Trillian's Depression Page
Fluoxetine
Brand name: Prozac
Contents
Antidepressant - Antiobsessional - Antibulimic
The antidepressant, antiobsessional, and antibulimic actions of fluoxetine
are presumed to be linked to its ability to inhibit the neuronal reuptake of
serotonin.
Fluoxetine preferentially inhibited the reuptake of serotonin into brain
synaptosomes and platelets in rats and humans. In receptor binding studies,
fluoxetine was shown to have only weak affinity for various receptor systems,
namely opiate, serotonergic 5HT(1), dopaminergic, beta-adrenergic,
alpha(2)-adrenergic, histaminergic, alpha(1)-adrenergic, muscarinic, and
serotonergic 5HT(2) receptors. Unlike most clinically effective
antidepressants, fluoxetine did not down-regulate beta-adrenergic receptors;
however, like all tested antidepressants, it caused up-regulation of GABA-B
receptors. Mixed effects have been observed on serotonergic receptor
sensitivity.
Pharmacokinetics:
Fluoxetine is well absorbed after oral administration. In man, following a
single 40 mg dose, peak plasma concentrations of fluoxetine ranged from 15 to
55 ng/mL 6 to 8 hours after dosing (range=1.5 to 12 hours). The capsule and
oral solution dosage forms of fluoxetine are bioequivalent. Food appears to
affect the rate but not the extent of absorption.
Fluoxetine is extensively metabolized in the liver to norfluoxetine, and
other, unidentified metabolites. Norfluoxetine, a desmethyl metabolite, is also
a serotonin reuptake inhibitor; its pharmacological activity being similar to
that of the parent drug. Norfluoxetine contributes to the long duration of
action of fluoxetine. Elimination of metabolites occurs primarily in the urine
with a smaller amount also being present in the feces.
Clinical Issues Related to Metabolism/Elimination:
The complexity of fluoxetine's metabolism has several consequences which may
potentially affect its clinical use.
Accumulation and Slow Elimination:
The half-life of fluoxetine after a single dose is 2 days (range 1 to 4
days) and after multiple dosing 4 days (range 2 to 7 days). The corresponding
values for norfluoxetine are similar after single and multiple dosing, i.e.,
8.6 and 9.3 days (range 4 to 15 days). After 30 days of dosing at 40 mg/day,
plasma concentrations of fluoxetine and norfluoxetine ranged from 91 to 302
ng/mL and 72 to 258 ng/mL respectively. Plasma concentrations of fluoxetine
were higher than those predicted from single dose studies, presumably because
fluoxetine's metabolism is not proportional to dose. Norfluoxetine, however,
appears to have linear pharmacokinetics.
Steady state plasma levels are attained after 4 to 5 weeks of continuous
drug administration. Patients receiving fluoxetine at doses of 40 to 80 mg/day
over periods as long as 3 years exhibited, on average, plasma concentrations
similar to those seen among patients treated for 4 to 5 weeks.
Similarly because of the long half-lives of fluoxetine and norfluoxetine, it
may take up to 1 to 2 months for the active drug substance to disappear from
the body. This is of potential consequence in withdrawal of fluoxetine (see
Warnings).
Protein Binding:
Approximately 94% of fluoxetine is protein bound. The interaction between
fluoxetine and other highly protein bound drugs has not been fully evaluated,
but may be important (see Precautions).
Liver Disease:
As might be predicted from its primary site of metabolism, liver impairment
can affect the elimination of fluoxetine. In patients with alcohol-induced
cirrhosis, the elimination half-life of fluoxetine was prolonged, with a mean
of 7.6 days compared to the range of 2 to 3 days seen in subjects without liver
disease; norfluoxetine elimination half-life 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 (see Precautions and Dosage).
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
severely impaired renal function and use of a lower or less frequent dose is
advised (see Precautions).
Age:
The effects of age upon the metabolism of fluoxetine have not been fully
explored. The disposition of single doses of fluoxetine in healthy elderly
subjects (greater than 65 years of age) did not differ significantly from that
in younger normal subjects. However, given the long half-life and nonlinear
disposition of the drug, a single-dose study is not adequate to rule out the
possibility of altered pharmacokinetics in the elderly, particularly if they
have systemic illness or are receiving multiple drugs for concomitant diseases.
Depression:
For the symptomatic relief of depressive illness.
Bulimia Nervosa:
Fluoxetine has been shown to significantly decrease binge-eating and purging
activity when compared with placebo treatment.
Obsessive-Compulsive Disorder:
Fluoxetine has been shown to significantly reduce the symptoms of
obsessive-compulsive disorder in double-blind, placebo-controlled clinical
trials.
The obsessions or compulsions must be experienced as intrusive, markedly
distressing, time-consuming, or interfering significantly with the person's
social or occupational functioning.
The efficacy of fluoxetine in hospitalized patients has not been studied.
The effectiveness of fluoxetine in long-term use (i.e., for more than 5 to 6
weeks in depression, for more than 16 weeks in bulimia nervosa, or for more
than 13 weeks in obsessive compulsive disorder), has not been systematically
evaluated in controlled trials. Therefore, the physician who elects to use
fluoxetine for extended periods should periodically re-evaluate the long-term
usefulness of the drug for the individual patient.
In patients with known hypersensitivity to the drug.
MAO Inhibitors:
There have been reports of serious, sometimes fatal, reactions (including
hypothermia, rigidity, myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that include extreme
agitation progressing to delirium and coma) in patients receiving fluoxetine in
combination with a MAO inhibitor and in patients who have recently discontinued
fluoxetine and then started on a MAO inhibitor. Some cases presented with
features resembling neuroleptic malignant syndrome. Therefore, fluoxetine
should not be used in combination with a MAO inhibitor or within 14 days of
discontinuing therapy with a MAO inhibitor. Since fluoxetine and its major
metabolite have very long elimination half-lives, at least 5 weeks should be
allowed after stopping fluoxetine before starting a MAO inhibitor. Limited
reports suggest that i.v. administered dantrolene or orally administered
cyproheptadine may benefit patients experiencing such reactions.
Allergic Reactions (Rash and Accompanying Events):
During pre-marketing testing of more than 5600 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 these allergic reactions include rash, 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 pre-marketing clinical trials 2 patients are known to have developed a
serious cutaneous systemic illness. In neither patient was there an unequivocal
diagnosis, but one was considered to have a leukocytoclastic vasculitis, and
the other severe desquamation that was considered variously to be a vasculitis
or erythema multiforms. Other patients have had systemic manifestations
suggestive of serum sickness.
Since the introduction of fluoxetine, systemic events, possibly related to
vasculitis, have developed in patients with rash. Although these events are
rare, they may be serious, involving the lung, kidney, or liver. Death has been
reported to occur in association with these systemic events.
Anaphylactoid events, including bronchospasm, angioedema, and urticaria
alone and in combination, have been reported.
Pulmonary events, including inflammatory processes of varying histopathology
and/or fibrosis, have been reported rarely. These events have occurred with
dyspnea as the only preceding symptom.
Whether these systemic events and rash have a common underlying cause or are
due to different etiologies or pathogenic processes is not known. Furthermore,
a specific underlying immunologic basis for these events has not been
identified. Upon the appearance of rash or of other allergic phenomena for
which an alternative etiology cannot be identified, fluoxetine should be
discontinued. Particular caution should be exercised in patients with a history
of allergic reactions.
Implications of the Long Elimination Half-Life of Fluoxetine:
Because of the long elimination half-lives of fluoxetine and its major
active metabolite norfluoxetine, changes in dose will not be fully reflected in
plasma for several weeks, affecting both strategies for titration to final dose
and withdrawal from treatment (see Pharmacology and Dosage). Even when dosing
is stopped, active drug substance will persist in the body for weeks due to the
long elimination half-lives of fluoxetine and norfluoxetine. This is of
potential consequence when drug discontinuation is required or when drugs are
prescribed that might interact with fluoxetine and norfluoxetine following
discontinuation of fluoxetine.
Anxiety and Insomnia:
During premarketing clinical trials, anxiety, nervousness and insomnia were
reported by 10 to 15% of patients treated with fluoxetine. These symptoms led
to discontinuation of the drug in 5% of the patients.
Weight Change:
Significant weight loss, especially in underweight depressed patients, may
be an undesirable result of treatment with fluoxetine.
Mania/Hypomania:
During premarketing clinical trials in a patient population comprised
primarily of unipolar depressives, hypomania or mania occurred in approximately
1% of fluoxetine treated patients. The incidence in a general patient
population which might also include bipolar depressives is unknown. The
likelihood of hypomanic or manic episodes may be increased at the higher dosage
levels. Such reactions require a reduction in dosage or discontinuation of the
drug.
Seizures:
Fluoxetine should be used with caution in patients with a history of
convulsive disorders. The incidence of seizures associated with fluoxetine
during clinical trials did not appear to differ from that reported with other
marketed antidepressants; however, patients with a history of convulsive
disorders were excluded from these trials.
Concurrent administration with electroshock therapy should be avoided
because of the absence of experience in this area. There have been rare reports
of a prolonged seizure in patients on fluoxetine receiving ECT treatment.
Hypokalemia:
Self-induced vomiting often leads to hypokalemia which may lower seizure
threshold and/or may lead to cardiac conduction abnormalities. Electrolyte
levels of bulimic patients should be assessed prior to initiation of treatment.
Suicide:
The possibility of a suicide attempt is inherent in depression and may
persist until significant remission occurs. Therefore, high risk patients
should be closely supervised throughout therapy and consideration should be
given to the possible need for hospitalization. In order to minimize the
opportunity for overdosage, prescriptions for fluoxetine should be written for
the smallest quantity of drug consistent with good patient management.
Concomitant Illness:
Clinical experience with fluoxetine in patients with concomitant systemic
illness is limited and it should be used cautiously in such patients,
especially those 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
pre-marketing clinical studies. Retrospective evaluation of ECGs in some of
these studies showed no conduction abnormalities that resulted in heart block.
The mean heart rate was reduced by approximately 3 beats/minute.
Fluoxetine should be given with caution to patients suffering from anorexia
nervosa and only if the expected benefits (e.g., co-morbid depression) markedly
outweigh the potential weight reducing effect of the drug.
In patients with diabetes, fluoxetine may alter glycemic control.
Hypoglycemia has occurred during therapy with fluoxetine 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
fluoxetine is instituted or discontinued.
Since fluoxetine is extensively metabolized, excretion of unchanged drug in
urine is a minor route of elimination. However, until adequate numbers of
patients with severe renal impairment have been evaluated in the course of
chronic treatment, fluoxetine should be used with caution in such patients.
Since clearances of fluoxetine and norfluoxetine may be decreased in
patients with impaired liver function including cirrhosis, a lower or less
frequent dose should be used in such patients.
Hyponatremia:
Several cases of hyponatremia (some with serum sodium lower than 110 mmol/L)
have been reported. The hyponatremia appeared to be reversible when fluoxetine
was discontinued. Although these cases were complex with varying possible
etiologies, some were possibly due to the syndrome of inappropriate
antidiuretic hormone secretion (SIADH). The majority of these occurrences have
been in older patients and in patients taking diuretics or who were otherwise
volume depleted.
Platelet Function:
There have been rare reports of altered platelet function and/or abnormal
results from laboratory studies in patients taking fluoxetine. While there have
been reports of abnormal bleeding in several patients taking fluoxetine, it is
unclear whether fluoxetine had a causative role.
Occupational Hazards:
Patients should be cautioned against driving an automobile or performing
hazardous tasks until they are reasonably certain that treatment with
fluoxetine does not affect them adversely.
Pregnancy and Lactation:
Safe use of fluoxetine during pregnancy and lactation has not been
established. Therefore, it should not be administered to women of childbearing
potential or nursing mothers unless, in the opinion of the treating physician,
the expected benefits to the patient markedly outweigh the possible hazards to
the child or fetus. 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 ng/mL. No adverse effects on the infant were reported.
Children:
Safety and effectiveness in patients below the age of 18 have not been
established.
Geriatrics:
Elderly patients should initially receive fluoxetine in low dosage with slow
progressive increases.
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