Drugs 43 (Suppl, 2): 48-54. 19920012-6667/92/0200-0048/$3.50/0© Adis International Limited. All rights reserved.

DRSUP3404

Review of Fluvoxamine Safety Database

W. Wagner, I B. Plekkenpol, I T.E. Gray, I H. Vlaskamp2 and H. Essers­I Solvay Pharmaceuticals Inc., Marietta, Georgia, USA2 Solvay Duphar B.V., Weesp, The Netherlands

Summary A review of the safety and tolerability of fluvoxamine in worldwide marketing studies in-volving 24 624 patients, predominantly receiving fluvoxamine treatment in uncontrolled studiesin depression, has been conducted. There was a marked preponderance of female patients andpatients aged between 30 and 50 years. The majority of patients were treated for 6 weeks, withthe most frequent modal total daily dose being 100mg. The greatest proportion of adverse ex­periences occurring, by COSTART body system, affected the digestive system (24.1%), the nerv­ous system (23.7%), and the body as a whole (15.3%). The only adverse experience with anincidence greater than 10%was nausea (15.7%), with somnolence (6.9%) and asthenia (6.2%) asthe next most frequent experiences. Notably, the rates of agitation and anxiety were only 1.4 and1.3%, respectively. The incidences of adverse experiences increased with age, and were slightlyhigher in females than males. 15.1% of patients discontinued treatment prematurely as a resultof adverse experiences, principally nausea, dizziness, vomiting, somnolence, abdominal pain, andheadache. The overall incidence of serious adverse events associated with fluvoxamine treatmentwas 2.5%, and the incidence of overall suicidality, including suicidal ideation, overdose, andintentional overdose as well as attempted and completed acts of suicide, was remarkably low at0.8%.

We have conducted a review of the safety andtolerability of fluvoxamine in marketing studiesworldwide, the main results of which are here pre­sented publicly for the first time. The data assem­bled represent probably the largest aggregate of in­formation regarding safety ever amassed andpublished for any antidepressant drug.

1. Methods

The data were analysed by a multinational taskforce assisted by 6 contract research organisations,with the entire review and data management beingcompleted in 13 months. In total, 25372 originalcase record forms in 7 languages were collected and

subjected to a medical review, to provide the re­quisite degree of rigour and consistency in the eval­uation of the safety profile. Subsequently, 4069narrative patient summaries were written and laterstored on an optical laser disc imaging system; allsafety data were double entered into intermediatedatabases that reflected the layout ofthe study caserecord form, then transferred into a standard in­dividual study database format, and finally mergedinto one global safety database. The data manage­ment and the analysis were conducted and moni­tored according to Good Clinical Practice (GCP)guidelines, and employed the US Food and DrugAdministration (FDA) criteria for defining 'seri­ous' adverse events.

Fluvoxamine Safety Database

2. Overview ofStudies

49

Table III. Demographic characteristics of the 24624 patients

treated with fluvoxamine

other indications (table II). Dosages employedranged from 50 to 300mg per day, while the dur­ation ofthe studies varied between 4 and 52 weeks.

As table I indicates, the majority of studies,namely 43, were conducted in depression, with 10trials in a variety of other indications, such as painstates, anxiety disorders, alcoholism etc., and 1 trialin obsessive-compulsive disorder. In total, 54 stud­ies were analysed, with 53 originating in Europeand I in Pakistan.

3. Exposure to Fluvoxamine

The total cohort receiving fluvoxamine for whichdata have been reviewed and analysed is 24 624patients. By far the greatest number of patients, ap­proximately 23 500, received fluvoxamine in un­controlled studies in depression, with only a verysmall proportion of patients treated with fluvox­amine in controlled studies in depression and in

Gender

Male

Female

No data available

Age (years)

< 18

18·3031-5051-64

~ 65

No data available

% of patients

28.4

69.3

2.3

0.1

14.1

44.125.514.41.7

Table II. Exposure to f1uvoxamine by indication

Table I. Overview of 54 studies

Indication

Depression

Other indications

Pain

Anxiety

Emotional instability

Alcoholism

Bulimia

Cardiovascular disease

Premenstrual syndrome

Obsessive-compulsive disorder

Indication

Depression

Controlled studies

Uncontrolled studies

Other indications

Controlled studies

Uncontrolled studies

Obsessive-compulsive disorder

Controlled studies

Total

No. of studies

43

10

No. of patients

818

23395

181

190

40

24624

4. Patient Demographic Characteristics

There was a marked predominance of femalepatients, approximately 70%, in accordance withthe general epidemiological distribution of the dis­order, and the largest proportion of patients wereaged between 30 and 50 years (table III). The sexand age distribution of patients was similar acrossstudies.

5. Duration of Treatment

Table IV indicates that a considerable numberof patients - 11 428 - were treated for 6 weeks,almost all of these in uncontrolled studies indepression. This reflects the conventional design ofmarketing studies with antidepressants. The sex andage distribution of patients was similar across therespective duration intervals.

6. Dosage

For all dose parameters - the modal, maximum,and mean total daily doses - the distribution ofdosages was similar across studies, and the sex andage distribution of patients was not significantlydifferent across dose ranges.

50 Drugs 43 (Suppl. 2) /992

a 98% in uncontrolled studies in depression.

The modal total daily dose represents the mostcommon or frequent dose offluvoxamine that wasmaintained during the patient's participation in thestudy. It reflects the attainment of a balance be­tween clinical efficacy and the occurrence of un­desired secondary effects. The majority of patientsreceived a relatively low modal total daily dose of100mg (46%) or 150mg (16%).

The maximum total daily dose is defined as thehighest dose ever prescribed for a single patient forat least I day. The maximum total daily dose wassimilarly low in the majority of patients, at 100mg(45%), 150mg (18%), or 200mg (14%).

The mean total daily dose of fluvoxamine (thesum of each dose level attained by the patient,multiplied by the number of days at that level, di­vided by the total duration of treatment in days)ranged between 100 and 150mg in 48% of patientsexposed. In terms ofthis safety review, we considerthe mean total daily dose to be a less reliable para­meter, since in essentially all studies, an initial ti­tration phase was involved, which would tend tomove the mean dose downwards relative to themaintenance dose at which patients were stabilised- i.e. this parameter tends to underestimate the truemean dose of maintenance therapy.

In terms of the relationship between dose andduration of treatment, the maintenance modal daily

a Denominator adjusted for gender-specific symptoms.

7. Adverse Drug Experiences

24.123.715.33.52.72.1

1.71.6a

1.51.30.1

< 0.1

Incidence (Ofo)

Digestive

Nervous

Body as a whole

Cardiovascular

Skin

Special senses

Musculoskeletal

Urogenital

Metabolic/nutritional

Respiratory

Haematic/lymphatic

Endocrine

Body system

Table V. Adverse experiences in the 24624 patients treated

with fluvoxamine, by COSTART body system

Adverse experiences were analysed employingthe most conservative approach based on FDA reg­ulations, i.e. no causality judgements were madebut all recorded events were regarded as advers~experiences; where some uncertainty existed, the'worst case scenario' for the drug was applied.Table V enumerates adverse experiences by CO­START body system, and indicates that the great­est proportion of adverse experiences occurringaffected the digestive system (24.1%), the nervoussystem (23.7%), and the body as a whole (15.3%).

Table VI lists the overall incidence of adverseexperiences. The only symptom that may be de­scribed as 'common', i.e. it occurred with an in­cidence of greater than 10%, was nausea (15.7%).The incidence of all other adverse experiences wasless than 10%; of these, somnolence (6.9%) and as­thenia (6.2%) were the next most frequent symp-

dose for 8 weeks' treatment or more was 100 to150mg in 71%of patients, and it is noteworthy thatthis is a rather low dose range. Finally, the maxi­mum total daily dose increased with increasingduration of treatment, reflecting the design of moststudies, which included a titration phase; a similarpattern was observed for the mean total daily dose.

No. of patients

11561223846

80710521742

11 428a

22951580515

883

1889

Treatment duration (weeks)

< 1

1

2

34

5

67

8·1213-5152-103

'" 104No data available

Table IV. Duration of fluvoxamine treatment

Fluvoxamine Safety Database 51

Table VI. Overall incidence of adverse experiences in the 24624patients treated with fluvoxamine

toms. It is noteworthy that agitation and anxietyare represented at very low incidences of 1.4 and1.3%, respectively. This is in marked contrast tothe adverse experience profile of other serotoninreuptake inhibitors.

The overall incidence of adverse experienceswasobserved to increase with age, and the highest rateswere observed in patients aged 65 years or more.An overall sex gradient was apparent, so that aslightly higher incidence was found in females.Similarly, relatively more females discontinuedfluvoxamine treatment because of adverse experi­ences (see below). In addition, some specific se­verity gradients were identified, so that in thedigestive and nervous systems symptoms were mildor moderate rather than severe, whereas in the bodyas a whole symptoms were moderate or severerather than mild.

8. Premature Discontinuation ofTreatment

Table VII. Principal reasons for discontinuation in the 15.1 %

of patientswithdrawing from fluvoxamine treatment as a resultof adverse experiences

Patients discontinuingtreatment (%)

4.51.61.51.21.11.1

Serious adverse events were defined accordingto FDA criteria, namely adverse events that arefatal, life-threatening, permanently disabling, or that

Of the 24 624 patients receiving fluvoxamine,17 133 (69.9%) completed their study treatment, ascompared with 545 of 723 (75.4%) on active con­trol and 15 of 25 (60.0%)on placebo. The reasonsfor premature discontinuation of fluvoxaminetreatment included adverse experiences (15.1%),administrative reasons (11.0%), lack of efficacy(2.1%), clinical improvement (2.1%), and intercur­rent illness (0.2%). Demographic characteristics ofpatients were distributed similarly with regard toreasons for discontinuation, with the exception thata relatively higher proportion of female than malepatients withdrew from treatment prematurely asa result of adverse experiences (15.7% and 13.0%,respectively).

With respect to the 15.1% of patients discontin­uing prematurely as a result of adverse experi­ences, 68.2% (2531 of 3709) withdrew during thefirst 2 weeksof treatment, and 72.4%(2684 of 3709)withdrew on a low total maximum daily dose(lOOmg or less). This again reflects the design ofmost studies, which included an initial titrationphase. The most frequent reasons for prematurediscontinuation due to adverse experience werenausea, dizziness, vomiting, somnolence, abdom­inal pain, and headache (table VII).

9. Serious Adverse Events

NauseaDizzinessVomitingSomnolenceAbdominal painHeadache

Symptom (COSTART term)

6.96.24.74.64.54.03.83.63.33.23.22.92.22.12.01.71.71.71.41.4

1.31.31.1

15.7

Incidence (%)

Frequentevents (> 1-10%incidence)SomnolenceAstheniaHeadacheDry mouthInsomniaAbdominal painDizzinessNervousnessTremorVomitingDyspepsiaConstipationDiarrhoeaAnorexiaVertigoSweatingPalpitationAbnormal thinkingGastrointestinal disorderAgitationAnxietyMalaiseAmnesia

Common events (> 10% incidence)Nausea

Symptom(COSTARTterm)

52 Drugs 43 (Suppl. 2) 1992

a Includes 18 suicides in studies of depression.

Table VIII. Serious adverse events in association with fluvox­amine treatment. I. Overall incidence

necessitate hospitalisation, as well as congenitalanomaly, cancer, and overdose. Thus, this is anoperational definition, based on outcome ratherthan on severity. The overall incidence of any se­rious adverse event in association with fluvox­amine treatment was 2.5% as compared with 3.0%with active control. The most frequent serious ad­verse event was hospitalisation, occurring in 496patients (2.0%), followed by suicide attempt (101patients; < 0.5%), death (47 patients; 0.2%), andany others « 0.08%) [table VIII). The 47 patientswho died during or after the studies included 18patients in depression trials who committed sui­cide. Of the remaining 29 deaths, many occurredin elderly patients with predisposing medical con­ditions. To reiterate, no attempt was made to as­cribe causality, and the most conservative ap­proach to interpretation was taken.

With respect to the 2.0% of patients hospital­ised, 43.8% of these were hospitalised because ofadverse experiences, most commonly exacerbationof depression or emergence of psychotic depression(table IX). Another 19.0% were hospitalised afterthe end of the study, usually for other medical rea­sons; 14.3% were hospitalised because of ineffec­tiveness, and 10.3% because of suicide attempt.

The incidence of overall suicidality, which in­cludes suicidal ideation and tendencies, overdoseand intentional overdose as wen as attempted andcompleted acts of suicide, was 0.8% with fluvox­amine, 0.7% with the active reference compounds,and 0% with placebo. However, the patient popu­lations in the 2 latter groups were too small (723and 25 patients, respectively) to permit direct com­parison of incidences. Table X provides further de-

Event

Hospitalisation

Suicide attemptDeath

Any other

Incidence (%)

2.0< 0.5

0.28

< 0.08

tail regarding suicidality in association with flu­voxamine treatment. Suicide attempts were madeby 101 « 0.5%) patients, including 98 patients withdepression and 3 patients with chronic alcoholism.The incidence of completed suicide was 0.08%,representing 18 patients being treated for depres­sion. Thus, the incidence of suicidality with flu­voxamine was remarkably low, and compares veryfavourably with the published literature concern­ing other antidepressant compounds.

Other serious adverse events recorded in asso­ciation with fluvoxamine treatment occurred withan incidence of less than 0.08%. The most clinic­any significant among these were carcinoma (19patients), 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 alcoholicneuritis (n = 1). In most cases, pre-existing medicalconditions were apparent, and in others there wasinsufficient data to determine the patient's history.Notably, the incidence of convulsions was ex­tremely low, confirming that fluvoxamine does notpossess proconvulsant activity. One of the IIpatients had a prior history of epilepsy, and in 4patients therapy with fluvoxamine was continuedafter a convulsion with no subsequent attacks.

Analysis of laboratory values from 17 studies in1630 patients, and of vital signs in 37 studies in

Table IX. Serious adverse events in association with fluvox­amine treatment. II. Hospitalisation(overall incidence 2%)

Incidence (%j

among patients

hospitalised

Reason for hospitalisationAdverse experience 43.8

(most frequently depression.psychotic depression, nausea.agitation, worsening of clinical state,

vomiting, anxiety, malaise)

Ineffectiveness 14.3Attempted suicide 10.3

Other reasons 11.0Unknown 1.6

Hospitalisation after completion of stUdy 19.0

Fluvoxamine Safety Database

Table X. Serious adverse events'In association with fluvoxamine treatment. III. Suicidality

53

Parameter

Overall suicidality

Suicide attempt

Suicide

Incidence (%)

fluvoxamine active control placebo

(n = 24624) (n = 723) (n = 2S)

0.8 0.7 None

< O.Sa 0.6 None

0.08b 0.3 None

a 98 patients with depression and 3 patients with chronic alcoholism.

b 18 patients with depression.

9689 patients, did not detect any consistent uni­directional effect of treatment. No cases of Zirnel­dine syndrome, bleeding syndrome or Guillain­Barre syndrome were identified in any of the stud­ies reviewed.

10. Conclusion

Fluvoxamine was safe and well tolerated in themajority of the 24 624 patients in worldwide mar­keting studies analysed in this review. No unex­pected serious adverse events were identified.Within the adverse experience profile, nausea wasthe only commonly occurring symptom, whilestimulating or activating symptoms were lessprominent than sedating symptoms, Finally, theincidence of suicidal ideation and of attempted orcompleted suicide in association with fluvoxaminetreatment appeared to be particularly low.

Correspondence and reprints: Dr med. W. Wagner, Solvay Pharomaceuticals Inc., 901 Sawyer Road, Marietta,GA 30062, USA.

Discussion

DrC.V. De Blecourt: I am aware of reports thatconcomitant treatment with fluvoxamine maydouble or even triple plasma concentrations ofclomipramine, and similarly theophylline. Do youhave any systematic data regarding such interac­tions?

Dr W. Wagner: Fluvoxamine undergoes exten­sive hepatic metabolism and therefore an interac-

tion with other extensively metabolised com­pounds is possible. We did not identify druginteractions in this database of marketing studies,but it must be acknowledged that the designof thesestudies in most cases limited or excluded concom­itant medications other than benzodiazepinesandexcluded patients with certain concurrent diseases.In the worldwide spontaneous reporting systemthere are a number of reports of interactions withpropranolol, theophylline, and also tricyclic anti­depressant drugs.

Dr Y. Lecrubier: What is meant by 'administra­tive reasons' for withdrawal from study?

Dr Wagner: This mainly refers to patients lostto follow-up for reasons unrelated to the studymedication,such as moving to another area. Whereany suspicionexisted that the drug could have beenimplicated, the 'worst case scenario' was appliedand the patient was recorded as a withdrawal dueto adverse experiences caused by the study drugs,

DrLecrubier: You mentioned that the incidenceof side effectswas higher in females than in males.Were there side effects specific to female patients?

Dr Wagner: No, the occurrence of particularsideeffects was in general distributed similarly acrossmale and female patients. We cannot account forthe higher overall incidenceamong female patients,but in my view it is likely that sex differences inbodily perception are involved.

DrLecrubier: Did you establish any relationshipbetween the incidence of side effects and efficacy?

Dr Wagner: We did not attempt to appraise ef­ficacy since most of these studies, being Phase IV

54

trials, were not conducted subject to the guidelines

for Good Clinical Practice (GCP), and could nothave been considered to provide reliable data re­garding efficacy. However, the fact that the major­ity of patients received a mean maintenance doseof 100mg appears to reflect simply the efficacy ofthis dose; although the titration schedule in earlymarketing studies provided for doses up to 300mg,in practice physicians seldom titrated the dose be­yond 150mg, and patients withdrawing from treat­ment mostly did so on the lower doses.

Drugs 43 (Suppl. 2) 1992

Dr G. Beaumont: Clinically significant sexualside effects such as delayed ejaculation andfemale anorgasmia have been described with someof the serotonin reuptake inhibitors, for instancefluoxetine. What is the incidence of sexual side ef­fects with fluvoxamine?

Dr Wagner: Less than 0.1% in this database.Moreover, there were no consistent unidirectionaleffects in these rare cases, e.g. some patients re­ported increased, others decreased, libido, so thatit is difficult to attempt any rigorous conclusion.