Included as part of the PRECAUTIONS section.
Clinical Worsening And Suicide Risk
Patients with major depressive disorder (MDD), both adult
and pediatric, may experience worsening of their depression and/or the
emergence of suicidal ideation and behavior (suicidality) or unusual changes in
behavior, whether or not they are taking antidepressant medications, and this
risk may persist until significant remission occurs. Suicide is a known risk of
depression and certain other psychiatric disorders, and these disorders
themselves are the strongest predictors of suicide. There has been a
long-standing concern, however, that antidepressants may have a role in
inducing worsening of depression and the emergence of suicidality in certain
patients during the early phases of treatment. Pooled analyses of short-term
placebo-controlled trials of antidepressant drugs (SSRIs and others) showed
that these drugs increase the risk of suicidal thinking and behavior
(suicidality) in children, adolescents, and young adults (ages 1824) with major
depressive disorder (MDD) and other psychiatric disorders. Short-term studies
did not show an increase in the risk of suicidality with antidepressants
compared to placebo in adults beyond age 24; there was a reduction with
antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in
children and adolescents with MDD, obsessive compulsive disorder (OCD), or
other psychiatric disorders included a total of 24 short-term trials of 9
antidepressant drugs in over 4400 patients. The pooled analyses of
placebo-controlled trials in adults with MDD or other psychiatric disorders
included a total of 295 short-term trials (median duration of 2 months) of 11
antidepressant drugs in over 77,000 patients. There was considerable variation
in risk of suicidality among drugs, but a tendency toward an increase in the
younger patients for almost all drugs studied. There were differences in
absolute risk of suicidality across the different indications, with the highest
incidence in MDD. The risk differences (drug vs placebo), however, were
relatively stable within age strata and across indications. These risk
differences (drug-placebo difference in the number of cases of suicidality per
1000 patients treated) are provided in Table 1.
TABLE 1 : DRUG-PLACEBO DIFFERENCES IN NUMBER OF CASES
OF SUICIDALITY PER 1000 PATIENTS TREATED
|Increases Compared to Placebo
| < 18
||14 Additional Cases
||5 Additional Cases
|Decreases Compared to Placebo
||1 Fewer Case
| ≥ 65
||6 Fewer Cases
No suicides occurred in any of
the pediatric trials. There were suicides in the adult trials, but the number
was not sufficient to reach any conclusion about the drug effect on suicide.
It is unknown whether the
suicidality risk extends to longer-term use, i.e., beyond several months.
However, there is substantial evidence from placebo-controlled maintenance
trials in adults with depression that the use of antidepressants can delay the
recurrence of depression.
All patients being treated
with antidepressants for any indication should be monitored appropriately and
observed closely for clinical worsening, suicidality, and unusual changes in
behavior, especially during the initial few months of a course of drug therapy,
or at times of dose changes, either increases or decreases.
The following symptoms,
anxiety, agitation, panic attacks, insomnia, irritability, hostility,
aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania,
and mania, have been reported in adult and pediatric patients being treated with
antidepressants for major depressive disorder as well as for other indications,
both psychiatric and nonpsychiatric. Although a causal link between the
emergence of such symptoms and either the worsening of depression and/or the
emergence of suicidal impulses has not been established, there is concern that
such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic
regimen, including possibly discontinuing the medication, in patients whose depression
is persistently worse, or who are experiencing emergent suicidality or symptoms
that might be precursors to worsening depression or suicidality, especially if
these symptoms are severe, abrupt in onset, or were not part of the patient's
If the decision has been made to discontinue treatment,
medication should be tapered, as rapidly as is feasible, but with recognition
that abrupt discontinuation can be associated with certain symptoms [see
DOSAGE AND ADMINISTRATION - Discontinuation of Treatment with
Fluvoxamine Maleate Tablets, for a description of the risks of
discontinuation of Fluvoxamine Maleate Tablets].
Families and caregivers of patients being treated with
antidepressants for major depressive disorder or other indications, both
psychiatric and nonpsychiatric, should be alerted about the need to monitor
patients for the emergence of agitation, irritability, unusual changes in
behavior, and the other symptoms described above, as well as the emergence of
suicidality, and to report such symptoms immediately to healthcare providers.
Such monitoring should include daily observation by families and caregivers.
Prescriptions for Fluvoxamine Maleate Tablets should be written for the
smallest quantity of tablets consistent with good patient management, in order
to reduce the risk of overdose.
Screening Patients for Bipolar Disorder: A major
depressive episode may be the initial presentation of bipolar disorder. It is
generally believed (though not established in controlled trials) that treating
such an episode with an antidepressant alone may increase the likelihood of
precipitation of a mixed/manic episode in patients at risk for bipolar
disorder. Whether any of the symptoms described above represent such a
conversion is unknown. However, prior to initiating treatment with an
antidepressant, patients with depressive symptoms should be adequately screened
to determine if they are at risk for bipolar disorder; such screening should
include a detailed psychiatric history, including a family history of suicide,
bipolar disorder, and depression. It should be noted that Fluvoxamine Maleate
Tablets are not approved for use in treating bipolar depression.
The development of a potentially life-threatening
serotonin syndrome has been reported with SNRIs and SSRIs, including
Fluvoxamine Maleate Tablets, alone but particularly with concomitant use of
serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl,
lithium, tramadol, tryptophan, busipirone, amphetamines, and St. John's Wort)
and with drugs that impair metabolism of serotonin (in particular MAOIs, both
those intended to treat psychiatric disorders and also others, such as
linezolid and intravenous methylene blue).
Serotonin syndrome symptoms may include mental status
changes (e.g., agitation, hallucinations, delirium, and coma), autonomic
instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis,
flushing, hyperthermia), neuromuscular aberrations (e.g., tremor, rigidity, myoclonus,
hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms
(e.g., nausea, vomiting, diarrhea). Patients should be monitored for the
emergence of serotonin syndrome.
The concomitant use of Fluvoxamine Maleate Tablets with
MAOIs intended to treat psychiatric disorders is contraindicated. Fluvoxamine
Maleate Tablets should also not be started in a patient who is being treated
with MAOIs such as linezolid or intravenous methylene blue. All reports with
methylene blue that provided information on the route of administration
involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No
reports involved the administration of methylene blue by other routes (such as
oral tablets or local tissue injection) or at lower doses. There may be
circumstances when it is necessary to initiate treatment with an MAOI such as
linezolid or intravenous methylene blue in a patient taking Fluvoxamine Maleate
Tablets. Fluvoxamine Maleate Tablets should be discontinued before initiating
treatment with the MAOI. [see CONTRAINDICATIONS and DOSAGE AND
If concomitant use of Fluvoxamine Maleate Tablets with
other serotonergic drugs, including triptans, tricyclic antidepressants,
fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St.
John's Wort is clinically warranted, patients should be made aware of a
potential increased risk for serotonin syndrome, particularly during treatment
initiation and dose increases.
Treatment with Fluvoxamine Maleate Tablets and any
concomitant serotonergic agents, should be discontinued immediately if the
above events occur and supportive symptomatic treatment should be initiated.
Angle Closure Glaucoma
The pupillary dilation that occurs following use of many antidepressant
drugs including Fluvoxamine Maleate Tablets may trigger an angle closure attack
in a patient with anatomically narrow angles who do not have a patent
Potential Thioridazine Interaction
The effect of fluvoxamine (25 mg b.i.d. for one week) on
thioridazine steady-state concentrations was evaluated in 10 male inpatients
with schizophrenia. Concentrations of thioridazine and its two active
metabolites, mesoridazine and sulforidazine, increased threefold following
coadministration of fluvoxamine.
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. It
is likely that this experience underestimates the degree of risk that might
occur with higher doses of thioridazine. Moreover, the effect of fluvoxamine
may be even more pronounced when it is administered at higher doses.
Therefore, fluvoxamine and thioridazine should not be
coadministered. [See CONTRAINDICATIONS].
Potential Tizanidine Interaction
Fluvoxamine is a potent inhibitor of CYP1A2 and
tizanidine is a CYP1A2 substrate. The effect of fluvoxamine (100 mg daily for 4
days) on the pharmacokinetics and pharmacodynamics of a single 4 mg dose of
tizanidine has been studied in 10 healthy male subjects. Tizanidine Cmax was
increased approximately 12-fold (range 5fold to 32-fold), elimination half-life
was increased by almost 3-fold, and AUC increased 33-fold (range 14fold to 103-fold).
The mean maximal effect on blood pressure was a 35 mm Hg decrease in systolic
blood pressure, a 20 mm Hg decrease in diastolic blood pressure, and a 4
beat/min decrease in heart rate. Drowsiness was significantly increased and
performance on the psychomotor task was significantly impaired. Fluvoxamine and
tizanidine should not be used together. [See CONTRAINDICATIONS].
Potential Pimozide Interaction
Pimozide is metabolized by the cytochrome P4503A4
isoenzyme, and it has been demonstrated that ketoconazole, a potent inhibitor
of CYP3A4, blocks the metabolism of this drug, resulting in increased plasma
concentrations of parent drug. An increased plasma concentration of pimozide
causes QT prolongation and has been associated with torsades de pointes-type
ventricular tachycardia, sometimes fatal. As noted below, a substantial
pharmacokinetic interaction has been observed for fluvoxamine in combination
with alprazolam, a drug that is known to be metabolized by CYP3A4. Although it
has not been definitively demonstrated that fluvoxamine is a potent CYP3A4
inhibitor, it is likely to be, given the substantial interaction of fluvoxamine
with alprazolam. Consequently, it is recommended that fluvoxamine not be used
in combination with pimozide. [See CONTRAINDICATIONS].
Potential Alosetron Interaction
Because alosetron is metabolized by a variety of hepatic
CYP drug metabolizing enzymes, inducers or inhibitors of these enzymes may
change the clearance of alosetron. Fluvoxamine is a known potent inhibitor of
CYP1A2 and also inhibits CYP3A4, CYP2C9, and CYP2C19. In a pharmacokinetic
study, 40 healthy female subjects received fluvoxamine in escalating doses from
50 mg to 200 mg a day for 16 days, with coadministration of alosetron 1 mg on
the last day. Fluvoxamine increased mean alosetron plasma concentration (AUC)
approximately 6-fold and prolonged the half-life by approximately 3-fold. [See
CONTRAINDICATIONS and Lotronex™ (alosetron) package insert].
Other Potentially Important Drug Interactions
Benzodiazepines: Benzodiazepines metabolized by
hepatic oxidation (e.g., alprazolam, midazolam, triazolam, etc.) should be used
with caution because the clearance of these drugs is likely to be reduced by
fluvoxamine. The clearance of benzodiazepines metabolized by glucuronidation
(e.g., lorazepam, oxazepam, temazepam) is unlikely to be affected by
Alprazolam -When fluvoxamine maleate (100 mg q.d.)
and alprazolam (1 mg q.i.d.) were coadministered to steady state, plasma
concentrations and other pharmacokinetic parameters (AUC, Cmax, T½) of
alprazolam were approximately twice those observed when alprazolam was
administered alone; oral clearance was reduced by about 50%. The elevated
plasma alprazolam concentrations resulted in decreased psychomotor performance
and memory. This interaction, which has not been investigated using higher
doses of fluvoxamine, may be more pronounced if a 300 mg daily dose is
coadministered, particularly since fluvoxamine exhibits non-linear
pharmacokinetics over the dosage range 100-300 mg. If alprazolam is
coadministered with Fluvoxamine Maleate Tablets, the initial alprazolam dosage
should be at least halved and titration to the lowest effective dose is
recommended. No dosage adjustment is required for Fluvoxamine Maleate Tablets.
Diazepam -The coadministration of Fluvoxamine
Maleate Tablets and diazepam is generally not advisable. Because fluvoxamine
reduces the clearance of both diazepam and its active metabolite,
Ndesmethyldiazepam, there is a strong likelihood of substantial accumulation of
both species during chronic coadministration.
Evidence supporting the conclusion that it is inadvisable
to coadminister fluvoxamine and diazepam is derived from a study in which
healthy volunteers taking 150 mg/day of fluvoxamine were administered a single
oral dose of 10 mg of diazepam. In these subjects (N=8), the clearance of
diazepam was reduced by 65% and that of N-desmethyldiazepam to a level that was
too low to measure over the course of the 2 week long study.
It is likely that this experience significantly
underestimates the degree of accumulation that might occur with repeated
diazepam administration. Moreover, as noted with alprazolam, the effect of
fluvoxamine may even be more pronounced when it is administered at higher
Accordingly, diazepam and fluvoxamine should not
ordinarily be coadministered.
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 coadministered. Patients should be closely monitored when
fluvoxamine maleate and clozapine are used concurrently.
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.
Mexiletine: The effect of steady-state fluvoxamine
(50 mg b.i.d. for 7 days) on the single dose pharmacokinetics of mexiletine
(200 mg) was evaluated in 6 healthy Japanese males. The clearance of mexiletine
was reduced by 38% following coadministration with fluvoxamine compared to
mexiletine alone. If fluvoxamine and mexiletine are coadministered, serum
mexiletine levels should be monitored.
Ramelteon: When fluvoxamine 100 mg twice daily was
administered for 3 days prior to single-dose coadministration of ramelteon 16
mg and fluvoxamine, the AUC for ramelteon increased approximately 190fold and
the Cmax increased approximately 70-fold compared to ramelteon administered
alone. Ramelteon should not be used in combination with fluvoxamine.
Theophylline: The effect of steady-state
fluvoxamine (50 mg bid) on the pharmacokinetics of a single dose of
theophylline (375 mg as 442 mg aminophylline) was evaluated in 12 healthy
non-smoking, male volunteers. The clearance of theophylline was decreased
approximately 3-fold. Therefore, if theophylline is coadministered with
fluvoxamine maleate, its dose should be reduced to one-third of the usual daily
maintenance dose and plasma concentrations of theophylline should be monitored.
No dosage adjustment is required for Fluvoxamine Maleate Tablets.
Warfarin and Other Drugs That Interfere With
Hemostasis (NSAIDs, Aspirin, etc.): Serotonin release by platelets plays an
important role in hemostasis. Epidemiological studies of the case-control and
cohort design have demonstrated an association between use of psychotropic
drugs that interfere with serotonin reuptake and the occurrence of upper
gastrointestinal bleeding. These studies have also shown that concurrent use of
an NSAID or aspirin may potentiate this risk of bleeding. Thus, patients should
be cautioned about the use of such drugs concurrently with fluvoxamine [see
Warfarin -When fluvoxamine maleate (50 mg t.i.d.)
was administered concomitantly with warfarin for two weeks, warfarin plasma
concentrations increased by 98% and prothrombin times were prolonged. Thus
patients receiving oral anticoagulants and Fluvoxamine Maleate Tablets should have
their prothrombin time monitored and their anticoagulant dose adjusted
accordingly. No dosage adjustment is required for Fluvoxamine Maleate Tablets.
Dicontinuation Of Treatment With Fluvoxamine Maleate
During marketing of Fluvoxamine Maleate Tablets and other
SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have
been spontaneous reports of adverse events occurring upon discontinuation of
these drugs, particularly when abrupt, including the following: dysphoric mood,
irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias,
such as electric shock sensations), anxiety, confusion, headache, lethargy,
emotional lability, insomnia, and hypomania. While these events are generally
self-limiting, there have been reports of serious discontinuation symptoms.
Patients should be monitored for these symptoms when
discontinuing treatment with Fluvoxamine Maleate Tablets. A gradual reduction
in the dose rather than abrupt cessation is recommended whenever possible. If
intolerable symptoms occur following a decrease in the dose or upon
discontinuation of treatment, then resuming the previously prescribed dose may
be considered. Subsequently, the physician may continue decreasing the dose but
at a more gradual rate. [See DOSAGE AND ADMINISTRATION].
SSRIs and SNRIs, including Fluvoxamine Maleate Tablets,
may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal
anti-inflammatory drugs, warfarin, and other anticoagulants may add to this
risk. Case reports and epidemiological studies (case-control and cohort design)
have demonstrated an association between use of drugs that interfere with
serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding
events related to SSRIs and SNRIs have ranged from ecchymoses, hematomas,
epistaxis, and petechiae to life-threatening hemorrhages.
Patients should be cautioned about the risk of bleeding
associated with the concomitant use of Fluvoxamine Maleate Tablets and NSAIDs,
aspirin, or other drugs that affect coagulation.
Activation Of Mania/Hypomania
During premarketing studies involving primarily depressed
patients, hypomania or mania occurred in approximately 1% of patients treated
with fluvoxamine. In a ten 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, Fluvoxamine
Maleate Tablets should be used cautiously in patients with a history of mania.
During premarketing studies, seizures were reported in
0.2% of fluvoxamine-treated patients. Caution is recommended when the drug is
administered to patients with a history of convulsive disorders. Fluvoxamine
should be avoided in patients with unstable epilepsy and patients with
controlled epilepsy should be carefully monitored. Treatment with fluvoxamine
should be discontinued if seizures occur or if seizure frequency increases.
Hyponatremia may occur as a result of treatment with
SSRIs and SNRIs, including Fluvoxamine Maleate Tablets. In many cases, this
hyponatremia appears to be the result of the syndrome of inappropriate
antidiuretic hormone (SIADH). Cases with serum sodium lower than 110 mmol/L have
been reported. Elderly patients may be at greater risk of developing
hyponatremia with SSRIs and SNRIs [see Use In Specific Population, Geriatric
Use]. Also, patients taking diuretics or who are otherwise volume depleted
may be at greater risk. Discontinuation of Fluvoxamine Maleate Tablets should
be considered in patients with symptomatic hyponatremia and appropriate medical
intervention should be instituted.
Signs and symptoms of hyponatremia include headache,
difficulty concentrating, memory impairment, confusion, weakness, and
unsteadiness, which may lead to falls. Signs and symptoms associated with more
severe and/or acute cases have included hallucination, syncope, seizure, coma,
respiratory arrest, and death.
Use In Patients With Concomitant Illness
Closely monitored clinical experience with Fluvoxamine
Maleate Tablets in patients with concomitant systemic illness is limited.
Caution is advised in administering Fluvoxamine Maleate Tablets to patients
with diseases or conditions that could affect hemodynamic responses or
Fluvoxamine Maleate 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.
Patients with Hepatic Impairment -In patients with liver
dysfunction, fluvoxamine clearance was decreased by approximately 30%. Patients
with liver dysfunction should begin with a low dose of Fluvoxamine Maleate
Tablets and increase it slowly with careful monitoring.
There are no specific laboratory tests recommended.
Patient Counseling Information
Prescribers or other health professionals should inform
patients, their families, and their caregivers about the benefits and risks
associated with treatment with Fluvoxamine Maleate Tablets and should counsel
them in the appropriate use. A patient Medication Guide about “Antidepressant
Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts
or Actions” is available for Fluvoxamine Maleate Tablets. The prescriber or
health professional should instruct patients, their families, and their
caregivers to read the Medication Guide and should assist them in understanding
its contents. Patients should be given the opportunity to discuss the contents
of the Medication Guide and to obtain answers to any questions they may have.
The complete text of the Medication Guide is reprinted at the end of this
Patients should be advised of the following issues and
asked to alert their prescriber if these occur while taking Fluvoxamine Maleate
Clinical Worsening And Suicide Risk
Patients, their families, and their caregivers should be
encouraged to be alert to the emergence of anxiety, agitation, panic attacks,
insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia
(psychomotor restlessness), hypomania, mania, other unusual changes in
behavior, worsening of depression, and suicidal ideation, especially early
during antidepressant treatment and when the dose is adjusted up or down.
Families and caregivers of patients should be advised to look for the emergence
of such symptoms on a day-to-day basis, since changes may be abrupt. Such
symptoms should be reported to the patient's prescriber or health professional,
especially if they are severe, abrupt in onset, or were not part of the
patient's presenting symptoms. Symptoms such as these may be associated with an
increased risk for suicidal thinking and behavior and indicate the need for
very close monitoring and possibly changes in the medication [see BOXED
WARNING and WARNINGS AND PRECAUTIONS].
Patients should be cautioned about the risk of serotonin
syndrome particularly with the concomitant use of fluvoxamine with other
serotonergic agents (including triptans, tricyclic antidepressants, fentanyl,
lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John's Wort)
[see WARNINGS AND PRECAUTIONS -Serotonin Syndrome].
Angle Closure Glaucoma
Patients should be advised that taking Fluvoxamine
Maleate Tablets can cause mild pupillary dilation, which in susceptible
individuals, can lead to an episode of angle closure glaucoma. Pre-existing
glaucoma is almost always open-angle glaucoma because angle closure glaucoma,
when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma
is not a risk factor for angle closure glaucoma. Patients may wish to be
examined to determine whether they are susceptible to angle closure, and have a
prophylactic procedure (e.g., iridectomy), if they are susceptible. [see
WARNINGS AND PRECAUTIONS]
Interference With Cognitive Or Motor Performance
Since any psychoactive drug may impair judgment,
thinking, or motor skills, patients should be cautioned about operating
hazardous machinery, including automobiles, until they are certain that
Fluvoxamine Maleate Tablets therapy does not adversely affect their ability to
engage in such activities.
Patients should be advised to notify their physicians if
they become pregnant or intend to become pregnant during therapy with Fluvoxamine
Maleate Tablets [see Use in Specific Populations].
Patients receiving Fluvoxamine Maleate Tablets should be
advised to notify their physicians if they are breastfeeding an infant. [See
Use In Specific Populations - Nursing Mothers].
Patients should be advised to notify their physicians if
they are taking, or plan to take, any prescription or overthe-counter drugs,
since there is a potential for clinically important interactions with
Fluvoxamine Maleate Tablets.
Patients should be cautioned about the concomitant use of
fluvoxamine and NSAIDs, aspirin, or other drugs that affect coagulation since
the combined use of psychotropic drugs that interfere with serotonin reuptake
and these agents has been associated with an increased risk of bleeding [see
WARNINGS AND PRECAUTIONS - Warfarin and Other Drugs That Interfere With
Because of the potential for the increased risk of
serious adverse reactions including severe lowering of blood pressure and
sedation when fluvoxamine and tizanidine are used together, fluvoxamine should
not be used with tizanidine [see WARNINGS AND PRECAUTIONS].
Because of the potential for the increased risk of
serious adverse reactions when fluvoxamine and alosetron are used together,
fluvoxamine should not be used with Lotronex™(alosetron) [see
WARNINGS AND PRECAUTIONS].
As with other psychotropic medications, patients should
be advised to avoid alcohol while taking Fluvoxamine Maleate Tablets.
Patients should be advised to notify their physicians if
they develop a rash, hives, or a related allergic phenomenon during therapy
with Fluvoxamine Maleate Tablets.
Impairment Of Fertility
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 dose of
240 mg/kg is approximately 6 times the maximum human daily dose on a mg/m² basis.
No evidence of genotoxic 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 a study in which male and female rats were
administered fluvoxamine (60, 120, or 240 mg/kg) prior to and during mating and
gestation, fertility was impaired at oral doses of 120 mg/kg or greater, as
evidenced by increased latency to mating, decreased sperm count, decreased
epididymal weight, and decreased pregnancy rate. In addition, the numbers of
implantations and embryos were decreased at the highest dose. The no effect
dose for fertility impairment was 60 mg/kg (approximately 2 times the maximum
recommended human dose [MRHD] on a mg/m² basis).
Use In Specific Populations
Pregnancy Category C: When pregnant rats were
given oral doses of fluvoxamine (60, 120, or 240 mg/kg) throughout the period
of organogenesis, developmental toxicity in the form of increased embryofetal
death and increased incidences of fetal eye abnormalities (folded retinas) was
observed at doses of 120 mg/kg or greater. Decreased fetal body weight was seen
at the high dose. The no effect dose for developmental toxicity in this study
was 60 mg/kg (approximately 2 times the MRHD on a mg/m² basis).
In a study in which pregnant rabbits were administered
doses of up to 40 mg/kg (approximately 2 times the MRHD on a mg/m² basis)
during organogenesis, no adverse effects on embryofetal development were
In other reproduction studies in which female rats were
dosed orally during pregnancy and lactation (5, 20, 80, or 160 mg/kg),
increased pup mortality at birth was seen at doses of 80 mg/kg or greater and
decreases in pup body weight and survival were observed at all doses (low
effect dose approximately 0.1 times the MRHD on a mg/m² basis).
Neonates exposed to Fluvoxamine Maleate Tablets and other
SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the
third trimester have developed complications requiring prolonged
hospitalization, respiratory support, and tube feeding. Such complications can
arise immediately upon delivery. Reported clinical findings have included
respiratory distress, cyanosis, apnea, seizures, temperature instability,
feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia,
hyperreflexia, tremor, jitteriness, irritability, and constant crying. These
features are consistent with either a direct toxic effect of SSRIs and SNRIs
or, possibly, a drug discontinuation syndrome. It should be noted that, in some
cases, the clinical picture is consistent with serotonin syndrome [see WARNINGS
Infants exposed to SSRIs in pregnancy may have an
increased risk for persistent pulmonary hypertension of the newborn (PPHN).
PPHN occurs in 1 - 2 per 1,000 live births in the general population and is
associated with substantial neonatal morbidity and mortality. Several recent
epidemiologic studies suggest a positive statistical association between SSRI
use (including Fluvoxamine Maleate Tablets) in pregnancy and PPHN. Other
studies do not show a significant statistical association.
Physicians should also note the results of a prospective
longitudinal study of 201 pregnant women with a history of major depression,
who were either on antidepressants or had received antidepressants less than 12
weeks prior to their last menstrual period, and were in remission. Women who
discontinued antidepressant medication during pregnancy showed a significant
increase in relapse of their major depression compared to those women who
remained on antidepressant medication throughout pregnancy.
When treating a pregnant woman with Fluvoxamine Maleate
Tablets, the physician should carefully consider both the potential risks of
taking an SSRI, along with the established benefits of treating depression with
an antidepressant. This decision can only be made on a case by case basis. [see
DOSAGE AND ADMINISTRATION].
Labor AND Delivery
The effect of fluvoxamine on labor and delivery in humans
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 fluvoxamine in the nursing infant as well as the potential
benefits of Fluvoxamine Maleate Tablets therapy to the mother.
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. In addition, 99 of these
outpatients continued open-label fluvoxamine maleate treatment for up to
another one to three years, equivalent to 94 patient years. The adverse event
profile observed in that study was generally similar to that observed in adult
studies with fluvoxamine. [See ADVERSE REACTIONS and WARNINGS AND
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 continued 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, cognitive behavioral 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
[see WARNINGS AND PRECAUTIONS - Clinical Worsening and Suicide Risk].
Safety and effectiveness in the pediatric population
other than pediatric patients with OCD have not been established. [See BOXED
WARNING and WARNINGS AND PRECAUTIONS - Clinical Worsening and
Suicide Risk]. Anyone considering the use of Fluvoxamine Maleate Tablets in
a child or adolescent must balance the potential risks with the clinical need.
Approximately 230 patients participating in controlled
premarketing studies with Fluvoxamine Maleate 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 response between the elderly and younger patients. However,
SSRIs and SNRIs, including Fluvoxamine Maleate Tablets, have been associated
with several cases of clinically significant hyponatremia in elderly patients,
who may be at greater risk for this adverse event [see WARNINGS AND
PRECAUTIONS]. Furthermore, the clearance of fluvoxamine is decreased by
about 50% in elderly compared to younger patients [see CLINICAL PHARMACOLOGY
- Elderly], and greater sensitivity of some older individuals also cannot
be ruled out. Consequently, a lower starting dose should be considered in
elderly patients and Fluvoxamine Maleate Tablets should be slowly titrated
during initiation of therapy.