CLINICAL PHARMACOLOGY
Pharmacodynamics
The mechanism of action of fluvoxamine maleate in Obsessive
Compulsive Disorder is presumed to be linked to its specific
serotonin reuptake inhibition in brain neurons. In preclinical
studies it was found that fluvoxamine inhibited neuronal
uptake of serotonin.
In in vitro studies fluvoxamine maleate had no significant
affinity for histaminergic, alpha or beta adrenergic,
muscarinic, or dopaminergic receptors. Antagonism of some
of these receptors is thought to be associated with various
sedative, cardiovascular, anticholinergic, and extrapyramidal
effects of some psychotropic drugs.
Pharmacokinetics
Bioavailability: The absolute bioavailability
of fluvoxamine maleate is 53%. Oral bioavailability is
not significantly affected by food.
In a dose proportionality study involving fluvoxamine
maleate at 100, 200 and 300 mg/day for 10 consecutive
days in 30 normal volunteers steady state was achieved
after about a week of dosing. Maximum plasma concentrations
at steady state occurred within 3-8 hours of dosing and
reached concentrations averaging 88, 283 and 546 ng/mL,
respectively. Thus, fluvoxamine had nonlinear pharmacokinetics
over this dose range, i. e., higher doses of fluvoxamine
maleate produced disproportionately higher concentrations
than predicted from the lower dose.
Distribution/Protein Binding: The mean
apparent volume of distribution for fluvoxamine is approximately
25 L/kg, suggesting extensive tissue distribution.
Approximately 80% of fluvoxamine is bound to plasma protein,
mostly albumin, over a concentration range of 20 to 2000
ng/mL.
Metabolism: Fluvoxamine maleate is extensively
metabolized by the liver, the main metabolic routes are
oxidative demethylation and deamination. Nine metabolites
were identified following a 5 mg radiolabelled dose of
fluvoxamine maleate, constituting approximately 85% of
the urinary excretion products of fluvoxamine. The main
human metabolite was fluvoxamine acid which, here with
its N-acetylated analog, accounted for about of the urinay
excretion products. A third metabolite, fluvoxethanol,
formed by oxidative deamination, accounted for about 10%.
Fluvoxamine acid and fluvoxethanol were tested in an in
vitro assay of serotonin and norepinephrine reuptake inhibition
in rats; they were inactive except for a weak effect of
the former metabolite on inhibition of serotonin uptake
(1-2 orders of magnitude less potent than the parent compound).
Approximately 2% of fluvoxamine was excreted in urine
unchanged. (See DRUG INTERACTIONS)
Elimination: Following a 14C oral dose
of fluvoxamine maleate (5 mg) an average 94% of drug-related
products was recovered in the urine within 71 hours.
The mean plasma half-life of fluvoxamine at steady state
after multiple oral doses of 100 mg/day in healthy, young
volunteers was 15.6 hours.
Elderly Subjects: In a study of LUVOX
Tablets at 50 and 100 mg comparing elderly (ages 66-73)
and young subjects (ages19-35), mean maximum plasma concentrations
in the elderly were 40% higher. The multiple dose elimination
half-life of fluvoxamine was 17.4 and 25.9 hours in the
elderly compared to 13.6 and 15.6 hours in the young subjects
at steady state for 50 and 100 mg doses, respectively.
In elderly patients, the clearance of fluvoxamine was
reduced by about 50% and therefore, LUVOX Tablets should
be slowly titrated during initiation of therapy.
Hepatic and Renal Disease: A cross study
comparison (healthy subjects vs. patients with hepatic
dysfunction) suggested a 30% decrease in fluvoxamine clearance
in association with hepatic dysfunction. The mean minimum
plasma concentrations in renally impaired patients (creatinine
clearance of 5 to 45 mL/min) after 4 and 6 weeks of treatment
(50 mg bid, N= 13) were comparable to each other, suggesting
no accumulation of fluvoxamine in these patients. (See
PRECAUTIONS -Use in Patients with Concomitant Illness).
Clinical Trials
Adult OCD Studies: The effectiveness
of LUVOX Tablets for the treatment of Obsessive Compulsive
Disorder (OCD) was demonstrated in two 10-week multicenter,
parallel group studies of adult outpatients. Patients
in these trials were titrated to a total daily fluvoxamine
maleate dose of 150 mg/day over the first two weeks of
the trial, following which the dose was adjusted within
a range of 100-300 mg/day (on a bid schedule), on the
basis of response and tolerance. Patients in these studies
had moderate to severe OCD (DSM-III-R), with mean baseline
ratings on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS),
total score of 23. Patients receiving fluvoxamine maleate
experienced mean reductions of approximately 4 to 5 units
on the Y-BOCS total score, compared to a 2 unit reduction
for palcebo patients.
The following table provides the outcome classification
by treatment group on the Global Improvement item of the
Clinical Global Impressions (CGI) scale for both studies
combined.
Exploratory analyses for age and gender effects on outcomes
did not suggest any differential responsiveness on the
basis of age or sex.
Pediatric OCD Study: The effectiveness
of LUVOX Tablets for the treatment of OCD was also demonstrated
in a 10-week multicenter, parallel group study in a pediatric
outpatient population (children and adolescents, ages
8-17). Patients in this study were titrated to a total
daily fluvoxamine dose of approximately 100 mg/day over
the first two weeks of the trial, following which the
dose was adjusted within a range of 50-200 mg/day (on
a bid schedule) on the basis of response and tolerance.
Patients in these studies had moderate to severe OCD (DSM-III-R)
with mean baseline ratings on the Children's Yale-Brown
Obsessive Compulsive Scale (CY-BOCS), total score of 24.
Patients receiving fluvoxamine maleate experienced mean
reductions of approximately 6 units on the CY-BOCS total
score, compared to a 3 unit reduction for placebo patients.
The following table provide the outcome classification
by treatment group on the Global Improvement item of the
Clinical Global Impression (CGI) scale for the pediatric
study.
OUTCOME CLASSIFICATION (%) ON CGI-GLOBAL IMPROVEMENT
ITEM FOR COMPLETERS IN PEDIATRIC STUDY
|
| Outcome
Classification |
Fluvoxamine (N = 38)
|
Placebo (N = 36)
|
| Very Much
Improved |
21%
|
11%
|
| Much Improved |
18%
|
17%
|
| Minimally
Improved |
37%
|
22%
|
| No Change |
16%
|
44%
|
| Worse |
8%
|
6%
|
Post hoc exploratory analyses for gender effects an outcomes
did not suggest any differential responsiveness on the
basis of gender. Further exploratory analyses revealed
a prominent treatment effect in the 8-11 age group and
essentially no effect in the 12-17 age group. The significance
of these results is not known at this time.
LUVOX Tablets are indicated for the treatment of obsessions
and compulsions in patients with Obsessive Compulsive
Disorder (OCD), as defined in the DSM-III-R. The obsessions
or compulsions cause marked distress, are time-consuming,
or significantly interfere with social or occupational
functioning.
The efficacy of LUVOX Tablets was established in three
10-week trials with obsessive compulsive outpatients with
the diagnosis of Obsessive Compulsive Disorder as defined
in DSM-III-R. (See Clinical Trials above.)
Obsessive Compulsive Disorder is characterized by recurrent
and persistent ideas, thoughts, impulses or images (obsessions)
that are ego-dystonic and/or repetitive, purposeful, and
intentional behaviors (compulsions) that are recognized
by the person as excessive or unreasonable.
The effectiveness of LUVOX Tablets for long-term use,
i.e., for more than 10 weeks, has not been systematically
evaluated in placebo-controlled trials. Therefore, the
physician who elects to use LUVOX Tablets for extended
periods should periodically re-evaluate the long-term
usefulness of the drug for the individual patient. (See
DOSAGE AND ADMINISTRATION)
Co-administration of terfenadine, astemizole, or cisapride
with LUVOX Tablets is contraindicated. (see WARNINGS and
PRECAUTIONS). LUVOX Tablets are contraindicated inpatients
with a history of hypersensitivity to fluvoxamine maleate.
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