6. ADVERSE REACTIONS
6.1 Adverse Reactions Leading to Treatment
Discontinuation
Of the 1087 OCD and depressed patients treated with fluvoxamine
maleate in controlled clinical trials in North America, 22% discontinued due to
an adverse reaction. Adverse reactions that led to discontinuation in at least
2% of fluvoxamine maleate-treated patients in these trials were: nausea (9%),
insomnia (4%), somnolence (4%), headache (3%), and asthenia, vomiting,
nervousness, agitation, and dizziness (2% each).
6.2 Incidence in Controlled Trials
Commonly Observed Adverse
Reactions in Controlled Clinical Trials: Fluvoxamine Maleate
Tablets have been studied in 10-week short-term controlled trials of OCD (N=320)
and depression (N=1350). In general, adverse reaction rates were similar in the
two data sets as well as in the pediatric OCD study. The most commonly observed
adverse reactions associated with the use of Fluvoxamine Maleate Tablets and
likely to be drug-related (incidence of 5% or greater and at least twice that
for placebo) derived from Table 2 were: nausea, somnolence, insomnia, asthenia, nervousness, dyspepsia,
abnormal ejaculation, sweating, anorexia, tremor, and
vomiting. In a pool of two studies involving only patients with OCD, the
following additional reactions were identified using the above rule: anorgasmia, decreased libido, dry mouth, rhinitis, taste
perversion, and urinary frequency. In a study
of pediatric patients with OCD, the following additional reactions were
identified using the above rule: agitation, depression,
dysmenorrhea, flatulence, hyperkinesia, and
rash.
Adverse Reactions Occuring at an
Incidence of 1%: Table 2 enumerates adverse
reactions that occurred in adults at a frequency of 1% or more, and were more
frequent than in the placebo group, among patients treated with Fluvoxamine
Maleate 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 group who
had at least one occurrence of a reaction at some time during their treatment.
Reported adverse reactions were classified using a standard COSTART-based
Dictionary terminology.
The prescriber 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.
Adverse Reactions in OCD Placebo
Controlled Studies Which are Markedly Different (defined as at least a two-fold
difference) in Rate from the Pooled Reaction Rates in OCD and Depression Placebo
Controlled Studies: The reactions in OCD studies with a two-fold
decrease in rate compared to reaction rates in OCD and depression studies were
dysphagia and amblyopia (mostly blurred vision). Additionally, there was an
approximate 25% decrease in nausea.
The reactions in OCD studies with a two-fold increase in rate compared to
reaction rates in OCD and depression studies were: asthenia,
abnormal ejaculation (mostly delayed ejaculation), anxiety, rhinitis, anorgasmia
(in males), depression, libido decreased, pharyngitis, agitation, impotence,
myoclonus/twitch, thirst, weight loss, leg cramps, myalgia, and urinary retention. These reactions are listed in order of
decreasing rates in the OCD trials.
6.3 Other Adverse Reactions in OCD Pediatric
Population
In pediatric patients (N=57) treated with Fluvoxamine Maleate
Tablets, the overall profile of adverse reactions was generally similar to that
seen in adult studies, as shown in Table 2. However, the
following adverse reactions, not appearing in Table 2, were reported in
two or more of the pediatric patients and were more frequent with Fluvoxamine
Maleate Tablets than with placebo: cough increase, dysmenorrhea, ecchymosis,
emotional lability, epistaxis, hyperkinesia, manic reaction, rash, sinusitis,
and weight decrease.
6.4 Male and Female Sexual Dysfunction with
SSRIs
Although changes in sexual desire, sexual performance and sexual
satisfaction often occur as manifestations of a psychiatric disorder and with
aging, they may also be a consequence of pharmacologic treatment. In particular,
some evidence suggests that selective serotonin reuptake inhibitors (SSRIs), can
cause such untoward sexual experiences.
Reliable estimates of the incidence and severity of untoward experiences
involving sexual desire, performance and satisfaction are difficult to obtain,
however, in part because patients and physicians may be reluctant to discuss
them. Accordingly, estimates of the incidence of untoward sexual experience and
performance cited in product labeling are likely to underestimate their actual
incidence.
Table 3 displays the
incidence of sexual side effects reported by at least 2% of patients taking
Fluvoxamine Maleate Tablets in placebo-controlled trials in depression and
OCD.
There are no adequate and well-controlled studies examining sexual
dysfunction with fluvoxamine treatment.
Fluvoxamine treatment has been associated with several cases of priapism. In
those cases with a known outcome, patients recovered without sequelae and upon
discontinuation of fluvoxamine.
While it is difficult to know the precise risk of sexual dysfunction
associated with the use of SSRIs, physicians should routinely inquire about such
possible side effects.
6.5 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 and 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.
6.6 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 fluvoxamine maleate and placebo.
6.7 ECG Changes
Comparisons of fluvoxamine maleate and placebo groups in separate
pools of short-term OCD and 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.
6.8 Other Reactions Observed During the Premarketing
Evaluation of Fluvoxamine Maleate 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 reactions 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 reactions without first
grouping similar types of untoward reactions into a limited (i.e., reduced)
number of standard reaction categories.
In the tabulations which follow, a standard COSTART-based Dictionary
terminology has been used to classify reported adverse reactions. If the COSTART
term for a reaction 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 doses of fluvoxamine
maleate who experienced a reaction of the type cited on at least one occasion
while receiving fluvoxamine maleate. All reported reactions are included in the
list below, with the following exceptions: 1) those reactions already listed in
Table 2, which tabulates incidence rates of common adverse experiences in
placebo-controlled OCD and depression clinical trials, are excluded; 2) those
reactions for which a drug cause was not considered likely are omitted; 3)
reactions for which the COSTART term was too vague to be clinically meaningful
and could not be replaced with a more informative term; and 4) reactions 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 reactions reported
did occur during treatment with fluvoxamine maleate, a causal relationship to
fluvoxamine maleate has not been established.
Reactions are further classified within body system categories and enumerated
in order of decreasing frequency using the following definitions: frequent
adverse reactions are defined as those occurring on one or more occasions in at
least 1/100 patients; infrequent adverse reactions are those occurring between
1/100 and 1/1000 patients; and rare adverse reactions are those occurring in
less than 1/1000 patients.
Body as a Whole – Frequent: malaise; Infrequent:
photosensitivity reaction and suicide attempt.
Cardiovascular System – Frequent: syncope.
Digestive System – Infrequent: gastrointestinal hemorrhage and melena; Rare: hematemesis.
Hemic and Lymphatic Systems – Infrequent: anemia and ecchymosis; Rare: purpura.
Metabolic and Nutritional Systems – Frequent: weight gain and weight loss.
Nervous System – Frequent:
hyperkinesia, manic reaction, and myoclonus; Infrequent: abnormal dreams, akathisia, convulsion,
dyskinesia, dystonia, euphoria, extrapyramidal syndrome, and twitching; Rare: withdrawal syndrome.
Respiratory System – Infrequent: epistaxis. Rare:
hemoptysis and laryngismus.
Skin – Infrequent:
urticaria.
Urogenital System* – Infrequent: hematuria, menorrhagia, and vaginal hemorrhage;
Rare: hematospermia.
* Based on the number of males or females, as appropriate.
6.9 Postmarketing Reports
Voluntary reports of adverse reactions in patients taking
Fluvoxamine Maleate Tablets that have been received since market introduction
and are of unknown causal relationship to Fluvoxamine Maleate Tablets use
include: acute renal failure, agranulocytosis, amenorrhea, anaphylactic
reaction, angioedema, aplastic anemia, bullous eruption, Henoch-Schoenlein
purpura, hepatitis, ileus, pancreatitis, porphyria, Stevens-Johnson syndrome,
toxic epidermal necrolysis, vasculitis, and ventricular tachycardia (including
torsades de pointes).
