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PDR® entry for
PROZAC
(DISTA PRODUCTS AND ELI LILLY AND
COMPANY)
DESCRIPTION:
Prozac® (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.
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Fluoxetine hydrochloride is a white to off-white crystalline
solid with a solubility of 14
mg/mL in water.
Each Pulvule® contains fluoxetine hydrochloride equivalent to 10 mg (32.3
micromol) or 20 mg (64.7 micromol) of fluoxetine. The Pulvules also contain F D
& C Blue No. 1, gelatin, iron oxide, silicone,
starch, titanium dioxide, and other inactive ingredients.
The oral solution contains fluoxetine hydrochloride equivalent to 20 mg/5 mL (64.7
micromol) of fluoxetine. It also contains alcohol 0.23%, benzoic acid, flavoring agent, glycerin,
purified water, and sucrose.
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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 Prozac.
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.
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CLINICAL STUDIES:
Clinical Trials:
Depression--The efficacy of Prozac for the treatment of patients with depression (>/=18 years of age) has been
studied in 5- and 6-week placebo-controlled
trials. Prozac was shown to
be significantly more effective than placebo as
measured by the Hamilton Depression Rating Scale (HAM-D). Prozac 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 Prozac, 20 mg, and placebo have shown Prozac, 20 mg daily, to be effective in the treatment of elderly patients (>/=60 years of
age) with depression. In these studies, Prozac 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. Prozac was well tolerated and
the rate of treatment discontinuations due to adverse events
did not differ between Prozac (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 Prozac 20 mg/day. These
patients (N=298) were randomized to continuation on double-blind Prozac 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 Prozac compared to those on
placebo.
Obsessive-Compulsive Disorder--The effectiveness of Prozac 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 Prozac 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 Prozac 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 Prozac 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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Prozac
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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 Prozac 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 Prozac or placebo
in the morning. Patients in the 16-week study
received a fixed Prozac 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, Prozac, 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 Prozac 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 Prozac, 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.
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INDICATIONS AND USAGE:
Depression--Prozac is indicated for the treatment of depression. The efficacy of Prozac 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 Prozac in hospitalized depressed patients has not been adequately
studied.
The efficacy of Prozac 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 Prozac for extended periods
should be reevaluated periodically (See Clinical
Trials Under ACTIONS/CLINICAL PHARMACOLOGY).
Obsessive-Compulsive Disorder--Prozac 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 Prozac 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 Prozac 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 Prozac for extended
periods should periodically reevaluate the long-term
usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Bulimia Nervosa--Prozac is indicated for the treatment of binge-eating and vomiting behaviors in patients with moderate to
severe bulimia nervosa.
The efficacy of Prozac 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 Prozac 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 Prozac for extended
periods should periodically reevaluate the long-term
usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
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CONTRAINDICATIONS:
Prozac 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, Prozac 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 Prozac before starting an MAOI.
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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 Prozac, 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, Prozac should be
discontinued.
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PRECAUTIONS:
General
ANXIETY AND INSOMNIA--In US placebo-controlled clinical trials for depression, 12% to 16% of patients treated with Prozac 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 Prozac and in 22% of
patients treated with placebo. Anxiety was reported in 14% of patients treated
with Prozac 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 Prozac, 60 mg, and
13% of patients treated with placebo. Anxiety and nervousness were reported respectively in 15% and
11% of patients treated with Prozac, 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 Prozac.
In US placebo-controlled clinical trials for depression, 11% of patients treated with Prozac and 2% of patients
treated with placebo reported anorexia (decreased appetite). Weight
loss was reported in 1.4% of patients treated with Prozac and in 0.5% of patients treated with placebo. However, only rarely have patients
discontinued treatment with Prozac because of anorexia or weight
loss.
In US placebo-controlled clinical trials for
OCD, 17% of patients treated
with Prozac and 10% of
patients treated with placebo reported anorexia (decreased appetite). One patient discontinued treatment with Prozac because of anorexia.
In US placebo-controlled clinical trials for bulimia nervosa, 8% of patients treated with Prozac, 60 mg, and 4% of
patients treated with placebo reported anorexia (decreased appetite). Patients treated with Prozac, 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 Prozac 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 Prozac and no patients treated with placebo. No patients reported
mania/hypomania in
US placebo-controlled clinical trials for bulimia. In all US Prozac 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 Prozac 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 Prozac clinical
trials, 0.2% of 10,782 patients reported convulsions. The percentage appears to
be similar to that associated with other marketed antidepressants. Prozac 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 Prozac
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 Prozac in patients with concomitant systemic illness
is limited. Caution is advisable in using Prozac 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 Prozac 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, Prozac may alter glycemic control. Hypoglycemia has occurred during therapy with Prozac, 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 Prozac 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 Prozac:
Because Prozac 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 Prozac in combination with other CNS active drugs has not
been systematically evaluated. Nonetheless, caution is advised if the concomitant administration of Prozac 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 Prozac 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 Prozac.
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/M2 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/M2 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/M2 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/M2 basis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD on
a mg/M2 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/M2 basis). Prozac should be used during
pregnancy only if the potential benefit justifies the potential risk to
the fetus.
Labor And Delivery--The effect of Prozac 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 Prozac is excreted in human
milk, nursing
while on Prozac 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 Prozac 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 Prozac 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 Prozac 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.
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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 Prozac in combination with other CNS active drugs has not
been systematically evaluated. Nonetheless, caution is advised if the concomitant administration of Prozac 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 Prozac 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 Prozac.
(See Also PRECAUTIONS.)
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ADVERSE REACTIONS:
Multiple doses of Prozac had been administered to 10,782 patients
with various diagnoses in US clinical trials as
of May 8, 1995. Adverse events were recorded by clinical investigators using descriptive
terminology of their own choosing. Consequently, it is not possible to provide a
meaningful estimate of the proportion of
individuals experiencing adverse events without first grouping similar types of
events into a limited (ie, reduced) number of
standardized event categories.
In the tables and tabulations that follow, COSTART Dictionary terminology has
been used to classify reported adverse events. The stated frequencies represent
the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or
worsened while receiving therapy following
baseline evaluation. It is important to
emphasize that events reported during therapy
were not necessarily caused by it.
The prescriber should be aware that the figures in the tables and tabulations
cannot be used to predict the incidence of side effects in the course of usual medical practice
where patient characteristics and other factors
differ from those that prevailed in the clinical
trials. Similarly, the cited frequencies cannot be compared with figures
obtained from other clinical investigations
involving different treatments, uses, and investigators. The cited figures,
however, do provide the prescribing physician
with some basis for estimating the relative
contribution of drug and nondrug factors to the
side effect incidence rate in
the population studied.
Incidence In US Placebo-Controlled Clinical Trials (excluding Data From Extensions Of Trials)--Table 1 enumerates the most common treatment-emergent adverse events associated with the use of
Prozac (incidence of at least 5% for Prozac and at least twice
that for placebo within at least one of the
indications) for the treatment of depression, OCD, and bulimia in US controlled clinical trials. Table 2 enumerates treatment-emergent adverse events that occurred in 2% or
more patients treated with Prozac and with incidence greater than placebo who participated in US controlled clinical trials comparing Prozac with placebo in the treatment of depression, OCD, or bulimia. Table 2
provides combined data for the pool of studies that are provided separately by indication in Table 1.
----------------------------------------------------------------------------
TABLE 1--MOST COMMON TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN US
DEPRESSION, OCD, AND BULIMIA PLACEBO-CONTROLLED CLINICAL TRIALS
----------------------------------------------------------------------------
Percentage of patients reporting event
----------------------------------------------------------------------------
Depression OCD Bulimia
----------------------------------------------------------------------------
Body System/ Prozac Placebo Prozac Placebo Prozac Placebo
Adverse Event (N=1728) (N=975) (N=266) (N=89) (N=450) (N=267)
----------------------------------------------------------------------------
BODY AS A WHOLE
Asthenia 9 5 15 11 21 9
Flu syndrome 3 4 10 7 8 3
CARDIOVASCULAR
SYSTEM
Vasodilatation 3 2 5 -- 2 1
DIGESTIVE SYSTEM
Nausea 21 9 26 13 29 11
Anorexia 11 2 17 10 8 4
Dry mouth 10 7 12 3 9 6
Dyspepsia 7 5 10 4 10 6
NERVOUS SYSTEM
Insomnia 16 9 28 22 33 13
Anxiety 12 7 14 7 15 9
Nervousness 14 9 14 15 11 5
Somnolence 13 6 17 7 13 5
Tremor 10 3 9 1 13 1
Libido decreased 3 -- 11 2 5 1
Abnormal dreams 1 1 5 2 5 3
RESPIRATORY SYSTEM
Pharyngitis 3 3 11 9 10 5
Sinusitis 1 4 5 2 6 4
Yawn -- -- 7 -- 11 --
SKIN AND
APPENDAGES
Sweating 8 3 7 -- 8 3
Rash 4 3 6 3 4 4
UROGENITAL SYSTEM
Impotence* 2 -- -- -- 7 --
Abnormal
ejaculation* -- -- 7 -- 7 --
----------------------------------------------------------------------------
* Denominator used was for males only (N=690 Prozac depression; N=410 placebo
depression; N=116 Prozac OCD; N=43 placebo OCD; N=14 Prozac bulimia; N=1
placebo bulimia).
--Incidence less than 1%.
----------------------------------------------------------------------------
|
TABLE 2.
TREATMENT-EMERGENT ADVERSE EVENTS:
INCIDENCE IN US DEPRESSION, OCD, AND BULIMIA
PLACEBO-CONTROLLED CLINICAL TRIALS
-----------------------------------------------------------------------------
Percentage of
Patients Reporting Event
-----------------------------------------------------------------------------
Depression, OCD,
and bulimia combined
-----------------------------------------------------------------------------
Body System/ Prozac Placebo
Adverse Event* (N=2444) (N=1331)
-----------------------------------------------------------------------------
BODY AS A WHOLE
Headache 21 20
Asthenia 12 6
Flu Syndrome 5 4
Fever 2 1
CARDIOVASCULAR SYSTEM
Vasodilatation 3 1
Palpitation 2 1
DIGESTIVE SYSTEM
Nausea 23 10
Diarrhea 12 8
Anorexia 11 3
Dry mouth 10 7
Dyspepsia 8 5
Flatulence 3 2
Vomiting 3 2
METABOLIC AND NUTRITIONAL
DISORDERS
Weight loss 2 1
NERVOUS SYSTEM
Insomnia 20 11
Anxiety 13 8
Nervousness 13 9
Somnolence 13 6
Dizziness 10 7
Tremor 10 3
Libido decreased 4 --
RESPIRATORY SYSTEM
Pharyngitis 5 4
Yawn 3 --
SKIN AND APPENDAGES
Sweating 8 3
Rash 4 3
Pruritus 3 2
SPECIAL SENSES
Abnormal vision 3 1
-----------------------------------------------------------------------------
* Included are events reported by at least 2% of patients taking Prozac,
except the following events, which had an incidence on placebo >/=Prozac
(depression, OCD, and bulimia combined): abdominal pain, abnormal dreams,
accidental injury, back pain, chest pain, constipation, cough increased,
depression (includes suicidal thoughts), dysmenorrhea, gastrointestinal
disorder, infection, myalgia, pain, paresthesia, rhinitis, sinusitis,
thinking abnormal.
--Incidence less than 1%.
|
Associated With Discontinuation In US Placebo-Controlled Clinical Trials (excluding Data From Extensions Of Trials)--Table 3 lists the adverse events associated with
discontinuation of Prozac
treatment (incidence at least twice that for placebo and at least 1% for Prozac in clinical trials) in depression, OCD, and bulimia.
----------------------------------------------------------------------------
TABLE 3--MOST COMMON ADVERSE EVENTS ASSOCIATED WITH DISCONTINUATION IN US
DEPRESSION, OCD AND BULIMIA PLACEBO-CONTROLLED CLINICAL TRIALS
----------------------------------------------------------------------------
Depression,
OCD, and
bulimia
combined Depression OCD Bulimia
----------------------------------------------------------------------------
-- -- Anxiety (2%) --
Insomnia (1%) Insomnia (1%) -- Insomnia (2%)
-- Nausea (1%) -- --
Nervousness (1%) Nervousness (1%) -- --
-- -- Rash (3%) --
----------------------------------------------------------------------------
|
Other Events Observed In All US Clinical
Trials--Following is a list of all treatment-emergent adverse events reported at anytime by
individuals taking fluoxetine in US clinical
trials (10,782 patients) except (1) those listed in the body or footnotes of Table 1 or 2 above or elsewhere in labeling; (2)
those for which the COSTART terms were uninformative or misleading; (3) those
events for which a causal relationship to Prozac use was considered
remote; and (4) events occurring in only 1 patient treated with Prozac and which did not have a substantial
probability of being acutely life-threatening.
Events are classified within body system categories using the following definitions:
frequent adverse events are defined as those occurring on 1 or more occasions in
at least 1/100 patients; infrequent adverse events are those occurring in 1/100
to 1/1,000 patients; rare events are those occurring in less than 1/1,000
patients.
BODY AS A WHOLE--Frequent: chills;
Infrequent: chills and fever, face edema,
intentional overdose, malaise, pelvic pain, suicide attempt; Rare: abdominal syndrome
acute, hypothermia, intentional injury, neuroleptic malignant syndrome, photosensitivity reaction.
CARDIOVASCULAR SYSTEM--Frequent: hemorrhage, hypertension; Infrequent: angina pectoris, arrhythmia, congestive heart
failure, hypotension, migraine, myocardial infarct, postural, hypotension, syncope, tachycardia, vascular headache; Rare: atrial fibrillation, bradycardia, cerebral embolism,
cerebral ischemia, cerebrovascular accident,
extrasystoles, heart arrest, heart block, pallor, peripheral vascular disorder, phlebitis, shock,
thrombophlebitis, thrombosis, vasospasm, ventricular arrhythmia, ventricular
extrasystoles, ventricular fibrillation.
DIGESTIVE SYSTEM--Frequent: increased appetite, nausea
and vomiting; Infrequent: aphthous stomatitis, cholelithiasis, colitis, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, glossitis, gum hemorrhage, hyperchlorhydria, increased salivation, liver
function tests abnormal, melena, mouth ulceration,
nausea/vomiting/diarrhea, stomach ulcer, stomatitis, thirst; Rare: biliary pain,
bloody diarrhea, cholecystitis, duodenal ulcer,
enteritis, esophageal ulcer,
fecal incontinence, gastrointestinal hemorrhage, hematemesis, hemorrhage of colon, hepatitis,
intestinal obstruction, liver fatty deposit, pancreatitis, peptic ulcer, rectal hemorrhage, salivary gland enlargement, stomach ulcer hemorrhage, tongue edema.
ENDOCRINE SYSTEM--Infrequent: hypothyroidism: Rare: diabetic acidosis,
diabetes mellitus.
HEMIC AND LYMPHATIC SYSTEM--Infrequent: anemia, ecchymosis; Rare: blood dyscrasia,
hypochromic anemia, leukopenia, lymphedema, lymphocytosis,
petechia, purpura, thrombocythemia, thrombocytopenia.
METABOLIC AND NUTRITIONAL--Frequent: weight gain; Infrequent: dehydration, generalized edema, gout, hypercholesteremia, hyperlipemia, hypokalemia, peripheral edema,
Rare: alcohol intolerance, alkaline phosphatase increased, BUN increased, creatine phosphokinase increased, hyperkalemia, hyperuricemia, hypocalcemia, iron deficiency anemia,
SGPT increased.
MUSCULOSKELETAL SYSTEM--Infrequent: arthritis, bone pain, bursitis,
leg cramps, tenosynovitis; Rare: arthrosis, chondrodystrophy, myasthenia, myopathy, myositis, osteomyelitis, osteoporosis, rheumatoid arthritis.
NERVOUS SYSTEM--Frequent: agitation, amnesia, confusion,
emotional lability, sleep
disorder; Infrequent: abnormal gait, acute brain syndrome, akathisia, apathy,
ataxia, buccoglossal syndrome, CNS depression, CNS stimulation, depersonalization, euphoria, hallucinations, hostility,
hyperkinesia,
hypertonia, hypesthesia, incoordination, libido increased, myoclonus, neuralgia, neuropathy, neurosis, paranoid reaction, personality disorder*, psychosis, vertigo; Rare: abnormal electroencephalogram, antisocial reaction, circumoral paresthesia, coma,
delusions, dysarthria, dystonia, extrapyramidal syndrome, foot drop, hyperesthesia, neuritis, paralysis, reflexes decreased, reflexes increased,
stupor.
RESPIRATORY SYSTEM--Infrequent: asthma, epistaxis,
hiccup, hyperventilation; Rare: apnea, atelectasis,
cough decreased, emphysema, hemoptysis, hypoventilation, hypoxia, larynx
edema, lung edema, pneumothorax, stridor.
SKIN AND APPENDAGES--Infrequent: acne, alopecia, contact dermatitis, eczema, maculopapular rash, skin
discoloration, skin ulcer, vesiculobullous rash; Rare: furunculosis, herpes zoster, hirsutism, petechial rash,
psoriasis, purpuric rash, pustular rash, seborrhea.
SPECIAL SENSES--Frequent: ear pain, taste perversion,
tinnitus; Infrequent: conjunctivitis, dry eyes,
mydriasis, photophobia; Rare: blepharitis, deafness, diplopia, exophthalmos, eye hemorrhage, glaucoma, hyperacusis, iritis, parosmia,
scleritis, strabismus, taste
loss, visual field defect.
UROGENITAL SYSTEM--Frequent: urinary frequency; Infrequent: abortion*, albuminuria, amenorrhea*,
anorgasmia, breast enlargement, breast pain, cystitis, dysuria, female
lactation*, fibrocystic breast*, hematuria, leukorrhea*, menorrhagia*, metrorrhagia*, nocturia, polyuria, urinary
incontinence, urinary retention, urinary urgency,
vaginal hemorrhage*; Rare: breast engorgement, glycosuria, hypomenorrhea*, kidney pain, oliguria, priapism*, uterine hemorrhage*, uterine fibroids enlarged*.
* Personality disorder is the COSTART term for designating non-aggressive objectionable behavior.
* Adjusted for gender
Postintroduction Reports--Voluntary reports
of adverse events temporally associated with Prozac that have been received since market
introduction and that may have no causal relationship with the drug include the following: aplastic anemia, atrial fibrillation, cerebral vascular
accident, cholestatic jaundice, confusion, dyskinesia (including, for example, a case of buccal-lingual-masticatory syndrome with involuntary tongue protrusion
reported to develop in a 77-year-old female after 5 weeks of fluoxetine therapy and which completely resolved over the
next few months following drug
discontinuation), eosinophilic pneumonia, epidermal necrolysis, exfoliative dermatitis, gynecomastia, heart arrest, hepatic failure/necrosis, hyperprolactinemia, immune-related hemolytic anemia,
kidney failure, misuse/abuse, movement disorders developing in patients with risk factors including drugs associated with such
events and worsening of preexisting movement
disorders, neuroleptic malignant syndrome-like events, pancreatitis, pancytopenia, priapism, pulmonary embolism, QT prolongation, Stevens-Johnson
syndrome, sudden unexpected death, suicidal ideation, thrombocytopenia, thrombocytopenic purpura, vaginal
bleeding after drug withdrawal,
and violent behaviors.
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DRUG ABUSE AND DEPENDENCE:
Controlled Substance Class--Prozac is not a controlled substance.
Physical And Psychological Dependence--Prozac has not been systematically studied, in
animals or humans, for its potential for abuse, tolerance or
physical dependence. While the premarketing clinical experience with Prozac did not reveal any tendency for a withdrawal syndrome or any drug-seeking behavior, these observations were not systematic and it is not possible to predict on
the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once
marketed. Consequently, physicians should carefully evaluate patients for
history of drug abuse and follow such patients closely, observing
them for signs of misuse or abuse of Prozac (eg, development of tolerance, incrementation of dose, drug-seeking behavior).
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OVERDOSAGE:
Human Experience--As of December 1987, there
were 2 deaths among approximately 38 reports of acute overdose with
fluoxetine, either alone or in
combination with other drugs and/or alcohol. One death
involved a combined overdose with approximately 1,800 mg of fluoxetine and an
undetermined amount of maprotiline. Plasma concentrations of fluoxetine and maprotiline were 4.57 mg/L and 4.18 mg/L,
respectively. A second death involved 3 drugs
yielding plasma concentrations as follows:
fluoxetine, 1.93 mg/L; norfluoxetine, 1.10 mg/L; codeine, 1.80 mg/L; temazepam, 3.80 mg/L.
One other patient who reportedly took 3,000
mg of fluoxetine experienced 2 grand mal seizures that remitted spontaneously
without specific anticonvulsant treatment (see Management of Overdose). The actual
amount of drug absorbed may have been less due
to vomiting.
Nausea and vomiting were prominent in overdoses involving
higher fluoxetine doses. Other prominent symptoms of overdose included
agitation, restlessness, hypomania, and other
signs of CNS excitation. Except for the 2
deaths noted above, all other overdose cases recovered without residua.
Since introduction, reports of death
attributed to overdosage of fluoxetine alone have been extremely rare.
Animal Experience--Studies in animals do not provide
precise or necessarily valid information about
the treatment of human overdose. However, animal experiments can provide useful insights into
possible treatment strategies.
The oral median lethal dose in rats and mice was found to be 452 and 248
mg/kg respectively. Acute high oral doses produced hyperirritability and
convulsions in several animal species.
Among 6 dogs purposely overdosed with oral
fluoxetine, 5 experienced grand mal seizures. Seizures stopped immediately upon
the bolus intravenous administration of a standard veterinary dose
of diazepam. In this short-term study, the
lowest plasma concentration at which a seizure occurred was only twice the maximum plasma
concentration seen in humans taking 80 mg/day, chronically.
In a separate single-dose study, the ECG in dogs given high doses did not
reveal prolongation of the PR, QRS, or QT intervals. Tachycardia and an increase in blood
pressure were observed. Consequently, the value
of the ECG in predicting cardiac toxicity is unknown. Nonetheless, the ECG should
ordinarily be monitored in cases of human overdose (see Management of Overdose).
Management Of Overdose--Establish and maintain an airway; ensure adequate oxygenation and ventilation. Activated charcoal, which may be used with sorbitol, may be as or more effective than emesis or lavage,
and should be considered in treating overdose.
Cardiac and vital signs monitoring is recommended, along with general symptomatic and supportive measures. Based on experience in animals, which may not be relevant
to humans, fluoxetine-induced seizures that fail to remit spontaneously may respond to diazepam.
There are no specific antidotes for Prozac.
Due to the large volume of distribution of
Prozac, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit.
In managing overdosage, consider the possibility of multiple drug
involvement. A specific caution involves
patients taking or recently having taken fluoxetine who might ingest by accident or intent, excessive quantities of a
tricyclic antidepressant. In such a case, accumulation of the parent tricyclic and an active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation (see Other Antidepressants
Under PRECAUTIONS).
The physician should consider contacting a
poison control
center on the treatment of any overdose. Telephone numbers of
certified poison control centers are listed in the Physicians' Desk
Reference (PDR)
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DOSAGE AND ADMINISTRATION:
Depression--
INITIAL TREATMENT--In controlled trials used
to support the efficacy of
fluoxetine, patients were administered
morning doses ranging from 20 mg to 80 mg/day. Studies comparing fluoxetine 20,
40, and 60 mg/day to placebo indicate that 20
mg/day is sufficient to obtain a satisfactory antidepressant response in most cases. Consequently, a dose of 20 mg/day administered in the morning, is
recommended as the initial dose.
A dose increase may be considered after several weeks if no clinical improvement is observed. Doses above 20
mg/day may be administered on a once a day (morning) or b.i.d. schedule (ie, morning and noon) and should not
exceed a maximum dose of 80 mg/day.
As with other antidepressants, the full antidepressant effect may be delayed until 4 weeks of treatment or longer.
As with many other medications, a lower or
less frequent dosage should be used in patients
hepatic impairment. A lower or less frequent dosage should also be considered for the elderly
(see Usage in the Elderly Under PRECAUTIONS), and for patients with concurrent
disease or on multiple concomitant medications. Dosage adjustments fro renal impairment
are not routinely necessary (See Liver Disease and Renal
Disease Under ACTIONS/CLINICAL PHARMACOLOGY, And Use in Patients with Concomitant Illness Under PRECAUTIONS).
MAINTENANCE/CONTINUATION/EXTENDED TREATMENT--It is generally agreed that acute episodes of depression require several months or longer of
sustained pharmacologic therapy. Whether the dose of antidepressant needed to induce remission
is identical to the dose needed to maintain
and/or sustain euthymia is unknown.
Systemic evaluation of Prozac has shown that its antidepressant efficacy is maintained for periods of up to 38 weeks following 12 weeks of open-label acute treatment (50 weeks total) at a dose of 20 mg/kg/day (See Clinical Trials Under ACTIONS/CLINICAL PHARMACOLOGY).
Obsessive-Compulsive Disorder--
INITIAL TREATMENT--In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of obsessive-compulsive disorder, patients were administered fixed daily
doses of 20, 40, or 60 mg of fluoxetine or placebo (see Clinical Trials Under Clinical Pharmacology). In one of these studies, no dose response relationship for effectiveness was demonstrated. Consequently, a dose of 20 mg/day, administered in the morning, is
recommended as the initial dose. Since there
was a suggestion of a possible dose response relationship for effectiveness in the second study, a dose increase may be considered after several weeks if insufficient clinical improvement is observed. The full therapeutic effect may be delayed until 5 weeks of treatment or longer.
Doses above 20 mg/day may be administered on a once a day (ie, morning or
b.i.d. schedule
(ie, morning and noon). A dose range of 20
to 60 mg/day is recommended, however, doses of up to 80 mg/day have been well
tolerated in open studies of
OCD. The maximum fluoxetine dose should not exceed 80 mg/day.
As with the use of Prozac in depression, a lower or less frequent dosage should be used in patients with hepatic impairment. A lower or less frequent dosage should also be considered for the elderly
(see Usage in the Elderly Under Precautions), and for patients with concurrent
disease or on multiple concomitant medications. Dosage adjustments for renal impairment
are not routinely necessary (See Liver Disease and Renal
Disease Under ACTIONS/CLINICAL PHARMACOLOGY, And Use in Patients with Concomitant Illness Under PRECAUTIONS).
MAINTENANCE/CONTINUATION TREATMENT--While
there are no systematic studies that answer the
question of how long to continue Prozac, OCD is a chronic condition
and it is reasonable to consider continuation for a responding patient. Although the efficacy of Prozac after 13 weeks has not been documented in controlled
trials, patients have been continued in therapy under double-blind conditions for up to an additional 6 months
without loss of benefit. However, dosage
adjustments should be made to maintain the patient on the lowest effective dosage, and patient should be periodically reassessed to
determine the need for treatment.
Bulimia Nervosa--
INITIAL TREATMENT--In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of bulimia nervosa, patients were administered fixed
daily fluoxetine doses of 20 or 60 mg, or placebo (see Clinical Trials Under Clinical Pharmacology). Only the 60 mg dose was statistically significantly superior to placebo in reducing the frequency of binge-eating
and vomiting. Consequently, the recommended dose is 60 mg/day, administered in the morning.
For some patients it may be advisable to titrate up to this target dose over
several days. Fluoxetine doses above 60 mg/day have not been systematically
studied in patients with bulimia.
As with the use of Prozac in depression and OCD, a lower or less frequent dosage should be used in patients with hepatic impairment. A lower or less frequent dosage should also be considered for the elderly
(see Usage in the Elderly Under Precautions), and for patients with concurrent
disease or on multiple concomitant medications. Dosage adjustments for renal impairment
are not routinely necessary (See Liver Disease and Renal
Disease Under ACTIONS/CLINICAL PHARMACOLOGY, And Use in Patients with Concomitant Illness Under PRECAUTIONS).
MAINTENANCE/CONTINUATION TREATMENT--While
there are no systematic studies that answer the
question of how long to continue Prozac, bulimia is a chronic condition
and it is reasonable to consider continuation for a responding patient. Although the efficacy of Prozac after 16 weeks has not been documented in controlled
trials, some patients have been continued in therapy under double-blind conditions for up to an additional 6 months
without loss of benefit. However, patients should be periodically reassessed to
determine the need for continued treatment.
Switching Patients To A Tricyclic Antidepressant (TCA)--Dosage of a 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 Other Antidepressants Under DRUG INTERACTIONS).
Switching Patients To Or From A Monoamine Oxidase
Inhibitor--At least 14 days should elapse
between discontinuation of an MAOI and initiation of therapy with Prozac. In addition, at least 5 weeks, perhaps longer, should be allowed after
stopping Prozac before
starting an MAOI (see Contraindications and
PRECAUTIONS).
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HOW SUPPLIED:
Pulvules
10 mg*, green and green (No. 3104)--(100s) NDC 0777-3104-02; (2000s)
NDC 0777-3104-07; (20 FlexPak$ blister cards of
31) NDC 0777-3104-82
20 mg*, green and off-white (No. 3105)--(30s) NDC 0777-3105-30; (100s)
NDC 0777-3105-02; (2000s) NDC 0777-3105-07; (ID*100) NDC 0777-3105-33; (20
FlexPak$ blister cards of 31) NDC 0777-3105-82
Liquid, Oral Solution:
20 mg*/5 mL, mint flavor (M-5120**)--(120
mL) NDC 0777-5120-58
-----------
*Fluoxetine base equivalent.
*Identi-Dose® (unit dose medication,
Dista).
**Dispense in a tight, light-resistant container.
$ FlexPak (flexible blister card, Lilly)
Store at controlled room temperature, 59° to
86° F (15° to 30° C).
CAUTION--Federal (USA) law prohibits dispensing without prescription.
Literature revised April 1, 1997
PV 2471 DPP: (040197)
DISTA PRODUCTS COMPANY
Division of Eli Lilly and Company
Indianapolis, Indiana 46285, USA
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PRODUCT PHOTO(S):NOTE: These photos can be used only for identification
by shape, color, and imprint. They do not depict actual or relative size.
Each photo may be enlarged for closer study by clicking on it.
The
product samples shown here have been supplied by the manufacturer and reproduced
in full color by PDR as a quick-reference identification aid. While every effort
has been made to assure accurate reproduction, please remember that any visual
identification should be considered preliminary. In cases of poisoning or
suspected overdosage, the drug's identity should be verified by chemical
analysis.
Prozac®
(fluoxetine HCl)
Click on image for larger view of drug.
 |
|
20 mg |
Product Classification: RX
Manufacturer: DISTA PRODUCTS
Prozac®
(fluoxetine HCl)
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|
|
10 mg |
Product Classification: RX
Manufacturer: DISTA PRODUCTS
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ANIMAL PHARMACOLOGY:
ANIMAL TOXICOLOGY
Phospholipids are increased in some tissues of mice, rats, and dogs given
fluoxetine chronically. This effect is reversible after cessation of fluoxetine treatment. Phospholipid accumulation in animals has been
observed with many cationic amphiphilic drugs, including
fenfluramine, imipramine, and rantidine. The significance of this effect to humans is unknown.
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