FLUOXETINE HCL
DESCRIPTION:
PRODEP (Fluoxetine Hydrochloride) is an antidepressant for oral
administration; it is chemically unrelated to tricyclic, tetracyclic, or other
available antidepressant agents. It is designated ()-N-methyl-3-phenyl- 3-
((alpha,alpha,alpha-trifluoro-p- tolyl)oxy)propylamine hydrochloride and has the
empirical formula of C17H18F3NO.HCl. Its molecular weight is 345.79.
Fluoxetine hydrochloride is a white to off-white crystalline solid with a
solubility of 14 mg/mL in water.
ACTIONS/CLINICAL PHARMACOLOGY:
Pharmacodynamics:
The antidepressant, antiobsessive-compulsive, and antibulimic actions of
fluoxetine are presumed to be linked to its inhibition of CNS neuronal uptake of
serotonin. Studies at clinically relevant doses in man 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 alpha1-adrenergic receptors has
been hypothesized to be associated with various anticholinergic, sedative, and
cardiovascular effects of classical tricyclic antidepressant drugs. Fluoxetine
binds to these and other membrane receptors from brain tissue much less potently
in vitro than do the tricyclic drugs.
Absorption, Distribution, Metabolism, And Excretion:
SYSTEMIC BIOAVAILABILITY--In man, 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.
The Pulvule and oral solution dosage forms of fluoxetine are bioequivalent. 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 alpha1-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. 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 4 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 tricyclic and other selective serotonin antidepressants, involves the
P450IID6 system, concomitant therapy with drugs also metabolized by this enzyme
system (such as the tricyclic antidepressants) 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 4-5 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 PRODEP.
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
PRECAUTIONS And DOSAGE AND ADMINISTRATION).
RENAL DISEASE--In depressed patients on dialysis (N=12), fluoxetine administered
as 20 mg once daily for two 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).
AGE--The disposition of single doses of fluoxetine in healthy elderly subjects
(greater than 65 years of age) did not differ significantly from that in younger
normal subjects. However, given the long half-life and nonlinear disposition of
the drug, a single-dose study is not adequate to rule out the possibility of
altered pharmacokinetics in the elderly, particularly if they have systemic
illness or are receiving multiple drugs for concomitant diseases. The effects of
age upon the metabolism of fluoxetine have been investigated in 260 elderly but
otherwise healthy depressed patients (>/=60 years of age) who received 20 mg
fluoxetine for 6 weeks. Combined fluoxetine plus norfluoxetine plasma
concentrations were 209.3 85.7 ng/mL at the end of 6 weeks. No unusual age-
associated pattern of adverse events was observed in those elderly patients.
CLINICAL STUDIES:
Clinical Trials:
Depression--The efficacy of PRODEP for the treatment of patients with depression
(>/=18 years of age) has been studied in 5- and 6-week placebo-controlled
trials. PRODEP was shown to be significantly more effective than placebo as
measured by the Hamilton Depression Rating Scale (HAM-D). PRODEP was also
significantly more effective than placebo on the HAM-D subscores for depressed
mood, sleep disturbance, and the anxiety subfactor.
Two 6-week controlled studies comparing PRODEP, 20 mg, and placebo have shown
PRODEP, 20 mg daily, to be effective in the treatment of elderly patients (>/=60
years of age) with depression. In these studies, PRODEP produced a significantly
higher rate of response and remission as defined respectively by a 50% decrease
in the HAM-D score and a total endpoint HAM-D score of =7. PRODEP was well
tolerated and the rate of treatment discontinuations due to adverse events did
not differ between PRODEP (12%) and placebo (9%).
A study was conducted involving depressed outpatients who had responded
(modified HAMD-17 score of =7 during each of the last 3 weeks of open-label
treatment and absence of major depression by DSM-III-R criteria) by the end of
an initial 12-week open treatment phase on PRODEP 20 mg/day. These patients
(N=298) were randomized to continuation on double-blind PRODEP 20 mg/day or
placebo. At 38 weeks (50 weeks total), a statistically significantly lower
relapse rate (defined as symptoms sufficient to meet a diagnosis of major
depression for 2 weeks of a modified HAMD-17 score of >/= 14 for 3 weeks) was
observed for patients taking PRODEP compared to those on placebo.
Obsessive-Compulsive Disorder--The effectiveness of PRODEP for the treatment for
obsessive- compulsive disorder (OCD) was demonstrated in two 13-week,
multicenter, parallel group studies (Studies 1 and 2) of adult outpatients who
received fixed PRODEP doses of 20, 40, or 60 mg/day (on a once a day schedule,
in the morning) or placebo. Patients in both studies had moderate to severe OCD
(DSM-III-R), with mean baseline ratings on the Yale-Brown Obsessive Compulsive
Scale (YBOCS, total score) ranging from 22 to 26. In Study 1, patients receiving
PRODEP experienced mean reductions of approximately 4 to 6 units on the YBOCS
total score, compared to a 1-unit reduction for placebo patients. In Study 2,
patients receiving PRODEP experienced mean reductions of approximately 4 to 9
units on the YBOCS total score, compared to a 1-unit reduction for placebo
patients. While there was no indication of a dose response relationship for
effectiveness in Study 1, a dose response relationship was observed in Study 2,
with numerically better responses in the 2 higher dose groups. The following
table provides the outcome classification by treatment group on the Clinical
Global Impression (CGI) improvement scale for studies 1 and 2 combined:
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Outcome Classification (%) on CGI Improvement Scale for
Completers in Pool of Two OCD Studies
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PRODEP
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Outcome
Classification Placebo 20 mg 40 mg 60 mg
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Worse 8% 0% 0% 0%
No Change 64% 41% 33% 29%
Minimally Improved 17% 23% 28% 24%
Much Improved 8% 28% 27% 28%
Very Much Improved 3% 8% 12% 19%
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Exploratory analyses for age and gender effects on outcome did not suggest any
differential responsiveness on the basis of age or sex.
Bulimia Nervosa--The effectiveness of PRODEP for the treatment of bulimia was
demonstrated in two 8-week and one 16-week, multicenter, parallel group studies
of adult outpatients meeting DSM- III-R criteria for bulimia. Patients in the 8-
week studies received either 20 mg/day or 60 mg/day of PRODEP or placebo in the
morning. Patients in the 16-week study received a fixed PRODEP dose of 60 mg/day
(once a day) or placebo. Patients in these 3 studies had moderate to severe
bulimia with median binge-eating and vomiting frequencies ranging from 7 to 10
per week and 5 to 9 per week, respectively. In these 3 studies, PRODEP, 60 mg,
but not 20 mg, was statistically significantly superior to placebo in reducing
the number of binge-eating and vomiting episodes per week. The statistically
significantly superior effect of 60 mg vs placebo was present as early as week 1
and persisted throughout each study. The PRODEP related reduction in bulimic
episodes appeared to be independent of baseline depression as assessed by the
Hamilton Depression Rating Scale. In each of these 3 studies, the treatment
effect, as measured by differences between PRODEP, 60 mg, and placebo on median
reduction from baseline in frequency of bulimic behaviors at endpoint, ranged
from 1 to 2 episodes per week for binge- eating and 2 to 4 episodes per week for
vomiting. The size of the effect was related to baseline frequency, with greater
reductions seen in patients with higher baseline frequencies. Although some
patients achieved freedom from binge-eating and purging as a result of
treatment, for the majority, the benefit was a partial reduction in the
frequency of binge- eating and purging.
INDICATIONS AND USAGE:
Depression--PRODEP is indicated for the treatment of depression. The efficacy of
PRODEP was established in 5- and 6-week trials with depressed outpatients (>/=18
years of age) whose diagnoses corresponded most closely to the DSM- III category
of major depressive disorder (see Clinical Trials Under ACTIONS/CLINICAL
PHARMACOLOGY).
A major depressive episode implies a prominent and relatively persistent
depressed or dysphoric mood that usually interferes with daily functioning
(nearly every day for at least 2 weeks); it should include at least 4 of the
following 8 symptoms: change in appetite, change in sleep, psychomotor agitation
or retardation, loss of interest in usual activities or decrease in sexual
drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or
impaired concentration, and a suicide attempt or suicidal ideation.
The antidepressant action of PRODEP in hospitalized depressed patients has not
been adequately studied.
The efficacy of PRODEP in maintaining an antidepressant response for up to 38
weeks following 12 weeks of open-label acute treatment (50 weeks total) was
demonstrated in a placebo- controlled trial. The usefulness of the drug in
patients receiving PRODEP for extended periods should be reevaluated
periodically (See Clinical Trials Under ACTIONS/CLINICAL PHARMACOLOGY).
Obsessive-Compulsive Disorder--PRODEP is indicated for the treatment of
obsessions and compulsions in patients with obsessive-compulsive disorder (OCD),
as defined in the DSM-III-R; ie, the obsessions or compulsions cause marked
distress, are time-consuming, or significantly interfere with social or
occupational functioning.
The efficacy of PRODEP was established in 13-week trials with obsessive-
compulsive outpatients whose diagnoses corresponded most closely to the DSM-III-
R category of obsessive-compulsive disorder (see Clinical Trials Under
ACTIONS/CLINICAL PHARMACOLOGY).
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 PRODEP in long-term use, ie, for more than 13 weeks, has
not been systematically evaluated in placebo-controlled trials. Therefore, they
physician who elects to use PRODEP for extended periods should periodically
reevaluate the long-term usefulness of the drug for the individual patient (see
DOSAGE AND ADMINISTRATION).
Bulimia Nervosa--PRODEP is indicated for the treatment of binge-eating and
vomiting behaviors in patients with moderate to severe bulimia nervosa.
The efficacy of PRODEP was established in 8 to 16 week trials for adult
outpatients with moderate to severe bulimia nervosa, ie, at least 3 bulimic
episodes per week for 6 months (see Clinical Trials Under ACTIONS/CLINICAL
PHARMACOLOGY).
The effectiveness of PRODEP in long-term use, ie, for more than 16 weeks, has
not been systematically evaluated in placebo-controlled trials. Therefore, the
physician who elects to use PRODEP for extended periods should periodically
reevaluate the long-term usefulness of the drug for the individual patient (see
DOSAGE AND ADMINISTRATION).
CONTRAINDICATIONS:
PRODEP is contraindicated in patients known to be hypersensitive to it.
Monoamine Oxidase Inhibitors--There have been reports of serious, sometimes
fatal, reactions (including hyperthermia, rigidity, myoclonus, autonomic
instability with possible rapid fluctuations of vital signs, and mental status
changes that include extreme agitation progressing to delirium and coma) in
patients receiving fluoxetine in combination with a monoamine oxidase inhibitor
(MAOI), and in patients who have recently discontinued fluoxetine and are then
started on an MAOI. Some cases presented with features resembling neuroleptic
malignant syndrome. Therefore, PRODEP should not be used in combination with an
MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI.
Since fluoxetine and its major metabolite have very long elimination half-
lives, at least 5 weeks (perhaps longer, especially if fluoxetine has been
prescribed chronically and/or at higher doses (See Accumulation and Slow
Elimination Under ACTIONS/CLINICAL PHARMACOLOGY)) should be allowed after
stopping PRODEP before starting an MAOI.
WARNINGS:
Rash And Possibly Allergic Events--In US fluoxetine clinical trials, 7% of
10,782 patients developed various types of rashes and/or urticaria. Among the
cases of rash and/or urticaria reported in premarketing clinical trials, almost
a third were withdrawn from treatment because of the rash and/or systemic signs
or symptoms associated with the rash. Clinical findings reported in association
with rash include fever, leukocytosis, arthralgias, edema, carpal tunnel
syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild
transaminase elevation. Most patients improved promptly with discontinuation of
fluoxetine and/or adjunctive treatment with antihistamines or steroids, and all
patients experiencing these events were reported to recover completely.
In premarketing clinical trials, 2 patients are known to have developed a
serious cutaneous systemic illness. In neither patient was there an unequivocal
diagnosis, but 1 was considered to have a leukocytoclastic vasculitis, and the
other, a severe desquamating syndrome that was considered variously to be a
vasculitis or erythema multiforme. Other patients have had systemic syndromes
suggestive of serum sickness.
Since the introduction of PRODEP, systemic events, possibly related to
vasculitis, have developed in patients with rash. Although these events are
rare, they may be serious, involving the lung, kidney, or liver. Death has been
reported to occur in association with these systemic events.
Anaphylactoid events, including bronchospasm, angioedema, and urticaria alone
and in combination, have been reported.
Pulmonary events, including inflammatory processes of varying histopathology
and/or fibrosis, have been reported rarely. These events have occurred with
dyspnea as the only preceding symptom.
Whether these systemic events and rash have a common underlying cause or are due
to different etiologies or pathogenic processes is not known. Furthermore, a
specific underlying immunologic basis for these events has not been identified.
Upon the appearance of rash or of other possibly allergic phenomena for which an
alternative etiology cannot be identified, PRODEP should be discontinued.
PRECAUTIONS:
General
ANXIETY AND INSOMNIA--In US placebo-controlled clinical trials for depression,
12% to 16% of patients treated with PRODEP and 7% to 9% of patients treated with
placebo reported anxiety, nervousness, or insomnia.
In US placebo-controlled clinical trials for obsessive-compulsive disorder,
insomnia was reported in 28% of patients treated with PRODEP and in 22% of
patients treated with placebo. Anxiety was reported in 14% of patients treated
with PRODEP and in 7% of patients treated with placebo.
In US placebo-controlled clinical trials for bulimia nervosa, insomnia was
reported in 33% of patients treated with PRODEP, 60 mg, and 13% of patients
treated with placebo. Anxiety and nervousness were reported respectively in 15%
and 11% of patients treated with PRODEP, 60 mg, and in 9% and 5% of patients
treated with placebo.
Among the most common adverse events associated with discontinuation in US
placebo-controlled fluoxetine clinical trials were anxiety (=2%), insomnia
(=2%) and nervousness (=1%) (see Table 3, below).
ALTERED APPETITE AND WEIGHT--Significant weight loss, especially in underweight
depressed or bulimic patients, may be an undesirable result of treatment with
PRODEP.
In US placebo-controlled clinical trials for depression, 11% of patients treated
with PRODEP and 2% of patients treated with placebo reported anorexia (decreased
appetite). Weight loss was reported in 1.4% of patients treated with PRODEP and
in 0.5% of patients treated with placebo. However, only rarely have patients
discontinued treatment with PRODEP because of anorexia or weight loss.
In US placebo-controlled clinical trials for OCD, 17% of patients treated with
PRODEP and 10% of patients treated with placebo reported anorexia (decreased
appetite). One patient discontinued treatment with PRODEP because of anorexia.
In US placebo-controlled clinical trials for bulimia nervosa, 8% of patients
treated with PRODEP, 60 mg, and 4% of patients treated with placebo reported
anorexia (decreased appetite). Patients treated with PRODEP, 60 mg, on average
lost 0.45 kg compared with a gain of 0.16 kg by patients treated with placebo in
the 16-week double-blind trial. Weight change should be monitored during
therapy.
ACTIVATION OF MANIA/HYPOMANIA--In US placebo- controlled clinical trials for
depression, mania/hypomania was reported in 0.1% of patients treated with PRODEP
and 0.1% of patients treated with placebo. Activation of mania/hypomania has
also been reported in a small proportion of patients with Major Affective
Disorder treated with marketed antidepressants.
In US placebo-controlled clinical trials for OCD, mania/hypomania was reported
in 0.8% of patients treated with PRODEP and no patients treated with placebo. No
patients reported mania/hypomania in US placebo-controlled clinical trials for
bulimia. In all US PRODEP clinical trials, 0.7% of 10,782 patients reported
mania/hypomania.
SEIZURES--In US placebo-controlled clinical trials for depression, convulsions
(or events described as possibly having been seizures) were reported in 0.1% of
patients treated with PRODEP and 0.2% of patients treated with placebo. No
patients reported convulsions in US placebo- controlled clinical trials for
either OCD or bulimia. In all US PRODEP clinical trials, 0.2% of 10,782 patients
reported convulsions. The percentage appears to be similar to that associated
with other marketed antidepressants. PRODEP should be introduced with care in
patients with a history of seizures.
SUICIDE--The possibility of a suicide attempt is inherent in depression and may
persist until significant remission occurs. Close supervision of high risk
patients should accompany initial drug therapy. Prescriptions for PRODEP should
be written for the smallest quantity of capsules consistent with good patient
management, in order to reduce the risk of overdose.
Because of well-established comorbidiy between OCD and depression and bulimia
and depression, the same precautions observed when treating patients with
depression should be observed when treating patients with OCD or bulimia.
THE LONG ELIMINATION HALF-LIVES OF FLUOXETINE AND ITS METABOLITES--Because of
the long elimination half-lives of the parent drug and its major active
metabolite, changes in dose will not be fully reflected in plasma for several
weeks, affecting both strategies for titration to final dose and withdrawal from
treatment (see ACTIONS/CLINICAL PHARMACOLOGY And DOSAGE AND ADMINISTRATION).
USE IN PATIENTS WITH CONCOMITANT ILLNESS- -Clinical experience with PRODEP in
patients with concomitant systemic illness is limited. Caution is advisable in
using PRODEP in patients with diseases or conditions that could affect
metabolism or hemodynamic responses.
Fluoxetine has not been evaluated or used to any appreciable extent in patients
with a recent history of myocardial infarction or unstable heart disease.
Patients with these diagnoses were systematically excluded from clinical studies
during the product's premarket testing. However, the electrocardiograms of 312
patients who received PRODEP in double-blind trials were retrospectively
evaluated; no conduction abnormalities that resulted in heart block were
observed. The mean heart rate was reduced by approximately 3 beats/min.
In subjects with cirrhosis of the liver, the clearances of fluoxetine and its
active metabolite, norfluoxetine, were decreased, thus increasing the
elimination half-lives of these substances. A lower or less frequent dose should
be used in patients with cirrhosis.
Studies in depressed patients on dialysis did not reveal excessive accumulation
of fluoxetine or norfluoxetine in plasma (See Renal Disease Under
ACTIONS/CLINICAL PHARMACOLOGY). Use of a lower or less frequent dose for renally
impaired patients is not routinely necessary (See DOSAGE AND ADMINISTRATION).
In patients with diabetes, PRODEP may alter glycemic control. Hypoglycemia has
occurred during therapy with PRODEP, and hyperglycemia has developed following
discontinuation of the drug. As is true with many other types of medication when
taken concurrently by patients with diabetes, insulin and/or oral hypoglycemic
dosage may need to be adjusted when therapy with PRODEP is instituted or
discontinued.
INTERFERENCE WITH COGNITIVE AND MOTOR PERFORMANCE--Any psychoactive drug may
impair judgment, thinking, or motor skills, and patients should be cautioned
about operating hazardous machinery, including automobiles, until they are
reasonably certain that the drug treatment does not affect them adversely.
Information For Patients--Physicians are advised to discuss the following issues
with patients for whom they prescribe PRODEP:
Because PRODEP may impair judgment, thinking, or motor skills, patients should
be advised to avoid driving a car or operating hazardous machinery until they
are reasonably certain that their performance is not affected.
Patients should be advised to inform their physician if they are taking or plan
to take any prescription or over-the-counter drugs or alcohol.
Patients should be advised to notify their physician if they become pregnant or
intend to become pregnant during therapy.
Patients should be advised to notify their physician if they are breast feeding
an infant.
Patients should be advised to notify their physician if they develop a rash or
hives.
Laboratory Tests--There are no specific laboratory tests recommended.
Drug Interactions--As with all drugs, the potential for interaction by a variety
of mechanisms (eg, pharmacodynamic, pharmacokinetic drug inhibition or
enhancement, etc) is a possibility (see Accumulation and Slow Elimination Under
ACTIONS/CLINICAL PHARMACOLOGY).
DRUGS METABOLIZED BY P450IID6--Approximately 7% of the normal population has a
genetic defect that leads to reduced levels of activity of the cytochrome P450
isoenzyme P450IID6. Such individuals have been referred to as "poor
metabolizers" of drugs such as debrisoquin, dextromethorphan, and tricyclic
antidepressants. Many drugs, such as most antidepressants including fluoxetine
and other selective uptake inhibitors of serotonin, are metabolized by this
isoenzyme; thus, both the pharmacokinetic properties and relative proportion of
metabolites are altered in poor metabolizers. However, for fluoxetine and its
metabolite the sum of the plasma concentrations of the 4 active enantiomers is
comparable between poor and extensive metabolizers (see Variability in
Metabolism Under ACTIONS/CLINICAL PHARMACOLOGY).
Fluoxetine, like other agents that are metabolized by P450IID6, inhibits the
activity of this isoenzyme, and thus may make normal metabolizers resemble "poor
metabolizers." Therapy with medications that are predominantly metabolized by
the P450IID6 system and that have a relatively narrow therapeutic index (see
list below), should be initiated at the low end of the dose range if a patient
is receiving fluoxetine concurrently or has taken it in the previous 5 weeks.
Thus, his/her dosing requirements resemble those of "poor metabolizers." If
fluoxetine is added to the treatment regimen of a patient already receiving a
drug metabolized by P450IID6, the need for decreased dose of the original
medication should be considered. Drugs with a narrow therapeutic index represent
the greatest concern (eg, flecainide, vinblastine, and tricyclic
antidepressants).
DRUGS METABOLIZED BY CYTOCHROME P450IIIA4--In an in vivo interaction study
involving co- administration of fluoxetine with single doses of terfenadine (a
cytochrome P450IIIA4 substrate), no increase in plasma terfenadine
concentrations occurred with concomitant fluoxetine. In addition, in vitro
studies have shown ketoconazole, a potent inhibitor of P450IIIA4 activity, to be
at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor
of the metabolism of several substrates for this enzyme, including astemizole,
cisapride, and midazolam. These data indicate that fluoxetine's extent of
inhibition of cytochrome P450IIIA4 activity is not likely to be of clinical
significance.
CNS ACTIVE DRUGS--The risk of using PRODEP in combination with other CNS active
drugs has not been systematically evaluated. Nonetheless, caution is advised if
the concomitant administration of PRODEP and such drugs is required. In
evaluating individual cases, consideration should be given to using lower
initial doses of the concomitantly administered drugs, using conservative
titration schedules, and monitoring of clinical status (see Accumulation and
Slow Elimination Under ACTIONS/CLINICAL PHARMACOLOGY).
ANTICONVULSANTS--Patients on stable doses of phenytoin and carbamazepine have
developed elevated plasma anticonvulsant concentrations and clinical
anticonvulsant toxicity following initiation of concomitant fluoxetine
treatment.
ANTIPSYCHOTICS--Some clinical data suggests a possible pharmacodynamic and/or
pharmacokinetic interaction between serotonin specific reuptake inhibitors
(SSRIs) and antipsychotics. Elevation of blood levels of haloperidol and
clozapine has been observed in patients receiving concomitant fluoxetine. A
single case report has suggested possible additive effects of primozide and
fluoxetine leading to bradycardia.
BENZODIAZEPINES--The half-life of concurrently administered diazepam may be
prolonged in some patients (see Accumulation and Slow Elimination Under
ACTIONS/CLINICAL PHARMACOLOGY). Coadministration of alprazolam and fluoxetine
has resulted in increased alprazolam plasma concentrations and in further
psychomotor performance decrement due to increased alprazolam levels.
LITHIUM--There have been reports of both increased and decreased lithium levels
when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity
and increased serotonergic effects have been reported. Lithium levels should be
monitored when these drugs are administered concomitantly.
TRYPTOPHAN--Five patients receiving PRODEP in combination with tryptophan
experienced adverse reactions, including agitation, restlessness, and
gastrointestinal distress.
MONOAMINE OXIDASE INHIBITORS--See Contraindications.
OTHER ANTIDEPRESSANTS--In two studies, previously stable plasma levels of
imipramine and desipramine have increased greater than 2 to 10-fold when
fluoxetine has been administered in combination. This influence may persist for
three weeks or longer after fluoxetine is discontinued. Thus, the dose of
tricyclic antidepressant (TCA) may need to be reduced and plasma TCA
concentrations may need to be monitored temporarily when fluoxetine is
coadministered or has been recently discontinued (see Accumulation and Slow
Elimination Under ACTIONS/CLINICAL PHARMACOLOGY, and Drugs Metabolized by
P450IID6 Under DRUG INTERACTIONS).
POTENTIAL EFFECTS OF COADMINISTRATION OF DRUGS TIGHTLY BOUND TO PLASMA PROTEINS-
-Because fluoxetine is tightly bound to plasma protein, the administration of
fluoxetine to a patient taking another drug that is tightly bound to protein
(eg, Coumadin, digitoxin) may cause a shift in plasma concentrations potentially
resulting in an adverse effect. Conversely, adverse effects may result from
displacement of protein bound fluoxetine by other tightly bound drugs (see
Accumulation and Slow Elimination Under ACTIONS/CLINICAL PHARMACOLOGY).
WARFARIN--Altered anti-coagulant effects, including increased bleeding, have
been reported when fluoxetine is co-administered with warfarin. Patients
receiving warfarin therapy should receive careful coagulation monitoring when
fluoxetine is initiated or stopped.
ELECTROCONVULSIVE THERAPY--There are no clinical studies establishing the
benefit of the combined use of ECT and fluoxetine. There have been rare reports
of prolonged seizures in patients on fluoxetine receiving ECT treatment.
Carcinogenesis, Mutagenesis, Impairment Of Fertility--There is no evidence of
carcinogenicity, mutagenicity, or impairment of fertility with PRODEP.
CARCINOGENICITY--The dietary administration of fluoxetine to rats and mice for 2
years at doses of up to 10 and 12 mg/kg/day, respectively (approximately 1.2 and
0.7 times, respectively, the maximum recommended human dose (MRHD) of 80 mg on a
mg/M(squared) basis), produced no evidence of carcinogenicity.
MUTAGENICITY--Fluoxetine and norfluoxetine have been shown to have no genotoxic
effects based on the following assays: bacterial mutation assay, DNA repair
assay in cultured rat hepatocytes, mouse lymphoma assay, and in vivo sister
chromatid exchange assay in Chinese hamster bone marrow cells.
IMPAIRMENT OF FERTILITY--Two fertility studies conducted in rats at doses of up
to 7.5 and 12.5 mg/kg/day (approximately 0.9 and 1.5 times the MRHD on a
mg/M(squared) basis), indicated that fluoxetine had no adverse effects on
fertility.
Pregnancy--Pregnancy Category C: In embryo-fetal development studies in rats and
rabbits, there was no evidence of teratogenicity following administration of up
to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times, respectively, the
maximum recommended human dose (MRHD) of 80 mg on a mg/M(squared) basis)
throughout organogenesis. However, in rat reproduction studies, an increase in
stillborn pups, a decrease in pup weight, and an increase in pup death during
the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day
(1.5 times the MRHD on a mg/M(squared) basis) during gestation or 7.5 mg/kg/day
(0.9 times the MRHD on a mg/M(squared) basis) during gestation and lactation.
There was no evidence of developmental neurotoxicity in the surviving offspring
of rats treated with 12 mg/kg/day during gestation. The no-effect dose for rat
pup mortality was 5 mg/kg/day (0.6 times the MRHD on a mg/M(squared) basis).
PRODEP should be used during pregnancy only if the potential benefit justifies
the potential risk to the fetus.
Labor And Delivery--The effect of PRODEP on labor and delivery in humans is
unknown. However, because fluoxetine crosses the placenta and because of the
possibility that fluoxetine may have adverse effects on the newborn, fluoxetine
should be used during labor and delivery only if the potential benefit justifies
the potential risk to the fetus.
Nursing Mothers--Because PRODEP is excreted in human milk, nursing while on
PRODEP is not recommended. In 1 breast milk sample, the concentration of
fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mother's
plasma was 295.0 ng/mL. No adverse effects on the infant were reported. In
another case, an infant nursed by a mother on PRODEP developed crying, sleep
disturbance, vomiting, and watery stools. The infant's plasma drug levels were
340 ng/mL of fluoxetine and 208 ng/mL of norfluoxetine on the second day of
feeding.
Pediatric Use--Safety and effectiveness in pediatric patients have not been
established.
Usage In The Elderly--Evaluation of patients over the age of 60 who received
PRODEP 20 mg daily revealed no unusual pattern of adverse events relative to the
clinical experience in younger patients. However, these data are insufficient to
rule out possible age-related differences during chronic use, particularly in
elderly patients who have concomitant systemic illnesses or who are receiving
concomitant drugs (see Age Under ACTIONS/CLINICAL PHARMACOLOGY).
Hyponatremia--Several cases of hyponatremia (some with serum sodium lower than
110 mmol/L) have been reported. The hyponatremia appeared to be reversible when
PRODEP was discontinued. Although these cases were complex with varying possible
etiologies, some were possibly due to the syndrome of inappropriate antidiuretic
hormone secretion (SIADH). The majority of these occurrences have been in older
patients and in patients taking diuretics or who were otherwise volume depleted.
In a placebo-controlled, double- blind trial, 10 of 313 fluoxetine patients and
6 of 320 placebo recipients had a lowering of serum sodium below the reference
range; this difference was not statistically significant. The lowest observed
concentration was 129 mmol/L. The observed decreases were not clinically
significant.
Platelet Function--There have been rare reports of altered platelet function
and/or abnormal results from laboratory studies in patients taking fluoxetine.
While there have been reports of abnormal bleeding in several patients taking
fluoxetine, it is unclear whether fluoxetine had a causative role.
DRUG INTERACTIONS:
As with all drugs, the potential for interaction by a variety of mechanisms (eg,
pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc) is a
possibility (see Accumulation and Slow Elimination Under ACTIONS/CLINICAL
PHARMACOLOGY).
DRUGS METABOLIZED BY P450IID6--Approximately 7% of the normal population has a
genetic defect that leads to reduced levels of activity of the cytochrome P450
isoenzyme P450IID6. Such individuals have been referred to as "poor
metabolizers" of drugs such as debrisoquin, dextromethorphan, and tricyclic
antidepressants. Many drugs, such as most antidepressants including fluoxetine
and other selective uptake inhibitors of serotonin, are metabolized by this
isoenzyme; thus, both the pharmacokinetic properties and relative proportion of
metabolites are altered in poor metabolizers. However, for fluoxetine and its
metabolite the sum of the plasma concentrations of the 4 active enantiomers is
comparable between poor and extensive metabolizers (see Variability in
Metabolism Under ACTIONS/CLINICAL PHARMACOLOGY).
Fluoxetine, like other agents that are metabolized by P450IID6, inhibits the
activity of this isoenzyme, and thus may make normal metabolizers resemble "poor
metabolizers." Therapy with medications that are predominantly metabolized by
the P450IID6 system and that have a relatively narrow therapeutic index (see
list below), should be initiated at the low end of the dose range if a patient
is receiving fluoxetine concurrently or has taken it in the previous 5 weeks.
Thus, his/her dosing requirements resemble those of "poor metabolizers." If
fluoxetine is added to the treatment regimen of a patient already receiving a
drug metabolized by P450IID6, the need for decreased dose of the original
medication should be considered. Drugs with a narrow therapeutic index represent
the greatest concern (eg, flecainide, vinblastine, and tricyclic
antidepressants).
DRUGS METABOLIZED BY CYTOCHROME P450IIIA4--In an in vivo interaction study
involving co- administration of fluoxetine with single doses of terfenadine (a
cytochrome P450IIIA4 substrate), no increase in plasma terfenadine
concentrations occurred with concomitant fluoxetine. In addition, in vitro
studies have shown ketoconazole, a potent inhibitor of P450IIIA4 activity, to be
at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor
of the metabolism of several substrates for this enzyme, including astemizole,
cisapride, and midazolam. These data indicate that fluoxetine's extent of
inhibition of cytochrome P450IIIA4 activity is not likely to be of clinical
significance.
CNS ACTIVE DRUGS--The risk of using PRODEP in combination with other CNS active
drugs has not been systematically evaluated. Nonetheless, caution is advised if
the concomitant administration of PRODEP and such drugs is required. In
evaluating individual cases, consideration should be given to using lower
initial doses of the concomitantly administered drugs, using conservative
titration schedules, and monitoring of clinical status (see Accumulation and
Slow Elimination Under ACTIONS/CLINICAL PHARMACOLOGY).
ANTICONVULSANTS--Patients on stable doses of phenytoin and carbamazepine have
developed elevated plasma anticonvulsant concentrations and clinical
anticonvulsant toxicity following initiation of concomitant fluoxetine
treatment.
ANTIPSYCHOTICS--Some clinical data suggests a possible pharmacodynamic and/or
pharmacokinetic interaction between serotonin specific reuptake inhibitors
(SSRIs) and antipsychotics. Elevation of blood levels of haloperidol and
clozapine has been observed in patients receiving concomitant fluoxetine. A
single case report has suggested possible additive effects of primozide and
fluoxetine leading to bradycardia.
BENZODIAZEPINES--The half-life of concurrently administered diazepam may be
prolonged in some patients (see Accumulation and Slow Elimination Under
ACTIONS/CLINICAL PHARMACOLOGY). Coadministration of alprazolam and fluoxetine
has resulted in increased alprazolam plasma concentrations and in further
psychomotor performance decrement due to increased alprazolam levels.
LITHIUM--There have been reports of both increased and decreased lithium levels
when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity
and increased serotonergic effects have been reported. Lithium levels should be
monitored when these drugs are administered concomitantly.
TRYPTOPHAN--Five patients receiving PRODEP in combination with tryptophan
experienced adverse reactions, including agitation, restlessness, and
gastrointestinal distress.
MONOAMINE OXIDASE INHIBITORS--See Contraindications.
OTHER ANTIDEPRESSANTS--In two studies, previously stable plasma levels of
imipramine and desipramine have increased greater than 2 to 10-fold when
fluoxetine has been administered in combination. This influence may persist for
three weeks or longer after fluoxetine is discontinued. Thus, the dose of
tricyclic antidepressant (TCA) may need to be reduced and plasma TCA
concentrations may need to be monitored temporarily when fluoxetine is
coadministered or has been recently discontinued (see Accumulation and Slow
Elimination Under ACTIONS/CLINICAL PHARMACOLOGY, and Drugs Metabolized by
P450IID6 Under DRUG INTERACTIONS).
POTENTIAL EFFECTS OF COADMINISTRATION OF DRUGS TIGHTLY BOUND TO PLASMA PROTEINS-
-Because fluoxetine is tightly bound to plasma protein, the administration of
fluoxetine to a patient taking another drug that is tightly bound to protein
(eg, Coumadin, digitoxin) may cause a shift in plasma concentrations potentially
resulting in an adverse effect. Conversely, adverse effects may result from
displacement of protein-bound fluoxetine by other tightly bound drugs (see
Accumulation and Slow Elimination Under ACTIONS/CLINICAL PHARMACOLOGY).
WARFARIN--Altered anti-coagulant effects, including increased bleeding, have
been reported when fluoxetine is co-administered with warfarin. Patients
receiving warfarin therapy should receive careful coagulation monitoring when
fluoxetine is initiated or stopped.
ELECTROCONVULSIVE THERAPY--There are no clinical studies establishing the
benefit of the combined use of ECT and fluoxetine. There have been rare reports
of prolonged seizures in patients on fluoxetine receiving ECT treatment.
Carcinogenesis, Mutagenesis, Impairment Of Fertility--There is no evidence of
carcinogenicity, mutagenicity, or impairment of fertility with PRODEP.
(See Also PRECAUTIONS.)