CLINICAL PHARMACOLOGY
Pharmacodynamics
The antidepressant action of paroxetine (and, for the
immediate-release tablets and oral suspension, its efficacy
in the treatment of social anxiety disorder (for the immediate-release
formulations), obsessive compulsive disorder [OCD], and
panic disorder [PD]) is presumed to be linked to potentiation
of serotonergic activity in the central nervous system
resulting from inhibition of neuronal reuptake of serotonin
(5-hydroxy-tryptamine, 5-HT). Studies at clinically relevant
doses in humans have demonstrated that paroxetine blocks
the uptake of serotonin into human platelets. In vitro
studies in animals also suggest that paroxetine is a potent
and highly selective inhibitor of neuronal serotonin reuptake
and has only very weak effects on norepinephrine and dopamine
neuronal reuptake. In vitro radioligand binding studies
indicate that paroxetine has little affinity for muscarinic,
alpha1-, alpha2-, beta-adrenergic-, dopamine (D2)-, 5-HT1-,
5-HT2- and histamine (H1)-receptors; antagonism of muscarinic,
histaminergic and alpha1-adrenergic receptors has been
associated with various anticholinergic, sedative and
cardiovascular effects for other psychotropic drugs.
Because the relative potencies of paroxetine's major
metabolites are at most 1/50 of the parent compound, they
are essentially inactive.
Pharmacokinetics
Immediate-Release Tablets and Oral Suspension
Paroxetine is equally bioavailable from oral
suspension and tablet.
Paroxetine HCl is completely absorbed after oral dosing
of a solution of the hydrochloride salt. In a study in
which normal male subjects (n=15) received 30 mg immediate-release
tablets daily for 30 days, steady-state paroxetine concentrations
were achieved by approximately 10 days for most subjects,
although it may take substantially longer in an occasional
patient. At steady state, mean values of Cmax, Tmax, Cmin,
and T½ were 61.7 ng/ml (CV 45%), 5.2 hr. (CV (10%),
30.7 ng/ml (CV 67%) and 21.0 hr. (CV 32%), respectively.
The steady-state Cmax and Cmin values were about 6 and
14 times what would be predicted from single-dose studies.
Steady-state drug exposure based on AUC0-24 was about
8 times greater than would have been predicted from single-dose
data in these subjects. The excess accumulation is a consequence
of the fact that one of the enzymes that metabolizes paroxetine
is readily saturable.
Immediate-Release Tablets, Oral Suspension,
and Controlled-Release Tablets
In steady-state dose proportionality studies involving
elderly and nonelderly patients, at doses of the immediate-release
tablets of 20 to 40 mg daily for the elderly and 20 to
50 mg daily for the nonelderly, some nonlinearity was
observed in both populations, again reflecting a saturable
metabolic pathway. In comparison to Cmin values after
20 mg daily, values after 40 mg daily were only about
2 to 3 times greater than doubled.
Paroxetine is extensively metabolized after oral administration.
The principal metabolites are polar and conjugated products
of oxidation and methylation, which are readily cleared.
Conjugates with glucuronic acid and sulfate predominate,
and major metabolites have been isolated and identified.
Data indicate that the metabolites have no more than 1/50
the potency of the parent compound at inhibiting serotonin
uptake. The metabolism of paroxetine is accomplished in
party by cytochrome P450IID6. Saturation of this enzyme
at clinical doses appears to account for the nonlinearity
of paroxetine kinetics with increasing dose and increasing
duration of treatment. The role of this enzyme in paroxetine
metabolism also suggests potential drug-drug interactions
(see DRUG INTERACTIONS).
Approximately 64% of a 30 mg oral solution dose of paroxetine
was excreted in the urine with 2% as the parent compound
and 62% as metabolites over a 10-day post-dosing period.
About 36% was excreted in the feces (probably via the
bile), mostly as metabolites and less than 1% as the parent
compound over the 10-day post-dosing period.
Distribution: Paroxetine distributes
throughout the body, including the CNS, with only 1% remaining
in the plasma.
Protein Binding: Approximately 95% and
93% of paroxetine is bound to plasma protein at 100 ng/ml
and 400 ng/ml, respectively. Under clinical conditions,
paroxetine concentrations would normally be less than
400 ng/ml. Paroxetine does not alter the in vitro protein
binding of phenytoin or warfarin.
Renal and Liver Disease: Increased
plasma concentrations of paroxetine occur in subjects
with renal and hepatic impairment. The mean plasma concentrations
in patients with creatinine clearance below 30 ml/min
was approximately 4 times greater than seen in normal
volunteers. Patients with creatinine clearance of 30 to
60 ml/min and patients with hepatic functional impairment
had about a 2-fold increase in plasma concentrations (AUC,
Cmax).
The initial dosage should therefore be reduced in patients
with severe renal or hepatic impairment, and upward titration,
if necessary, should be at increased intervals (see DOSAGE
AND ADMINISTRATION).
Elderly Patients: In a multiple-dose
study in the elderly at daily paroxetine doses of 20,
30, and 40 mg of the immediate-release tablet formulation,
Cmin concentrations were about 70% to 80% greater than
the respective Cmin concentrations in nonelderly subjects.
Therefore the initial dosage in the elderly should be
reduced (see DOSAGE AND ADMINISTRATION).
Additional Information for Immediate-Release Tablets
and Oral Suspension: The effects of food on the bioavailability
of paroxetine were studied in subjects administered a
single dose with and without food. AUC was only slightly
increased (6%) when drug was administered with food but
the Cmax was 29% greater, while the time to reach peak
plasma concentration decreased from 6.4 hours post-dosing
to 4.9 hours.
Controlled-Release Tablets
Based on studies using immediate-release formulations,
steady-state drug exposure based on studies using standard
tablet formulations, AUC0-24 was several-fold greater
than would have been predicted from single-dose data in
these subjects. The excess accumulation is a consequence
of the fact that one of the enzymes that metabolizes paroxetine
is readily saturable.
Paroxetine HCl controlled-release tablets contain a degradable
polymeric matrix designed to control the dissolution rate
of paroxetine over a period of approximately 4 to 5 hours.
In addition to controlling the rate of drug release in
vivo, an enteric coat delays the start of drug release
until paroxetine HCl controlled-release tablets have left
the stomach.
Paroxetine HCl is completely absorbed after oral dosing
of a solution of the HCl salt. In a study in which normal
male and female subjects (n=23) received single oral doses
of paroxetine HCl controlled-release tablets at four dosage
strengths (12.5 mg, 25 mg, 37.5 mg and 50 mg), paroxetine
Cmax and AUC0-¥ increased disproportionately with
dose (as seen also with immediate-release formulations).
Mean Cmax and AUC0-¥ values at these doses were 2.0,
5.5, 9.0, and 12.5 ng/ml, and 121, 261, 338, and 540 ng.hr./ml,
respectively. Tmax was observed typically between 6 and
10 hours post-dose, reflecting a reduction in absorption
rate compared with immediate-release formulations. The
mean elimination half-life of paroxetine was 15 to 20
hours throughout this range of single paroxetine HCl controlled-release
tablets doses. The bioavailability of 25 mg paroxetine
HCl controlled-release tablets is not affected by food.
During repeated administration of paroxetine HCl controlled-release
tablets (25 mg once daily), steady state was reached within
two weeks (i.e., comparable to immediate-release formulations).
In a repeat-dose study in which normal male and female
subjects (n=23) received paroxetine HCl controlled-release
tablets (25 mg daily), mean steady state Cmax,
Cmin and AUC0-24 values were 30 ng/ml, 20 ng/ml
and 550 ng.hr./ml, respectively.
CLINICAL STUDIES
Immediate-Release Tablets and Oral Suspension
Depression
The efficacy of paroxetine HCl as a treatment for depression
has been established in 6 placebo-controlled studies of
patients with depression (ages 18 to 73). In these studies
paroxetine HCl was shown to be significantly more effective
than placebo in treating depression by at least 2 of the
following measures: Hamilton Depression Rating Scale (HDRS),
the Hamilton depressed mood item, and the Clinical Global
Impression (CGI)¾Severity of Illness. Paroxetine
HCl was significantly better than placebo in improvement
of the HDRS sub-factor scores, including the depressed
mood item, sleep disturbance factor and anxiety factor.
A study of depressed outpatients who had responded to
immediate-release paroxetine HCl tablets (HDRS total score
<8) during an initial 8-week open-treatment phase and
were then randomized to continuation on immediate-release
paroxetine HCl tablets or placebo for 1 year demonstrated
a significantly lower relapse rate for patients taking
immediate-release paroxetine HCl tablets (15%) compared
to those on placebo (39%). Effectiveness was similar for
male and female patients.
Obsessive Compulsive Disorder
The effectiveness of paroxetine HCl in the treatment
of obsessive compulsive disorder (OCD) was demonstrated
in two 12-week multicenter placebo-controlled studies
of adult outpatients (Studies 1 and 2). Patients in all
studies had moderate to severe OCD (DSM-IIIR) with mean
baseline ratings on the Yale Brown Obsessive Compulsive
Scale (YBOCS) total score ranging from 23 to 26. Study
1, a dose-range finding study where patients were treated
with fixed doses of 20, 40 or 60 mg of paroxetine/day
demonstrated that daily doses of paroxetine 40 and 60
mg are effective in the treatment of OCD. Patients receiving
doses of 40 and 60 mg paroxetine experienced a mean reduction
of approximately 6 and 7 points, respectively, on the
YBOCS total score which was significantly greater than
the approximate 4 point reduction at 20 mg and a 3 point
reduction in the placebo-treated patients. Study 2 was
a flexible dose study comparing paroxetine (20 to 60 mg
daily) with clomipramine (25 to 250 mg daily). In this
study, patients receiving paroxetine 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 the placebo-treated patients.
TABLE 1 provides the outcome classification by treatment
group on Global Improvement items of the Clinical Global
Impressions (CGI) scale for Study 1.
| TABLE 1 Outcome
Classification (%) on CGI-Global Improvement Item
for Completers in Study 1 |
| Outcome Classification |
Placebo (n=74) |
Paroxetine HCl 20 mg (n=75) |
Paroxetine HCl 40 mg (n=66) |
Paroxetine HCl 60 mg (n=66) |
| Worse |
14% |
7% |
7% |
3% |
| No Change |
44% |
35% |
22% |
19% |
| Minimally Improved |
24% |
33% |
29% |
34% |
| Much Improved |
11% |
18% |
22% |
24% |
| Very Much Improved |
7% |
7% |
20% |
20% |
Subgroup analyses did not indicate that there were any differences
in treatment outcomes as a function of age or gender.
The long-term maintenance effects of paroxetine HCl in
OCD were demonstrated in a long-term extension to Study
1. Patients who were responders on paroxetine during the
3-month double-blind phase and a 6-month extension on
open-label paroxetine (20 to 60 mg/day) were randomized
to either paroxetine or placebo in a 6-month double-blind
relapse prevention phase. Patients randomized to paroxetine
were significantly less likely to relapse than comparably
treated patients who were randomized to placebo.
Panic Disorder
The effectiveness of paroxetine HCl in the treatment
of panic disorder was demonstrated in three 10- to 12-week
multicenter, placebo-controlled studies of adult outpatients
(Studies 1-3). Patients in all studies had panic disorder
(DSM-IIIR), with or without agoraphobia. In these studies,
paroxetine HCl was shown to be significantly more effective
than placebo in treating panic disorder by at least 2
out of 3 measures of panic attack frequency and on the
Clinical Global Impression Severity of Illness score.
Study 1 was a 10-week dose-range finding study; patients
were treated with fixed paroxetine doses of 10, 20, or
40 mg/day or placebo. A significant difference from placebo
was observed only for the 40 mg/day group. At endpoint,
76% of patients receiving paroxetine 40 mg/day were free
of panic attacks, compared to 44% of placebo-treated patients.
Study 2 was a 12-week flexible-dose study comparing paroxetine
(10 to 60 mg daily) and placebo. At endpoint, 51% of paroxetine
patients were free of panic attacks compared to 32% of
placebo-treated patients.
Study 3 was a 12-week flexible-dose study comparing paroxetine
(10 to 60 mg daily) to placebo in patients concurrently
receiving standardized cognitive behavioral therapy. At
endpoint, 33% of the paroxetine-treated patients showed
a reduction to 0 or 1 panic attacks compared to 14% of
placebo patients.
In both Studies 2 and 3, the mean paroxetine dose for
completers at endpoint was approximately 40 mg/day of
paroxetine.
Long-term maintenance effects of paroxetine HCl in panic
disorder were demonstrated in an extension to Study 1.
Patients who were responders during the 10-week double-blind
phase and during a 3-month double-blind extension phase
were randomized to either paroxetine (10, 20, or 40 mg/day)
or placebo in a 3-month double-blind relapse prevention
phase. Patients randomized to paroxetine were significantly
less likely to relapse than comparably treated patients
who were randomized to placebo.
Subgroup analyses did not indicate that there were any
differences in treatment outcomes as a function of age
or gender.
Social Anxiety Disorder
The effectiveness of paroxetine HCl in the treatment
of social anxiety disorder was demonstrated in three 12-week,
multicenter, placebo-controlled studies (Studies 1-3)
of adult outpatients with social anxiety disorder (DSM-IV).
In these studies, the effectiveness of paroxetine HCl
compared to placebo was evaluated on the basis of (1)
the proportion of responders, as defined by a Clinical
Global Impressions (CGI) Improvement score of 1 (very
much improved) or 2 (much improved), and (2) change from
baseline in the Liebowitz Social Anxiety Scale (LSAS).
Studies 1 and 2 were flexible-dose studies comparing
paroxetine (20 to 50 mg daily) and placebo. Paroxetine
demonstrated statistically significant superiority over
placebo on both the CGI Improvement responder criterion
and the Liebowitz Social Anxiety Scale (LSAS). In Study
1, for patients who completed to week 12, 69% of paroxetine-treated
patients compared to 29% of placebo-treated patients were
CGI Improvement responders. In Study 2, CGI Improvement
responders were 77% and 42% for the paroxetine- and placebo-treated
patients, respectively.
Study 3 was a 12-week study comparing fixed paroxetine
doses of 20, 40, or 60 mg/day with placebo. Paroxetine
20 mg was demonstrated to be significantly superior to
placebo on both the LSAS Total Score and the CGI Improvement
responder criterion; there were trends for superiority
over placebo for the 40 and 60 mg/day dose groups. There
was no indication in this study of any additional benefit
for doses higher than 20 mg/day.
Subgroup analyses did not indicate differences in treatment
outcomes as a function of age, race, or gender.
Controlled-Release Tablets
Depression
The efficacy of paroxetine HCl controlled-release tablets
as a treatment for depression has been established in
two 12-week, flexible dose, placebo-controlled studies
of patients with DSM-IV Major Depressive Disorder. One
study included patients in the age range 18-65 years,
and a second study included elderly patients, ranging
in age from 60 to 88 years. In both studies, paroxetine
HCl controlled-release tablets were shown to be significantly
more effective than placebo in treating depression as
measured by the following: Hamilton Depression Rating
Scale (HDRS), the Hamilton depressed mood item, and the
Clinical Global Impression (CGI)-Severity of Illness score.
A study of depressed outpatients who had responded to
immediate-release paroxetine HCl tablets (HDRS total score
<8) during an initial 8-week open-treatment phase and
were then randomized to continuation on immediate-release
paroxetine HCl tablets or placebo for 1 year demonstrated
a significantly lower relapse rate for patients taking
immediate-release paroxetine HCl tablets (15%) compared
to those on placebo (39%). Effectiveness was similar for
male and female patients.
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