| MadSci Network: Medicine |
Scientifically we can not prove that Prozac increases anxiety. It may be a
side affect or it may be actually augmentation of the symptoms the patient
was having prior to taking the medication. In reviewing the drug trials
below, although anxiety was listed as a side affect, it did not markedly
differ from a placebo affect. However, I have not found it extremely helpful
in treating anxiety alone, rather in combination with a benzodiazapine.
(Valium or Xanax)
Prozac
Fluoxetine Hydrochloride
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-tri-fluoro-p-tolyl)oxy]propylamine hydrochloride and has the empirical
formula of C17 H18 F3 NO.HCl. Its molecular weight is 345.79. The structural
formula is:
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 mu
mol) or 20 mg (64.7 mu mol) of fluoxetine. The Pulvules also contain F D & C
Blue No. 1, gelatine, iron oxide, silicone, starch, titanium dioxide, and
other inactive ingredients.
The oral solution contains fluoxetine hydrochloride equivalent to 20 mg/5 mL
(64.7 mu mol) of fluoxetine. It also contains alcohol 0.23%, benzoic acid,
flavoring agent, glycerin, purified water, and sucrose.
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Clinical Pharmacology
Pharmacodynamics:
The antidepressant and antiobsessive-compulsive action of fluoxetine is
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 durgs 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-
and S-fluoxetine. R-norfluoxetine is significally less potent than the
parent durg 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 unlabled 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 adminisitration
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 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,
previos 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 single dose studies, the pharmacokinetics of fluoxetine
and norfluoxetine were similar among subjects with all levels of impaired
renal function including anephric patients on chronic hemodialysis. However,
with chronic administration, additional accumulation of fluoxetine or its
metabolites (possibly including some not yet identified) may occur in
patients with severly impaired renal function and use of a lower or less
frequent dose is advised (see Precautions).
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 possiblity 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 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 the 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 highter 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%).
Obsessive Compulsive Disorder--The effectiveness of Prozac for the treatment
of 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 sever 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 receiveing 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 CGI improvement scale
for studies 1 and 2 combined:
Outcome Classification (%) On CGI Improvement Scale for
Completers in Pool of Two OCD Studies
Outcome Placebo Prozac Prozac Prozac
Classification 20 mg 40 mg 60 mg
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%
Exploratory analysis for age and gender effects on outcome
did not suggest any differential responsiveness on the basis
of age or sex.
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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 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 effectiveness of Prozac in long-term use, that is, for more than 5 to 6
weeks, has not been systematically evaluated in 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.
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 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 that person as excessive or unreasonable.
The effectiveness of Prozac in long-term, ie, for more than 13 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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Contraindictions
Prozac is contraindicted 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 agitations pregressing 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 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 Clinical Pharmacology]) should be
allowed after stopping Prozac before starting an MAOI.
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Warnings
Rash and Possibly Allergic Events--During premarketing testing of more than
5,600 US patients given fluoxetine, approximately 4% developed a rash and/or
urticaria. Among these cases, 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 illness. In neither patient was there an unequivocal
diagnoses, 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 occured 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 apprearance of rash or of other possibly
allergic phenomenafor which an alternative etiology cannot be identified,
Prozac should be discontinued.
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Precautions
General
Anxiety and Insomnia--Anxiety, nervousness, and insomnia were reported by
10% to 15% of patients treated with Prozac. These symptoms led to drug
discontinuation in 5% of patients treated with Prozac.
In controlled clinical trials for obsessive-compulsive disorder, insomnia
was reported in 30% of patients treated with Prozac and in 22% or patients
treated with placebo. Anxiety was reported in 14% of patients treated with
Prozac and in 7% or patients treated with placebo. These 2 symptoms led to
drug discontinuation in 2% of patients treated with Prozac and no patients
treated with placebo.
Altered Appetite and Weight--Significant weight loss, especially in
underweight depressed patients, may be an undesirable result of treatment
with Prozac.
In controlled clinical trials, approximately 9% of patients treated with
Prozac experienced anorexia. This incidence is approximately sixfold that
seen in placebo controls. A weight loss of greater than 5% of body weight
occured in 13% of patients treated with Prozac compared to 4% of placebo and
3% of patients treated with tricyclics. However, only rarely have patients
discontinued treatment with Prozac because of weight loss.
In controlled clinical trials for OCD, 17% of patients treated with Prozac
and 10% of patients treated with placebo reported anorexia. One patient
discontinued treatment with Prozac because of anorexia.
Activation of Mania/Hypomania--During premarketing testing, hypomania or
mania occurred in approximately 1% of fluoxetine treated patients.
Activation of mania/hypomania has also been reported in a small proportion
of patients with Major Affective Disorder treated with other marketed
antidepressants. Mania/hypomania was reported in 1% of patients treated with
fluoxetine in controlled clinical OCD trials.
Seizures--Twelve patients among more than 6,000 evaluated worldwide in the
course of premarketing development of fluoxetine experienced convulsions (or
events described as possibly having been seizures), a rate of 0.2% that
appears to be similar to that associated with other marketed
antidepressants. Prozac should be introduced with care in patients with a
history of seizures.
In controlled clinical trials for OCD, 1 patient treated with fluoxetine
experienced a seizure.
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 comorbidity between OCD and depression, the same
precautions observed when treating patients with depression should be
observed when treating patients with OCD.
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
withdrawl from treatment (see 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 clearance 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.
Since fluoxetine is extensively metabolized, excretion of unchanged drug in
urine is a minor route of elimination. However, until adequate numbers of
patients with sever renal impairment have been evaluated during chronic
treatment with fluoxetine, it should be used with caution in such patients.
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.
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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 thier 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.
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Laboratory Tests
There are no specific laboratory tests recommended.
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Drug Interactions
As with all drugs, the potential for interaction by a variety of mechanisms
(eg, pharmacodynamics, pharmacokinetic drug inhibition or enhancement, etc)
is a possibility (see Accumulation and Slow Elimination under Clinical
Pharmacology).
Drugs Metabolized by P450IID6--Approximately 7% of the normal population has
a genetic defect that leads to reduce 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 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 receiveing 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, carbamazepine, and tricyclic antidepressants).
Tryptophan--Five patients receiving Prozac in combination with tryptophan
experienced adverse reactions, including agitation, restlessness, and
gastrointestinal distress.
Monoamine Oxidase Inhibitors--See Contraindictions.
Other Antidepressants--There have been greater than 2-fold increases of
previously stable plasma levels of other antidepressants when Prozac has
been administered in combination with these agents (see Accumulation and
Slow Elimination under Clinical Pharmacology).
Lithium--There have been reports of both increased and decreased lithium
levels when lithium was used concomitantly with fluoxetine. Cases of lithium
toxicity have been reported. Lithium levels should be monitored when these
drugs are administered concomitantly.
Diazepam Clearance--The half-life of concurrently administered diazepam may
be prolonged in some patients (see Accumulation and Slow Elimination under
Clinical Pharmacology).
Phenytoin--Patients on stable doses of phenytoin have developed elevated
plasma phenytoin concentrations and clinical phenytoin toxicity follwoing
initiation of concomitant fluoxetine treatment.
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 casue 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 Clinical Pharmacology).
CNS Active Drugs--The risk of using Prozac in combination with other CNS
active drugs has not been systematically evaluated. Consequently, caution is
advised if the concomitant administration of Prozac and such drugs is
required (see Accumulation and Slow Elimination under Clinical
Pharmacology).
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.
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Carcinogenesis, Mutagenesis, Impairment of Fertility
There is no evidence of carcinogenicity, mutagenicity, or impairment of
fertility with Prozac.
The dietary administration of fluoxetine to rats and mice for 2 years at
levels equivalent to approximately 7.5 and 9.0 times the maximum human dose
(80 mg) respectively produced no evidence of carcinogenicity.
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.
Two fertility studies conducted in rats at doses of approximately 5 and 9
times the maximum human dose (80 mg) indicated that fluoxetine had no
adverse effects on fertility. A slight decrease in neonatal survival was
noted, but this was probably associated with depressed maternal food
consumption and suppressed weight gain.
Pregnancy--Teratogenic Effects--Pregnancy Category B Reproduction studies
have been performed in rats and rabbits at doses 9 and 11 times the maximum
daily human dose (80 mg) respectively and have revealed no evidence of harm
to the fetus due to Prozac. There are, however, no adequate and
well-controlled studies in pregnant women. Because animal reproduction
studies are not always predictive of human response, the drug should be used
during pregnancy only if clearly needed.
Labor and Delivery--The effect of Prozac on labor and delivery in humans is
unknown.
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 240 ng/mL of fluoxetine and 208 ng/mL norfluoxetine on the
second day of feeding.
Usage in Children Safety and effectiveness in children 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 pattery 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 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 those
occurrences have been in older patients and in patients taking diuretics of
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. Where 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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Adverse Reactions
Commonly Observed--The most commonly observed adverse events associated with
the use of Prozac and not seen at an equivalent incidence among
placebo-treated patients were: nervous system complaints, including anxiety,
nervousness, and insomnia; drowsiness and fatigue or asthenia; tremor;
sweating; gastrointestingal complaints, including anorexia, nausea, and
diarrhea; and dizziness or light headedness.
In controlled clinical trials for OCD using fixed doses of 20, 40 or 60 mg
daily, adverse events observed at an incidence of at least 5% for Prozac and
for which the incidence was approximately twice or more the incidence among
placebo-treated patients included: somnolence, anxiety, tremor, nausea,
dyspepsia, gastrointestinal disorder, vasodilatation, dry mouth, sweating,
rash, abnormal vision, yawn, decreased libido, and abnormal ejaculation.
Associated With Discontinuation of Treatment--Fifteen percent of
approximately 4,000 patients who received Prozac in US premarketing clinical
trials discontinued treatment due to an adverse event. The more common
events causing discontinuation included: psychiatric (5.3%), primarily
nervousness, anxiety, and insomnia; digestive (3.0%), primarily nausea;
nervous system (1.6%), primarily dizziness; body as a whole (1.5%),
primarily asthenia and headache; and skin (1.4%), primarily rash and
pruritus.
In controlled clinical trials for OCD, 12% of patients treated with Prozac
discontinued treatment due to adverse events. The most common events were
anxiety (2%) and rash/urticaria (2%).
Incidence in Controlled Clinical Trials
Depression--Table 1 enumerates adverse events that occurred at a frequency
of 1% or more among patients treated with Prozac who participated in
controlled trials comparing Prozac with placebo.
Obsessive-Compulsive Disorder--Table 2 enumerates adverse events that
occurred at a frequency of 2% or more among patients on Prozac who
participated in controlled trials comparing Prozac with placebo in the
treatment of OCD.
The prescriber should be aware that the figures in Tables 1 and 2 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.
TABLE 1
Treatment-Emergent Adverse Experience
Incidence in Placebo-Controlled Clinical Trials
Percentage of Patients Reporting Event
Body System/Preferred Term(*) Prozac(N=1730) Placebo(N=799)
Nervous
Headache 20.3 15.5
Nervousness 14.9 8.5
Insomnia 13.8 7.1
Drowsiness 11.6 6.3
Anxiety 9.4 5.5
Tremor 7.9 2.4
Dizziness 5.7 3.3
Fatigue 4.2 1.1
Sedated 1.9 1.3
Sensation disturbance 1.7 2.0
Libido decreased 1.6 -
Light headedness 1.6 -
Concentration decreased 1.5 -
Digestive
Nausea 21.1 10.1
Diarrhea 12.3 7.0
Mouth dryness 9.5 6.0
Anorexia 8.7 1.5
Dyspepsia 6.4 4.3
Constipation 4.5 3.3
Pain, abdominal 3.4 2.9
Vomiting 2.4 1.3
Taste change 1.8 -
Flatulence 1.6 1.1
Gastroenteritis 1.0 1.4
Skin and Appendages
Sweating, excessive 8.4 3.8
Rash 2.7 1.8
Pruitus 2.4 1.4
Body as a Whole
Asthenia 4.4 1.9
Infection, viral 3.4 3.1
Pain, limb 1.6 1.1
Fever 1.4 -
Pain, chest 1.3 1.1
Allergy 1.2 1.1
Influenza 1.2 1.5
Respiratory
Upper respiratory infection 7.6 6.0
Flu-like syndrome 2.8 1.9
Pharyngitis 2.7 1.3
Nasal congestion 2.6 2.3
Headache, sinus 2.3 1.8
Sinusitis 2.1 2.0
Cough 1.6 1.6
Dyspnea 1.4 -
Cardivascular
Hot Flushes 1.8 1.0
Palpitations 1.3 1.4
Musculoskeletal
Pain, back 2.0 2.4
Pain, joint 1.2 1.1
Pain, muscle 1.2 1.0
Urogenital
Menstruation, painful(1) 2.6 2.4
Sexual dysfunction 1.9 -
Impotence, sexual(2) 1.7 0.4
Frequent micturition 1.6 -
Urinary tract infection 1.2 -
Special Senses
Vision disturbance 2.8 1.8
Notes: (*) Events reported by at least 1% of patients treated
with Prozac are included.
(1) Denominator used was females only
(N=1210 Prozac, N=523 placebo).
(2) Denominator used was males only
(N=520 Prozac, N=276 placebo).
- Incidence less than 1%.
TABLE 2
Treatment Emergent Adverse Experience Incidence in
Placebo-Controlled Clinical Trials for Obsessive-Compulsive Disorder
Percentage of Patients Reporting Event
Body System/Preferred Term(*) Prozac(N=264) Placebo(N=89)
Nervous
Insomnia 30 22
Somnolence 17 7
Anxiety 14 7
Dizziness 13 11
Libido, decreased 11 2
Tremor 9 1
Abnormal dreams 5 2
Thinking, abnormal 4 2
Sleep disorder 3 1
Confusion 2 1
Myoclonus 2 -
Agitation 2 1
Amnesia 2 1
Digestive
Nausea 27 13
Diarrhea 18 13
Anorexia 17 10
Dry Mouth 12 3
Dyspepsia 10 4
Gastrointestinal disorder 6 1
Melena 2 -
Skin and Appendages
Sweating 7 -
Rash 6 3
Pruritus 3 1
Acne 2 1
Body as a Whole
Headache 33 24
Asthenia 15 10
Flu syndrome 10 7
Pain 6 4
Injury, accidental 4 2
Surgical procedure 3 -
Chest pain 3 1
Allergic reaction 3 -
Fever 2 1
Respiratory
Pharyngitis 11 9
Yawn 7 -
Sinusitis 5 2
Cough, increased 3 2
Cardiovascular
Vasodilatation 5 -
Palpitations 2 1
Musculoskeletal
Myalgia 5 4
Arthralgia 3 2
Urogenital
Urinary frequency 4 1
Abnormal ejaculation(1) 7 -
Hemic and Lymphatic
Lymphadenopathy 2 -
Metabolic and Nutritional
Weight loss 5 3
Special Senses
Amblyopia 3 1
Abnormal vision 2 -
Taste perversion 2 1
Tinnitus 2 -
Notes: (*) Events reported by at least 2% of patients treated with
Prozac, except the following events which had an
incidence on placebo > = Prozac: abdominal pain,
back pain, constipation, depression, dysmenorrhea,
flatulence, infection, menstrual disorder, nervousness,
rhinitis, tooth disorder, and twitching.
(1) Denominator used was males only (N=116 Prozac; N=43 placebo).
- Adverse event not reported by placebo-treated patients.
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Other Events Observed During Premarketing Evaluation of Prozac
During clinical testing in the US, multiple doses of Prozac were
administered to approximately 5,600 subjects. Untoward events associated
with this exposure 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 untoward events into
a limited (ie, reduced) number of standardized event categories.
In the tabulations that follow, a standard COSTART Dictionary terminology
has been used to classify reported adverse events. The frequencies
presented, therefore, represent the proportion of the 5,600 individuals
exposed to Prozac who experienced an event of the type cited on at least 1
occasion while receiving Prozac. All reported events are included except
those already listed in Table 1, those COSTART terms so general as to be
uninformative, and those events where a drug cause was remote. It is
important to emphasize that, although the events reported did occur during
treatment with Prozac, they were not necessarily caused by it.
Events are further classified within the body system categories and
enumerated in order of decreasing frequency 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 1/1000 patients; rare events are those occurring in
less than 1/1000 patients.
Body as a Whole--Frequent: chills; Infrequent: chills and fever, cyst, face
edema, hangover effect, jaw pain, malaise, neck pain, neck rigidity, and
pelvic pain; Rare: abdomen enlarged, cellulitis, hydrocephalus, hypothermia,
LE syndrome, moniliasis, and serum sickness.
Cardiovascular System--Infrequent: angina pectoris, arrhythmia, hemorrhage,
hypertension, hypotension, migraine, postural hypotension, syncope, and
tachycardia; Rare: AV block first degree, bradycardia, bundle branch block,
cerebral ischemia, myocardial infarct, thrombophlebitis, vascular headache,
and ventricular arrhythmia.
Digestive System--Frequent: increased appetite; Infrequent: aphthous
stomatitis, dysphagia, eructation, esophagitis, gastritis, gingivitis,
glossitis, liver function tests abnormal, melena, stomatitis, thirst; Rare:
bloody diarrhea, cholecystitis, cholelithiasis, colitis, duodenal ulcer,
enteritis, fecal incontinence, hematemesis, hepatitis, hepatomegaly,
hyperchlorhydria, increased salivation, jaundice, liver tenderness, mouth
ulceration, salivary gland enlargement, stomach ulcer, tongue discoloration,
and tongue edema.
Endocrine System--Infrequent: hypothyroidism; Rare: goiter and
hyperthyroidism.
Hemic and Lymphatic System--Infrequent: anemia and lymphadenopathy; Rare:
bleeding time increased, blood dyscrasia, leukopenia, lymphocytosis,
petechia, purpura, sedimentation rate increased, and thrombocythemia.
Metabolic and Nutritional--Frequent: weight loss; Infrequent: generalized
edema, hypoglycemia, peripheral edema, and weight gain; Rare: dehydration,
gout, hypercholesteremia, hyperlipemia, hypoglycemic reaction, hypokalemia,
hyponatremia, and iron deficiency anemia.
Musculoskeletal System--Infrequent: arthritis, bone pain, bursitis,
tenosynovitis, and twitching; Rare: bone necrosis, chondrodystrophy, muscle
hemorrhage, myositis, osteoporosis, pathological fracture, and rheumatoid
arthritis.
Nervous System--Frequent: abnormal dreams and agitation; Infrequent:
abnormal gait, acute brain syndrome, akathisia, amnesia, apathy, ataxia,
buccoglossal syndrome, CNS stimulation, convulsion, delusions,
depersonalization, emotional lability, euphoria, hallucinations, hostility,
hyperkinesia, hypesthesia, incoordination, libido increased, manic reaction,
neuralgia, neuropathy, paranoid reaction, psychosis, and vertigo; Rare:
abnormal electroenthesia, CNS depression, coma, dysarthria, dystonia,
extrapyramidal syndrome, hypertonia, hysteria, myoclonus, nystagmus,
paralysis, reflexes decreased, stupor, and torticollis.
Respiratory System--Frequent: bronchitis, rhinitis, and yawn; Infrequent:
asthma, epistaxis, hiccup, hyperventilation, and pneumonia; Rare: apnea,
hemoptysis, hypoxia, larynx edema, lung edema, lung fibrosis/alveolitis, and
pleural effusion.
Skin and Appendages--Infrequent: acne, alopecia, contact dermititis, dry
skin, herpes simplex, maculopapular rash, and urticaria; Rare: eczema,
erythema multiforme, fungal dermititis, herpes zoster, hirsutism, psoriasis,
purpuric rash, pustular rash, seborrhea, skin discoloration, skin
hypertrophy, subcutaneous nodule, and vesiculobullous rash.
Special Senses--Infrequent: amblyopia, conjunctivitis, ear pain, eye pain,
mydriasis, photophobia, and tinnitus; Rare: blepharitis, cataract, corneal
lesion, deafness, diplopia, eye hemorrhage, glaucoma, iritis, ptosis,
strabismus, and taste loss.
Urogenital System--Infrequent: abnormal ejaculation, amenorrhea, breast
pain, cystitis, dysuria, fibrocystic breast, leukorrhea, menopause,
menorrhagia, ovarian disorder, urinary incontinence, urinary retention,
urinary urgency, urination impaired, and vaginitis; Rare: abortion,
albuminuria, breast enlargement, dyspareunia, epididymitis, female
lactation, hematuria, hypomenorrhea, kidney calculus, metrorrhagia,
orchitis, polyuria, pyelonephritis, pyuria, salpingitis, urethral pain,
urethritis, urinary tract disorder, urolithiasis, uterine hemorrhage,
uterine spasm, and vaginal hemorrhage.
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Postintroduction Reports
Voluntary reports of adverse events temporally associated with Prozac that
have been received since market introduction, that are not listed above, and
that may have no causal relationship with the drug include the following:
aplastic anemia, cerebral vascular accident, 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,
hyperprolactinemia, immune-related hemolytic anemia, 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, suicidal
ideation, thrombocytopenia, thrombocytopenic purpura, vaginal breeding after
drug withdrawl, 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 withdrawl 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
anitconvulsant 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 is rat 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 of 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
shouldordinarily 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 not 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 one
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 with renal and/or hepatic impairment. A lower or less
frequent dosage should also be considered for patients, such as the elderly
(see Usage in the Elderly under Precautions), with concurrent disease or on
multiple medications.
Maintenance/Continuation/Extended Treatment--There is no body of evidence
available to answer the question of how long the patient treated with
fluoxetine should remain on it. It is generally agreed among expert psychoph
armacologist (circa 1987) 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.
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
possible dose response relationship for the 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 or 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 renal and/or hepatic impairment. A lower or
less frequent dosage should also be considered for patients, such as the
elderly (see Usage in the Elderly under Precautions), with concurrent
disease or on multiple medications.
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 patients should be periodically
reassessed to determine the need for treatment.
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How Supplied
Pulvules:
10 mg{1}, green and gray (No.3104)-(100s) NDC 0777-3104-02
20 mg{1}, green and off-white (No.3105)-(100s) NDC 0777-3105-02; (ID{2}100)
NDC 0777-3105-33
Liquid, Oral Solution:
20 mg{1}/5 mL, mint flavor (M-5120{3})-(120 mL) NDC 0777-5120-58
Notes: {1} Fluoxetine base equivalent.
{2} Identi-Dose (unit dose medication, Dista).
{3} Dispense in a tight, light-resistant container.
Store at controlled room temperature, 59 to 86F (15 to 30C).
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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. Phaspholipid accumulation in animals has been observed
with many cationic amphiphilic drugs, including fenfluramine, imipramine,
and ranitidine. The significance of this effect in humans is unknown.
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CAUTION--Federal (USA) law prohibits dispensing without prescription.
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Literature revised March 14, 1994
DISTA PRODUCTS COMPANY
Prozac
Fluoxetine Hydrochloride
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-tri-fluoro-p-tolyl)oxy]propylamine hydrochloride and has the empirical
formula of C17 H18 F3 NO.HCl. Its molecular weight is 345.79. The structural
formula is:
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 mu
mol) or 20 mg (64.7 mu mol) of fluoxetine. The Pulvules also contain F D & C
Blue No. 1, gelatine, iron oxide, silicone, starch, titanium dioxide, and
other inactive ingredients.
The oral solution contains fluoxetine hydrochloride equivalent to 20 mg/5 mL
(64.7 mu mol) of fluoxetine. It also contains alcohol 0.23%, benzoic acid,
flavoring agent, glycerin, purified water, and sucrose.
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Clinical Pharmacology
Pharmacodynamics:
The antidepressant and antiobsessive-compulsive action of fluoxetine is
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 durgs 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-
and S-fluoxetine. R-norfluoxetine is significally less potent than the
parent durg 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 unlabled 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 adminisitration
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 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,
previos 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 single dose studies, the pharmacokinetics of fluoxetine
and norfluoxetine were similar among subjects with all levels of impaired
renal function including anephric patients on chronic hemodialysis. However,
with chronic administration, additional accumulation of fluoxetine or its
metabolites (possibly including some not yet identified) may occur in
patients with severly impaired renal function and use of a lower or less
frequent dose is advised (see Precautions).
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 possiblity 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 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 the
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 highter 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%).
Obsessive Compulsive Disorder--The effectiveness of Prozac for the treatment
of 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 sever 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 receiveing 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 CGI improvement scale
for studies 1 and 2 combined:
Outcome Classification (%) On CGI Improvement Scale for
Completers in Pool of Two OCD Studies
Outcome Placebo Prozac Prozac Prozac
Classification 20 mg 40 mg 60 mg
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%
Exploratory analysis for age and gender effects on outcome
did not suggest any differential responsiveness on the basis
of age or sex.
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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 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 effectiveness of Prozac in long-term use, that is, for more than 5 to 6
weeks, has not been systematically evaluated in 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.
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 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 that person as excessive or unreasonable.
The effectiveness of Prozac in long-term, ie, for more than 13 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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Contraindictions
Prozac is contraindicted 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 agitations pregressing 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 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 Clinical Pharmacology]) should be
allowed after stopping Prozac before starting an MAOI.
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Warnings
Rash and Possibly Allergic Events--During premarketing testing of more than
5,600 US patients given fluoxetine, approximately 4% developed a rash and/or
urticaria. Among these cases, 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 illness. In neither patient was there an unequivocal
diagnoses, 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 occured 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 apprearance of rash or of other possibly
allergic phenomenafor which an alternative etiology cannot be identified,
Prozac should be discontinued.
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Precautions
General
Anxiety and Insomnia--Anxiety, nervousness, and insomnia were reported by
10% to 15% of patients treated with Prozac. These symptoms led to drug
discontinuation in 5% of patients treated with Prozac.
In controlled clinical trials for obsessive-compulsive disorder, insomnia
was reported in 30% of patients treated with Prozac and in 22% or patients
treated with placebo. Anxiety was reported in 14% of patients treated with
Prozac and in 7% or patients treated with placebo. These 2 symptoms led to
drug discontinuation in 2% of patients treated with Prozac and no patients
treated with placebo.
Altered Appetite and Weight--Significant weight loss, especially in
underweight depressed patients, may be an undesirable result of treatment
with Prozac.
In controlled clinical trials, approximately 9% of patients treated with
Prozac experienced anorexia. This incidence is approximately sixfold that
seen in placebo controls. A weight loss of greater than 5% of body weight
occured in 13% of patients treated with Prozac compared to 4% of placebo and
3% of patients treated with tricyclics. However, only rarely have patients
discontinued treatment with Prozac because of weight loss.
In controlled clinical trials for OCD, 17% of patients treated with Prozac
and 10% of patients treated with placebo reported anorexia. One patient
discontinued treatment with Prozac because of anorexia.
Activation of Mania/Hypomania--During premarketing testing, hypomania or
mania occurred in approximately 1% of fluoxetine treated patients.
Activation of mania/hypomania has also been reported in a small proportion
of patients with Major Affective Disorder treated with other marketed
antidepressants. Mania/hypomania was reported in 1% of patients treated with
fluoxetine in controlled clinical OCD trials.
Seizures--Twelve patients among more than 6,000 evaluated worldwide in the
course of premarketing development of fluoxetine experienced convulsions (or
events described as possibly having been seizures), a rate of 0.2% that
appears to be similar to that associated with other marketed
antidepressants. Prozac should be introduced with care in patients with a
history of seizures.
In controlled clinical trials for OCD, 1 patient treated with fluoxetine
experienced a seizure.
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 comorbidity between OCD and depression, the same
precautions observed when treating patients with depression should be
observed when treating patients with OCD.
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
withdrawl from treatment (see 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 clearance 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.
Since fluoxetine is extensively metabolized, excretion of unchanged drug in
urine is a minor route of elimination. However, until adequate numbers of
patients with sever renal impairment have been evaluated during chronic
treatment with fluoxetine, it should be used with caution in such patients.
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.
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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 thier 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.
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Laboratory Tests
There are no specific laboratory tests recommended.
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Drug Interactions
As with all drugs, the potential for interaction by a variety of mechanisms
(eg, pharmacodynamics, pharmacokinetic drug inhibition or enhancement, etc)
is a possibility (see Accumulation and Slow Elimination under Clinical
Pharmacology).
Drugs Metabolized by P450IID6--Approximately 7% of the normal population has
a genetic defect that leads to reduce 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 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 receiveing 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, carbamazepine, and tricyclic antidepressants).
Tryptophan--Five patients receiving Prozac in combination with tryptophan
experienced adverse reactions, including agitation, restlessness, and
gastrointestinal distress.
Monoamine Oxidase Inhibitors--See Contraindictions.
Other Antidepressants--There have been greater than 2-fold increases of
previously stable plasma levels of other antidepressants when Prozac has
been administered in combination with these agents (see Accumulation and
Slow Elimination under Clinical Pharmacology).
Lithium--There have been reports of both increased and decreased lithium
levels when lithium was used concomitantly with fluoxetine. Cases of lithium
toxicity have been reported. Lithium levels should be monitored when these
drugs are administered concomitantly.
Diazepam Clearance--The half-life of concurrently administered diazepam may
be prolonged in some patients (see Accumulation and Slow Elimination under
Clinical Pharmacology).
Phenytoin--Patients on stable doses of phenytoin have developed elevated
plasma phenytoin concentrations and clinical phenytoin toxicity follwoing
initiation of concomitant fluoxetine treatment.
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 casue 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 Clinical Pharmacology).
CNS Active Drugs--The risk of using Prozac in combination with other CNS
active drugs has not been systematically evaluated. Consequently, caution is
advised if the concomitant administration of Prozac and such drugs is
required (see Accumulation and Slow Elimination under Clinical
Pharmacology).
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.
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Carcinogenesis, Mutagenesis, Impairment of Fertility
There is no evidence of carcinogenicity, mutagenicity, or impairment of
fertility with Prozac.
The dietary administration of fluoxetine to rats and mice for 2 years at
levels equivalent to approximately 7.5 and 9.0 times the maximum human dose
(80 mg) respectively produced no evidence of carcinogenicity.
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.
Two fertility studies conducted in rats at doses of approximately 5 and 9
times the maximum human dose (80 mg) indicated that fluoxetine had no
adverse effects on fertility. A slight decrease in neonatal survival was
noted, but this was probably associated with depressed maternal food
consumption and suppressed weight gain.
Pregnancy--Teratogenic Effects--Pregnancy Category B Reproduction studies
have been performed in rats and rabbits at doses 9 and 11 times the maximum
daily human dose (80 mg) respectively and have revealed no evidence of harm
to the fetus due to Prozac. There are, however, no adequate and
well-controlled studies in pregnant women. Because animal reproduction
studies are not always predictive of human response, the drug should be used
during pregnancy only if clearly needed.
Labor and Delivery--The effect of Prozac on labor and delivery in humans is
unknown.
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 240 ng/mL of fluoxetine and 208 ng/mL norfluoxetine on the
second day of feeding.
Usage in Children Safety and effectiveness in children 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 pattery 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 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 those
occurrences have been in older patients and in patients taking diuretics of
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. Where 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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Adverse Reactions
Commonly Observed--The most commonly observed adverse events associated with
the use of Prozac and not seen at an equivalent incidence among
placebo-treated patients were: nervous system complaints, including anxiety,
nervousness, and insomnia; drowsiness and fatigue or asthenia; tremor;
sweating; gastrointestingal complaints, including anorexia, nausea, and
diarrhea; and dizziness or light headedness.
In controlled clinical trials for OCD using fixed doses of 20, 40 or 60 mg
daily, adverse events observed at an incidence of at least 5% for Prozac and
for which the incidence was approximately twice or more the incidence among
placebo-treated patients included: somnolence, anxiety, tremor, nausea,
dyspepsia, gastrointestinal disorder, vasodilatation, dry mouth, sweating,
rash, abnormal vision, yawn, decreased libido, and abnormal ejaculation.
Associated With Discontinuation of Treatment--Fifteen percent of
approximately 4,000 patients who received Prozac in US premarketing clinical
trials discontinued treatment due to an adverse event. The more common
events causing discontinuation included: psychiatric (5.3%), primarily
nervousness, anxiety, and insomnia; digestive (3.0%), primarily nausea;
nervous system (1.6%), primarily dizziness; body as a whole (1.5%),
primarily asthenia and headache; and skin (1.4%), primarily rash and
pruritus.
In controlled clinical trials for OCD, 12% of patients treated with Prozac
discontinued treatment due to adverse events. The most common events were
anxiety (2%) and rash/urticaria (2%).
Incidence in Controlled Clinical Trials
Depression--Table 1 enumerates adverse events that occurred at a frequency
of 1% or more among patients treated with Prozac who participated in
controlled trials comparing Prozac with placebo.
Obsessive-Compulsive Disorder--Table 2 enumerates adverse events that
occurred at a frequency of 2% or more among patients on Prozac who
participated in controlled trials comparing Prozac with placebo in the
treatment of OCD.
The prescriber should be aware that the figures in Tables 1 and 2 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.
TABLE 1
Treatment-Emergent Adverse Experience
Incidence in Placebo-Controlled Clinical Trials
Percentage of Patients Reporting Event
Body System/Preferred Term(*) Prozac(N=1730) Placebo(N=799)
Nervous
Headache 20.3 15.5
Nervousness 14.9 8.5
Insomnia 13.8 7.1
Drowsiness 11.6 6.3
Anxiety 9.4 5.5
Tremor 7.9 2.4
Dizziness 5.7 3.3
Fatigue 4.2 1.1
Sedated 1.9 1.3
Sensation disturbance 1.7 2.0
Libido decreased 1.6 -
Light headedness 1.6 -
Concentration decreased 1.5 -
Digestive
Nausea 21.1 10.1
Diarrhea 12.3 7.0
Mouth dryness 9.5 6.0
Anorexia 8.7 1.5
Dyspepsia 6.4 4.3
Constipation 4.5 3.3
Pain, abdominal 3.4 2.9
Vomiting 2.4 1.3
Taste change 1.8 -
Flatulence 1.6 1.1
Gastroenteritis 1.0 1.4
Skin and Appendages
Sweating, excessive 8.4 3.8
Rash 2.7 1.8
Pruitus 2.4 1.4
Body as a Whole
Asthenia 4.4 1.9
Infection, viral 3.4 3.1
Pain, limb 1.6 1.1
Fever 1.4 -
Pain, chest 1.3 1.1
Allergy 1.2 1.1
Influenza 1.2 1.5
Respiratory
Upper respiratory infection 7.6 6.0
Flu-like syndrome 2.8 1.9
Pharyngitis 2.7 1.3
Nasal congestion 2.6 2.3
Headache, sinus 2.3 1.8
Sinusitis 2.1 2.0
Cough 1.6 1.6
Dyspnea 1.4 -
Cardivascular
Hot Flushes 1.8 1.0
Palpitations 1.3 1.4
Musculoskeletal
Pain, back 2.0 2.4
Pain, joint 1.2 1.1
Pain, muscle 1.2 1.0
Urogenital
Menstruation, painful(1) 2.6 2.4
Sexual dysfunction 1.9 -
Impotence, sexual(2) 1.7 0.4
Frequent micturition 1.6 -
Urinary tract infection 1.2 -
Special Senses
Vision disturbance 2.8 1.8
Notes: (*) Events reported by at least 1% of patients treated
with Prozac are included.
(1) Denominator used was females only
(N=1210 Prozac, N=523 placebo).
(2) Denominator used was males only
(N=520 Prozac, N=276 placebo).
- Incidence less than 1%.
TABLE 2
Treatment Emergent Adverse Experience Incidence in
Placebo-Controlled Clinical Trials for Obsessive-Compulsive Disorder
Percentage of Patients Reporting Event
Body System/Preferred Term(*) Prozac(N=264) Placebo(N=89)
Nervous
Insomnia 30 22
Somnolence 17 7
Anxiety 14 7
Dizziness 13 11
Libido, decreased 11 2
Tremor 9 1
Abnormal dreams 5 2
Thinking, abnormal 4 2
Sleep disorder 3 1
Confusion 2 1
Myoclonus 2 -
Agitation 2 1
Amnesia 2 1
Digestive
Nausea 27 13
Diarrhea 18 13
Anorexia 17 10
Dry Mouth 12 3
Dyspepsia 10 4
Gastrointestinal disorder 6 1
Melena 2 -
Skin and Appendages
Sweating 7 -
Rash 6 3
Pruritus 3 1
Acne 2 1
Body as a Whole
Headache 33 24
Asthenia 15 10
Flu syndrome 10 7
Pain 6 4
Injury, accidental 4 2
Surgical procedure 3 -
Chest pain 3 1
Allergic reaction 3 -
Fever 2 1
Respiratory
Pharyngitis 11 9
Yawn 7 -
Sinusitis 5 2
Cough, increased 3 2
Cardiovascular
Vasodilatation 5 -
Palpitations 2 1
Musculoskeletal
Myalgia 5 4
Arthralgia 3 2
Urogenital
Urinary frequency 4 1
Abnormal ejaculation(1) 7 -
Hemic and Lymphatic
Lymphadenopathy 2 -
Metabolic and Nutritional
Weight loss 5 3
Special Senses
Amblyopia 3 1
Abnormal vision 2 -
Taste perversion 2 1
Tinnitus 2 -
Notes: (*) Events reported by at least 2% of patients treated with
Prozac, except the following events which had an
incidence on placebo > = Prozac: abdominal pain,
back pain, constipation, depression, dysmenorrhea,
flatulence, infection, menstrual disorder,
nervousness, rhinitis, tooth disorder, and twitching.
(1) Denominator used was males only (N=116 Prozac; N=43 placebo).
- Adverse event not reported by placebo-treated patients.
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Other Events Observed During Premarketing Evaluation of Prozac
During clinical testing in the US, multiple doses of Prozac were
administered to approximately 5,600 subjects. Untoward events associated
with this exposure 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 untoward events into
a limited (ie, reduced) number of standardized event categories.
In the tabulations that follow, a standard COSTART Dictionary terminology
has been used to classify reported adverse events. The frequencies
presented, therefore, represent the proportion of the 5,600 individuals
exposed to Prozac who experienced an event of the type cited on at least 1
occasion while receiving Prozac. All reported events are included except
those already listed in Table 1, those COSTART terms so general as to be
uninformative, and those events where a drug cause was remote. It is
important to emphasize that, although the events reported did occur during
treatment with Prozac, they were not necessarily caused by it.
Events are further classified within the body system categories and
enumerated in order of decreasing frequency 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 1/1000 patients; rare events are those occurring in
less than 1/1000 patients.
Body as a Whole--Frequent: chills; Infrequent: chills and fever, cyst, face
edema, hangover effect, jaw pain, malaise, neck pain, neck rigidity, and
pelvic pain; Rare: abdomen enlarged, cellulitis, hydrocephalus, hypothermia,
LE syndrome, moniliasis, and serum sickness.
Cardiovascular System--Infrequent: angina pectoris, arrhythmia, hemorrhage,
hypertension, hypotension, migraine, postural hypotension, syncope, and
tachycardia; Rare: AV block first degree, bradycardia, bundle branch block,
cerebral ischemia, myocardial infarct, thrombophlebitis, vascular headache,
and ventricular arrhythmia.
Digestive System--Frequent: increased appetite; Infrequent: aphthous
stomatitis, dysphagia, eructation, esophagitis, gastritis, gingivitis,
glossitis, liver function tests abnormal, melena, stomatitis, thirst; Rare:
bloody diarrhea, cholecystitis, cholelithiasis, colitis, duodenal ulcer,
enteritis, fecal incontinence, hematemesis, hepatitis, hepatomegaly,
hyperchlorhydria, increased salivation, jaundice, liver tenderness, mouth
ulceration, salivary gland enlargement, stomach ulcer, tongue discoloration,
and tongue edema.
Endocrine System--Infrequent: hypothyroidism; Rare: goiter and
hyperthyroidism.
Hemic and Lymphatic System--Infrequent: anemia and lymphadenopathy; Rare:
bleeding time increased, blood dyscrasia, leukopenia, lymphocytosis,
petechia, purpura, sedimentation rate increased, and thrombocythemia.
Metabolic and Nutritional--Frequent: weight loss; Infrequent: generalized
edema, hypoglycemia, peripheral edema, and weight gain; Rare: dehydration,
gout, hypercholesteremia, hyperlipemia, hypoglycemic reaction, hypokalemia,
hyponatremia, and iron deficiency anemia.
Musculoskeletal System--Infrequent: arthritis, bone pain, bursitis,
tenosynovitis, and twitching; Rare: bone necrosis, chondrodystrophy, muscle
hemorrhage, myositis, osteoporosis, pathological fracture, and rheumatoid
arthritis.
Nervous System--Frequent: abnormal dreams and agitation; Infrequent:
abnormal gait, acute brain syndrome, akathisia, amnesia, apathy, ataxia,
buccoglossal syndrome, CNS stimulation, convulsion, delusions,
depersonalization, emotional lability, euphoria, hallucinations, hostility,
hyperkinesia, hypesthesia, incoordination, libido increased, manic reaction,
neuralgia, neuropathy, paranoid reaction, psychosis, and vertigo; Rare:
abnormal electroenthesia, CNS depression, coma, dysarthria, dystonia,
extrapyramidal syndrome, hypertonia, hysteria, myoclonus, nystagmus,
paralysis, reflexes decreased, stupor, and torticollis.
Respiratory System--Frequent: bronchitis, rhinitis, and yawn; Infrequent:
asthma, epistaxis, hiccup, hyperventilation, and pneumonia; Rare: apnea,
hemoptysis, hypoxia, larynx edema, lung edema, lung fibrosis/alveolitis, and
pleural effusion.
Skin and Appendages--Infrequent: acne, alopecia, contact dermititis, dry
skin, herpes simplex, maculopapular rash, and urticaria; Rare: eczema,
erythema multiforme, fungal dermititis, herpes zoster, hirsutism, psoriasis,
purpuric rash, pustular rash, seborrhea, skin discoloration, skin
hypertrophy, subcutaneous nodule, and vesiculobullous rash.
Special Senses--Infrequent: amblyopia, conjunctivitis, ear pain, eye pain,
mydriasis, photophobia, and tinnitus; Rare: blepharitis, cataract, corneal
lesion, deafness, diplopia, eye hemorrhage, glaucoma, iritis, ptosis,
strabismus, and taste loss.
Urogenital System--Infrequent: abnormal ejaculation, amenorrhea, breast
pain, cystitis, dysuria, fibrocystic breast, leukorrhea, menopause,
menorrhagia, ovarian disorder, urinary incontinence, urinary retention,
urinary urgency, urination impaired, and vaginitis; Rare: abortion,
albuminuria, breast enlargement, dyspareunia, epididymitis, female
lactation, hematuria, hypomenorrhea, kidney calculus, metrorrhagia,
orchitis, polyuria, pyelonephritis, pyuria, salpingitis, urethral pain,
urethritis, urinary tract disorder, urolithiasis, uterine hemorrhage,
uterine spasm, and vaginal hemorrhage.
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Postintroduction Reports
Voluntary reports of adverse events temporally associated with Prozac that
have been received since market introduction, that are not listed above, and
that may have no causal relationship with the drug include the following:
aplastic anemia, cerebral vascular accident, 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,
hyperprolactinemia, immune-related hemolytic anemia, 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, suicidal
ideation, thrombocytopenia, thrombocytopenic purpura, vaginal breeding after
drug withdrawl, 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 withdrawl 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
anitconvulsant 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 is rat 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 of 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 not 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 one
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 with renal and/or hepatic impairment. A lower or less
frequent dosage should also be considered for patients, such as the elderly
(see Usage in the Elderly under Precautions), with concurrent disease or on
multiple medications.
Maintenance/Continuation/Extended Treatment--There is no body of evidence
available to answer the question of how long the patient treated with
fluoxetine should remain on it. It is generally agreed among expert
psychopharmacologist (circa 1987) 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.
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
possible dose response relationship for the 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 or 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 renal and/or hepatic impairment. A lower or
less frequent dosage should also be considered for patients, such as the
elderly (see Usage in the Elderly under Precautions), with concurrent
disease or on multiple medications.
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 patients should be periodically
reassessed to determine the need for treatment.
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How Supplied
Pulvules:
10 mg{1}, green and gray (No.3104)-(100s) NDC 0777-3104-02
20 mg{1}, green and off-white (No.3105)-(100s) NDC 0777-3105-02; (ID{2}100)
NDC 0777-3105-33
Liquid, Oral Solution:
20 mg{1}/5 mL, mint flavor (M-5120{3})-(120 mL) NDC 0777-5120-58
Notes: {1} Fluoxetine base equivalent.
{2} Identi-Dose (unit dose medication, Dista).
{3} Dispense in a tight, light-resistant container.
Store at controlled room temperature, 59 to 86F (15 to 30C).
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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. Phaspholipid accumulation in animals has been observed
with many cationic amphiphilic drugs, including fenfluramine, imipramine,
and ranitidine. The significance of this effect in humans is unknown.
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CAUTION--Federal (USA) law prohibits dispensing without prescription.
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Literature revised March 14, 1994
DISTA PRODUCTS COMPANY
Short response from the Doctors Info net:
Prozac for stress and anxiety
Question: I am presently under tremendous pressure and I am having severe
anxiety attacks. My friend, who is a doctor, has recommended Prozac as a
solution. I am a 50 year old male and am in need of relief. Your input would
be appreciated.
Answer: All the SRI drugs have been used for the last several years to treat
different types of anxiety and panic disorders. I'd try them. You might need
to add drugs like valium, xanax, etc., but they often are very effective.
Prozac
Question: I have been on Prozac since 1993; starting at 10mg/day, then 30,
and in the last 6 months to 30mg/day. It has been effective in treating my
depression. Suddenly, I have become incapacitated: extreme dizziness, bad
headaches, urinary hesitancy, no appetite. It's back into deep depression,
but is it the Prozac shutting down? Or possibly a disconnected malady? A
switch to Effexor is suggested. Any ideas?
Answer: I'm not sure this is all depression. The urinary hesitancy and
headaches are common side effects of Prozac-- especially in larger doses.
Vertigo would occasionally occur as a side effect. The lack of appetite
could be depression. Do you feel like the "old depression"? Many of these
sound like side effects to the drug. If this is so, a switch to a different
class might be helpful, and Effexor or Wellbutrin is what most physicians
would pick.
http://www.druginfonet.com/faq/faqproz.htm
Thanks for your question.
Linda
Dr. Linda J. Weyandt MD/ CRNA
Try the links in the MadSci Library for more information on Medicine.