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Pharmacotherapeutic Group: Antidepressant (Selective Serotonin Reuptake Inhibitor).
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, gammaaminobutyric 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 hydrochloride (Zoloft) 50 mg/day to 200 mg/day. These patients (N=295) were randomized to continuation for 44 weeks on double-blind Sertraline hydrochloride (Zoloft) 50 mg/day to 200 mg/day or placebo. A statistically significantly lower relapse rate was observed for patients taking Sertraline hydrochloride (Zoloft) 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 hydrochloride (Zoloft) 50 mg/day to 200 mg/day (n=224) were randomized to continuation of Sertraline hydrochloride (Zoloft) 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 hydrochloride (Zoloft) 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.
Pre-menstrual Dysphoric Disorder (PMDD): The effectiveness of Sertraline hydrochloride (Zoloft) for the treatment of PMDD was established in two double-blind, parallel group, placebo-controlled flexible dose trials (Studies 1 and 2), conducted over 3 menstrual cycles. Patients in Study 1 met DSM-III-R criteria for Late Luteal Phase Dysphoric Disorder (LLPDD), the clinical entity now referred to as Pre-menstrual Dysphoric Disorder (PMDD) in DSM-IV. Patients in Study 2 met DSM-IV criteria for PMDD. Study 1 utilized daily dosing throughout the study, while Study 2 utilized luteal phase dosing for the 2 weeks prior to the onset of menses. The mean duration of PMDD symptoms for these patients was approximately 10.5 years in both studies. Patients on oral contraceptives were excluded from these trials; therefore, the efficacy of Sertraline hydrochloride (Zoloft) in combination with oral contraceptives for the treatment of PMDD is unknown.
Efficacy was assessed with the Daily Record of Severity of Problems (DRSP), a patient rated instrument that mirrors the diagnostic criteria for PMDD as identified in the DSMIV, and includes assessments for mood, physical symptoms, and other symptoms. Other efficacy assessments included the Hamilton Depression Rating Scale (HAMD-17), and the Clinical Global Impression of Severity of Illness (CGI-S) and Improvement (CGI-I) scores.
In Study 1, involving n=251 randomized patients, Sertraline hydrochloride (Zoloft) treatment was initiated at 50 mg/day and administered daily throughout the menstrual cycle. In subsequent cycles, patients were dosed in the range of 50-150 mg/day on the basis of clinical response and toleration. The mean dose for completers was 102 mg/day. Sertraline hydrochloride (Zoloft) administered daily throughout the menstrual cycle was significantly more effective than placebo on change from baseline to endpoint on the DRSP total score, the HAMD-17 total score, and the CGI-S score, as well as the CGI-I score at endpoint.
In Study 2, involving n=281 randomized patients, Sertraline hydrochloride (Zoloft) treatment was initiated at 50 mg/day in the late luteal phase (last 2 weeks) of each menstrual cycle and then discontinued at the onset of menses. In subsequent cycles, patients were dosed in the range of 50-100 mg/day in the luteal phase of each cycle, on the basis of clinical response and toleration. Patients who were titrated to 100 mg/day received 50 mg/day for the first 3 days of the cycle then 100 mg/day for the remainder of the cycle. The mean Sertraline hydrochloride (Zoloft) dose for completers was 74 mg/day. Sertraline hydrochloride (Zoloft) administered in the late luteal phase of the menstrual cycle was significantly more effective than placebo on change from baseline to endpoint on the DRSP total score and the CGI-S score, as well as the CGI-I score at endpoint.
There was insufficient information to determine the effect of race or age on outcome in these studies.
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 hydrochloride (Zoloft) 50 mg/day to 200 mg/day (n=183) were randomized to continuation of Sertraline hydrochloride (Zoloft) 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 hydrochloride (Zoloft) 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 hydrochloride (Zoloft) 50 mg/day to 200 mg/day (n=96) were randomized to continuation of Sertraline hydrochloride (Zoloft) or to substitution of placebo for up to 28 weeks of observation for relapse. Patients receiving continued Sertraline hydrochloride (Zoloft) 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 hydrochloride (Zoloft) (50 mg/day to 200 mg/day) to placebo were re-randomized for an additional 24 weeks to either Sertraline hydrochloride (Zoloft) continuation treatment (within 50 mg/day to 200 mg/day) or placebo substitution, while placebo responders remained on placebo. Patients receiving Sertraline hydrochloride (Zoloft) 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 hydrochloride (Zoloft) and placebo (11.666 msec) was greater than the predefined threshold of 10 msec at the 4-hour post dose time point. Exposure-response analysis indicated a slightly positive relationship between QTcF and Sertraline hydrochloride (Zoloft) 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 hydrochloride (Zoloft) (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).
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 hydrochloride (Zoloft) 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 hydrochloride (Zoloft) 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 hydrochloride (Zoloft) 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 hydrochloride (Zoloft) has a large apparent volume of distribution. The pharmacokinetics of Sertraline hydrochloride (Zoloft) in pediatric OCD patients have been shown to be comparable to adults (although pediatric patients metabolize Sertraline hydrochloride (Zoloft) 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 hydrochloride (Zoloft) undergoes extensive first-pass hepatic metabolism. The principal metabolite in plasma, N-desmethylsertraline, is substantially less active (about 20 times) than Sertraline hydrochloride (Zoloft) 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 hydrochloride (Zoloft) 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 hydrochloride (Zoloft) is excreted in urine.
Food does not significantly change the bioavailability of Sertraline hydrochloride (Zoloft) film-coated tablets.
Toxicology: Preclinical Safety Data: Extensive chronic safety evaluation studies in animals show that Sertraline hydrochloride (Zoloft) is generally well tolerated at doses that are appreciable multiples of those that are clinically effective. Sertraline hydrochloride (Zoloft) 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 hydrochloride (Zoloft) were administered orally to male and female rats on post-natal Days 21 through 56, with a non-dosing recovery phase up to post-natal Day 196. The administration of 80 mg/kg of Sertraline hydrochloride (Zoloft) to males and females on post-natal 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 hydrochloride (Zoloft)-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 hydrochloride (Zoloft)-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 hydrochloride (Zoloft)-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 post-natal 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 hydrochloride (Zoloft) 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 hydrochloride (Zoloft) has not been established.
Animal Studies on Fertility: In two studies conducted in rats, collective evidence did not show an effect on fertility parameters.
