A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Sarafem Pharmacology, Pharmacokinetics, Studies, Metabolism - Fluoxetine Hydrochloride
Sarafem Pharmacology, Pharmacokinetics, Studies, Metabolism - Fluoxetine Hydrochloride
CLINICAL PHARMACOLOGY
Pharmacodynamics:
The mechanism of action of fluoxetine in premenstrual dysphoric
disorder (PMDD) is unknown, but is presumed to be linked to its inhibition of
CNS neuronal uptake of serotonin. Studies at clinically relevant doses in humans
have demonstrated that fluoxetine blocks the uptake of serotonin into human
platelets. Studies in animals also suggest that fluoxetine is a much more potent
uptake inhibitor of serotonin than of norepinephrine.
Antagonism of muscarinic, histaminergic, and µ1-adrenergic
receptors has been hypothesized to be associated with various anticholinergic,
sedative, and cardiovascular effects of certain psychoactive drugs. Fluoxetine
has little affinity for these receptors.
Absorption, Distribution, Metabolism, and Excretion:
Systemic Bioavailability--In humans, following a single oral
40-mg dose, peak plasma concentrations of fluoxetine from 15 to 55 ng/mL are
observed after 6 to 8 hours.
Food does not appear to affect the systemic bioavailability
of fluoxetine, although it may delay its absorption inconsequentially. Thus,
fluoxetine may be administered with or without food.
Protein Binding--Over the concentration range from 200
to 1,000 ng/mL, approximately 94.5% of fluoxetine is bound in vitro to
human serum proteins, including albumin and µ
1 glycoprotein. The interaction between fluoxetine and
other highly protein-bound drugs has not been fully evaluated, but may
be important (see PRECAUTIONS).
Enantiomers--Fluoxetine is a racemic mixture (50/50) of R-fluoxetine
and S-fluoxetine enantiomers. In animal models, both enantiomers are specific
and potent serotonin uptake inhibitors with essentially equivalent pharmacologic
activity. The S-fluoxetine enantiomer is eliminated more slowly and is the predominant
enantiomer present in plasma at steady state.
Metabolism--Fluoxetine is extensively metabolized in the liver
to norfluoxetine and a number of other unidentified metabolites. The only identified
active metabolite, norfluoxetine, is formed by demethylation of fluoxetine.
In animal models, S-norfluoxetine is a potent and selective inhibitor of serotonin
uptake and has activity essentially equivalent to R- or S-fluoxetine. R-norfluoxetine
is significantly less potent than the parent drug in the inhibition of serotonin
uptake. The primary route of elimination appears to be hepatic metabolism to
inactive metabolites excreted by the kidney.
Clinical Issues Related to Metabolism/Elimination--The complexity
of the metabolism of fluoxetine has several consequences that may potentially
affect fluoxetine's clinical use.
Variability in Metabolism--A subset (about 7%) of the population
has reduced activity of the drug metabolizing enzyme cytochrome P450IID6. Such
individuals are referred to as "poor metabolizers" of drugs such as debrisoquin,
dextromethorphan, and the tricyclic antidepressants (TCAs). In a study involving
labeled and unlabeled enantiomers administered as a racemate, these individuals
metabolized S-fluoxetine at a slower rate and thus achieved higher concentrations
of S-fluoxetine. Consequently, concentrations of S-norfluoxetine at steady state
were lower. The metabolism of R-fluoxetine in these poor metabolizers appears
normal. When compared with normal metabolizers, the total sum at steady state
of the plasma concentrations of the four active enantiomers was not significantly
greater among poor metabolizers. Thus, the net pharmacodynamic activities were
essentially the same. Alternative, nonsaturable pathways (non-IID6) also contribute
to the metabolism of fluoxetine. This explains how fluoxetine achieves a steady-state
concentration rather than increasing without limit.
Because fluoxetine's metabolism, like that of a number of other
compounds including TCAs and other SSRIs, involves the P450IID6 system, concomitant
therapy with drugs also metabolized by this enzyme system (such as the TCAs)
may lead to drug interactions (see Drug Interactions under PRECAUTIONS).
Accumulation and Slow Elimination--The relatively slow elimination
of fluoxetine (elimination half-life of 1 to 3 days after acute administration
and 4 to 6 days after chronic administration) and its active metabolite, norfluoxetine
(elimination half-life of 4 to 16 days after acute and chronic administration),
leads to significant accumulation of these active species in chronic use and
delayed attainment of steady state, even when a fixed dose is used. After 30
days of dosing at 40 mg/day, plasma concentrations of fluoxetine in the range
of 91 to 302 ng/mL and norfluoxetine in the range of 72 to 258 ng/mL have been
observed. Plasma concentrations of fluoxetine were higher than those predicted
by single-dose studies, because fluoxetine's metabolism is not proportional
to dose.
Norfluoxetine, however, appears to have linear pharmacokinetics.
Its mean terminal half-life after a single dose was 8.6 days and after multiple
dosing was 9.3 days. Steady-state levels after prolonged dosing are similar
to levels seen at 4 to 5 weeks.
The long elimination half-lives of fluoxetine and norfluoxetine
assure that, even when dosing is stopped, active drug substance will persist
in the body for weeks (primarily depending on individual patient characteristics,
previous dosing regimen, and length of previous therapy at discontinuation).
This is of potential consequence when drug discontinuation is required or when
drugs are prescribed that might interact with fluoxetine and norfluoxetine following
the discontinuation of SARAFEM.
Liver Disease--As might be predicted from its primary site
of metabolism, liver impairment can affect the elimination of fluoxetine. The
elimination half-life of fluoxetine was prolonged in a study of cirrhotic patients,
with a mean of 7.6 days compared to the range of 2 to 3 days seen in subjects
without liver disease; norfluoxetine elimination was also delayed, with a mean
duration of 12 days for cirrhotic patients compared to the range of 7 to 9 days
in normal subjects. This suggests that the use of fluoxetine in patients with
liver disease must be approached with caution. If fluoxetine is administered
to patients with liver disease, a lower or less frequent dose should be used
(see Use in Patients with Concomitant Illness under PRECAUTIONS
and DOSAGE AND ADMINISTRATION).
Renal Disease--In depressed patients on dialysis (N=12), fluoxetine
administered as 20 mg once daily for 2 months produced steady-state fluoxetine
and norfluoxetine plasma concentrations comparable to those seen in patients
with normal renal function. While the possibility exists that renally excreted
metabolites of fluoxetine may accumulate to higher levels in patients with severe
renal dysfunction, use of a lower or less frequent dose is not routinely necessary
in renally impaired patients (see Use in Patients with Concomitant Illness under
PRECAUTIONS and DOSAGE
AND ADMINISTRATION).
Clinical Trials:
Premenstrual Dysphoric Disorder (PMDD)--The effectiveness of
SARAFEM for the treatment of PMDD was established in two placebo-controlled
trials. Patients in these trials met Diagnostic and Statistical Manual-3rd
edition revised (DSM-IIIR) criteria for Late Luteal Phase Dysphoric Disorder
(LLPDD), the clinical entity now referred to as Premenstrual Dysphoric Disorder
(PMDD) in the Diagnostic and Statistical Manual-4th edition (DSM-IV).
Patients on oral contraceptives were excluded from these trials; therefore,
the efficacy of fluoxetine in combination with oral contraceptives for the treatment
of PMDD is unknown.
In the first double-blind, parallel group study of 6 months
duration involving N=320 patients, fixed doses of fluoxetine 20 and 60 mg/day
given continuously throughout the menstrual cycle were shown to be significantly
more effective than placebo as measured by a Visual Analogue Scale (VAS) total
score (including mood and physical symptoms). The average total VAS score decreased
7% on placebo treatment, 36% on 20 mg, and 39% on 60 mg fluoxetine. The difference
between the 20-mg and 60-mg doses was not statistically significant. The following
table shows the percentage of patients meeting criteria for either moderate
or marked improvement on the VAS total score:
|
Percentage of Patients Moderately and Markedly Improved
(>50% and 75% reduction, respectively, from baseline Luteal Phase VAS
total score)
|
|
|
Improvement
|
N
|
Placebo
|
N
|
Fluox 20 mg
|
N
|
Fluox 60 mg
|
|
Moderate
|
94
|
11%
|
95
|
37%
|
85
|
38%
|
|
Marked
|
94
|
4%
|
95
|
6%
|
85
|
18%
|
In a second double-blind, cross-over study, patients (N=19)
were treated with fluoxetine 20 to 60 mg/day (mean dose=27 mg/day) and placebo
continuously throughout the menstrual cycle for a period of 3 months each. Fluoxetine
was significantly more effective than placebo as measured by within cycle follicular
to luteal phase changes in the VAS total score (mood, physical, and social impairment
symptoms). The average VAS total score (follicular to luteal phase increase)
was 3.8 times higher during placebo treatment than what was observed during
fluoxetine treatment.
In a third double-blind, parallel group study, patients with
LLPDD (N=42) were treated with fluoxetine 20 mg/day, bupropion 300 mg/day, or
placebo for 2 months. Neither fluoxetine nor bupropion was shown to be superior
to placebo on the primary endpoint, i.e., response rate [defined as a rating
of 1 (very much improved) or 2 (much improved) on the CGI], possibly due to
sample size.
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