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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 hyperthermia,
rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital
signs, and mental status changes that include extreme agitation progressing to delirium
and coma) in patients receiving fluoxetine in combination with a 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 premarketing 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 premarketing 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 multiforme. 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 premarketing 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.
