under the C max for the dose of 20 mg is 6.6 (7.9) msec. Escitalopram 30 mg given once daily resulted in mean C max of 1.7-fold higher than the mean C max for the maximum recommended dose of another escitalopram product at steady state (20 mg).

The exposure under the 30 mg dose is similar to the steady state concentrations expected in CYP2C19 poor metabolizers following a dose of 20 mg.

14 CLINICAL STUDIES

14.1Major Depressive Disorder The efficacy of Escitalopram Capsules 15 mg once daily for the treatment for major depressive disorder (MDD) in adults younger than 65 years of age and pediatric patients 12 years of age and older is based upon adequate and well-controlled studies of another escitalopram product with dosing ranging from 10 to 20 mg once daily. The results of these adequate and well-controlled studies are presented below. Adults The efficacy of escitalopram for the treatment of MDD in adults was established in three, 8-week, placebo-controlled studies conducted in outpatients between 18 and 65 years of age who met DSM-IV criteria for MDD.

The primary outcome in all three studies was change from baseline to endpoint in the Montgomery Asberg Depression Rating Scale (MADRS). A fixed-dose study compared 10 mg daily escitalopram and 20 mg daily escitalopram to placebo and 40 mg daily citalopram. The 10 mg daily and 20 mg daily escitalopram treatment groups showed statistically significant greater mean improvement compared to placebo on the MADRS.

The 10 mg and 20 mg escitalopram groups were similar on this outcome measure. In a second fixed-dose study of 10 mg daily escitalopram and placebo, the 10 mg daily escitalopram treatment group showed statistically significant greater mean improvement compared to placebo on the MADRS. In a flexible-dose study, comparing escitalopram, titrated between 10 mg and 20 mg daily, to placebo and citalopram, titrated between 20 mg and 40 mg daily, the escitalopram treatment group showed statistically significant greater mean improvement compared to placebo on the MADRS.

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. In a longer-term trial, 274 patients meeting (DSM-IV) criteria for MDD, who had responded during an initial 8 week, open-label treatment phase with escitalopram 10 mg or 20 mg daily, were randomized to continuation of escitalopram at their same dose, or to placebo, for up to 36 weeks of observation for relapse. Response during the open-label phase was defined by having a decrease of the MADRS total score to ≤ 12.

Relapse during the double-blind phase was defined as an increase of the MADRS total score to ≥ 22, or discontinuation due to insufficient clinical response. Patients receiving continued escitalopram experienced a statistically significant longer time to relapse compared to those receiving placebo. Pediatric Patients 12 Years of Age and Older The efficacy of escitalopram for the treatment of MDD in pediatric patients 12 to 17 years of age was established in an 8-week, flexible-dose, placebo-controlled study that compared escitalopram (10 mg to 20 mg daily) to placebo in outpatients 12 to 17 years of age inclusive who met DSM-IV criteria for MDD.

The primary outcome was change from baseline to endpoint in the Children’s Depression Rating Scale - Revised (CDRS-R). In this study, escitalopram showed statistically significant greater mean improvement compared to placebo on the CDRS-R. The efficacy of escitalopram for the treatment of MDDin pediatric patients 12 to 17 years of age was established, in part, on the basis of extrapolation from the 8-week, flexible-dose, placebo-controlled study with racemic citalopram 20 mg to 40 mg daily.

In this outpatient study in pediatric patients 7 to 17 years of age who met DSM-IV criteria for MDD, citalopram treatment showed statistically significant greater mean improvement from baseline, compared to placebo, on the CDRS-R; the positive results for this trial largely came from the 12 to 17 year subgroup. Two additional flexible-dose, placebo-controlled MDD studies (one escitalopram study in patients ages 7 to 17 years and one citalopram study in patients ages 13 to 18 years) did not demonstrate efficacy. The safety and effectiveness of Escitalopram Capsules have not been established in… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Racemic 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 racemic citalopram in mice receiving up to 240 mg/kg/day. There was an increased incidence of small intestine carcinoma in rats receiving 8 or 24 mg/kg/day racemic citalopram.

A no-effect dose for this finding was not established. The relevance of these findings to humans is unknown. Mutagenesis Racemic 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. Racemic 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.

Impairment of Fertility When racemic 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. Gestation duration was increased at 48 mg/kg/day .

13.2Animal 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 racemic citalopram. There was an increase in both incidence and severity of retinal pathology in both male and female rats receiving 80 mg/kg/day. Similar findings were not present in rats receiving 24 mg/kg/day of racemic citalopram for two years, in mice receiving up to 240 mg/kg/day of racemic citalopram for 18 months, or in dogs receiving up to 20 mg/kg/day of racemic citalopram for one year.

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. Cardiovascular Changes in Dogs In a one-year toxicology study, 5 of 10 beagle dogs receiving oral racemic citalopram doses of 8 mg/kg/day died suddenly between weeks 17 and 31 following initiation of treatment. Sudden deaths were not observed in rats at doses of racemic citalopram up to 120 mg/kg/day, which produced plasma levels of citalopram and its metabolites demethylcitalopram and didemethylcitalopram (DDCT) similar to those observed in dogs at 8 mg/kg/day.

A subsequent intravenous dosing study demonstrated that in beagle dogs, racemic DDCT caused QT prolongation, a known risk factor for the observed outcome in dogs.