Sertraline HCl 150 mg Capsule, 30-count — NDC 69238-2789-1 (Billing 69238-2789-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Sertraline potentiates serotonergic activity in the central nervous system through inhibition of neuronal reuptake of serotonin (5-HT).

12.2Pharmacodynamics Studies at clinically relevant doses have demonstrated that sertraline blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that sertraline is a potent and selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro studies have shown that sertraline has no significant affinity for adrenergic (alpha1, alpha2, beta), cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5HT1A, 5HT1B, 5HT2), or benzodiazepine receptors.

The chronic administration of sertraline was found in animals to down regulate brain norepinephrine receptors. Sertraline does not inhibit monoamine oxidase. Alcohol In healthy subjects, the acute cognitive and psychomotor effects of alcohol were not potentiated by sertraline.

Cardiac Electrophysiology The effect of sertraline on the QTc interval was evaluated in a randomized, double-blind, placebo-and positive-controlled three-period crossover thorough QTc study in 54 healthy adult subjects. At 2-fold the maximum recommended daily dose (~3-fold the steady-state exposure for sertraline and N­-desmethylsertraline), the largest mean ΔΔQTc was 10 ms with upper bound of two-sided 90% confidence interval of 12 ms. The length of the QTc interval was also positively correlated with serum concentrations of sertraline and N-desmethylsertraline concentrations.

These concentration-based analyses, however, indicated a lesser effect on QTc at maximally observed concentration than in the primary analysis [see Warnings and Precautions (5.10), Adverse Reactions (6), Drug Interactions (7.1), Overdosage (10)].

12.3Pharmacokinetics Absorption Following a single dose of Sertraline HCl Capsule at 150 mg, the mean peak plasma concentrations (C max ) of sertraline occurred between 4.5 hours to 8.4 hours post-dosing. The average terminal elimination half-life of plasma sertraline is about 26 hours. Consistent with the terminal elimination half-life, there is an approximately two-fold accumulation up to steady-state concentrations, which are achieved after one week of once-daily dosing.

Linear dose-proportional pharmacokinetics are likely over a range of 150 mg to 200 mg. Effect of Food Administration of Sertraline HCl Capsules with food causes a small increase in C max and AUC. Distribution In vitro protein binding studies performed with radiolabeled 3H-sertraline showed that sertraline is highly bound to serum proteins (98%) in the range of 20 ng/mL to 500 ng/mL.

However, at up to 300 ng/mL and 200 ng/mL concentrations, respectively, sertraline and N-desmethylsertraline did not alter the plasma protein binding of two other highly protein bound drugs, warfarin and propranolol. Elimination Metabolism Sertraline undergoes extensive first pass metabolism. The principal initial pathway of metabolism for sertraline is N-demethylation.

N-desmethylsertraline has a plasma terminal elimination half-life of 62 hours to 104 hours. Both in vitro biochemical and in vivo pharmacological testing have shown N-desmethylsertraline to be substantially less active than sertraline. Excretion Both sertraline and N-desmethylsertraline undergo oxidative deamination and subsequent reduction, hydroxylation, and glucuronide conjugation.

In a study of radiolabeled sertraline involving two healthy male subjects, sertraline accounted for less than 5% of the plasma radioactivity. About 40% to 45% of the administered radioactivity was recovered in urine in 9 days. Unchanged sertraline was not detectable in the urine.

For the same period, about 40% to 45% of the administered radioactivity was accounted for in feces, including 12% to 14% unchanged sertraline. Desmethylsertraline exhibits time-related, dose dependent increases in AUC (0 h… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Sertraline potentiates serotonergic activity in the central nervous system through inhibition of neuronal reuptake of serotonin (5-HT).

12.3Pharmacokinetics Absorption Following a single dose of Sertraline HCl Capsule at 150 mg, the mean peak plasma concentrations (C max ) of sertraline occurred between 4.5 hours to 8.4 hours post-dosing. The average terminal elimination half-life of plasma sertraline is about 26 hours. Consistent with the terminal elimination half-life, there is an approximately two-fold accumulation up to steady-state concentrations, which are achieved after one week of once-daily dosing.

Linear dose-proportional pharmacokinetics are likely over a range of 150 mg to 200 mg. Effect of Food Administration of Sertraline HCl Capsules with food causes a small increase in C max and AUC. Distribution In vitro protein binding studies performed with radiolabeled 3H-sertraline showed that sertraline is highly bound to serum proteins (98%) in the range of 20 ng/mL to 500 ng/mL.

However, at up to 300 ng/mL and 200 ng/mL concentrations, respectively, sertraline and N-desmethylsertraline did not alter the plasma protein binding of two other highly protein bound drugs, warfarin and propranolol. Elimination Metabolism Sertraline undergoes extensive first pass metabolism. The principal initial pathway of metabolism for sertraline is N-demethylation.

N-desmethylsertraline has a plasma terminal elimination half-life of 62 hours to 104 hours. Both in vitro biochemical and in vivo pharmacological testing have shown N-desmethylsertraline to be substantially less active than sertraline. Excretion Both sertraline and N-desmethylsertraline undergo oxidative deamination and subsequent reduction, hydroxylation, and glucuronide conjugation.

In a study of radiolabeled sertraline involving two healthy male subjects, sertraline accounted for less than 5% of the plasma radioactivity. About 40% to 45% of the administered radioactivity was recovered in urine in 9 days. Unchanged sertraline was not detectable in the urine.

For the same period, about 40% to 45% of the administered radioactivity was accounted for in feces, including 12% to 14% unchanged sertraline. Desmethylsertraline exhibits time-related, dose dependent increases in AUC (0 hour to 24-hour), C max and C min , with about a 5-fold to 9-fold increase in these pharmacokinetic parameters between day 1 and day 14. Specific Populations Pediatric Patients Sertraline pharmacokinetics were evaluated in a group of 61 pediatric patients (29 aged 6 years to 12 years, 32 aged 13 years to 17 years) including both males (N = 28) and females (N = 33).

Relative to the adults, pediatric patients aged 6 years to 12 years and 13 years to 17 years showed about 22% lower AUC (0-24 hr) and C max values when plasma concentration was adjusted for weight. The half-life was similar to that in adults, and no gender-associated differences were observed [see Dosage and Administration (2.1), Use in Specific Populations (8.4)]. Geriatric Patients Sertraline plasma clearance in a group of 16 (8 male, 8 female) elderly patients treated with 100 mg/day of another sertraline HCl product for 14 days was approximately 40% lower than in a similarly studied group of younger (25 years to 32 years old) individuals.

Steady-state, therefore, was achieved after 2 weeks to 3 weeks in older patients. The same study showed a decreased clearance of desmethylsertraline in older males, but not in older females [see Use in Specific Populations (8.5)]. Patients with Hepatic Impairment In patients with chronic mild liver impairment (N = 10: 8 patients with Child-Pugh scores of 5 to 6; and 2 patients with Child-Pugh scores of 7-8) who received 50 mg of another sertraline HCl product per day for 21 days, sertraline clearance was reduced, resulting in approximately 3-fold greater exposure compared to age-matched volunteers with normal hepatic function (N = 10).

The exposure to desmethylsertraline was approximately 2-fold greater in patients with mild hepatic impairment compared to age-matched volunteers with normal hepatic function. There were no significant differe… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Studies at clinically relevant doses have demonstrated that sertraline blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that sertraline is a potent and selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro studies have shown that sertraline has no significant affinity for adrenergic (alpha1, alpha2, beta), cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5HT1A, 5HT1B, 5HT2), or benzodiazepine receptors.

The chronic administration of sertraline was found in animals to down regulate brain norepinephrine receptors. Sertraline does not inhibit monoamine oxidase. Alcohol In healthy subjects, the acute cognitive and psychomotor effects of alcohol were not potentiated by sertraline.

Cardiac Electrophysiology The effect of sertraline on the QTc interval was evaluated in a randomized, double-blind, placebo-and positive-controlled three-period crossover thorough QTc study in 54 healthy adult subjects. At 2-fold the maximum recommended daily dose (~3-fold the steady-state exposure for sertraline and N­-desmethylsertraline), the largest mean ΔΔQTc was 10 ms with upper bound of two-sided 90% confidence interval of 12 ms. The length of the QTc interval was also positively correlated with serum concentrations of sertraline and N-desmethylsertraline concentrations.

These concentration-based analyses, however, indicated a lesser effect on QTc at maximally observed concentration than in the primary analysis [see Warnings and Precautions (5.10), Adverse Reactions (6), Drug Interactions (7.1), Overdosage (10)].

14 CLINICAL STUDIES

14.1Major Depressive Disorder The efficacy of Sertraline HCl Capsules for the treatment of major depressive disorder (MDD) in adult patients is based upon adequate and well-controlled studies of another sertraline HCl product (referred to as “sertraline” in this section). The results of these adequate and well-controlled studies of sertraline are presented below. The efficacy of sertraline as a treatment for MDD was established in two randomized, double-blind, placebo-controlled studies and one double-blind, randomized-withdrawal study following an open label study in adult (ages 18 to 65) outpatients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-III) criteria for MDD (studies MDD-1 and MDD-2).

Study MDD-1 was an 8-week, 3-arm study with flexible dosing of sertraline, amitriptyline, and placebo. Adult patients received sertraline (N = 126, in a daily dose titrated weekly to 50 mg, 100 mg, or 200 mg), amitriptyline (N = 123, in a daily dose titrated weekly to 50 mg, 100 mg, or 150 mg), or placebo (N = 130). Study MDD-2 was a 6-week, multicenter parallel study of three fixed doses of sertraline administered once daily at 50 mg (N = 82), 100 mg (N = 75), and 200 mg (N = 56) doses and placebo (N = 76) in the treatment of adult outpatients with MDD.

Overall, these studies demonstrated sertraline to be superior to placebo on the Hamilton Rating Scale for Depression (HAMD-17) and the Clinical Global Impression Severity (CGI-S) of Illness and Global Improvement (CGI-I) scores. Study MDD-2 was not readily interpretable regarding a dose response relationship for effectiveness. A third study (Study MDD-3) involved adult outpatients meeting the DSM-III criteria for MDD who had responded by the end of an initial 8-week open treatment phase on sertraline 50 mg/day to 200 mg/day.

These patients (n = 295) were randomized to continuation on double-blind sertraline 50 mg/day to 200 mg/day or placebo for 44 weeks. A statistically significantly lower relapse rate was observed for patients taking sertraline compared to those on placebo: sertraline [n = 11 (8%)] and placebo [n = 31 (39%)]. The mean sertraline dose for completers was 70 mg/day.

Analyses for gender effects on outcome did not suggest any differential responsiveness on the basis of sex.

14.2Obsessive-Compulsive Disorder The efficacy of Sertraline HCl Capsules for the treatment of OCD in adults and pediatric patients ages 6 years to 17 years is based upon adequate and well-controlled studies of another sertraline HCl product (referred to as “sertraline” in this section). The results of these adequate and well-controlled studies of sertraline are presented below. Adults with OCD The effectiveness of sertraline in the treatment of OCD was demonstrated in three multicenter placebo-controlled studies of adult (age 18 to 65) non-depressed outpatients (Studies OCD-1, OCD-2, and OCD-3).

Patients in all three studies had moderate to severe OCD (DSM-III or DSM-III-R) with mean baseline ratings on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) total score ranging from 23 to 25. Study OCD-1 was an 8-week randomized, placebo-controlled study with flexible dosing of sertraline in a range of 50 mg/day to 200 mg/day, titrated in 50 mg increments every 4 days to a maximally tolerated dose; the mean dose for completers was 186 mg/day. Patients receiving sertraline (N = 43) experienced a mean reduction of approximately 4 points on the Y-BOCS total score which was statistically significantly greater than the mean reduction of 2 points in placebo-treated patients (N = 44).

The mean change in Y­-BOCS from baseline to last visit (the primary efficacy endpoint) was -3.79 (sertraline) and -1.48 (placebo). Study OCD-2 was a 12-week randomized, placebo-controlled fixed-dose study, including sertraline doses of 50 mg/day, 100 mg/day, and 200 mg/day. Sertraline (N = 240) was titrated to the assigned dose over two weeks in 50 mg increments every 4 days.

Patients re… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Lifetime carcinogenicity studies were carried out in CD-1 mice and Long-Evans rats at doses up to 40 mg/kg/day. These doses correspond to 1 times (mice) and 2 times (rats) the maximum recommended human dose (MRHD) of 200 mg/day on a mg/m 2 basis. There was a dose-related increase of liver adenomas in male mice receiving sertraline at 10 mg/kg to 40 mg/kg (0.25 times to 1.0 times the MRHD on a mg/m 2 basis).

No increase was seen in female mice or in rats of either sex receiving the same treatments, nor was there an increase in hepatocellular carcinomas. Liver adenomas have a variable rate of spontaneous occurrence in the CD-1 mouse and are of unknown significance to humans. There was an increase in follicular adenomas of the thyroid in female rats receiving sertraline at 40 mg/kg (2 times the MRHD on a mg/m 2 basis); this was not accompanied by thyroid hyperplasia.

While there was an increase in uterine adenocarcinomas in rats receiving sertraline at 10 mg/kg to 40 mg/kg (0.5 times to 2.0 times the MRHD on a mg/m 2 basis) compared to placebo controls, this effect was not clearly drug related. Mutagenesis Sertraline had no genotoxic effects, with or without metabolic activation, based on the following assays: bacterial mutation assay; mouse lymphoma mutation assay; and tests for cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes. Impairment of Fertility A decrease in fertility was seen in one of two rat studies at a dose of 80 mg/kg (approximately 4 times the maximum recommended human dose on a mg/m 2 basis in adults).