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Safety Database on Fluvoxamine: Analysis and Report
W. Wagner l , B. Plekkenpoll, T. E. GrayJ, H. Vlaskamp 2, H. Essers 2
I Solvay Phannaeeutieals, Ine., Marietta, Georgia, USA
2 Solvay Duphar B. v., Weesp, The Netherlands

Summary Datenbank zur sicheren Anwendung
und Verträglichkeit von Fluvoxamin:
A review was conducted of the safety and Analyse und Bericht
tolerability of fluvoxamine in 54 worldwide marketing studies
that enrolled 24,624 patients, the majority of whom were Übersicht über die Anwendungssicherheit
treated with fluvoxamine in uncontrolled studies in depres- und Verträglichkeit von Fluvoxamin aufgrund von 54 weltwei-
sion. In accordance with the general epidemiologie distribu- ten Marketingstudien, die insgesamt 24624 Patienten umfaß-

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tion of depressive disorder, female patients and patients aged ten, die in der Mehrzahl mit Fluvoxamin in unkontrollierten
between 30 and 50 years predominated. The majority of Studien bei Depressionen behandelt wurden. Es überwogen
patients were treated for 6 weeks, the most frequent, or modal, die Patientinnen einerseits und Patienten im Alter zwischen 30
total daily dose being 100 mg. Overall, 57.4 % of the patients und 50 Jahren andererseits, in Übereinstimmung mit der all-
exposed to fluvoxamine did not have any adverse experiences. gemeinen epidemiologischen Verteilung des manisch-depres-
The greatest proportion of adverse experiences, as defined siven Krankheitsbildes. Die Mehrzahl der Patienten wurde für
using COSTART body systems, affected the digestive system einen Zeitraum von 6 Wochen behandelt, wobei die häufigste
(24.1 %), the nervous system (23.7 %), and the body as a oder modale tägliche Gesamtdosis 100 mg betrug. Insgesamt
whole (15.3 %). The only adverse experience with an inci- traten bei 57,4 % der mit Fluvoxamin behandelten Patienten
dence greater than 10% was nausea (15.7%); somnolence keine nachteiligen Wirkungen auf. Die Hauptanteile der nach-
(6.9 %) and asthenia (6.2 %) were the next most frequent ad- teiligen Wirkungen (nach den Definitionen gemäß den CO-
verse experiences. Notably, the rates of agitation and anxiety START-Körpersystemen) betrafen das Verdauungssystem
were only 1.4 % and 1.3 %, respectively. The incidences of (24,1 %), das Nervensystem (23,7 %) und den gesamten Kör-
adverse experiences generally increased with age and were per (15,3 %). Die einzige als unangenehm empfundene Ne-
slightly higher in females than in males. In total, 15.1 % of benwirkung mit einer Häufigkeit von mehr als 10% war Übel-
patients discontinued treatment prematurely as a result of ad- keit (15,3 %), während Somnolenz (6,9 %) und Asthenie
verse experiences, principally nausea, dizziness, vomiting, (6,2%) an zweiter und dritter Stelle rangierten. Die Häufig-
somnolence, abdominal pain, and headache. The overall inci- keitsraten von Erregtheit und Angst betrugen bemerkenswer-
dence of serious adverse events in association with fluvox- terweise nur 1,4 bzw. 1,3 %. Die Häufigkeitsraten der uner-
amine treatment was 2.5 % when U. S. Food and Drug Admin- wünschten Nebenwirkungen nahmen im allgemeinen mit fort-
istration criteria and the most conservative approach, without schreitendem Alter zu und waren bei den Patientinnen ein
causality judgments, were used. The rare occurrence of con- wenig höher als bei den Patienten. Insgesamt brachen 15, I %
vulsions (lI cases) confirmed the lack ofproconvulsant activ- der Patienten die Behandlung vorzeitig ab aufgrund unange-
ity of fluvoxamine, and the incidence of overall suicidality, nehmer Wirkungen, hauptsächlich Übelkeit, Schwindelgefühl,
inc1uding psychotic depression, suicidal ideation, and over- Erbrechen, Somnolenz, Leibschmerzen und Kopfschmerz. Bei
dose, as weil as attempted and completed acts of suicide, was Anwendung der Kriterien der amerikanischen Nahrungs- und
remarkably low (0.8 %) in that population of predominantly Arzneimittelbehörde und konservativster Auswertungen ohne
depressed patients. Ursachenbewertung war die Gesamthäufigkeit ernster Neben-
wirkungen im Zusammenhang mit der Fluvoxaminbehand-
lung 2,5 %. Die geringe Inzidenz von Krampfanfällen (11 Fäl-
le) bestätigte, daß Fluvoxamin keine kramptrordernde Wir-
kung ausübt. Die Häufigkeit suizidaler Tendenzen, einschließ-
lich psychotischer Depressionen, Suizidgedanken und Über-
dosierung sowie versuchten und vollendeten Suizids, war in
dieser Gesamtpopulation vorwiegend depressiver Patienten
bemerkenswert niedrig (0,8 %).

Phannaeopsyehiat. 26 (1993) (Supplement) 10-16
© Georg Thierne Verlag Stuttgart . New York
Safety Database on Fluvoxamine: Analysis and Report Pharmacopsychiat. 26 (1993) 11

Introduction Medical review process
The authors conducted a review of the safety The medical review was performed by medi-
and tolerability offluvoxamine in worldwide marketing studies. cally trained professionals (research nurses, physicians, phar-
The data assembled represent the largest aggregate of informa- macists, c1inical research associates) and was supervised in
tion on safety ever amassed and published for any selective each institution by a fully Iicenced physician with at least 2
serotonin reuptake inhibitor (SSRI) and probably for any an- years of experience in c1inical research. The review process
tidepressant drug. The studies reviewed were not planned, im- consisted of three major parts: case record form review, com-
plemented, performed, or monitored according to consistent re- pletion of a patient safety summary form, and production of a
search guidelines; thus, the information on the case record narrative summary report based on the outcome of the case
forms was often incomplete, inconsistent, or even contradictory, record form review.
and sometimes iIIegible or unreliable. However, because of the
much less stringent inclusion and exclusion criteria applied in Case record form review: Each case record
those studies compared with the criteria applied in preregistra- form was completely reviewed, regardless of study medication
tion trials, the findings c10sely approximate those that would be and regardless of whether the patient had completed the study
expected from the use of fluvoxamine under everyday condi- or had been prematurely terminated. All handwritten com-
tions in psychiatric and general medical practice. Because of ments by the investigator, including comments written in the
that representation and the impressive sampIe size exposed to margins or on the backs of the form and in the comments
the compound, the collected data constitute valuable supporting section, were reviewed. The case record form was regarded as

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safety information. the sole source of information. If medical information required
for proper evaluation of a case was missing, that fact was so
Methods stated in the narrative summary report. When there was con-
flicting information, no assumptions were made by the re-
The wide range of studies performed and data- viewer.
collection methods used during the 8-year period during which
fluvoxamine was first being marketed in Europe and other Patient safety summary form: After the case
countries made the consolidation and computer-assisted review record form was thoroughly reviewed, a patient safety summary
ofthe key safety variables very difficult. So that the evaluation form was completed, the patient being c1assified as one who
ofthe fluvoxamine safety profile would be done with sufficient had completed or prematurely terminated the study. In addition,
rigor and uniformity, the decision was made to conduct a the patient was categorized as either one who did or one who
complete review of all original case record forms. did not experience a serious adverse event as defined by the
U. S. Federal Regulations for Investigational New Drug Appli-
To accomplish that huge task, the sponsor ap- cation, IND Safety Reports. For each patient who had prema-
pointed a multinational, multidisciplinary task force consisting turely terminated, the reason for discontinuation was indicated.
of five experts from various Solvay organizations and freed If more than one reason was specified or if the reason was
them for one year from their regular obligations and responsi- unclear, the worst-case scenario for the study drug was selected.
bilities to manage the inventory, collection, medical review, When an adverse experience was mentioned on the last assess-
data management, quality assurance, and safety evaluation of ment date, the patient was c1assified as prematurely terminated
the fluvoxamine marketing studies. The group was composed of because of adverse experiences, even when the investigator
a project manager, medical director, database consultant, senior stated the reason for discontinuation to be inefTectiveness, im-
c1inical research associate, and statistician, with offices and provement, or administrative. The information on the patient
secretaries available in Europe as weil as in the United States. safety summary form was subsequently entered into the
With the collaboration of the national Solvay Duphar organiza- database.
tions in several European countries, who had locally sponsored
those trials, and with the support of the international medical Narrative summary report: A narrative sum-
department of Solvay Duphar in Weesp, The Netherlands, all mary report (NSR) was written for each patient who could be
fluvoxamine marketing studies for which the c1inical phase had assigned to one of the following categories, as defined by the
been completed by December 31, 1990, were inventoried and Code ofU.S. Federal Regulations 312.32:
the original case record forms collected. The medical review of
the original case record forms and the management of the safety - Serious adverse event(s), fatal (NSR CodeOI)
data were subsequently contracted out to five contract research - Serious adverse event(s), life-threatening (NSR Code 02)
organizations in four European countries: Parexel in London - Serious adverse event(s), permanently disabling (NSR
(England), ITEM in Paris (France), MIRAI in Amsterdam (The Code 03)
Netherlands), Staticon in Munich (Germany), and ICTA in - Serious adverse event(s), requiring in-patient hospi-
Dijon (France). Each of those organizations was contractually talisation (NSR Code 04)
obliged to strictly follow the guidelines, policies, and proce- - Serious adverse event(s), congenital anomaly
dures developed by Solvay's task force. Those requirements (NSR Code 05)
were based on principles of good clinical practice and were - Serious adverse event(s), cancer (NSR Code 06)
regularly updated in newsletters that were distributed to all - Serious adverse event(s), overdose (NSR Code 07)
participating institutions. Premature termination due to adverse event(s)
(NSR Code 08)
12 Pharmacopsychiat. 26 (1993) W. Wagner et al.

If a case bad two or more NSR codes applied description (i.e., investigator term). If a checklist was used to
to it, the lowest-numbered code was employed (worst-case describe adverse experiences, the description from the checklist
scenario). A standard format was provided to ensure the struc- was entered. Each institute was required to assign a preferred
tural consistency of the narrative summary report. Each term from the COSTART code dictionary. When the investiga-
completed report was hand-signed by the respective supervising tor term was in a foreign language, it was translated into Eng-
physician for completeness and correctness. In total, 4,069 nar- lish and both terms were entered into the database. When a
rative summary reports were prepared and later stored on an COSTART code was assigned, the (translated) original term had
optical laser disk imaging system. to be linked to its appropriate COSTART code in the COSTART
dictionary so tbat no interpretation was necessary. If the inves-
Data management tigator term was not present in the COSTART code list, a new
term was assigned by the medical director of the task force.
The key safety variables from the studies re- Consistency was ensured by having the new investigator terms
viewed were managed using methods that would guarantee con- with their assigned preferred terms sent to all contract research
sistency between the data on the case record forms and in the organizations.
database. The data-management process for each individual
study consisted of four major steps: development of a data-man- Quality assurance
agement guideline, double data entry into an intermediate
database, conversion to a standardized database structure, and For a task of such magnitude and complexity,
coding of the adverse experiences. QA played a decisive role throughout the project. Different QA

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measures were therefore combined to achieve the required
Development 0/ a data-management guideline: quality standards.
Because the assessment of safety data varied so widely among
the different studies and it was difficult to enter that information Frequent on-site audits were considered the
into the database with a standardized predetermined structure, most important QA measures. In total, the task force conducted
it became necessary to develop extensive guidelines for each 38 audits at the contract research organizations. A description
study. That step guaranteed that all essential safety data were of all QA policies and procedures, a summary of the audit
captured and that necessary standardization was performed con- results and corrective actions taken after the audits, and all
sistently and reliably across all studies. documents resulting from QA measures were collected in a
formal audit file. When the medical review was completed, all
Double data entry into an intermediate serious adverse events were cross-checked with the inter-
database: An intermediate database reflecting the layout of the national database of the Adverse Drug Experience Unit of Sol-
case record form was developed for each study. In addition, the vay Duphar. That database contains all spontaneously reported
validity and logical consistency of all data entered were verified adverse drug events from clinical trials in all countries where
using a set of computer-based checks developed according to fluvoxamine is marketed. It was confirmed that no further seri-
task force guidelines. Those checks were then reviewed by the ous adverse events from these marketing studies, as defined by
task force group. All changes and corrective actions that re- current U. S. Food and Drug Administration (FDA) regulations,
sulted from the checks were documented in aseparate quality were present in that database.
assurance (QA) log.
Upon completion of the data-management
Conversion to a standardized database struc- process and the final quality checks on the database, program-
ture: The data were transferred from the intermediate database ming and production of the tabulations for the safety summary
to a standardized dedicated database, the format of which was began. A portion ofthose tabulations was produced in-house by
defined by the task force. During that process, laboratory data the task force group, and the remaining portion was produced
were converted to a set of standard units, coded variables were by a contract research organization - Quintiles - in Raleigh,
recoded according to conventions described in the guidelines, North Carolina, U.S.A.. Each tabulation was quality-assured
and dosage information was put in a standard format. and checked for consistency with the tabulation guidelines by
the task force group. Tabulations were approved only if they
An extensive set of feasibility checks was met all those standards.
developed by the task force and provided to each contract re-
search organization, to check the validity and logical con- Scope of Investigation
sistency of the data found in the standardized dedicated
Overview 0/ studies
database. The checks were run on each final study database by
the contract institutes and repeated by the task force upon re- In total, 54 controlled and uncontrolled market-
ceipt of each study database. The study databases were accepted ing studies conducted in Belgium, France, Germany, Italy, The
only if no discrepancies were found. Netherlands, Pakistan, Portugal, Spain, Switzerland, and Eng-
land were analyzed. Most (43) ofthe studies were conducted on
Coding 0/ the adverse experiences using depression. Ten trials assessed use of fluvoxamine in a variety
COSTART·: Each adverse experience reported in open ques- of other indications, such as pain states, anxiety disorders, alco-
tionnaires was entered into the database using the investigator's holism, bulimia, depression with cardiovascular diseases,
emotional instability, and premenstrual syndrome. One trial was
• Coding Symbols fOT Thesaurus of Adverse Reaction Tenns (1989) on obsessive-compulsive disorder (Table 1).
(FDA Center fOT Drug Evaluation and Research, Rockville, Mary-
land, USA)
Safety Database on Fluvoxamine: Analysis and Report Pharmacopsychiat. 26 (1993) 13

Table 1 Overview of 54 studies with fluvoxamine. Table 2 Exposure to fluvoxamine by indication.

Indieation No. of studies Indieation No. of patients

Depression 43 Depression
Other indieations 10 Controlled studies 818
Pain 1 Uneontrolled studies 23,395
Anxiety 2 Other indieations
Emotional instability 1 Controlled studies 181
AJeoholism 2 Uneontrolled studies 190
Bulimia 2 Obsessiv~ompulsive disorder
Cardiovaseular disease 1 Controlled study 40
Premenstrual syndrome 1
Obsessive-compulsive disorder 1 Total 24,624

Exposure to fluvoxamine Table 3 Demographie eharaeteristies of the 24,624 patients treated
with fluvoxamine.
The total cohort treated with fluvoxamine for
which data were reviewed and analyzed was 24,624 patients.

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Charaeteristie % of patients
Most of those patients, approximately 23,500, received fluvox-
amine in uncontrolled studies on depression; only a small num- Sex
ber of patients were treated with fluvoxamine in controlled Male 28.4
studies on depression and other indications (Table 2). Dosages Female 69.3
employed ranged from 50-300mg/day, and the duration ofthe No data available 2.3
studies varied between 4 and 52 weeks. Age (years)
<18 0.1
18-30 14.1
Demographie Characteristies
31-50 44.1
51-64 25.5
In accordance with the distribution of depres- ~65 14.4
sive disorders in the general population, the majority ofpatients No data available 1.7
(approximately 70%) were female. The largest percentage of
patients were between 30 and 50 years of age (Table 3). The sex
and age distribution of the patients who received fluvoxamine
was very similar in the controlled and uncontrolled trials and Table 4 Duration of fluvoxamine treatment.
across the various types of studies.
Treatment duration (weeks) No. of patients
Duration of Treatment and Dosage 1,156
1 1,223
Data used to calculate treatment duration were 2 846
taken from the dosage record pages of the case record form for 3 807
each individual patient and broken out by weeks of treatment. 4 1,052
For most of the patients it was difficult to obtain reliable data 5 1,742
on the actual dosage intake. Therefore, an attempt was made to 6 11,428 a
7 2,295
reconstruct the prescribed dosing schedule for each patient and
8-12 1,580
to identify the start date and the stop date of the study medica- 13-51 515
tion. In that procedure, no assumptions were allowed; the differ- 52-103 88
ence in days between the stop date and the start date plus 1 ~ 104 3
constituted the duration of treatment. The number of weeks No data available 1,889
equaled the total number of days of treatment divided by 7, and
fractions were truncated. a 98 % in uncontrolled studies on depression

The patients were c1assified into three groups
according to the duration of exposure to fluvoxamine: patients expected to terminate therapy at that point. The interval of 8
who terminated after short-term therapy less than or equal to 2 weeks or longer corresponded to information from a number of
weeks; patients who terminated at 6 weeks; and patients ex- studies of longer duration about which, because of the varia-
posed for 8 weeks or longer. Those three duration categories tions in study length, only very general remarks can be made.
corresponded to key experimental design features in the 54
studies analyzed. The short-term treatment period corresponded The overall combined population exhibited the
to the initial dose titration phase, during which patients were expected peaks of patient numbers at the three key treatment
exposed to rapidly escalating doses of fluvoxamine and had not durations: 13.1 % of all fluvoxamine-exposed patients termi-
yet reached steady-state plasma concentrations. The 6-week nated at or before 2 weeks of treatment; 46.4 % terminated at 6
point represents the maximum planned duration of therapy for weeks; and 8.8 % were treated for 8 weeks or longer. In total,
most of the studies, so a large percentage of patients could be 91 patients were exposed for at least one year (Table 4). The sex
14 Pharmacopsychiat. 26 (1993) W Wagner et al.

fable 5 Adverse experienees in the 24,624 patients treated with used a titration phase that tended to move the mean dose
fluvoxamine, by COSTART body system. downward relative to the maintenance dose, at which patients
should have stabilised. The distribution of the patients across
Body system Incidenee (%) the mean doses was very similar to their distribution across the
Digestive 24.1 modal and maximum doses, and no major differences were
Nervous 23.7 noted in the distribution of demographie variables as a function
Body as a whole 15.3 of mean total daily dose.
Cardiovaseular 3.5
Skin 2.7 In terms of the relationship between dose and
Special senses 2.1 duration of treatment, the maintenance modal daily dose for 8
Museuloskeletal 1.7 weeks of treatment or more was 100 or 150 mg in 71 % of
Urogenital 1.6 a patients, and it is noteworthy that that is a rather low dose range.
Metabolie/ nutritional 1.5
Respiratory Finally, the maximum total daily dose increased with increasing
Haematologie /Iymphatie 0.1 duration of treatment, reflecting the titration design of most
Endoerine <0.1 studies; a similar pattern was observed for the mean total daily
aDenominator adjusted tor sex-specific symptoms
Adverse Drug Experiences

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Adverse experiences were defined as all signs
and age distribution of patients was similar across the respective and symptoms that were reported during the course of the stu-
duration intervals. dies after the initiation of treatment. No distinction was made
between spontaneous reporting, general patient questioning,
The modal total daily dose reflected the most and checklists. The overall incidences represent the percentages
common or frequent dose maintained during a patient's partici- of patients who experienced at least one episode of the listed
pation in the study and could have been affected by such factors adverse experiences. Multiple occurrences of the same adverse
as the underlying disease state, the patient's motivation, con- experience in the same patient were counted as one event, selec-
comitant medications, the age and sex of the patient, and the tion being made according to maximum intensity.
dosage schedule employed. In general, the modal total daily
dose can be assumed to indicate the dosage at which a balance All adverse experiences were analyzed employ-
was likely to have been achieved between unwanted effects and ing the most conservative approach, as described in FDA regu-
clinical benefit, because the investigator was free to increase or lations; that is, no causality judgments were made, but all re-
decrease the dosage after an initial titration period, depending corded events were regarded as adverse experiences. Where
on the patient's clinical response. The overall distribution ofthe some uncertainty existed, the worst-case scenario for the study
modal total daily dose was dictated by the vast predominance drug was applied.
ofpatients with depression. The most pronounced concentration
of patients occurred in the low modal dose range (100 and Overall, for 57.4% (14,125/24,624) of those
150mg/day). More than 60% ofthe patients fell in this range, patients exposed to fluvoxamine, no adverse experiences were
indicating that the lower end of the planned dose range of 100- reported, whereas for 42.6% (10,499/24,624) of the patients
300mg/day was given for the longest period. No pronounced exposed to fluvoxamine at least one adverse experience was
differences in the distribution of demographie characteristics reported in the case record form. The highest incidences of
were evident as a function of modal total daily dose. adverse experiences (defined using COSTART body systems)
occurred in the digestive system, the nervous system, and the
Maximum total daily dose was defined as the body as a whole (Table 5).
highest dose ever prescribed for a patient, even if only for a
single day. The distribution of patients across maximum doses The adverse experiences that were reported
can be assumed to provide an indication of the upper limit of most frequently during the course of treatment with fluvox-
tolerance for different doses within a given population. Again, amine were nausea, somnolence, asthenia, headache, dry
the largest concentration of patients occurred in the low-maxi- mouth, and insomnia (Table 6). The only adverse experience
mum-dose range, indicating that over 60 % of the exposed with an incidence greater than 10% was nausea (15.7%). The
population reached a maximum of 100-150mg/day. As with serotonergic activity of fluvoxamine was apparent especially
modal daily dose, no pronounced demographie differences were with adverse gastrointestinal effects and to a lesser degree with
noted as a function of maximum daily dose. those effects associated with sleep disturbance, namely, som-
nolence and insomnia. Those results are consistent with the
Mean total daily dose, defined as the sum of well-known pharmacologic effects of SSRls.
each dose level a patient attained, multiplied by the number of
days the patient remained at that level, divided by the total Among fluvoxamine-treated patients, symp-
duration of treatment in days, was influenced not only by the toms associated with the digestive and nervous systems were
maximum dose level the patient achieved but also by the more likely to be mild or moderate than severe. A slightly
amount of time the patient was treated within a given dosage different pattern was observed for adverse effects occurring in
range. Thus, mean total daily dose was considered less reliable the body as a whole system: Those symptoms were more likely
than maximum total daily dose as an indicator of the balance to be moderate or severe than mild.
between tolerance and clinical benefit, since all studies but one
Safety Database on Fluvoxamine: Analysis and Report Pharmacopsychiat. 26 (1993) 15

Table 6 Overall incidenee of adverse experienees in the 24,624 Premature Discontinnation
patients treated with fluvoxamine.
Of 24,624 patients exposed to fluvoxamine,
Symptom (COSTART term) Ineidenee (%)
69.6 % completed the study as scheduled. In total, 15.1 % ofthe
Common events (> 10 % ineidenee) fluvoxamine-treated patients discontinued medication prema-
Nausea 15.7 turely because ofadverse experiences. Ofthose patients, 68.2 %
Frequent events (> 1-10 % ineidenee) dropped out within the first 2 weeks of exposure. The majority
Somnolenee 6.9 (72.4%) of the patients who terminated early because of ad-
Asthenia 6.2 verse experiences had received lower maximum doses « 100
Headaehe 4.7 mg/day). Although the fact that low doses eaused more toler-
Dry mouth 4.6 anee problems than higher doses may appear contrary to con-
Insomnia 4.5 ventional prineiples oftoxicology, it should be kept in mind that
Abdominal pain 4.0 in studies in which titration schedules were used, acute adverse
Dizziness 3.8
experienees usually occurred during the initial phase of rapidly
Nervousness 3.6
Tremor 3.3 changing fluvoxamine plasma concentrations, before steady-
Vomiting 3.2 state levels were attained.
Dyspepsia 3.2
Constipation 2.9 Additional causes of premature termination
Diarrhoea 2.2 among patients exposed to fluvoxamine were improvement

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Anorexia 2.1 (2.1 %), lack of effect (2.1 %), intercurrent illness (0.2 %), and
Vertigo 2.0 administrative reasons (11.0 %).
Sweating 1.7
Palpitation 1.7
Abnormal thinking 1.7 The demographie characteristics ofthe patients
Gastrointestinal disorder 1.4 did not in general appear to be related to the reasons for discon-
Agitation 1.4 tinuation; however, the proportion of females who discontinued
Anxiety 1.3 because of adverse experiences seemed to be slightly higher
Malaise 1.3 than that of males. The most frequent reasons for premature
Amnesia 1.1 diseontinuation due to adverse experienee were nausea, dizzi-
ness, vomiting, somnolence, abdominal pain, and headache.

Serions Adverse Events
Table 7 Serious adverse events in assoeiation with fluvoxamine
treatment. I. Overall ineidenee.
Serious adverse events were defined according
Event Ineidenee (%) to FDA criteria - namely, adverse events that are fatal, life-
threatening, or permanently disabling, that necessitate hospi-
Hospitalisation 2.0 talisation, or that can be classified as congenital anomaly,
Suicide attempt < 0.5 cancer, or overdose. That definition is an operational one based
Death 0.2 a on outeome rather than on severity. The overall incidence of any
Any other <0.08 serious adverse event in assoeiation with fluvoxamine treatment
was 2.5 %, compared with 3.0 % for active controls. The most
a Includes 18 suicides in studies of depression
frequent serious adverse event was hospitalisation, which oe-
curred in 496 patients (2.0 %), followed by suicide attempt
(101 patients; < 0.5 %), death (47 patients; 0.2 %), and any
Overall, the ineidence rates of adverse ex- others « 0.08 %) (Table 7). The 47 patients who died during or
periences increased with age, the highest rates being reported after the studies included 18 patients in depression trials who
for elderly patients (~65 years of age). Within a given age committed suicide. Many of the remaining 29 deaths occurred
stratum, incidence rates were higher for females than for males. in elderly patients with predisposing medical conditions. To
That finding was true for all COSTART body systems. Nausea, reiterate, no attempt was made to ascribe causality, and the most
the only common adverse experience, showed an age gradient conservative approach to interpretation was taken.
for both sexes and was more common in females than in males.
In the urogenital system, sexual dysfunetion was reported in- With respect to the 2.0 % of patients who were
frequently (denominator adjusted for sex) and was somewhat admitted to the hospital, 43.8 % were hospitalised because of
more common in males (impotence, abnormal ejaculation) than adverse experiences, most commonly exaeerbation of depres-
in females. sion or emergence of psychotie depression (Table 8). Another
19.0 % were hospitalised after the end of the study, usually for
Finally, it is noteworthy that the incidences of other medical reasons; 14.3 % were hospitalised because of in-
agitation, anxiety, and nervousness were reported to be very low effectiveness, and 10.3 % because of suicide attempt.
(1.4,1.3, and 3.6 %, respectively). Those findings are in marked
contrast with the adverse-experienee profiles of other SSRIs, The ineidence of overall suicidality, which in-
indicating that SSRIs differ greatly in their side effeets although c1udes suicidal ideation and tendencies, accidental overdose,
they exert comparable pharmacologic effeets on the serotoner- and intentional overdose in addition to attempted and
gic system. completed acts of suicide, was 0.8 % with fluvoxamine, 0.7%
with the active reference compounds, and 0 % with placebo.
16 Pharmacopsychiat. 26 (1993) W Wagner et al.

Table 8 Serious adverse events in association with fluvoxamine No cases of Zime1dine syndrome, bleeding syndrome, or Guil-
treatment. 11. Hospitalisation (overall incidence 2 %). lain-Barre syndrome were reported in any of the studies re-
Incidence (%) among
patients hospitalised
Reason for hospitalisation
Adverse experience 43.S Fluvoxamine was found to be generally safe
(most freQuently depression, psychotic and weil tolerated in 24,624 patients who were treated with the
depression. nausea. agitation, worsening of agent in worldwide marketing studies.
clinical state. vomiting, anxiety. malaise)
Ineffectiveness 14.3 In the adverse experience profile for fluvox-
Attempted suicide 10.3 amine, nausea was the only common symptom, the incidence
Other reasons 11.0 rate being 15.7%. Stimulating/activating effects of fluvox-
Unknown 1.6 amine were less prominent than sedating properties, with the
Hospitalisation after completion of study 19.0 incidences of nervousness, agitation, and anxiety being partic-
ularly small.

In the study population of predominantly
Table 9 serious adverse events in association with fluvoxamine treat- depressed patients, the incidence of overall suicidality, includ-

Downloaded by: University of Pennsylvania Libraries. Copyrighted material.
ment. 111. Suicidality. ing suicidal ideation, psychotic depression, and overdose, as
weil as attempted and completed acts of suicide, was remark-
Parameter Incidence (%) ably low in association with fluvoxamine treatment. The rare
Fluvoxamine Active control Placebo occurrence of convulsions confirmed the lack of proconvulsant
(n =24,624) (n = 723) (n =25) effects of the compound.
Overall suicidality O.S 0.7 none
Suicide attempt <0.5 a 0.6 none The conclusion from these findings is that,
Suicide O.OSb 0.3 none within the context of common knowledge about other psycho-
tropic agents used to treat depression and obsessive-compulsive
~ 98 patients with depression and 3 patients with chronic alcoholism disorder, fluvoxamine provides a very acceptable degree of
18 patients with depression
tolerance and safety.


However. the patient populations in the two latter groups were Wagner, W. B. Plekkenpol. T. E. Gray, H. Vlaskamp. H. Essers: Review
too small (723 and 25 patients, respectively) to permit direct offluvoxamine safety database. Drugs 43, suppt. 2 (1992) 48-54
comparison of incidences. Table 9 provides further detail on
suicidality in association with fluvoxamine treatment. Suicide
attempts were made by 101 «0.5 %) patients, including 98 Wolfgang Wagner, MD
patients with depression and 3 patients with chronic a1coholism. International Clinical Director
The incidence of completed suicide was 0.08 %, representing Solvay Pharmaceuticals, Inc.
18 patients being treated for depression. Thus, the incidence of Marietta, Georgia
suicidality with fluvoxamine was remarkably low and compares U.SA
very favorably with the incidences reported in the published
literature on other antidepressant compounds.

The incidence of any other serious adverse
event recorded in association with fluvoxamine treatment was
less than 0.08 %. The most c1inically significant among these
were carcinoma (19 patients), convulsion (n = 11), syncope (n =
10), myocardial infarction (n=9), coma (n=4), hepatitis (n=3),
cerebrovascular accident (n = 3), gastrointestinal haemorrhage
(n = 2), and alcoholic neuritis (n = 1). In most cases, preexisting
medical conditions were apparent, and in others there were
insufficient data to determine the patient's history. Notably, the
incidence of convulsions was extremely low, confirming that
fluvoxamine does not possess proconvulsant activity. One of
the 11 patients had a prior history of epilepsy, and in 4 patients
treatment with fluvoxamine was continued after a convulsion,
with no subsequent attacks.

Analysis ofIaboratory values for 1,630 patients
in 17 studies and of vital signs for 9,689 patients in 37 studies
did not reveal any consistent unidirectional effect of treatment.