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Pharmacology: Pharmacodynamics: Sertraline is a potent and selective inhibitor of neuronal serotonin (5-HT) reuptake in vitro, which results in the potentiation of the effects of 5-HT in animals. It has only very weak effects on norepinephrine and dopamine neuronal reuptake. At clinical doses, sertraline blocks the uptake of serotonin into human platelets. It is devoid of stimulant, sedative or anticholinergic activity or cardiotoxicity in animals. In controlled studies in normal volunteers, sertraline did not cause sedation and did not interfere with psychomotor performance. In accord with its selective inhibition of 5-HT uptake, sertraline does not enhance catecholaminergic activity. Sertraline has no affinity for muscarinic (cholinergic), serotonergic, dopaminergic, adrenergic, histaminergic, gamma-aminobutyric acid (GABA) or benzodiazepine receptors. The chronic administration of sertraline in animals was associated with down regulation of brain norepinephrine receptors as observed with other clinically effective antidepressants and anti-obsessional drugs.
Sertraline has not demonstrated potential for abuse. In a placebo-controlled, double-blind randomized study of the comparative abuse liability of sertraline, alprazolam and d-amphetamine in humans, sertraline did not produce positive subjective effects indicative of abuse potential. In contrast, subjects rated both alprazolam and d-amphetamine significantly greater than placebo on measures of drug liking, euphoria and abuse potential. Sertraline did not produce either the stimulation and anxiety associated with d-amphetamine or the sedation and psychomotor impairment associated with alprazolam. Sertraline does not function as a positive reinforcer in rhesus monkeys trained to self-administer cocaine, nor does it substitute as a discriminative stimulus for either d-amphetamine or pentobarbital in rhesus monkeys.
Clinical Trials: Major Depressive Disorder: A study was conducted that involved depressed outpatients 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 for 44 weeks on double-blind sertraline 50 mg/day to 200 mg/day or placebo. A statistically significantly lower relapse rate was observed for patients taking sertraline compared to those on placebo. The mean dose for completers was 70 mg/day.
Obsessive-Compulsive Disorder: In a long-term study, patients meeting DSM-III-R criteria for OCD who had responded during a 52-week single-blind trial on sertraline 50 mg/day to 200 mg/day (n=224) were randomized to continuation of sertraline or to substitution of placebo for up to 28 weeks of observation for discontinuation due to relapse or insufficient clinical response. Patients receiving continued sertraline treatment experienced a significantly lower rate of discontinuation due to relapse or insufficient clinical response over the subsequent 28 weeks compared to those receiving placebo. This pattern was demonstrated in male and female subjects.
Panic Disorder: In a long-term study, patients meeting DSM-III-R criteria for panic disorder who had responded during a 52 week open trial on sertraline 50 mg/day to 200 mg/day (n=183) were randomized to continuation of sertraline or to substitution of placebo for up to 28 weeks of observation for discontinuation due to relapse or insufficient clinical response. Patients receiving continued sertraline treatment experienced a significantly lower rate of discontinuation due to relapse or insufficient clinical response over the subsequent 28 weeks compared to those receiving placebo. This pattern was demonstrated in male and female subjects.
Post-traumatic Stress Disorder: In a long-term study, patients meeting DSM-III-R criteria for PTSD who had responded during a 24-week open trial on sertraline 50 mg/day to 200 mg/day (n=96) were randomized to continuation of sertraline or to substitution of placebo for up to 28 weeks of observation for relapse. Patients receiving continued sertraline treatment experienced significantly lower relapse rates over the subsequent 28 weeks compared to those receiving placebo. This pattern was demonstrated in male and female subjects.
Social Phobia (Social Anxiety Disorder): In a social phobia relapse prevention study, patients who were responders at the end of a 20-week, multicenter, flexible-dose study that compared sertraline (50 mg/day to 200 mg/day) to placebo were re-randomized for an additional 24 weeks to either sertraline continuation treatment (within 50 mg/day to 200 mg/day) or placebo substitution, while placebo responders remained on placebo. Patients receiving sertraline continuation treatment experienced a statistically significantly lower relapse rate over this 24-week study than patients randomized to placebo substitution treatment.
Cardiac Electrophysiology: In a dedicated thorough QTc study, conducted at steady-state at supratherapeutic exposures in healthy volunteers (treated with 400 mg/day, twice the maximum recommended daily dose), the upper bound of the 2-sided 90% CI for the time matched Least Square mean difference of QTcF between sertraline and placebo (11.666 msec) was greater than the predefined threshold of 10 msec at the 4-hour postdose time point. Exposure-response analysis indicated a slightly positive relationship between QTcF and sertraline plasma concentrations [0.036 msec/(ng/mL); p<0.0001]. Based on the exposure-response model, the threshold for clinically significant prolongation of the QTcF (i.e., for predicted 90% CI to exceed 10 msec) is at least 2.6-fold greater than the average Cmax (86 ng/mL) following the highest recommended dose of sertraline (200 mg/day) (see Precautions, Interactions, Adverse Reactions and Overdosage).
Pediatric Population: Post-marketing safety study SPRITES: An observational post-approval study of 941 patients aged 6 to 16 years was conducted to evaluate the long-term safety of treatment with sertraline (with and without psychotherapy) compared with psychotherapy on cognitive, emotional, physical, and pubertal maturation for up to 3 years. This study was conducted in clinical practice settings in children and adolescents with primary diagnoses of obsessive compulsive disorder, depression, or other anxiety disorders and evaluated cognition [assessed by the Trails B test and the Metacognition Index from the Behavior Rating Inventory of Executive Function (BRIEF), behavioral/emotional regulation (assessed by the Behavioral Regulation Index from the BRIEF) and physical/pubertal maturation (assessed by standardized height/weight/body mass index (BMI) and Tanner Stage)]. Sertraline is approved in the pediatric population only for patients aged 6 years of age and older with OCD (see Indications/Uses).
Standardization of each primary outcome measure based on sex and age norms showed that the overall results were consistent with normal development. No statistically significant differences were observed for the primary outcome measures, with the exception of weight. A statistically significant finding for standardized weight was observed in comparative analyses; however, the magnitude of the change in weight was small [mean (SD) change in standardized z-scores <0.5 SD] and observed mainly at higher doses.
Pharmacokinetics: Sertraline exhibits dose-proportional pharmacokinetics over the range of 50 mg to 200 mg. In man, following oral once-daily dosing over the range of 50 mg to 200 mg for 14 days, peak plasma concentrations (Cmax) of sertraline occur at about 4.5 to 8.4 hours post-dosing. The pharmacokinetic profile in either adolescents or the elderly is not significantly different from that in adults between 18 and 65 years. The mean half-life of sertraline for young and elderly men and women ranges from 22 to 36 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. Approximately 98% of the circulating drug is bound to plasma proteins. Animal studies indicate that sertraline has a large apparent volume of distribution. The pharmacokinetics of sertraline in pediatric OCD patients have been shown to be comparable to adults (although pediatric patients metabolize sertraline with slightly greater efficiency). However, lower doses may be advisable for pediatric patients, given their lower body weights (especially those patients aged 6-12 years), in order to avoid excessive plasma levels.
Sertraline undergoes extensive first-pass hepatic metabolism. The principal metabolite in plasma, N-desmethylsertraline, is substantially less active (about 20 times) than sertraline in vitro, and there is no evidence of activity in in vivo models of depression. The half-life of N-desmethylsertraline is in the range of 62 to 104 hours. Sertraline and N-desmethylsertraline are both extensively metabolized in man and the resultant metabolites excreted in feces and urine in equal amounts. Only a small amount (<0.2%) of unchanged sertraline is excreted in urine.
Food does not significantly change the bioavailability of sertraline tablets.
Toxicology: Preclinical Safety Data: Extensive chronic safety evaluation studies in animals show that sertraline is generally well tolerated at doses that are appreciable multiples of those that are clinically effective. Sertraline has also been shown to be devoid of mutagenic effects.
Juvenile Animal Studies: In a juvenile toxicology study in Sprague-Dawley rats, dose levels of 0, 10, 40 or 80 mg/kg/day of sertraline were administered orally to male and female rats on postnatal Days 21 through 56, with a non-dosing recovery phase up to postnatal Day 196. The administration of 80 mg/kg of sertraline to males and females on postnatal Days 21 to 56 resulted in dehydration, chromorhinorrhea and reduced average body weight gain. In addition, rales, hunched posture and reduced food consumption also occurred in male rats given 80 mg/kg/day. Delays in sexual maturation occurred in males (80 mg/kg/day) and females (≥10 mg/kg/day), but despite this finding there were no sertraline-related effects on any of the male (organ weights, mating and fertility, sperm motility or sperm concentration) or female (estrous cycling, mating and fertility, or ovarian and uterine parameters) reproductive endpoints that were assessed. There were no sertraline-related effects on any behavior parameter (learning and memory, auditory startle response, and locomotor activity) in males, while a decrease in auditory startle response occurred in females at 40 and 80 mg/kg/day. There were no sertraline-related effects on male or female femur lengths, brain weights, gross necropsy or microscopic observations at any dose level. In juvenile males, the no-observed-adverse-effect level (NOAEL) for general toxicity was 40 mg/kg/day (correlating to a Cmax of 262 ng/mL and an AUC0-t of 3170 ng·hr/mL on postnatal Day 56). In juvenile females, the NOAEL could not be established based on the delays in sexual maturation that occurred at ≥10 mg/kg. All of the aforementioned effects attributed to the administration of sertraline were reversed at some point during the non-dosing recovery phase of the study. The clinical relevance of these effects observed in rats administered sertraline has not been established.
Animal studies on fertility: In two studies conducted in rats, collective evidence did not show an effect on fertility parameters.
