A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Sarafem Warnings, Precautions, Pregnancy, Nursing, Abuse - Fluoxetine Hydrochloride
Sarafem Warnings, Precautions, Pregnancy, Nursing, Abuse - Fluoxetine Hydrochloride
WARNINGS
Rash and Possibly Allergic Events—In three premarketing clinical
trials for PMDD, 5% of 243 patients treated with SARAFEM 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(both receiving 60 mg) were withdrawn from treatment because of rash and/or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 US fluoxetine clinical trials for conditions other than
PMDD, 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almost a third were withdrawn from treatment because of the rash and/or systemic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, two 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, 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 for other indications,
systemic events, possibly related to vasculitis and including lupus-like syndrome,
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, laryngospasm,
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, SARAFEM 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 a placebo-controlled trial of
fluoxetine in PMDD, treatment-emergent adverse events were assessed. Rates
were as follows for SARAFEM 20 mg (the recommended dose), SARAFEM 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 SARAFEM 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 US 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 2 under
ADVERSE REACTIONS).
Altered Appetite and Weight--In a placebo-controlled
trial of fluoxetine in PMDD, 4% of patients on SARAFEM 20 mg (the recommended
dose), 13% on SARAFEM 60 mg, and 3% of placebo patients reported anorexia.
In two placebo-controlled trials (only one of which included a dose of
60 mg/day), potentially clinically significant weight gain (t 7%) occurred
in 8% of patients on SARAFEM 20 mg, 6% of patients on SARAFEM 60 mg, and
1% of patients on placebo. Potentially clinically significant weight loss
(t 7%) occurred in 7% of patients on SARAFEM 20 mg, 12% of patients on
SARAFEM 60 mg, and 3% of patients on placebo. In US placebo-controlled
clinical trials of fluoxetine for other approved indications, changes
in appetite and weight have also been reported (see Table 2 and Other
Events Observed in US Clinical Trials under ADVERSE
REACTIONS).
Activation of Mania/Hypomania--No patients treated with SARAFEM
in three PMDD clinical trials (N=243) reported mania/hypomania. In all US 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--No patients treated with SARAFEM in three PMDD clinical
trials (N=243) reported seizures. In all US 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--No patients treated with SARAFEM 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 for a condition
other than PMDD 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 Liver Disease under CLINICAL
PHARMACOLOGY). 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 Renal Disease under
CLINICAL PHARMACOLOGY). Use of a lower or
less frequent dose for renally impaired patients is not routinely necessary
(see DOSAGE AND ADMINISTRATION).
In patients with diabetes, 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.
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