CONTRAINDICATIONS
Fluoxetine is contraindicated in patients known to be hypersensitive to it.
Monoamine Oxidase Inhibitors: There have been reports of serious, sometimes fatal,
reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible
rapid fluctuations of vital signs, and mental status changes that include extreme agitation
progressing to delirium and coma) in patients receiving fluoxetine in combination with a
monoamine oxidase inhibitor (MAOI), and in patients who have recently discontinued
fluoxetine and are then started on an MAOI. Some cases presented with features
resembling neuroleptic malignant syndrome. Therefore, fluoxetine should not be used in
combination with an MAOI, or within a minimum of 14 days of discontinuing therapy
with an MAOI. Since fluoxetine and its major metabolite have very long elimination
half-lives, at least 5 weeks (perhaps longer, especially if fluoxetine has been prescribed
chronically and/or at higher doses [see CLINICAL PHARMACOLOGY, Accumulation
and Slow Elimination]) should be allowed after stopping fluoxetine before starting an
MAOI.
Thioridazine: Thioridazine should not be administered with fluoxetine or within a
minimum of 5 weeks after fluoxetine has been discontinued (see WARNINGS).
WARNINGS
Rash and Possibly Allergic Events
In three premarketing clinical trials for PMDD, 5% of 243 patients treated with fluoxetine
reported rash and/or urticaria. None of these cases were classified as serious and 2 of
243 patients (both receiving 60 mg) were withdrawn from treatment because of rash
and/or urticaria.
In U.S. fluoxetine clinical trials, 7% of 10,782 patients developed various types of rashes
and/or urticaria. Among the cases of rash and/or urticaria reported in premarketing
clinical trials, almost a third were withdrawn from treatment because of the rash and/or
systemic signs or symptoms associated with the rash. Clinical findings reported in
association with rash include fever, leukocytosis, arthralgias, edema, carpal tunnel
syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild transaminase
elevation. Most patients improved promptly with discontinuation of fluoxetine and/or
adjunctive treatment with antihistamines or steroids, and all patients experiencing these
events were reported to recover completely.
In premarketing clinical trials of fluoxetine for conditions other than PMDD, 2 patients are
known to have developed a serious cutaneous systemic illness. In neither patient was
there an unequivocal diagnosis, but 1 was considered to have a leukocytoclastic
vasculitis, and the other, a severe desquamating syndrome that was considered variously
to be a vasculitis or erythema multiforme. Other patients have had systemic syndromes
suggestive of serum sickness.
Since the introduction of 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 possibly allergic phenomena for which an alternative
etiology cannot be identified, fluoxetine should be discontinued.
Potential Interaction With Thioridazine
In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators
of debrisoquin, a single 25 mg oral dose of thioridazine produced a 2.4-fold higher Cmax
and a 4.5-fold higher AUC for thioridazine in the slow hydroxylators compared to the
rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level
of cytochrome P450IID6 isozyme activity. Thus, this study suggests that drugs which
inhibit P450IID6, such as certain SSRIs, including fluoxetine, will produce elevated
plasma levels of thioridazine (see PRECAUTIONS).
Thioridazine administration produces a dose-related prolongation of the QTc interval,
which is associated with serious ventricular arrhythmias, such as torsades de pointes-type
arrhythmias, and sudden death. This risk is expected to increase with fluoxetine-induced
inhibition of thioridazine metabolism (see CONTRAINDICATIONS).
PRECAUTIONS
General
Anxiety and Insomnia
In U.S. placebo-controlled clinical trials for depression, 12-16% of patients treated with
fluoxetine and 7-9% of patients treated with placebo reported anxiety, nervousness, or
insomnia.
In U.S. placebo-controlled clinical trials for obsessive-compulsive disorder, insomnia was
reported in 28% of patients treated with fluoxetine and in 22% of patients treated with
placebo. Anxiety was reported in 14% of patients treated with fluoxetine and in 7% of
patients treated with placebo.
In U.S. placebo-controlled clinical trials for bulimia nervosa, insomnia was reported in
33% of patients treated with fluoxetine, 60 mg, and 13% of patients treated with
placebo. Anxiety and nervousness were reported respectively in 15% and 11% of
patients treated with fluoxetine, 60 mg, and in 9% and 5% of patients treated with
placebo.
Among the most common adverse events associated with discontinuation (incidence at
least twice that for placebo and at least 1% for fluoxetine in clinical trials collecting only a
primary event associated with discontinuation) in U.S. placebo-controlled fluoxetine
clinical trials were anxiety (2% in OCD), insomnia (1% in combined indications and 2%
in bulimia), and nervousness (1% in depression) (see TABLE 4).
In a placebo-controlled trial of fluoxetine in premenstrual dysphoric disorder (PMDD),
treatment-emergent adverse events were assessed. Rates were as follows for fluoxetine
20 mg (the recommended dose), fluoxetine 60 mg and placebo, respectively: anxiety
(5%, 9%, and 6%), nervousness (7%, 9%, and 4%), and insomnia (9%, 26%, and 7%).
Events associated with discontinuation for fluoxetine 20 mg, 60 mg, and placebo,
respectively were: anxiety (0%, 6%, and 2%), nervousness (2%, 0%, and 1%), and
insomnia (1%, 4%, and 1%). In U.S. placebo-controlled clinical trials of fluoxetine for
other approved indications, anxiety, nervousness, and insomnia have been among the
most commonly reported adverse events (see TABLE 4).
Altered Appetite and Weight
Significant weight loss, especially in underweight depressed or bulimic patients may be an
undesirable result of treatment with fluoxetine.
In U.S. placebo-controlled clinical trials for depression, 11% of patients treated with
fluoxetine and 2% of patients treated with placebo reported anorexia (decreased
appetite). Weight loss was reported in 1.4% of patients treated with fluoxetine and in
0.5% of patients treated with placebo. However, only rarely have patients discontinued
treatment with fluoxetine because of anorexia or weight loss.
In U.S. placebo-controlled clinical trials for OCD, 17% of patients treated with fluoxetine
and 10% of patients treated with placebo reported anorexia (decreased appetite). One
patient discontinued treatment with fluoxetine because of anorexia.
In U.S. placebo-controlled clinical trials for bulimia nervosa, 8% of patients treated with
fluoxetine, 60 mg, and 4% of patients treated with placebo reported anorexia (decreased
appetite). Patients treated with fluoxetine, 60 mg, on average lost 0.45 kg compared with
a gain of 0.16 kg by patients treated with placebo in the 16 week double-blind trial.
Weight change should be monitored during therapy.
In a placebo-controlled trial of fluoxetine in PMDD, 4% of patients on fluoxetine 20 mg
(the recommended dose), 13% on fluoxetine 60 mg, and 3% of placebo patients
reported anorexia. In two placebo-controlled trials, potentially clinically significant weight
gain (³7%) occurred in 8% of patients on fluoxetine 20 mg, 6% of patients on fluoxetine
60 mg, and 1% of patients on placebo. Potentially clinically significant weight loss (³7%)
occurred in 7% of patients on fluoxetine 20 mg, 12% of patients on fluoxetine 60 mg, and
3% of patients on placebo.
Activation of Mania/Hypomania
In U.S. placebo-controlled clinical trials for depression, mania/hypomania was reported
in 0.1% of patients treated with fluoxetine and 0.1% of patients treated with placebo.
Activation of mania/hypomania has also been reported in a small proportion of patients
with Major Affective Disorder treated with other marketed antidepressants.
In U.S. placebo-controlled clinical trials for OCD, mania/hypomania was reported in
0.8% of patients treated with fluoxetine and no patients treated with placebo. No patients
reported mania/hypomania in U.S. placebo-controlled clinical trials for bulimia. In all U.S.
fluoxetine clinical trials, 0.7% of 10,782 patients reported mania/hypomania.
No patients treated with fluoxetine in three PMDD clinical trials (N=243) reported
mania/hypomania. In all U.S. fluoxetine clinical trials for conditions other than PMDD,
0.7% of 10,782 patients reported mania/hypomania. Activation of mania/hypomania may
occur with medications used to treat depression, especially in patients predisposed to
Bipolar Affective Disorder.
Seizures
In U.S. placebo-controlled clinical trials for depression, convulsions (or events described
as possibly having been seizures) were reported in 0.1% of patients treated with
fluoxetine and 0.2% of patients treated with placebo. No patients reported convulsions in
U.S. placebo-controlled clinical trials for either OCD or bulimia. In all U.S. fluoxetine
clinical trials, 0.2% of 10,782 patients reported convulsions. The percentage appears to
be similar to that associated with other marketed antidepressants. Fluoxetine should be
introduced with care in patients with a history of seizures.
No patients treated with fluoxetine in three PMDD clinical trials (N=243) reported
seizures. In all U.S. fluoxetine clinical trials for conditions other than PMDD, 0.2% of
10,782 patients reported seizures. Antidepressant medication should be introduced with
care in patients with a history of seizures.
Suicide
The possibility of a suicide attempt is inherent in depression and may persist until
significant remission occurs. Close supervision of high risk patients should accompany
initial drug therapy. Prescriptions for fluoxetine 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 both OCD and depression and bulimia
and depression, the same precautions observed when treating patients with depression
should be observed when treating patients with OCD or bulimia.
No patients treated with fluoxetine in three PMDD clinical trials (N=243) attempted
suicide. The possibility of a suicide attempt is inherent in mood disorders and may persist
until significant remission occurs. In PMDD patients with a significant mood disturbance,
close supervision should accompany drug therapy. In high-risk patients, prescriptions for
antidepressant medication should be written for the smallest quantity of medication
consistent with good patient management, in order to reduce the risk of overdose.
The Long Elimination Half-Lives of Fluoxetine and Its Metabolites
Because of the long elimination half-lives of the parent drug and its major active
metabolite, changes in dose will not be fully reflected in plasma for several weeks,
affecting both strategies for titration to final dose and withdrawal from treatment (see
CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Use in Patients With Concomitant Illness
Clinical experience with fluoxetine in patients with concomitant systemic illness is limited.
Caution is advisable in using fluoxetine 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
fluoxetine in double-blind trials were retrospectively evaluated; no conduction
abnormalities that resulted in heart block were observed. The mean heart rate was
reduced by approximately 3 beats/min.
In subjects with cirrhosis of the liver, the clearances of fluoxetine and its active
metabolite, norfluoxetine, were decreased, thus increasing the elimination half-lives of
these substances (see CLINICAL PHARMACOLOGY, Liver Disease). A lower or
less frequent dose should be used in patients with cirrhosis (see DOSAGE AND
ADMINISTRATION).
Studies in depressed patients on dialysis did not reveal excessive accumulation of
fluoxetine or norfluoxetine in plasma (see CLINICAL PHARMACOLOGY, Renal
Disease). Use of a lower or less frequent dose for renally impaired patients is not
routinely necessary (see DOSAGE AND ADMINISTRATION).
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.
Interference With Cognitive and Motor Performance
Any psychoactive drug may impair judgment, thinking, or motor skills, and patients
should be cautioned about operating hazardous machinery, including automobiles, until
they are reasonably certain that the drug treatment does not affect them adversely.
Information for the Patient
Physicians Are Advised to Discuss the Following Issues With Patients for Whom They
Prescribe Fluoxetine:
Because fluoxetine may impair judgment, thinking, or motor skills, patients should
be advised to avoid driving a car or operating hazardous machinery until they are
reasonably certain that their performance is not affected.
Patients should be advised to inform their physician if they are taking or plan to
take any prescription or over-the-counter drugs, or alcohol.
Patients should be advised to notify their physician if they become pregnant or
intend to become pregnant during therapy.
Patients should be advised to notify their physician if they are breastfeeding an
infant.
Patients should be advised to notify their physician if they develop a rash or hives.
PMDD: Also see the PATIENT PACKAGE INSERT for additional information.
Laboratory Tests
There are no specific laboratory tests recommended.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
There is no evidence of carcinogenicity, mutagenicity, or impairment of fertility with
fluoxetine.
Carcinogenesis: The dietary administration of fluoxetine to rats and mice for 2 years at
doses of up to 10 and 12 mg/kg/day, respectively (approximately 1.2 and 0.7 times,
respectively, the maximum recommended human dose [MRHD] of 80 mg on a mg/m2
basis), produced no evidence of carcinogenicity.
Mutagenicity: Fluoxetine and norfluoxetine have been shown to have no genotoxic
effects based on the following assays: bacterial mutation assay, DNA repair assay in
cultured rat hepatocytes, mouse lymphoma assay, and in vivo sister chromatid exchange
assay in Chinese hamster bone marrow cells.
Impairment of Fertility: Two fertility studies conducted in rats at doses of up to 7.5 and
12.5 mg/kg/day (approximately 0.9 and 1.5 times the MRHD on a mg/m2 basis)
indicated that fluoxetine had no adverse effects on fertility.
Pregnancy Category C
In embryo-fetal development studies in rats and rabbits, there was no evidence of
teratogenicity following administration of up to 12.5 and 15 mg/kg/day, respectively (1.5
and 3.6 times, respectively, the maximum recommended human dose [MRHD] of 80 mg
on a mg/m2 basis) throughout organogenesis. However, in rat reproduction studies, an
increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during
the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (1.5
times the MRHD on a mg/m2 basis) during gestation or 7.5 mg/kg/day (0.9 times the
MRHD on a mg/m2 basis) during gestation and lactation. There was no evidence of
developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day
during gestation. The no-effect dose for rat pup mortality was 5 mg/kg/day (0.6 times the
MRHD on a mg/m2 basis). Fluoxetine should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
Labor and Delivery
The effect of fluoxetine on labor and delivery in humans is unknown. However, because
fluoxetine crosses the placenta and because of the possibility that fluoxetine may have
adverse effects on the newborn, fluoxetine should be used during labor and delivery only
if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
Because fluoxetine is excreted in human milk, nursing while on fluoxetine is not
recommended. In one 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 fluoxetine developed crying, sleep disturbance, vomiting, and watery stools.
The infant's plasma drug levels were 340 ng/ml of fluoxetine and 208 ng/ml of
norfluoxetine on the second day of feeding.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
U.S. fluoxetine clinical trials (10,782 patients) included 687 patients ³65 years of age and
93 patients ³75 years of age. The efficacy in geriatric patients has been established (see
CLINICAL STUDIES). For pharmacokinetic information in geriatric patients see
CLINICAL PHARMACOLOGY, Age. No overall differences in safety or effectiveness
were observed between these subjects and younger subjects, and other reported clinical
experience has not identified differences in responses between the elderly and younger
patients, but greater sensitivity of some older individuals cannot be ruled out. As with
other SSRIs, fluoxetine has been associated with cases of clinically significant
hyponatremia in elderly patients (see Hyponatremia).
PMDD: The diagnosis of PMDD is not applicable to postmenopausal women.
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. In two 6 week controlled
studies in patients ³60 years of age, 10 of 323 fluoxetine patients and 6 of 327 placebo
recipients had a lowering of serum sodium below the reference range; this difference was
not statistically significant. The lowest observed concentration was 129 mmol/L. The
observed decreases were not clinically significant.
Platelet Function
There have been rare reports of altered platelet function and/or abnormal results from
laboratory studies in patients taking fluoxetine. While there have been reports of
abnormal bleeding in several patients taking fluoxetine, it is unclear whether fluoxetine had
a causative role.