SIDE EFFECTS
Associated with Discontinuation of Treatment
Of the 1087 OCD and depressed patients treated with fluvoxamine
maleate in controlled clinical trials conducted in North
America, 22% discontinued treatment due to an adverse
event. The most common events (> 1%,) associated with
discontinuation and considered to be drug related (i.e.,
those events associated with dropout at a rate at least
twice that of placebo) included:
Table 1: ADVERSE EVENTS ASSOCIATED WITH DISCONTINUATION
OF TREATMENT IN OCD AND DEPRESSION POPULATIONS
BODY
SYSTEM
ADVERSE EVENT |
PERCENTAGE OF PATIENTS
|
FLUVOXAMINE
|
PLACEBO
|
| BODY
AS A WHOLE |
|
| Headache
|
3%
|
1%
|
| Asthenia
|
2%
|
<1%
|
| Abdominal
Pain |
1%
|
0%
|
| DIGESTIVE
|
|
| Nausea
|
0%
|
1%
|
| Diarrhea
|
1%
|
<1%
|
| Vomiting
|
2%
|
<1%
|
| Anorexia
|
1%
|
<1%
|
| Dyspepsia
|
1%
|
<1%
|
| NERVOUS
SYSTEM |
|
| Insomnia
|
4%
|
1%
|
| Somnolence
|
4%
|
<1%
|
| Nervousness
|
2%
|
<1%
|
| Agitation
|
2%
|
<1%
|
| Dizziness
|
2%
|
<1%
|
| Anxiety
|
1%
|
<1%
|
| Dry
Mouth |
1%
|
<1%
|
Incidence In Controlled Trials
Commonly Observed Adverse Events In Controlled Clinical
Trials LUVOX Tablets have been studied in controlled trials
of OCD (N= 320) and depression (N= 1350). In general,
adverse event rates were similar in the two data sets
as well as in the pediatric OCD study. The most commonly
observed adverse events associated with the use of LUVOX
Tablets and likely to be drug-related (incidence of 5%
or greater and at least twice that for placebo) derived
from Table 2 were, somnolence, insomnia, nervousness,
tremour, nausea, dyspepsia, and anorexia, vomiting, abnormal
ejaculation asthenia and sweating. In a p.o. of two studies
involving only patients with OCD, the following additional
events were identified using the above rule: dry mouth,
decreased libido; urinary frequency, anorgasmia, rhinitis
and taste perversion. In a study of pediatric patients
with O.D. the following addition al events were identified
using the above rule: agitation, depression, dysmenorrhea,
flatulence, hyperkinesia, and rash.
Adverse Events Occurring at an Incidence of 1%:
Table 2 enumerates adverse events that occurred in adults
at a frequency of 1% or more, and were more frequent than
in the placebo group, among patients treated with LUVOX
Tablets in two short-term placebo controlled OCD trials
(10 week) and depression trials (6 week) in which patients
were dosed in a range of generally 100 to 300 mg/day.
This table shows the percentage of patients in each who
had at least one occurrence of an event at some during
their treatment. Reported adverse events were classified
using a standard COSTART-based Dictionary terminology.
The precriber should be aware that these figures cannot
be used to predict the incidence of side effects in the
course of usual medical practice where patient characteristics
and other factors may differ from those that prevailed
in the clinical trials. Similarly, the cited frequencies
cannot be compared with figures obtained from other clinical
investigations involving different treatments, uses, and
investigators. The cited figures, however, do provide
the prescribing physician with some basis for estimating
the relative contribution of drug and non-drug factors
to the side-effect incidence rate in the population studied.
Table 2: TREATMENT-EMERGENT ADVERSE EVENT INCIDENCE
RATES BY BODY SYSTEM IN ADULT OCD AND DEPRESSION POPULATIONS
COMBINED
|
BODY
SYSTEM/
ADVERSE EVENT |
Percentage of patients Reporting Event
|
FLUVOXAMINE
N= 892
|
PLACEBO
N= 778
|
| BODY
AS WHOLE |
|
| Headache
|
22
|
20
|
| Asthenia
|
14
|
6
|
| Flu
Syndrome |
3
|
2
|
| Chills
|
2
|
1
|
| CARDIOVASCULAR
|
|
| Palpitations
|
3
|
2
|
| DIGESTIVE
SYSTEM |
|
| Nausea
|
40
|
14
|
| Diarrhea
|
11
|
7
|
| Constipation
|
10
|
8
|
| Dypepsia
|
10
|
5
|
| Anorexia
|
6
|
2
|
| Vomiting
|
5
|
2
|
| Flatulence
|
4
|
3
|
| Tooth
Disorder |
3
|
1
|
| Dysphagia
|
2
|
1
|
| NERVOUS
SYSTEM |
|
| Somnolence
|
22
|
8
|
| Insomnia
|
21
|
10
|
| Dry
Mouth |
14
|
10
|
| Nervousness
|
12
|
5
|
| Dizziness
|
11
|
6
|
| Tremor
|
5
|
1
|
| Anxiety
|
5
|
3
|
| Vasodilatation
|
3
|
1
|
| Hypertonia
|
2
|
1
|
| Agitation
|
2
|
1
|
| Decreased
Libido |
2
|
1
|
| Depression
|
2
|
1
|
| CNS
Stimulation |
2
|
1
|
| RESPIRATORY
SYSTEM |
|
| Upper
Respiratory Infection |
9
|
5
|
| Dyspnea
|
2
|
1
|
| Yawn
|
2
|
0
|
| SKIN
|
|
| Sweating
|
7
|
3
|
| SPECIAL
SENSES |
|
| Taste
Perversion |
3
|
1
|
| Amblyopia
|
3
|
2
|
| UROGENITAL
|
|
| Abnormal
Ejaculation |
8
|
1
|
| Urinary
Frequency |
3
|
2
|
| Impotence
|
2
|
1
|
| Anorgasmia
|
2
|
0
|
| Urinary
Retention |
1
|
0
|
Events for which fluvoxamine meleate incidence was equal
to or less than placebo are not listed in the table above,
but include the following: abdominal pain, abnormal dreams,
appetite increase, back pain, chest pain, confusion, dys
menorrhea, fever, infection, leg cramps, migraine, myalgia,
pain, paresthesia, pharyngitis, postural hypotension,
pruritus, rash, rhinitis, thirst and tinnitus.
Indudes "toothache," "tooth extraction
and abscess” and “caries”. Mostly feeling
warm, hot, or flushed. Mostly "blurred vision”.
Mostly “delayed ejaculation". Incidence based
on number of male patients.
Adverse Events In OCD Placebo Controlled Studies
While Rate Markedly Different (defined as at least a
two-fold difference) In Rate from the Pooled Event Rates
in OCD and Depression Placebo Controlled Studies: The
events in OCD studies with a two-fold decrease in rate
compared to event rates in OCD and depression studies
were dysphagia and amblyopia (mostly blurred vision).
Additionally, there was an approximate 25% decrease in
nausea.
The events in OCD studies with a two-fold increase in
rate compared to event rates in OCD and depression studies
were: esthenia, abnormal ejaculation (mostly delayed ejaculation),
anxiety, infection, rhinitis, anorgasmia (in males), depression,
libido decreased, pharyngitis, agitation, impotence, myoclonus/twitch,
thirst, weight loss, leg cramps, myalgia and urinary retention.
These events are listed in order of decreasing rates in
the OCD trials.
Other Adverse Events in OCD Pediatric Population
In pediatric patients (N= 57) treated with LUVOX Tablets,
the overall profile of adverse events was generally similar
to that seen in adult studies, as shown in Table 2. However,
the following adverse events, not appearing in Table 2,
were reported in two or more of the pediatric patients
and were more frequent with LUVOX Tables Own with placebo:
abnormal thinking, cough increase, dysmenorrhea, ecchymosis,
emotional lability, epistaxis, hyperkinesia, infection,
manic reaction, rash, sinusitis, and weight decrease.
Vital Sign Changes
Comparisons of fluvoxamine maleate and placebo groups
in separate pools of short-term OCD and depression trials
on (1) median change from baseline on various vital signs
variables end on (2) incidence of patients meeting criteria
for potentially important changes from baseline on various
vital signs variables revealed no important differences
between fluvoxamine maleate and placebo.
Laboratory Changes
Comparisons of fluvoxamine maleate and placebo groups
in separate pools of short-term OCD and depression trials
on (1) median change from baseline on various serum chemistry,
hematology, and urinalysis variables and on (2) incidence
of patients meeting criteria for potentially important
changes from baseline on various serum chemistry, hematology,
and urinalysis variables revealed no important differences
between luvoxamine maleate and placebo.
ECG Changes
Comparisons of fluvoxamine maleate and placebo groups
in separate pools of short-term OCD end depression trials
on (1) mean change from baseline on various ECG variables
and on (2) incidence of patients meeting criteria for
potentially important changes from baseline on various
ECG variables revealed no important differences between
fluvoxamine maleate and placebo.
Other Event Observed During the Premarketing
Evaluation of LUVOX Tablets
During premarketing clinical trials conducted in North
America and Europe, multiple doses of fluvoxamine maleate
were administered for a combined total of 2737 patient
exposures in patients suffering OCD or Major Depressive
Disorder. Untoward events associated with this exposure
were recorded by clinical investigators using descriptive
terminology of their own choosing. Consequently, it is
not possible to provide a meaningful estimate of the proportion
of individuals experiencing adverse events without first
grouping similar types of untoward events into a limited
(i.e., number of standard event categories).
In the tabulations which follow, a standard COSTART-based
Dictionary terminology has been used to classify reported
adverse events. If the COSTART term for an event was so
general as to be uninformative, it was replaced with a
more informative term. The frequencies presented, therefore,
represent the proportion of the 2737 patient exposures
to multiple of fluvoxamine maleate who experienced an
event of the type cited on at least one occasion while
receiving fluvoxamine maleate. All reported events are
included in the list below, with the following exceptions:
1) those events already listed in Table 2, which tabulates
incidence rates of common adverse experience in placebo-controlled
OCD and deperssion clinical trials, are excluded; 2) those
events for which a drug cause was considered remote (i.e.,
neoplasia, gastroin testinal carcinoma, herpes simplex,
herpes zoster, application site reaction, and unintended
pregnancy) are omitted; and 3) events which were reported
in only one patient and judged to not be potentially serious
are not included. It is important to emphasize that, although
the events reported did occur during treatment with fluvoxamine
maleate, a causal relationship to fluvoxamine maleate
has not been established.
Events are further classified within body system categories
and enumerated in order of decreasing frequency using
the following definitions: frequently adverse events are
defined as those occurring on one or more occasions in
at least 1/100 patients; infrequent adverse events are
those occurring between 1/100 and 1/1000 patients; and
rare adverse events are those occurring in less than 1/1000
patients.
Body as a Whole: Frequent: accidental
injury malaise; Infrequent: allergic reaction, neck pain,
neck rigidity, over dose, photosensitivity reaction, suicide
attempt; Rare: cyst, pelvic pain, sudden death.
Cardiovascular System: Frequent: hypertension,
hypotension, syncope, tachycardia; Infrequent: angina
pectoris, bradycardia, cardiomyopathy, cardiovascular
disease, cold extremities, conduction delay, heart failure,
myocardial infarction, pallor, pulse irregular, ST segment
changes; Rare: AV block, cerebrovascular accident, coronary
artery disease, embolus, pericarditis, phlebitis, pulmonary
infarction, supraventricular extrasystoles.
Digestive System: Frequent: elevated
liver transaminases; Infrequent: colitis, eructation esophagitis,
gastritis, gastroenteritis, gastrointestinal hemorrphage,
gastrointestinal ulcer gingivitis, glossitis, hemorrhoids,
melena, rectal hemorrhage, stomatitis; Rare: biliary pain,
cholecystitis, cholelithiasis, fecal incontinence, hematemesis,
intestinal obstruction, jaundice.
Endocrine System: Infrequent: hypothyroidism;
Rare: goiter.
Hemic and Lymphotic Systems: Infrequent: anemia, ecchy
mosis, leukocytosis, lymphadenopathy, thrombocytopenia;
Rare: leukopenia, purpura.
Metabolic and Nutritional Systems: Frequent:
edema, weight gain, weight loss; Infrequent: dehydration,
hypercholesterolemia; Rare: diabetes mellitus, hyperglycemia,
hyperlipidemia, hypoglycemia, hypokalemia, lacate dehydrogenase
increased.
Musculoskeletal System: Infrequent:
arthralgia, arthritis, bursitis, generalized muscle spasm,
myasthenia, tendinous contracture, tenosynovitis; Rare:
arthrosis, myopathy, pathological fracture.
Nervous System: Frequent: amnesia, apathy,
hyperkinesia. hypokinesia, manic reaction, myoclonus,
psychotic reaction; Infrequent: agoraphobia, akathisia,
ataxia, CNS depression, convulsion, delirium, delusion,
depersonalization, drug dependence, dyskinesia, dystonia,
emotional lability, euphoria, extrapyramidal syndrome,
gait unsteady, hallucinations, hemiplegia, hostility,
hypersomnia, hypochondriasis, hypotonia, hysteria incoordination,
increased salivation, increased libido, neuralgia, paralysis,
paranoid reaction, phobia, psychosis, sleep disorder,
stupor, twitching vertigo; Rare: akinesis, coma, fibrillations
mutism, obsessions, reflexes decreased, slurred speech,
tardive dyskinesia, tarticollis, trismus, withdrawal syndrome.
Respiratory System: Frequent: cough
increased, sinusitis; Infrequent: asthma, bronchitis,
epistaxis, hoarseness, hyper ventilation; Rare: apnea,
congestion of upper airway, hemoptysis, hiccups, laryngismus,
obstructive pulmonary disease, pneumonia.
Skin: Infrequent: ,acne, alopecia, dry
skin, eczema, exfolia tive dermatitis, furunculosis, seborrhea,
skin discoloration, urticaria.
Special Senses: Infrequent: accommodation
abnormal, conjunctivitis, deafness, diplopia, dry eyes,
ear pain, eye pain, mydriasis, otitis media, parosmia,
photophobia, taste loss, visual field defect; Rare: corneal
ulcer, retinal detachment.
Urogenital System: Infrequent: anuria,
breast pain, cystitis, delayed menstruation, dysuria,
female lactation, hematuria, menopause, menorrhagia, metrorrmagia,
nocturia, polyuria, premenstrual syndrome, urinary incontinence,
urinary tract infection, urinary urgency, urination impaired,
vaginal hemorrhage, vaginitis, Rare: kidney calculus,
hematospermia oliguria. Based on the number of females.
Based on the number of males.
Non-US Postmarketing Reports
Voluntary reports of adverse events in patients taking
LUVOX Tablets that have been received since market introduction
and are of unknown causal relationship to LUVOX Tablets
use include: toxic epidermal necrolysis, Stevens-Johnson
syndrome, Henoch-Schoernlein purpura, bullous eruption,
priapism, agranulocytosis, neuropathy, aplastic anemia,
anaphylactic reaction, hyponatremia, acute renal failure,
hemor and severe akinesia with fever when fluvoxamine
was co-administered with antipsychotic medication.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class
LUVOX Tablets are not controlled substances.
Physical and Psychological Dependence
The potential for abuse, tolerance and physical dependence
with fluvoxamine maleate has been studied in a nonhuman
primate model. No evidence of dependency phenomena was
found. The discontinuation effects of LUVOX Tablets were
not systematically evaluated in controlled clinical trials.
LUVOX Tablets were not systematically studied in clinical
trials for potential for abuse, but there was no indication
of drug-seeking behavior in clinical trials. It should
be noted, however, that patients at risk for drug dependency
was systematically excluded from investigational studies
of fluvoxamine maleste. Generally, it is not possible
to predict on the basis of preclinical or premarketing
clinical experience the extent to which a CNS active drug
will be misused, diverted, and or abused once marketed.
Consequently physicians should carefully evaluate patients
for a history of drug abuse and follow such patients closely,
observing them for signs of fluvoxamine maleate misuse
or abuse (i.e., development of tolerance, incrementation
of dose, drug-seeking behavior).
DRUG INTERACTIONS
Potential for Interaction with Monoamine Oxidase
Inhibitors
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.
Potential Terfenadine, Astemizole, and Cisapride
Interactions
Terfenadine, astemizole and cisapride are all metabolized
by the cytochrome P450IIIA4 isozyme, and it has been demonstrated
that ketoconazole, a potent inhibitor of IIIA4, blocks
the metabolism of these drugs, resulting in increased
plasma concentrations of parent drug. Increased plasma
concentrations of terfenadine, astemizole, and cisapride
cause QT prolongation and have been associated with torsades
de pointes-type ventricular tachycardia, sometimes fatal.
As noted below, a sub- for fluvoxamine in combination
with alprazolam, a drug that is known to be metabolized
by the IIIA4 isozyme. Although it has not been definitively
demonstrated that fluvoxamine is a potent IIIA4 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 either
terbinafine, astemizole, or cisapride (see PRECAUTIONS).
Other Potentially Important Drug Interactions:
(Also see PRECAUTIONS)
Benzodiazepines: Benzodiazepines metabolized
by hepatic oxidation (e.g., alprazolam, midazolam, triazolam
elc.) 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 fluvoxamine.
Alprazolam: When fluvoxamine maleate
(100 mg qd) and alprazolam (1 mg q.d. were co-administered
to steady state, plasma concentration and other pharmacokinetics
parameters (AUC, Cmax, T1/2,) 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 co-administered, particularly since fluvoxamine
exhibits non-linear pharmacokinetics over the dosage range
100-300 mg. If alprazolam is co-administered with LUVOX
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 LUVOX Tablets.
Diazepam: The co-administration of LUVOX
Tablets and diazepam is generally not advisable. Because
fluvoxamine reduces the clearance of both diazepam and
its active metabolite, N-desmethyldiazepam, there is a
strong likelihood of substantial accumulation of both
species during chronic co-administration.
Evidence supporting the conclusion that it is inadvisable
to co-administer 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 (R= B), 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 experience significantly underestimates
the degree of accumulation that might occur with repealed
diazepam administration. Moreover, as noted with alprazolam,
the effect of fluvoxamine may even be more pronounced
when it is administered at higher doses. Accordingly,
diazepam and fluvoxamine should not ordinarily be co-administered.
Theophylline: The effect of steady-state
fluvoxamine l50 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 co-administered
with fluvoxamine maleate, its dose should be reduced to
one third of the usual daily maintenance dose and plasma
concentrations of theophylline should to monitored. No
dosage adjustment is required for LUVOX Tablets.
Warfarin: When fluvoxamine maleate (50
mg tid) 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 LUVOX Tablets should
have their prothrombin time monitored and their anticoagulant
dose adjusted accordingly. No dosage adjustment is required
for LUVOX Tablets
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