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CLINICAL PHARMACOLOGY
Pharmacodynamics
The mechanism of action of sertraline is presumed
to be linked to its inhibition of CNS neuronal uptake
of serotonin (5HT). Studies at clinically relevant doses
in man 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; antagonism of such receptors has been hypothesized
to be associated with various anticholinergic, sedative,
and cardiovascular effects for other psychotropic drugs.
The chronic administration of sertraline was found in
animals to downregulate brain norepinephrine receptors,
as has been observed with other clinically effective antidepressants.
Sertraline does not inhibit monoamine oxidase.
Pharmacokinetics
Systemic Bioavailability: In man, following
oral once-daily dosing over the range of 50 to 200 mg
for 14 days, mean peak plasma concentrations (Cmax)
of sertraline occurred between 4.5 to 8.4 hours post-dosing.
The average terminal elimination half-life of plasma sertraline
is about 26 hours. Based on this pharmacokinetic parameter,
steady-state sertraline plasma levels should be achieved
after approximately one week of once-daily dosing. Linear
dose-proportional pharmacokinetics were demonstrated in
a single dose study in which the Cmax and area
under the plasma concentration time curve (AUC) of sertraline
were proportional to dose over a range of 50 to 200 mg.
Consistent with the terminal elimination half-life, there
is an approximately two-fold accumulation, compared to
a single dose, of sertraline with repeated dosing over
a 50 to 200 mg dose range. The single-dose bioavailability
of sertraline tablets is approximately equal to an equivalent
dose of solution.
In a relative bioavailability study comparing the pharmacokinetics
of 100 mg sertraline as the oral solution to a 100 mg
sertraline tablet in 16 healthy adults, the solution to
tablet ratio of geometric mean AUC and Cmax
values were 114.8% and 120.6%, respectively. Ninety percent
(90%) confidence intervals (CI) were within the range
of 80-125% with the exception of the upper 90% CI limit
for Cmax which was 126.5%.
The effects of food on the bioavailability of sertraline
were studied in subjects administered a single-dose with
and without food. AUC was slightly increased when drug
was administered with food but the Cmax was
25% greater, while the time to reach peak plasma concentration
decreased from 8 hours post-dosing to 5.5 hours. For the
oral concentrate, Tmax was slightly prolonged
from 5.9 hours to 7.0 hours with food.
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 to 104
hours. Both in vitro biochemical and in vivo
pharmacological testing have shown N-desmethylsertraline
to be substantially less active than sertraline. 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 40-45%
of the administered radioactivity was recovered in urine
in 9 days. Unchanged sertraline was not detectable in
the urine. For the same period, about 40-45% of the administered
radioactivity was accounted for in feces, including 12-14%
unchanged sertraline.
Desmethylsertraline exhibits time-related, dose dependent
increases in AUC (0-24 hour), Cmax and Cmin,
with about a five to nine-fold increase in these pharmacokinetic
parameters between day 1 and day 14.
Protein Binding: 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 to 500 ng/ml. However, at up
to 300 and 200 ng/ml concentrations, respectively, sertraline
and N-desmethylsertraline did not alter the plasma protein
binding of two other highly protein bound drugs, viz.,
warfarin and propranolol (see PRECAUTIONS).
Pediatric Pharmacokinetics: Sertraline pharmacokinetics
were evaluated in a group of 61 pediatric patients (29
aged 6-12 years, 32 aged 13-17 years) with a DSM-III-R
diagnosis of depression or obsessive-compulsive disorder.
Patients included both males (n=28) and females (n=33).
During 42 days of chronic sertraline dosing, sertraline
was titrated up to 200 mg/day and maintained at that dose
for a minimum of 11 days. On the final day of sertraline
200 mg/day, the 6-12 year old group exhibited a mean sertraline
AUC(0-24 hr) of 3107 ng·hr/ml, mean
Cmax of 165 ng/ml, and mean half-life of 26.2
hr. The 13-17 year old group exhibited a mean sertraline
AUC(0-24 hr) of 2296 ng-hr/ml, mean Cmax
of 123 ng/ml, and mean half-life of 27.8 hr. Higher plasma
levels in the 6-12 year old group were largely attributable
to patients with lower body weights. No gender associated
differences were observed. By comparison, a group of 22
separately studied adults between 18 and 45 years of age
(11 male, 11 female) received 30 days of 200 mg/day sertraline
and exhibited a mean sertraline AUC(0-24 hr)
of 2570 ng·hr/ml, mean Cmax of 142 ng/ml,
and mean half-life of 27.2 hr. Relative to the adults,
both the 6-12 year olds and the 13-17 year olds showed
about 22% lower AUC(0-24 hr) and Cmax
values when plasma concentration was adjusted for weight.
These data suggest that pediatric patients metabolize
sertraline with slightly greater efficiency than adults.
Nevertheless, lower doses may be advisable for pediatric
patients given their lower body weights, especially in
very young patients, in order to avoid excessive plasma
levels (see DOSAGE AND ADMINISTRATION).
Age: Sertraline plasma clearance in a group
of 16 (8 male, 8 female) elderly patients treated for
14 days at a dose of 100 mg/day was approximately 40%
lower than in a similarly studied group of younger (25
to 32 years old) individuals. Steady state, therefore,
should be achieved after 2 to 3 weeks in older patients.
The same study showed a decreased clearance of desmethylsertraline
in older males, but not in older females.
Liver Disease: As might be predicted from
its primary site of metabolism, liver impairment can effect
the elimination of sertraline. The elimination of half-life
of sertraline was prolonged in a single dose study of
patients with mild, stable cirrhosis, with a mean of 52
hours compared to 22 hours seen in subjects without liver
disease. In hepatically impaired patients, it was observed
that the Cmax and AUC were increased by 1.7
and 4.4 fold, respectively, compated to healthy subjects.
This suggests that the use of sertraline in patients with
liver disease must be approached with caution. If sertraline
HCl is administered to patients with liver disease, a
lower or less frequent dose should be used (see PRECAUTIONS
and DOSAGE AND ADMINISTRATION).
Renal Disease: The pharmacokinetics of sertraline
HCl in patients with significant renal dysfunction have
not been determined.
CLINICAL STUDIES
Depression
The efficacy of sertraline HCl as a treatment for
depression was established in two placebo-controlled studies
in adult outpatients meeting DSM-III criteria for major
depression. Study 1 was an 8-week study with flexible
dosing of sertraline HCl in a range of 50 to 200 mg/day:
the mean dose for completers was 145 mg/day. Study 2 was
a 6-week fixed-dose study, including sertraline HCl doses
of 50, 100, and 200 mg/day. Overall, these studies demonstrated
sertraline HCl to be superior to placebo on the Hamilton
Depression Rating Scale and the Clinical Global Impression
Severity and Improvement scales. Study 2 was not readily
interpretable regarding a dose response relationship for
effectiveness.
Study 3 involved depressed outpatients who had responded
by the end of an initial 8-week open treatment phase on
sertraline HCl 50-200 mg/day. These patients (N=295) were
randomized to continuation for 44 weeks on double-blind
sertraline HCl 50-200 mg/day or placebo. A statistically
significantly lower relapse rate was observed for patients
taking sertraline HCl compared to those on placebo. The
mean dose for completers was 70 mg/day.
Analyses for gender effects on outcome did not suggest
any differential responsiveness on the basis of sex.
Obsessive-Compulsive Disorder (OCD)
The effectiveness of sertraline HCl in the treatment
of OCD was demonstrated in three multicenter placebo-controlled
studies of adult outpatients (Studies 1-3). Patients in
all studies had moderate to severe OCD (DSM-III or DSM-III-R)
with mean baseline ratings on the Yale Brown Obsessive-Compulsive
Scale (YBOCS) total score ranging from 23 to 25.
Study 1 was an 8-week study with flexible dosing of sertraline
HCl in a range of 50 to 200 mg/day, the mean dose for
completers was 186 mg/day. Patients receiving sertraline
HCl experienced a mean reduction of approximately 4 points
on the YBOCS total score which was significantly greater
than the mean reduction of 2 points in placebo-treated
patients.
Study 2 was a 12-week fixed-dose study including sertraline
HCl doses of 50, 100, and 200 mg/day. Patients receiving
sertraline HCl doses of 50 and 200 mg/day experienced
mean reductions of approximately 6 points on the YBOCS
total score which were significantly greater than the
approximately 3 point reduction in placebo-treated patients.
Study 3 was a 12-week study with flexible dosing of sertraline
HCl in a range of 50 to 200 mg/day, the mean dose for
completers was 185 mg/day. Patients receiving sertraline
HCl experienced a mean reduction of approximately 7 points
on the YBOCS total score which was significantly greater
than the mean reduction of approximately 4 points in placebo-treated
patients.
Analyses for age and gender effects on outcome did not
suggest any differential responsiveness on the basis of
age or sex.
The effectiveness of sertraline HCl for the treatment
of OCD was also demonstrated in a 12-week, multicenter,
parallel group study in a pediatric outpatient population
(children and adolescents, ages 6-17). Patients in this
study were initiated at doses of either 25 mg/day (children,
ages 6-12) or 50 mg/day (adolescents, ages 13-17), and
then titrated over the next four weeks to a maximum dose
of 200 mg/day, as tolerated. The mean dose for completers
was 178 mg/day. Dosing was once a day in the morning or
evening. Patients in this study had moderate to severe
OCD (DSM-III-R) with mean baseline ratings on the Children's
Yale-Brown Obsessive-Compulsive Scale (CYBOCS) total score
of 22. Patients receiving sertraline experienced a mean
reduction of approximately 7 units on the CYBOCS total
score which was significantly greater than the 3 unit
reduction for placebo patients.
Analyses for age and gender effects on outcome did not
suggest any differential responsiveness on the basis of
age or sex.
Panic Disorder: The effectiveness of sertraline
HCl in the treatment of panic disorder was demonstrated
in three double-blind, placebo-controlled studies (Studies
1-3) of adult outpatients who had a primary diagnosis
of panic disorder (DSM-III-R), with or without agoraphobia.
Studies 1 and 2 were 10-week flexible dose studies. Sertraline
HCl was initiated at 25 mg/day for the first week, and
then patients were dosed in a range of 50-200 mg/day on
the basis of clinical response and toleration. The mean
sertraline HCl doses for completers to 10 weeks were 131
mg/day and 144 mg/day, respectively, for studies 1 and
2. In these studies, sertraline HCl was shown to be significantly
more effective than placebo on change from baseline in
panic attack frequency and on the Clinical Global Impression
Severity of Illness and Global Improvement scores. The
difference between sertraline HCl and placebo in reduction
from baseline in the number of full panic attacks was
approximately 2 panic attacks per week in both studies.
Study 3 was a 12-week fixed-dose study, including sertraline
HCl doses of 50, 100, and 200 mg/day. Patients receiving
sertraline HCl experienced a significantly greater reduction
in panic attack frequency than patients receiving placebo.
Study 3 was not readily interpretable regarding a dose
response relationship for effectiveness.
Subgroup analyses did not indicate that there were any
differences in treatment outcomes as a function of age,
race, or gender.
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