WARNINGS
In patients receiving another serotonin reuptake inhibitor
drug in combination with monoamine oxidase inhibitors
(MAOI), 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. These
reactions have also been reported in patients who have
discontinued that drug and have been started on a MAOI.
Some cases presented with features resembling neuroleptic
malignant syndrome. Therefore, it is recommended that
LUVOX Tablets not be used in combination with MAOIs, or
within 14 days of discontinuing treatment with a MAOI.
After stopping LUVOX Tablets, at least 2 weeks should
be allowed before starting a MAOI.
Also see DRUG INTERACTIONS section.
PRECAUTIONS
General
Activiation of Mania/Hypomania: During
premarketing studies involving primarily depressed patients,
hypomania or mania occurred in approximately 1% of patients
treated with fluvoxamine. In a 10 week pediatric OCD study,
2 out of 57 patients (4%) treated with fluvoxamine experienced
manic reactions compared to none of 63 placebo patients.
Activation of mania/hypomania has also been reported in
a small proportion of patients with major affective disorder
who were treated with other marketed antidepressants.
As with all antidepressants, LUVOX Tablets should be used
cautiously in patients with a history of mania.
Seizures: During premarketing studies,
seizures were reported in 0.2% of fluvoxamine -treated
patients. LUVOX Tablets should be used cautiously in patients
with a history of seizures. It should be discontinued
in any patient who develops Seizures.
Suicide: The possibility of a suicide
attempt is inherent in patients with depressive symptoms,
whether these occur in primary depressive or in association
with another primary disorder such as O.D. Close supervision
of high risk patients should accompany initial drug therapy.
Prescriptions for LUVOX Tablets should be written for
the smallest quantity of tablets consistent with good
patient management in order to reduce the risk of overdose.
Use in Patients with Concomitant Illness:
Closely monitored clinical experience with LUVOX Tablets
in patients with concomitant systemic illness is limited.
Caution is advised in administering LUVOX Tablets to patients
with diseases or conditions that could affect hemodynamic
responses or metabolism. LUVOX Tablets have 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 many clinical studies during the product's premarketing
testing. Evaluation of the electrocardiograms for patients
with depression or OCD who participated in premarketing
studies revealed no differences between fluvoxamine and
placebo in the emergence of clinically important ECG changes.
In patients with liver dysfunction, fluvoxamine clearance
was decreased by approximately 30%, LUVOX Tablets should
be slowly titrated in patients with liver dysfunction
during the initiation of treatment.
Laboratory Tests
There are no specific laboratory tests recommended.
Potential Interactions with Drugs that Inhibit
or are Metabolized by CytoChrome P450 Isozymes
Multiple hepatic cytochrome P450 (CYP450) enzymes are
involved in the oxidative biotransformation of a large
number of structurally different drugs and endogenous
compounds. The available knowledge concerning the relationship
of fluvoxamine and the CYP450 enzyme system has been obtained
mostly from pharmacokinetic interaction studies conducted
in healthy volunteers, but some preliminary in vitro data
are also available. Based on a finding of substantial
interactions of fluvoxamine with certain of these drugs
(see later parts of this section and also DRUG INTERACTIONS
for details) and limited in vitro data for the IIIA4 isozyme,
it appears that fluvoxemine inhibits the following isozymes
that are known to be involved in the metabolism of the
listed drugs:
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IA2
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IIC9
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IIIA4
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| Warfarin
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Warfarin |
Alprazolam
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| Theophylline
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| Propranolol
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In vitro data suggest that fluvoxamine is a relatively
weak inhibitor of the IID6 isozyme.
Approximately 7% of the normal population has a genetic
defect that leads to reduced levels of activity of the
cytochrome P450IID6 isozyme. Such individuals have been
referred to as "poor metabolizers" (PM) of drugs
such as debrisoquin, dextromethorphan, and tricyclic antidepressants.
While none of the drugs studied for drug interactions
significantly affected the pharmacokinetics of fluvoxamine,
an in vivo study of fluvoxamine single-dose pharmacokinetics
in 13 PM subjects demonstrated altered pharmacokinetic
properties compared to 16 "extensive metabolizers”
(EM): mean Cmax, AUC, and half-life were increased by
52%, 200%, and 62%, respectively, in the PM impaired to
the EM group. This suggests that fluvoxamine is metabolized,
at least in part, by the IID6 isozyme. Caution is indicated
in patients known to have reduced levels of P450IID6 activity
and those receiving concomitant drugs known to inhibit
this isozyme (e. g. quinidine).
The metabolism of fluvoxamine has not been fully characterized
and the effects of potent P450 isozyme inhibition, such
as the ketoconazole inhibition of IIIA4, on fluvoxamine
metabolism have not been studied.
A clinically significant fluvoxamine interaction is possible
with drugs having a narrow therapeutic ratio such as terfenadine,
astemizole, or cisapride, warfarin, theophylline, certain
benzodiazepines and phenytoin. If LUVOX Tablets are to
be administered together with a drug that is eliminated
via oxidative metabolism and has a narrow therapeutic
window, plasma levels and/or pharmacodynamic effects of
the latter drug should be monitored closely, at least
until steady-state conditions are reached (See DRUG INTERACTIONS).
CNS Active Drugs
Manoamine Oxidase Inhibitors: See DRUG
INTERACTIONS.
Alprazolam: See DRUG INTERACTIONS.
Diazepam: See DRUG INTERACTIONS.
Alcohol: Studies involving single 40
g doses of ethanol (oral administration in one study and
intravenous in the other) and multiple dosing with fluvoxamine
maleate (50 mg body revealed no effect of either drug
on the pharmacokinetics or pharmacodynamics of the other.
Carbamazepine: Elevated carbamazepine
levels and symptoms of toxicity have been reported with
the co-administration of fluvoxamine maleate and carbamazepine.
Clozapine: Elevated serum levels of
clozapine have been reported in patients taking fluvoxamine
maleate and clozapine. Since clozapine related seizures
and orthostatic hypotension appear to be dose related.
the risk of these adverse events may be higher when fluvoxamine
and clozapine are co-administered. Patients should be
closely monitored when fluvoxamine maleate and clozapine
are used concurrently.
Lithium: As with other serotonergic
drugs, lithium may enhance the serotonergic effects of
fluvoxamine and therefore, the combination should be used
with caution. Seizures have been reported with the co-administration
of fluvoxamine maleate and lithium.
Lorazepam: A study of multiple doses
of fluvoxamine maleate (50 mg body in healthy male volunteers
(N= 12) and a single dose of lorazepam (4 mg single dose)
indicated no significant pharmacokinetic interaction.
On average, both lorazepam alone and lorazepam with fluvoxamine
produced substantial decrements in cognitive functioning;
however, the co-administration of fluvoxamine and lorazepam
did not produce larger mean decrements compared to lorazepam
alone.
Methadone: Significantly increased methadone
(plasma level: dose) ratios have been reported when fluvoxamine
maleate was administered to patients receiving maintenance
methadone treatment, with symptoms of opioid intoxication
in one patient. Opioid withdrawal symptoms were reported
following fluvoxamine maleate discontinuation in another
patient.
Sumatriptan: There have been rare postmarketing
reports describing patients with weakness, hyperreflexia,
and incoordination following the use of a selective serotonin
reuptake inhibitor (SSRI) and sumatriptan. If concomitant
treatment with sumatriptan and an SSRI (eg., fluoxetine
fluvoxamine, paroxetine, sertraline) is clinically warranted,
appropriate observation of the patient is advised.
Tacrine: In a study of 13 healthy, male
volunteers, a single 40 mg dose of tacrine added to fluvoxamine
100 mg/day administered at steady-state was associated
with five- and eight- fold increases in tacrine Cmax and
A.C. respectively, compared to the administration of tacrine
alone. Five subjects experienced nausea, vomiting, sweating,
and diarrhea following co-administration, consistent with
the cholinergic effects of tacrine.
Tricyclic Antidepressants (TCAs): Significantly
increased plasma TCA levels have been reported with the
co-administrstion of fluvoxamine maleate and amitriptyline,
clomipramine or imipramine. Caution is indicated with
the coadministration of LUVOX Tablets and TCAs; plasma
TCA concentrations may need to be monitored, and the dose
of TCA may need to be reduced.
Tryptophan: Tryptophan may enhance the
serotonergic effects of fluvoxamine, and the combination
should, therefore, be used with caution. Severe vomiting
has been reported with the co-administration of fluvoxamine
maleate and tryptophan.
Other Drugs
Theophylline: See DRUG INTERACTIONS
Warfarin: See DRUG INTERACTIONS
Digoxin: Administration of fluvoxamine
maleate 100 mg daily for 18 days (N-8) did not significantly
affect the pharmacokinetics of a 1.25 mg single intravenous
dose of digoxin.
Diltiazem: Bradycardia has been reported
with the co-administration of fluvoxamine maleate and
diltiazem.
Propranolol and Other Beta-Blockers:
Co-administration of fluvoxamine maleate 100 mg per day
and propranolol 160 mg per day in normal volunteers resulted
in a mean five-fold increase (range 2 to 17) in minimum
propranolol plasma concentrations. In this study, there
was a slight potentiation of the propranolol-induced reduction
in heart rate and reduction in the exercise diastolic
pressure.
One case of bradycardia and hypotension and a second
case of orthostatic hypotension have been reported with
the coadministration of fluvoxamine maleate and metoprolol.
If propranolol or metaprolol is co-administered with
LUVOX Tablets, a reduction in the initial beta-blocker
dose and more cautious dose titration is recommended.
No dosage adjustment is required for LUVOX Tablets.
Co-administration of fluvoxamine maleate 100 mg per day
with atenolol 100 mg per day (N= 6) did not affect the
plasma concentrations of atenolol. Unlike propranolol
and metoprolol which undergo hepatic metabolism, atenolol
is eliminated primarily by renal excretion.
Effects of Smoking on Fluvoxamine Metabolism:
Smokers had a 25% increase in the metabolism of fluvoxamine
compared nonsmokers.
Electroconvulsive Therapy (ECT): There
are no clinical studies establishing the benefits or risks
of combined use of ECT and fluvoxamine maleate.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis: There is no evidence
of carcinogenicity, mutagenicity or impairment of fertility
with fluvoxamine maleate.
There was no evidence of carcinogenicity in rats treated
orally with fluvoxamine maleate for 30 months or hamsters
treated orally with fluvoxamine maleate for 20 (females)
or 26 (males) months. The daily doses in the high dose
groups in these studies were increased over the course
of the study from a minimum of 160 mg/kg to a maximum
of 240 mg/kg in rats and from a minimum of 135 mg/kg to
a maximum of 240 mg/kg in hamsters. The maximum of 240
mg/kg is approximately 6 times the maximum human daily
dose on a mg/m2 basis.
Mutagenesis: No evidence of mutagenic
potential was observed in a mouse micronucleus test, an
in vitro chromosome aberration test, or the Ames microbial
mutagen test with or without metabolic activation.
Impairment of Fertility: In fertility
studies of male and Female rats, up to 80 mg/kg/day orally
of fluvoxamine maleate, (approximately 2 times the maximum
human daily dose on a mg/m2 basis) had no effect on mating
performance, duration of gestation, or pregnancy rate.
Pregnancy
Teratogenic Effects - Pregnancy Category C: In
teratalogy studies in rats and rabbit, daily oral doses
of fluvoxamine maleate of up to 80 and 40 mg/kg, respectively
(approximately 2 times the maximum human daily dose on
a mg/m2 basis) caused no fetal malformations. However,
in other reproduction studies in which pregnant rats were
dosed through weaning there was (1) an increase in pup
mortality at birth (seen at 80 mg/kg and above but not
at 20 mg/kg), and (2) decreases in postnatal pup weights
(seen at 160 but not at 80 mg/kg) and survival (seen at
all doses; lowest dose tested = 5 mg/kg). (Doses of 5,
20, 80, and 160 mg/kg are approximately 0.1, 0.5 2, and
4 times the maximum human daily dose on a mg/m2 basics).
While the result of a cross fostering study implied that
at least some of these results likely occurred secondarily
to maternal toxicity, the role of a direct drug effect
on the fetuses or pups could not be ruled out. There are
no adequate and well controlled studies in pregnant women.
Fluvoxamine maleate should be used during pregnancy only
if the potential benefit justifies the potential risk
to the fetus.
Labor and Delivery: The effect of fluvoxamine
on labor and delivery in humans is unknown.
Nursing Mothers
As for many other drugs, fluvoxamine is secreted in human
breast milk. The decision of whether to discontinue nursing
or to discontinue the drug should take into account the
potential for serious adverse effects from exposure to
fluvoxemine in the nursing infant as well as the potential
benefits of LUVOX (fluvoxamine maleate) Tablets therapy
to the mother.
Pediatric Use
The efficacy of fluvoxamine maleate for the treatment
of Obsessive Compulsive Disorder was demonstrated in a
10-week multicenter placebo controlled study with 120
outpatients ages 8-17. The adverse event profile observed
in that study was generally similar to that observed in
adult studies with fluvoxamine (See ADVERSE REACTIONS
and DOSAGE AND ADMINISTRATION.)
Decreased appetite and weight loss have been observed
in association with the use of fluvoxamine as well as
other SSRIs. Consequently, regular monitoring of weight
and growth is recommended if treatment of a child with
an SSRI is to be controlled long term.
The risks, if any, that may be associated with fluvoxamine's
extended use in children and adolescents with OCD have
not been systematically assessed. The prescriber should
be mindful that the evidence relied upon to conclude that
fluvoxamine is safe for use in children and adolescents
derives from relatively short term clinical studies and
from extrapolation of experience gained with adult patients.
In particular, there are no studies that directly evaluate
the effects of long term fluvoxamine use on the growth,
development, and maturation of children and adolescents.
Although there is no affirmative finding to suggest that
fluvoxamine possesses a capacity to adversely affect growth,
development or maturation, the absence of such findings
is not compelling evidence of the absence of the potential
of fluvoxamine to have adverse effects in chronic use.
Geriatric Use
Approximately 230 patients participating in controlled pre-marketing
studies with LUVOX Tablets were 65 years of age or over.
No overall differences in safety were observed between these
patients and younger patients. Other reported clinical experience
has not identified differences in responses between the
elderly and younger patients. However, the clearance of
fluvoxamine is decreased by about 50% in elderly compared
to younger patients (see Pharmacokinetics under CLINICAL
PHARMACOLOGY), and greater sensitivity of some older individuals
also cannot be ruled out. Consequently, LUVOX Tablets should
be slowly titrated during initiation of therapy.
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