adverse reactions of selective ., serotonin reuptake...

Drug Sofei 1999 Me 20(3) 277middot 2b7ORIGINAL RESEARCH ARTICLE QJlol-5QI6990C1J3-0277S05 ~O -

Adverse Reactions of Selective

Serotonin Reuptake Inhibitors

Reports from a Spontaneous Reporting System -

Olav Spigset

Adverse Drug Reactions Monitoring Center Division of Clinical Pharmacology Norrland University Hospital Umea Sweden and Department of Clinical Pharmacology Regional and University Hospital Trondheim Norway -

i

Abstract Objective The selective serotonin (5-hydroxytryptamine 5-HT) reuptake inshy

hibitors (SSRls) are extensively used in the treatment of depression panic disorshyder and obsess ive-compulsive disorder and are now being evaluated in the treatment of a number of other psychiatric disorders The aim of this study was to investigate the pattern of adverse reactions reported on SSRIs in Sweden and assess possible risk factors associated with the occurrence of adverse reactions to these agents

Methods A survey was made of 1202 reports describing 1861 adverse reacshy tions to SSRIs submitted to the Swedish Adverse Drug Reactions Advisory Comshy

miltee Results The most often reported adverse reactions were neurological sympshy

toms (2249d psychiatric symptoms (J 9Sk) and gastrointestinal symptoms (180) however dermatological symptoms (114) and general symptoms (98) were also frequent Compared with other drugs gastrointestinal sympshy toms were more often reported for fluvoxamine psychiatric symptoms were more

(

often reponed for sertraline and dermatological symptoms were more often reshy ~ (ported for f1uoxetine In total the diagnoses most frequently reported were nausea

(n = 139) rash (n =90) anxiety (n =84) paraesthesias (n =69) headache (n = 63) and diarrhoea (n = 63)

Parkinsonism confusion hallucinations euphoria hyponatraemia bradycarshydia and hypotension were more often reponed in the elderly whereas urticaria akathisia and haematological endocrinological sexual and some visual reacshy tions were more often reponed in individuals who were younger than average -

Dermatological reactions fatigue hyponatraemia and cough were more common in women hereas dyskinesiasakathisia and aggression more often were seen in men

(

The median SSRI dosages were above average in patients experiencing seizures Jhypomaniamania personality changes malaise bodyweight gain gynaecomastia

and hyperprolactinaemiaigalactorrhoea Severe symptoms such as seizures ~

hyponatraemia and the serotonin syndrome were rarely reported Conclusion Although the design of the study makes it difficult to draw conshy

clusions about causality a variety of adverse reactions were reported Therefore

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the aareness that a particular symptom in a patient treated with an SSRI might be an adverse reaction should he high

The selective serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitors (SSRIs) are extensively used in the treatment of depression panic disorder and obsessive-compulsive disorder and are now being evaluated in the treatment of a number of other psychiatric disorders Aderse reactions asshysociated with the SSRIs are less prominent than and qualitatively different from those assoc iated with the tricycl ic antidepressantsllc l Nevertheshyless adverse reactions of SSRI s cover a broad specshytrum ranging from mild gastrointestinal symptoms to severe although rare events such as seizures IJI hypollatraemiaI~1 and the serotonin syndromeIgt1 In view of the increasing lise of these drugs the pattern of adverse reactions reported on SSRls in Sweden is presented and pos~ible risk factors idenshytified in this study

Materials and Methods

Since 1965 Sweden has had a system for sponshytaneous reporting of adcrse drug reactions to the Swedish Adverse Drug Rcactions Advisory Com-

Table I WHO criteria for causality assessment

mittee Since 1975 the reporting of serious or fatal reactions and new reactions has been compUlsory or the SSRls available in Sweden fluvoxamine was approved in June 1990 paroxetine in June 1991 citalopram in October 1992 sertraline in January 1995 and tluoxetine in September 1995

All reports received up to December 3 I 1997 were re viewed but only reactions that were classishyfied as having a possible probablelikely or certain causal relationship with the drug according to the WHO criteria (table I) and that were reported 3 times or more were included in lhis suney Moreshyover reports concerning overdoses and pharmacoshykinetic interactions which did not cause any adshyverse reactions were excluded

The classification of the reports was made by the monitoring centre staff From each report the following information was obtained bull age and gender of (he patient bull name and dosage of the suspected as well as

other drug or drugs bull outcome of dechallengerechallenge

Certain A clinical event including laboratory test abnormality occurring in a plausible time relationship to drug administration and which cannot be expfained by concurrent disease or other drugs or chemicals The response to withdrawal of the drug (dechallenge) should be clinically plausible The evenl must be definitive pharmacologically or phenomenofogically using a satisfactory rechallenge procedure il necessary

Probablellikely A clinical event incfuding laboratory test abnormality with reasonabfe lime sequence 10 administration 01 the drug unlikely to be aHributed to concurrent disease or other drugs or Chemicals and which follows a clinically reasonabfe response on withdrawal (dechallengel Rechallenge information is not required 10 fulfif Ihis definition

Possible

A Clinical event including laboratory tesl abnormality with a reasonable tesl sequence to adminislration of the drug bul which could also be explained by concurrent disease or other drugs or chemicals Information on drug withdrawal may be lacking or unclear

Unlikely

A clinical event including laboratory test abnormality with a temporal relationship 10 drug administration which makes a causal relationship improbable and in which other drugs chemicafs or underlying disease provide plausible expfanations

Conditionalunclassified A clinical event including laboratory test abnormality reported as an adverse reaction about which more data are essentiat for a proper assessment or the additional data are under examination

Unassessibfelunclassifiable

A report suggesting an adverse drug reaction which cannot be judged because information is insuHicient or contradictory and which cannot be supplemented or verified

Aderse r~actinl

20 eFluvox - ParoX u ro

OCitatOi iii DSertra 0- 15 6fluoxe ~ c ~ 0 ro L= 10 0 0 0

0 0

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Fig 1 Sales of selt reuptake inhibftors daily doses (000) 04 in 1991 15n 273 in 1996 anc citalopram fiuoxe 150mg tor liuvoxa

bull other potent bull time interv3

appearance Only repan

unkllown dech Ilot stopped 1

negative decha Total drug s

computerised s total amount 0

illacy and can terillS or in tt (ODDs) The 1 dose of a drug I adults for SSf ately severe d( sold per 1000 i although gross drug in the pOI are 20mg for ( tine 50mg for amineJ71

Results

Sales statist figure I The te

~ Adis Internolionalli I Adis InternOhOflol limiled All nghts reserveC Drug SOfely 1999 Mor 20 (3)

Ited with an SSRI mighl

~ pOrling of serious or ratal

Ins has been compulsory

in Sweden nuvoxalllilll

990 paroxctine in Junt

tober 1992 serlralinc ill

tille in September 1995

Ip to December I 1997

eactions that were classishy

probableI ikely or certain

the drug according to the

middotlIld that were reported

Ided in this survey Moreshy

lVerdoses and pharmacoshy

h did not causc any dshy

uded

he reports was made by ff From each report the

IS obtained

oatient

he suspected as well as

erechallcnge

inislralion and which cannol lechallenge) should be tory rechalenge procedure il

te drug unlikely to be onse on withdrawal

he drug but which could also king or unclear

ich makes a causal nations

ta are essential for a proper

conlradictory and which

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279 Adverse Reactions of SSRIs

20 bull Fluvoxamine bull Paroxetine

0 OCrtalopram o Serlraline a 15 6 Fluoxetine C ltfl

0 r 10 0 0 0

0 0

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O~~~~~~==~~~~--- 1990 1991 1992 1993 1994 1995 1996 1997

Year

Fig 1 Sales 01 selective serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitors (SSRls) in Sweden Total sales [in delined daily doses (000)1 000 inhabitants per day] for the SSRls were 04 in 199115 in 199243 in 199398 in 1994206 in 1995 273 in 1996 and 237 in 1997 The OOOs were 20mg for citalopram lIuoxetine and paroxetine 50mg for sertraline and 150mg for lIuvoxamine

bull other potential risk factors bull time interval between start of the trea tment and

appearance of the reaction Only reports with positive dechallenge with

unknown dechallenge or where drug therapy was not stopped were included whereas reports with

negative dechallenge were excluded Total drug sales statistics in Sweden have been

computerised since 1972 These statistics show the total amount of every drug sol d from each pharshymacy and can be expressed in volume monetary term s or in the number of defined daily doses (DDDs) The DDD is the assumed average daily dose of a drug prescribed for its main indication in adults for SSRIs that is the treatment of modershy

ately severe depression 16) The number of DDDs sold per 1000 inhabitants per day is thus a useful although gross measure of the consumption of a drug in the population The DDDs for the SSRls are 20mg for citalopram fluoxetine and paroxeshytine 50mg for sertraline and 150mg for fluvoxshyaminePI

Results

Sales statistics for the SSRls are presented in figure I The total sales from the time of introducshy

laquo Adls Inte rnational Limited All rights reserved

lion of the agent in question until the end of Deshycember 1997 in million DDDs was 1838 for citalopram 591 Cor paroxetine 223101 scrtraline

16 9 for tluoxetinc and 143 for flulOxamine A total of 1202 reports describing 1861 adverse

reactions re lated to SSRltreatmcnt were reviewed There wcre no ratal adcrse reaction The number of reports per ycar is illustrated in figure 2 In towl 67Yk of the reports concerncd women and 32 7~~ concerned men The median age or the patients as

49 yea rs For comparison 66CJr or thc DDDs sold during the years 1994 to 1997 were prescribed to women and 4cr to men and the median age of

these patients was 53 years The distribution of reports by organ system is

presented in table [I Compared with other SSR]s fluvoxamine was morc frequently repo rted to cause gastrointestinal adverse reactions (265 ~t- IS

a mean of 18 lt7c ) sCrlralinc was morc frequently reported to cause psychiatric symptoms (255 J IS a mean or 195lk) and Iluoxetinc was more often reported to cause dermatological symptoms

(17 A9c FS a mean of I 149C )

Neurologicol Reoctions

Neurological adverse reactions reported are presented in table Ill The predominating diagnoshy

200 bull Fluvoxamine bull Paroxetine o Cilalopram o Serlraline

150 6 Fluoxetine

~

a 100 a ci z

50

O~~~-amp--~--~~~~=-~ 1990 1991 1992 1993 1994 1995 1996 1997

Year

Fi9 2 Annual numbers of adverse reaction reports for selective serolonin (5-hydroxytryptamine 5-HT) reuptake inhibitors in Sweden In general reporting is specifically encouraged in the year of approval and lhe following 2 years

Drug Sorelv I Q9Q MOl 20 (3)

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280 Spigset

Table II Organ groups implicaled in 1861 adverse reactions reported in patients receiving seleclive serotonin (S-hydroxytryptamine 5-HT) reuptake inhibitors For specilic diagnoses within each group see tables III-VIII

Reaction No 01 reports ()a

Citalopram Fluoxetine Fluvoxamine Paroxetine Sertraline Total no of reports ()

Neurological 132 (206) 22 (239) 71 (207) 161 (260) 30 (182) 416 (224)

Mental 121 (189) 19 (207) 67 (196) 113(182) 42 (255) 362 (195)

Gastrointestinal 104 (162) 12 (130) 91 (265) 105 (169) 23 (139) 336 (180)

Dermatological 83 (129) 16 (174) 32 (93) 56 (90) 26 (158) 213 (114)

General 67 (105) 9 (98) 34 (99) 62 (100) 11 (67) 183 (98)

Other 134 (209) 14 (152) 48 (140) 123 (198) 33 (200) 352 (189)

Total 641 (100) 92 (100) 343 (100) 620 (99_9) 165 (1001) 1861 (100)

a The percentage value indicates the percentage of the total number of reactions reported lor that individual drug

b The percentage value indicates the percentage of the total number of reactions reported for all drugs

ses were paraesthesias (n = 69) headache (n = 63)

dizziness (n = 60) Jnd tremor (n = 50) Headache

was the most typical initial reaction Other adverse

reaclions wjth an early onset were dizziness musshy

cle weakness muscle stiffness increased muscle

tone tremor and paraesthesias For the exshy

trapyramidal symptoms akathisia and dyskinesias

more than half of the reports concerned men Pashy

tients who developed parkinsonism were olda

than average whereas patients with dyskinesias

were generally young Patients experiencing seishy

zures were taking a median daily dose of 133

ODDs whereas patients experiencing other neuroshy

logical adverse reactions were taking a median daily dose of I DOD or less

Psychiatric Reactions

Psychiatric adverse reactions reported are preshysented in table I V The predominating diagnoses

were anxiety (n =84) confusion (n =32) hallucinations (0 = 30) and sleep disturbances (n = 23) Aggression was predominantly reported in men Patients who developed hypomaniamania had most often been treated with an SSRI for a long period of time Confusion typically occurred in patients of advanced age Patients experiencing

Table III Neurological adverse reactions reported in patienls receiving selective serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitors

Reaction No of reports Percentage of reports Median age in years Median time inteNala (range) involving women (range)

Paraesthesias 69 78 60 (23middot81) 6 days (O daysmiddot2y)

Headache 63 77 48 (25-88) 2 days (0 days-4wk)

Dizziness 60 77 48 (21middot88) 4 days (0 daysmiddot3mo)

Tremor 50 77 63 (23-88) 6 days (0 days-3mo)

Seizures 27 71 57 (18middot92) 2wk (1 day-2y)

Acute dystonia 14 67 42 (23-80) 6 days (2 days-9mo)

Dyskinesia 14 33 55 (44middot84) 2mo (1 day-6mo)

Muscle cramps 12 91 46 (23-77) 13 days (2 daysmiddot5mo)

Muscle weakness 10 80 42 (22middot74) 1 day (1 daymiddot3mo) Parkinsonism 8 57 74 (47middot87) 2wk (1 day-l mol

Muscle stiffness 8 50 54 (19-60) 6 days (1 day-2wk)

Akathisia 7 43 36 (26-57) 4wk (2wkmiddot4mo) Myoclonus 6 50 50 (24middot74) 4wk (1 day-6mo) Extrapyramidal symptoms 5 80 63 (38-87) 3wk (0 days-6wk) Increased muscle tone 4 25 51 (31-76) 5 days (3 days-7 days)

Migraine 4 100 51 (25middot62) 6wk (1 daymiddot2y)

Adverse Reactions of ~

Table IV Mental adverse

Reaction

Anxiety

Confusion

Hallucinations

Sleep disturbances

Hypomaniamania

Depersonalisation

Amnesia

Nightmares

Aggression

Insomnia

Psychosis

Concentration impaired

Agilation

Personality change

Euphoria

Pathological inebriation

a InteNal between the sla

hypomaniamania we

of 175 ODDs while t

were taking a median

tients experiencing ot

tions were taking a Ill

less

Gostrointestinof RE

Gastrointestinal ad

presented in table V T were nallsea (n = 139)

tients with constipati(

however no slich age

with dry mouth Nause

und dyspepsia mainly

of the treatment On glossitis parotitis and

were adverse reaclion~

reactions were mostly

elevated serum levels

increased levels ofy-gl

phosphatase and bilin

ported Patients expeJi

adverse reaction were a InteNaJ between the start of the treatment and the appearance of the adverse reaction of 1 DOD or less

1( Adis JnlernOfionoJ Limited lU fights reserved

Owner
Highlight

--

nin (5-hydroxytryptamine 5-HT)

line Total no of reports ()b

82) 416 (224) ~5 5) 362 (195) - 39) 336 (180) 58) 213 (114)

7) 183 (98) 00) 352 (189) 100_1) 1861 (100) ual drug

- were taking a median ~ss _

actions reported are pnshy)redominating diagnoses nfusion (n == 32) hallucishyp disturbances (n == 2J)

inantly reported in men hypomaniamania haJ

with an SSRI for a long JI1 typically occurred in Patients experiencing

mine 5-HT) reuptake inhibitors Median time inteNala (range)

6 days (0 days-2y) 2 days (0 days-4wk) 4 days (0 days-3mo) 6days (0 days-3mo) 2wk (1 day-2y) 3 days (2 days-9mo) ~mo (1 day-6mo) 13 days (2 days-5mo) I day (1 day-3mo) wk (1 day-l mol days (1 day-2wk) wk (2wk-4mo) wk (1 day-6mo) wk (0 days-6wk) days (3 days-7 days) Nk (1 day-2y)

Drug Sofely t999Mor 20 (3

-281Adverse Reactions If SSRls

Table IV_ Mental adverse reactions reported in patients receiving selective serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitors Reaction No of reports Percentage of reports

involving women Anxiety 84 61 Confusion 32 50 Hallucinations 30 76 Steep disturbances 23 64 Hypomaniamania 21 58 Depersonalisation 15 6-4

Amnesia 15 54 Nightmares 14 86 Aggression 13 38 Insomnia 10 63 Psychosis 10 78 Concentration impaired 9 50 Agitation 7 57 Personality change 6 75 Euphoria 5 60 Pathological inebrialion 3 67

Median age in years Median time inteNala (range) (range) 47 (22-84) 4 days (0 days-6mo) 74 (26-90) 3wk (0 days-ll mol 68 (19-96) 3wk (1 day-llmo) 42 (22-78) 3 days (0 days-4mo) 47 (21-85) 2mo (7 days-7mo) 42 (20-74) 8 days (0 days-9mo) 47 (23-88) 2mo (6wk-3y) 44 (23-83) 2wk (1 day-8mo) 46 (26-75) 2wk (2 days-4mo) 55 (29-76) 4 days (0 days-2wk) 48 (41-85) 2wk (1 day-3mo) 46 (13-58) 2wk (0 days-8mo) 63 (24 -86) 3wk (2 days -9mo) 53 (38-63) 2wk (6 days-9mo) 85 (36-96) 3 days (1 day-7mo) 36 (32-50) 8mo (7wk-8mo)

a InteNal between the start of the treatment and the appearance 01 the adverse drug reaction

hypomaniamania were taking a median daily dose of 175 DDDs while those with personality change were taking a median daily dose of 15 DDDs Pashytients experiencing other psychiatric adverse reacshytions were taking a median daily dose of I DDD or less

Gastrointestinal Reactions

Gastrointestinal adverse reactions reported are presented in table Y The predominating diagnoses were nausea (n == 139) and diarrhoea (n == 63) Pashytients with constipation were older than average however no such age effect was seen in patients with dry mouth Nausea vomiting abdominal pain and dyspepsia mainly occurred early in the course of the treatment On the other hand stomatitis glossitis parotitis and elevated liver enzyme levels were adverse reactions with a late onset The liver reactions were mostly of hepatocellular type with elevated serum levels of ALT and AST but also increased levels ofy-glutamyl transferase alkaline phosphatase and bilirubin were occasionally reshyported Patients experiencing any gastrointestinal adverse reaction were taking a median daily dose of I DDD or less

e Adls Intemo lionoJ limited All ighfs reserved

Dermatological Reactions

Dermatological adverse reactions reported are presented in table VI The predominating diagnoshyses were rash (n == 90) urticaria (n == 42) and prushyritus (n == 40) Of the rashes IS9c were characshyterised as maculopapular 70 as vesicobullous and 5k as erythematous whereas the nature of the reshylnainder of the rashes was not specified The proshyportion of women experiencing all dermatological reactions but particularly angioedema and photoshysensitivity was higher than expected The median time from the stan of treatment until appearance of the reaction was somewhat shorter for rash (5 days) than for urticariaangioedema (approximately 2 weeks) Patients experiencing any dermatological 3dverse reaction were taking a median daily dose of I DDD or less

General Reactions

General adverse reactions reported are preshysented in tahle VII The predominating diagnoses were f3tigue (n = 42) hyperhidrosis (n == 37) and oedema (n == 33) Also bodyweight gain was reshyported in several patients Patients with bodyshyweight gain were somewhat younger than average and they had been treated with an SSRI for a long

Drug Solety 1999 Mar 20 (3)

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3 a c (C c ~ pound c o ~ 2 co E (]) c t- shy

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Owner
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282 Spigscl

Table V Gastrointestinal adverse drug reactions reported in patients receiving selective serotonin (5-hydroxytryptamine 5-HT) reuptake ~ inhibitorsrshyC1l

Reaction No 01 reports Percentage of reports Median age in years Median time intervala 3 OJ involving women (range)

~ Nausea 139 69 ~ Diarrhoea 63 69 o gt Vomiting 31 72 5 Hepatic enzymes levels increased 25 580 0 Mouth dryness OJ to Abdominal pain

C1l

Dyspepsia OJ Ugt Constipalion 18 Stomalitisglossitis-0

Parotitis~gt

14 64

14 75

11 40

8 63

7 71

4 50

49 (19-86)

49 (24-87)

54 (28-84)

48(17-90)

53 (30-78)

47 (28-74)

61 (30-75)

63 (55-88)

55 (46-81)

78 (75-84)

a Ishy a Interval between the start 0 the treatment and the appearance 01 the adverse drug reaction

(range)

5 days (0 daysmiddot9mo)

10 days (0 days-6mo)

5 days (0 days-4wk)

4wk (3 days-9mo)

7 days (1 day-5mo)

2 days (1 day-6 days)

4 days (1 day-1mo)

7 days (2 days-1mo)


12 days (8 days-2wk)

3 5 C1l o Q period of time Patienr ltxperiencing bodyweight CD poundl gain were taking a median daily dose of 2 ODDs o gt Those with mahfise ere taking a median daily o- dose of 13 ODDs whertas patients experiencing r i C1l other general adverse rtactions ere taking a meshyz ~ dian daily dose of I DOD or less omiddot gt ~ shy Other Reactionscr 03 -lt Adverse reactions il1olving other organ sysshyS s tems are presented in table VII I Haematological en a reactions (haematoma ~pistaxis and thromhocytoshyomiddot smiddot penial as well as cough and hyperprolactinaemia etgt CY were reported almost eclusitly in women-lt CiJ Among the cardiovascular reactions palpitations 5

and tachycardia were the predominating diagnoses a o in younger individuals middothereas hradycardia and OJ

~ hypotension most orten ere re[Jortctl in older inshyOJ dividuals Hyperprolactinaemia galactorrhoea and OJ 0

menstrual disorders werlt nactions of a late onset 3 ru lt that mainly occurred in -nung intlimiddotiduals Cough r 0 J

and haematological disorders also had a late onset In women with galactorrhoea the highest serum prolactin le el measured was 43 IlgL although many patienls had prolaclin levels within the norshymal range Hyponatraemia and the syndrome of inshyappropriate antidiuretic secretion urinary retenshytion and urinary incontinence were more common in women of advanced age Patients with increasetl serum creatinine levels were al so elderly and they had all complicating di seases such as diabetes melshylitlls congestive heart failure or impaired renal function Patients experiencing gynaecomastia were taking a median daily dose of two ODDs and those experiencing hyperprolactinaemial galactorrhoea were taking a median daily dose of 125 ODDs whereas the median daily dose was I ODDs or lower for patients experiencing the other diagnoses

Withdrawal symptoms were more often reshyported in women in young individuals and in Ihose trealed with an SSRI for a long period of lime

Table VI Dermatological advers eactions reported in patients receiving selective serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitO~ii

Reaction No 01 reports Percentage 01 reports Median age in years Median time interval ii gt r Rash 90

Urticaria 42

Pruritus 40

Angioedema 10

Photosensitivity 5

lt

involving women (range) (range)

73 52 (18-88) 5 days (1 day-3y)

74 38 (14-77) 2wk (2 days-5mo)

76 49 (27-83) 3wk (1 day-15mo)

90 37 (24-77) 13 days (1 day-2mo)

80 44 (27-52) 2mo (3 days-2y) a Interval between the start 01 the treatment and the appearance of the adverse drug reaction

~ Adis ntefnotionol limrled AU rig - middote servec

dvers Reactions ()f SSRI

However there was no being taken in patients symptoms were above sy mptoms most often (62 CIc ) paraesthesias (4

toms such as anxiety an eral the symptoms star treatment had been stor I to 2 weeks

Three patients deve drome The drug combir serotonin syndrome ir fluoxetine clomipramin ine and mian se rin aI

J11ianserin All 3 patient~ ithin a few days after I stopped The correspond tile 3 patients were (i)

reflexia and agitation ( md hyper-retlexia and myoclonus

Discussion

Spontaneous reportir tions represents an impl infrequent reactions Homiddot Ihe trlle incidence calli method since the even ported For example in

Table VII General adverse react

Reaction

Fatigue

Hyperhidrosis

Oedema

BOdyweight gainb

Syncope

Pain

Fever

Malaise

Faintness

Somnolence

Anorexia

Chills a Interval between the start of It

b Two reports of bOdyweight gai

3

283 Sligsrl

nin (5-hydroxytryptamine 5-HT) reuptake

ge in years Median time interval shy(range)

5 days (0 days-9mo) shy


5 days (0 days-4wk)

4wk (3 days-9mo)

7 days (1 day-5mo)


4 days (1 day- lmo)

7 days (2 days-lmo)

13 days (7 daYS-3mo)


disorders also had a late onse actorrhoea the highest serum

Isured was 43 I1gL although Ifolactin levels within the Ilorshyraemia and the syndrome or illshyretic secretion urinary relcllshyHltinence were more comillon cd age Patients with increltJscu

els were also elderly and they diseases such as diabetes llIeI shyart failure or impaired rClla

experiencing gynaecomltlstia an daily dose of two ODDs ncing hyperprolactinaemia aking a median daily dose of the median daily dose WltJS I

Hients experiencing the other

gttoms were more often reshyoung individuals and in those

[ for a long period of time

ytryplamine 5middotHT) reuptake inhib~ors

Median time interval (range)

5 days (1 daymiddot3y)

2wk (2 days-5mo)

3wk (1 day-15mo)

13 days (1 day-2mo)

2mo (3 days-2y)

Drug Solely 1 Q99 Mor 70 (3)

Adver~e Reactions of SSRls

However there was no indication that the dosages being taken in patients experiencing withdrawal symptoms werc above average The withdrawal symptoms most oftcn reported were dizziness (62) paraesthesias (410() and psychiatric sympshyIOms such as anxiety and agitation (31 or) In gcnshyeral the symptoms started 0 to I days after SSRI treatment had been slOpped and had a duration of I to 2 weeks

Three patients developed the serotonin synshydrome The drug combinations associated with the serotonin syndrome ill each patient were (i)

tluoxetine clomipramine and lithium Oi) sertralshyine and mianserin and (iii) citalopram and mianserin All 3 patients recovered spontaneously within a few days after the drug therapy had been stopped The corresponding symptoms reported in the 3 patients were (i) confu sion tremor hypershyretlexia and agitation (ii) conrusion diaphoresis and hyper-refexia and (iii) confusion fever and myoclonus

Discussion

SpontaneoLis reponing of adverse drug reacshytions represents an important means of detecting infrequent reactions However information ahout the true incidence cannot be obtained by this method since the events are always under-reshyported For example in epidemiological studies

only I to 5ck of mild and 10 to 800k of serious

adverse drug reactions have becn founu to he re- j

ported I~lt)1 Moreover even though correcteu for (

sales figures spontaneous reponing cannot bc l

used to incstigate whether differenccs in the oc- ~ currence of specific adverse rcactillns exist be- L

(

Iween drug because the extent of under-reporting 0 E

Inost pn1bahly varies hctween drugs The fre- -c

qucncy or reports may be influenced by factors ~

(l

such as puh lic knowledge of the uses and adverse 2t

effects of a dru g physicians allention to specific ~ prohlenb and the year of introuuctionl lOl E

As illustrated in figurc 2l11ost adverse reactions ~ c

for each S5 R I were reported during the first I years a c

following approval of the drug A high initia~ rc- middotc

porting rate is a well known phenomenon which at ~ least in pan is 1 result of the national recommen- 0 dations for ach middoterse urug reaction reponing Due to ~

these factors and hecause none of the diagnoses 3 were reported exclusi vely for I drug the SSRIs ro

c hlVe bee n studied cxclusively as a group whcn the 0

~ specific diagnoses have been considered z

The ob ~ el middot ational character of studies using ~ data from spontaneous reporting systems makes it 0 difficlIll to draA conclusions abollt cau sality ai- sectnthough it scems reasonahle that the prohahility of

o a connection increases A ith an increasing number 0 Q)

of report s Therefore diagnoses reported less than s I times wcre excluded from the present s urvey On g

0 Q)

6 a o

Reaction No 01 reports Percentage 01 reports Median age in years involving women (range)

Fatigue 42 76 48 (23middot89)

Hyperhidrosis 37 67 54 (23middot88)

Oedema 33 72 48 (29-82)

80dyweight gainb 12 73 39 (21middot60)

Syncope 10 67 38 (25middot71 )

Pain 8 57 48 (33middot63)

Fever 7 100 42 (34-48)

Malaise 5 40 49 (41 -43)

Faintness 4 75 66 (50middot79)

Somnolence 4 100 64 (50-81)

Anorexia 3 67 44 (28-75)

Chills 3 67 53 (43-65)

a Interval between the start 01 the trealment and the appearance of the adverse drug reaction

b Two reports 01 bodyweight gain due 10 oedema were excluded

ii Adis Infernolionollimlled All tights reserved

Median time interval (range) en ro ~

7 days (0 days-3mo)

9 days (0 days-4mo)

8 days (0 days-3mo)

3mo (12 daysmiddot4mo)

5 days (1 day-3mo)

1 day (1 day-5mo)

3wk (3 days-6wk)

2wk (2 days-2mo)

7 days (0 days-4mo)


10 days (not reported)


Q)

Ol ro 0

stn

c a ro ~ ro E Q) c f-

DIU Sofely 1909 Mor 20 (3)

1-shy

---i T CD

3 ()

~ ~ 0 gt

3 ihmiddot -0 ()

lt0 CD () U)

()

0 -0

CD Cl

(3 3 3 CD ()

Q CD l amiddot J

8shy3 [ CD

z ~ amiddot J r middot 6 ill -lt 8shy$ CD a nmiddot 5middot (1)

cr lt )

3 a I

c ~ shyu J shy3 u c -r 0 J 3 nshy)

D l

r f)

J )

~ shyT

234 Spigset

Table VIII Other adverse reactions reported in patients receiving selective serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitors

Reaction No of reports Percentage of reports Median age in years (range) Median time intervala (range) involving women

Haematological Haematomalepistaxis 10 80 37 (23-74) 7wk (3wk-5mo)

Thrombocytopenia 4 100 45 (41 middot81) 7wk (4wk-3mo)

Cardiovascular Palpitations 15 79 50 (22middot72) 7 days (I day-6mo)

Hypotension 8 75 71 (47-85) 1 days (0 days-3 days)

Tachycardia 7 71 52 (31-72) 2 days (1 day-3wk)

Bradycardia 4 67 70 (50middot80) 2 days (1 day-2mo)

Endocrinological

Hyperprolactinaemial II 100 32 (25-46) 4mo (2mo-llmo) galactorrhoea

Menstrual disorder 7 l00b 39 (20-49) 4wk (3wk-2mo)

Gynaecomastia 6 Ob 53 (38-57) 9mo (3mo-9mo)

Metabolic

HyponatraemiaiSIADH 24 79 80 (52middot94) 2wk (2 days -15y)

Sexual Libido decreased 29 52 43 (25-56) 5wk (7 daysmiddot4mo)

Ejaculation failure 20 Ob 44 (22-65) 2wk (0 days-4mo)

Erection disturbance 8 0 43 (28middot54) Not reported

Impotence 7 Ob 39 (28-71) 10 days (7 days-3wk)

Respiratory

Cough 10 89 43 (27-69) 6wk (4wkmiddot2mo)

Musculoskelelal

Myalgia 9 56 41 (32middot61) 6wk (3 days-7mo)

Arthralgia 8 75 39 (28-65) 9 days (1 day-l mol

Urinary Micturition disorder 18 65 39(22-77) 9 days (1 day-3wk)

Urinary relention 14 77 63 (28middot83) 3 days (0 daysmiddot3wk)

Urinary incontinence 9 67 62 (24-86) 4 days (0 days-2wk)

Serum creatinine level 4 50 84 (65-91) 3mo (5 daysmiddot4mo) increased

Visual

Vision blurred 10 60 49 (26middot82) 10 days (1 daymiddot4mo)

Vision decreased 9 50 61 (38-78) lmo (8 dayS-limo)

Mydriasis 4 75 34 (21 middot59) 1 day (1 day-l day) Accommodation abnormat 3 67 29 (25middot37) 4 days (1 day-7 days)

Audilory Tinnitus 18 65 46 (30-81) 10 days (1 daymiddot6wk)

Other

Withdrawal symptoms 29 69 37 (19middot71) 8mo (4wk-2y) Serotonin syndrome 3 0 52 (50middot69) Not reported

a Interval between the start ot the treatment and the appearance ot the adverse drug reaction

b Gender-specific diagnosis

SIADH ~ syndrome ot inappropriate antidiuretic hormone secretion

Adverse Reactions of S~

the other hand spont an interesting tool il

quent reactions and te factors may exist for adverse drug reaction are age gender treat[ term treatment the p eases and concomitan should be emphasisee tion of age gender c uncertain for the rea( reports exist In this SI

actions middotere sometim expected adverse react which is a common n frequently reported co adverse reaction ofbo( inconsistency might b dations from reportin) phasis has been put 0

unexpected reactions The high frequency

reactions associated w ent study is in accordat that this drug causes nmiddot SSRIs However 2 fat account First fIuvoxa tion of zimeldine (zime duced onto the Swedisl phenomenon that the IT

tions for a new drug cl1 ror the first drug mark( drugs subsequently mar have the same frequenl ondly when most repor registered a higher sta currently recommended blind studies fluvoxam 50 mgday has been rep intestinal adverse reac Whereas fluvoxamine ill

mgday has been reporte lions than citalopramf [2

The relatively high fr adverse reactions assoc

Ii __ _ _n_ _ rlt_ ~ _ bullbull __ _ 11~) Adis Inlernational Limited All righls reserved

1_- ---- shy

SpissCI

ne 5-HT) reuptake inhibitors

le) Median time interval (rang)

7wk (3wk-5mo)

7wk (4wk-3mo)

7 days (1 day-6mo)

1 days (0 days-3 days)

2 days (1 day-3wk)

2 days (1 day-2mo)

4mo (2mo-11mo)

4wk (3wk-2mo)

9mo (3mo-9mo)

2wk (2 days -1 5y)

5wk (7 days-4mo)

2wk (0 days-4mo)

Not reported


6wk (4wk-2mo)

6wk (3 days-7mo)

9 days (1 day-1 mol

9 days (1 day-3wk)

3 days (0 days-3wk)

4 days (O days-2wk)

3mo (5 days-4mo)

10 days (1 day-4mo)

1mo (8 days-l1 mol

1 day (1 day-1 day)


10 days (1 day-6wk)

8mo (4wk-2y)

NOl reported

Drug Sofely 1m Mor 20 (3)

285Adverse Reactions of SSRIs

the other hand spontaneous reporting systems are an interesting tool in order to investigate infreshyquent reactions and to screen whether specific risk factors may exist for the development of various

adverse drug reactions Such potential risk factors are age gender treatment with high dosages long term treatment the presence of concomitant disshyeases and concomitant drug treatment However it should be emphasised that the estimated distribushytion of age gender dosages and time to onset is uncertain for the reactions for which only a few reports exist In this study unexpected adverse reshyactions were sometimes more often reported than

expected adverse reactions Forexample anorexia which is a common reaction with SSRIs was inshyfrequently reported compared with the uncommon adverse reaction of body weight gain This apparent inconsistency might be a result of the recommenshydations from reporting authorities in which emshyphasis has been put on the reporting of new and unexpected reactions

The high frequency of gastrointestinal adverse reactions associated with fluvoxamine in the presshy

I ent study is in accordance with the common belief j that this drug causes more such effects than other SSRIs However 2 factors need to be taken into I account First fluvoxamine was [with the excepshy1 tion of zimeldine (zimelidine)] the first SSRI introshy

duced onto the Swedish market and it is a general phenomenon that the most common adverse reacshytions for a new drug class are more often reported

1for the first drug marketed in that class although i drugs subsequently marketed in the same class can J have the same frequency of these reactions Secshy

ondly when most reports of adverse reactions were registered a higher starting dosage than the one currently recommended was being used In double-

j blind studies fluvoxamine at a starting dosage of 1 50 mgday has been reported to cause less gastroshy

intestinal adverse reactions than fl uoxetinelll] whereas fluvoxamine at a starting dosage of 100 mgday has been reported to cause more such reacshytions than citalopramtI2 ]

The relatively high frequency of dermatological adverse reactions associated with fluoxctine use

copy Ads Inlemo1ional Umlled All righls reserved

seen in the present survey is consistent with the findings of a double-blind study in which fluoxetshyinc was compared with paroxetine I13 ] However as the pattern of differences in the frequency of speshycific adverse reactions in clinical studies is someshywhat inconsistent there is generally a need for more randomised double-blind studies specificshyally designed to compare adverse reactions beshytween the SSRIs before firm conclusions can be drawn For infrequent adverse reactions epidemishyological studies will be more helpful in revealing risk factors

Most of the adverse reactions identified in this

survey have already been reported sporadically ill the literature but comprehensive studies are genshyerally lacking With the exception of case repons and a few formal studies adverse reaction data on the SSRls are most often found in publications not subject to peer review or in drug catalogues based upon data supplied by the manufacturer In such publications adverse events with less stringent reshyquirements of causality than in the present study are often presented This review has generaJJy conshyfirmed the adverse drug reaction profiles of the SSRIs as presented in the data sheets provided by the manufacturers However a number of adverse reactions not included in the drug data sheets were identified For these reports the clustering in the database suggests a possible causal association

In addition some of the adverse reactions seen more frequently in the present study have been only sparsely discussed in the literature earlier Exshyamples of such reactions are rash pruritus urtishycaria paraesthesias oedema and elevated liver enshyzyme levels Moreover several reactions found occasionally in this survey such as tinnitus mishygraine parotitisglossitis cough fever syncope myalgiaarthralgia pathological inebriation and thrombocytopenia have not been discussed at all in the literature In contrast severe adverse reacshytions such as seizures hyponatraemia and the seshyrotonin syndrome have been more thoroughly deshyscribed earlierY-51 although drug combinations with mianserin have not previously been reported to cause the serotonin syndrome This finding is

Drug Sofely 1999 Mar 20 (3)

286 SJligser c _________________ ______________________________________________________

interesting because mianserin is regularly used as verse reactions during treatment with tricyclic anshy-lr add-on therapy to SSRls and because both tidepressants increases with increasing age and the 3 (1)

mianserin and its two metabolites desmethylshy age distribution for constipation and urinary retenshyru mianserin and 8-hydroxy-mianserin exert seroshy tion found in the present study indicates that the ~

~ tonergic effectsII~1 ri sk of peudo-antichoinergic effects with SSRIs 0 J The withdrawal symptoms reported in the presshy might also increase with increasing age of 0 ent study are principally the same as those seen in As most adverse reactions are expected to be

D ru a large survey of cases reported to the WHO dose dependent they are in principle avoidable ltD (1) database11 51 with dizziness and paraesthesias being However based 011 the fact that the majority of ru the 2 most prominent ~y mptoI11s In the same surshyUgt adverse reactions reported in this study were obshy() 0 vey11 il it was also noted that psychiatric symptoms served in patients who had been treated with standshyDroO were more common among patients who had been 0

a ard dosages one may speculate that the dose-effect

treated with f]uoxetlne whereas neurological curve for many of these adverse reactions is close 3 symptoms were morc common among patients to even or shi fted to the left side of the correspondshy3 i who had been treated Ilith paroxetine or sertraline (1)

ing cllJe for the antidepressant effect Alternashy()

Q When considering all adverse reactions reported in tively sudden increases in drug concentration l I the present study neurological symptoms were 10

might be a more important factor than the absolute 5 I

J more often reported following the withdrawal of drug concentration for some adverse reactions The ~ paroxetine and psychiatric symptoms were more I possible development of tolerance might also modshy~ often reported following the ithdrawal of sertralshyz ify the response of the individual patient to some ~ ine whereas there was no clear pattern for tluoxetshy adverse reactions Treatment with high dosages ~ ine L might be a risk factor at least for the adverse reacshy

Most adverse reactions caused by SSRls can be J tions for which high median dosages were used

explained by effects on the saotonergic system3 such as seizures hypomaniamania body weight

The occurrence of haematomas and epistaxis can ~ gain gynaecomastia personality change malaise

be explained by an impairment of blood platelet

)

L and hyperprolactinaemiaJgalaclorrhoea function caused by SSRls1161 Serotonin is involved

As all SSRIs to a larger or smaller extent are metabshyj in the pathophysiology or nauseaJvomitingl171 and olised by the polymorphic cytochrome P450 (CYP) migraineIIXI and it is an important neurotransmitshyliver en zymes CY P2C 19 andor CYP2D61~1I1ter for the regulation of body temperature bodyshyindividualised drug dosage based on the putients weight sexual behaviour water balance and pro shyspecific metabolic capacity might reduce the risk lactin secretion In addition a high proportion of of dose-dependent (concentration -dependent) adshythe neuromuscular psychiatric and autonomic versc reactions However idiosyncraticimmunoshysymptoms seen with the serotonin syndrome in hushy

mans are seen animals as welLI 51 Although SSRls logical reactions such as rash and urticaria can prinshycipally not be prevented by optimising Ihe drughave very little or no anticholinergic effects con shy

stipation dry mouth and urinary retention are not dosage

uncommon For paroxtline these symptoms can be 11 conclusion treatment with SSRls can give

explained by its weak muscarine receptor blocking rise to a variety of adverse reactions mainly of

properties for tluvoxarnine it has been sugges ted neurological gastrointestinal and psychiatric nashy

that interactions with histamine HI and aI-adrenshy ture Severe symptoms are rarely reported As more

ergic receptors may cause so-called pseudo-antishy than 90 different adverse reaction diagnoses were cholinergic effects 1I~I However slich pseudo-antishy reported in this survey the awareness that a particshy

cholinergic adverse reactions are reported also for ular symptom in a patient treated with an SSRI the other SSRIs The risk for anticholinergic ad- might be an adverse reaction should be high

I Adis Inlerno lio noJ umHed A I I ns rese rved

Adverse Reacti()n~ of S~

Acknowledgell

Martin Backstrom anI

Products Agency are 1l

database search

References I Song F Freemantie N ~

r~uplake inhibitors n abililY BMJ 1993 JOe

2 Bor2 S Brodin K Anlidmiddot to Ivkyler s sid~ df Elsevier 1992 30-78

3 Spigset O Hedenmalm K lonus associated wim 31

potenlial risk facwrs polymorphisms and Ire p ychiatr Scand 1997 lt

~ Spigset O Heuenmalm K inoppropriatc nnliltIiure duced by psychotropic

5 Sporer KA The serOlooin 6 WHO collaborating cen

Guidelines for defined ( Iborating ccnlfe for dn

7 WHO collaborating cenlno awmical therapeutic chi cluding defined daily ( Oslo WHO coliaborniT ology 1997

8 Wiholm BmiddotE Olsson S i systems oUlSide thc Unitlt macocpiltIcmiology 2nd 199~ 139middot55

9 Dllk~s MNG The impoffiu ulation Drug Sal I 99)

10 Rawlins MD Spontaneous Br J Cl in Phmacol 19Xmiddot

-1shy

treatment with tricyclic al1shy

with increasing age and the

stipation and urinary relclI_

nt study indicates that Ihe

inergic effects with SSRls h increasing age

lelions are expeclcd 10 he

reo in principle avoidahle

fact that the majorit) or fed in this study were ohshy

ad been treated with slalld shy

eculate that the dosc-clfeci

adverse reactions is close

left side of the correspondshy

epressant effect Alternashy

s in drug concentralioll

nt factor than the ahsoltlle

-me adverse reactions Th~

tolerance might also modshy

ldividual patient 10 some

ment with high dosage

least for the adverse reacshy

dian dosages were used

laniaimania bodywcifh

sonalily change malaise

galactorrhoea

lr smaller extent are l11eahshy

cytochrome P450 (CYPJ 19 andor CYP2D6Icfli

~e based on the patients

ty might reduce the risk

ntratioLl-dependent ) adshy

idiosyncratiCimmunoshy

lth and urticaria can prillshy

by optimising the drug

nt with SSRls can give

se reactions mainly or nal and psychiatric 11lt1shy

mrely reported As more

eaction diagnoses were

awareness that a partieshy

t treated with an SSRI

)n should be high

Drug Safety J9X Mar 20 (3)

287Adverse Reactions 01 SSRls -Acknowledgements

Martin BlickslroJ1l anel Ihe staff II Ihe Swedish Medical Products Agency are acknowledged for help wilh Ihe database search

References I SOllg F FrCCnlltlI11ic N Sheldon TA ~I al $ckcli c ~Imiddotnll onill

r~lIrtakc inhihi(pr rn(ta middot~Il~t1ysis of cffichy flO aCImiddotcptshy

ahilily BMJ I ~1)1 30( (~ 1 -7

2 Borg S Brodin K Alllidcpre s lIlt dnlgs Ill Duke MNG cdishylor Mcy lcr~ siut efrects or drug- 121h Id AmsltrdJm Elsevier 1992 10-7~

3 Spigset O Hcuenmalm K Dahl M-L t1 al Seizure and myoc shylonus associalcu wilh Jlltidcprcssant Ircatmcnt a-SessnlCIiI or potential risk faclOrs including CYP2D6 ond CYP2C 19 polymorphisllls and trciltmcul wilh CYP1D6 inhihitors Acta Psychiur Sea lid 1997 96 179-84

4 Spigsel O Hcdcllnwlm K Hyponalrcmi nd Ihe syndrome of inappropriale anlidiurelic hormonc cxcrelion (SIADHI in middot duced by psychOlropic drugs Drug Sar 1995 12 209-225

5 Sporer KA The erolonin syndrome Drug Saf 1995 13 94-10-1 6 WHO col lnboratin CCIHrc for drue stalistics melhodolo~

Guidelincs for defilled daily dascs-CODD) Oslo WHO c~Ishylahoratin~ ccntrt for dru slui s(ics mClllOdoiov 199 J 76

7 WHO colllbontling c~n(re ~for drug s(alisties meth~tlolog) An ~ aromical therapctHic chemical (ATe) chlssificafion index inshycluding defined daily doscs (DOD) for plain subSlances Oslo WHO colilboraling cCnlrc ror drug st)listics methodshyology 1997

8 Wiholm B-E Olsson S Moore N el al Sp0nlancous reponing syslem~ outside Ihe Uniled Sales In Sirom BL edilor Pharshymacoepidemiology 2nd cd Chichsler John Wiley and Sons 1994 139-55

9 Dukes MNG TIle importance or ad verse r~ac[ions in drug reg shyulalion Drug Saf 1990 5 3-6

10 Rawlins MD SponlilllcoHS reponing of ndcrsc drug r~a(fiol1 Br J Clin Pharmacol 1988 26 I-S

Adis Inemotional Umifed AU rights reserved

II Raptport M Coccaro E Sheline Y el ltII A cOJ1lpi(rj~orl of tht(lxamillc and nlloxctinc in the lrtotlmcnl of Hl1jor d(lr- - shy-ion J Clin I-ychopharmacol 1996 16 173-H

12 Hoffmans PMI Timmean L Hoogduill CAL and the LUCIshyFER lfOUp EOicacy and locrability of dwloprall1 ill lOOl shy

pIfi soll with flu(lXJminc in dcprc--cJ outpaticilts 1

d(lUhlc -blillll IHulticClllfC ~ltIt1y 1111 Clin rsychophanl1~l(ol 1996 I I 157 middot( -1

ll Dc Villtk 1 SjlitT- R Mcrtclls C ct 1 A uouhlc hlind Iolllparshy

ltllin multicclllcc study cOInparing pr()dinc jlb IltloxcImiddot illL in deprls-co pllill1rs AIw rychi t lr Scand 1993 ~7 1-11middot5

14 Pinder RM lvliallscrin pharmilcological and clinicHI cornlalcs Nord J P-ychilr 199 I 45 Suppl 24 11-26

IS Slabl MMS Lilltiquisl 1-4 PellcTSon M el al Wilhdral reaemiddot lioll - wilil s~kctic -e rot(l))in rC-llpt~lkc inbibitors as rcporl ld 10 Ihe WHO systel11 ElIrl Clin Pharncol 1997 53 I (1-~

16 Skop BP Brown TM POlclltial vascular and bleeding rOillplimiddot clions o treatment ith selective serotonin r~lIptake inhihshyilor Pychoso11lltllics 1996 37 12-6

17 tv itchcbon F Pharmacological ag~nls afre-Clinpound cl11esi - iI r~shyview Ipart I) Drugs I~92 43 295-315

IS Lancc W Lamncrt GA Goadsby PJ el al 5-hydrox)JryplltlIlline and its pUlative actiological involvement in migraine CcpilshyIalgio 1989 9 Supp 9 7- 11

I) Rielkl v 111 Prtlg Hl1 Avoiding and managing anticholinshycrgic dfec of anlidcpres~anls eNS Drugs 1995 3 245middot5~

20 Benilssoll L Dhl M-L Polymorphic drug oxidalion Releshyvance [0 the treatment of psychituric disordcrs eNS Ortlgs 1996 3 200middot23

--------------------------------------shyCorrespondence and reprints Dr Ohm Spigt Department of Clinical Pharmacology Regional and Uniersity Hospital N-7006 Trondheim Norway E-mail Ola-5pigsetrelisritno

Drug Safety 19X Mar 20 (3)

D Q)

0 8 vgt ro ~ Q) 0gt ro a -~ S c o ro 2 ttl E

5 a -0 ru

lt ru J a 3 ru lt cr CD -0

o ro cgt ro a cr lt C (J)

() o -0

~ lt3 r

ru ~

278 ------~---------~~~--------- -~------------

the aareness that a particular symptom in a patient treated with an SSRI might be an adverse reaction should he high

The selective serotonin (5-hydroxytryptamine 5-HT) reuptake inhibitors (SSRIs) are extensively used in the treatment of depression panic disorder and obsessive-compulsive disorder and are now being evaluated in the treatment of a number of other psychiatric disorders Aderse reactions asshysociated with the SSRIs are less prominent than and qualitatively different from those assoc iated with the tricycl ic antidepressantsllc l Nevertheshyless adverse reactions of SSRI s cover a broad specshytrum ranging from mild gastrointestinal symptoms to severe although rare events such as seizures IJI hypollatraemiaI~1 and the serotonin syndromeIgt1 In view of the increasing lise of these drugs the pattern of adverse reactions reported on SSRls in Sweden is presented and pos~ible risk factors idenshytified in this study

Materials and Methods

Since 1965 Sweden has had a system for sponshytaneous reporting of adcrse drug reactions to the Swedish Adverse Drug Rcactions Advisory Com-

Table I WHO criteria for causality assessment

mittee Since 1975 the reporting of serious or fatal reactions and new reactions has been compUlsory or the SSRls available in Sweden fluvoxamine was approved in June 1990 paroxetine in June 1991 citalopram in October 1992 sertraline in January 1995 and tluoxetine in September 1995

All reports received up to December 3 I 1997 were re viewed but only reactions that were classishyfied as having a possible probablelikely or certain causal relationship with the drug according to the WHO criteria (table I) and that were reported 3 times or more were included in lhis suney Moreshyover reports concerning overdoses and pharmacoshykinetic interactions which did not cause any adshyverse reactions were excluded

The classification of the reports was made by the monitoring centre staff From each report the following information was obtained bull age and gender of (he patient bull name and dosage of the suspected as well as

other drug or drugs bull outcome of dechallengerechallenge

Certain A clinical event including laboratory test abnormality occurring in a plausible time relationship to drug administration and which cannot be expfained by concurrent disease or other drugs or chemicals The response to withdrawal of the drug (dechallenge) should be clinically plausible The evenl must be definitive pharmacologically or phenomenofogically using a satisfactory rechallenge procedure il necessary

Probablellikely A clinical event incfuding laboratory test abnormality with reasonabfe lime sequence 10 administration 01 the drug unlikely to be aHributed to concurrent disease or other drugs or Chemicals and which follows a clinically reasonabfe response on withdrawal (dechallengel Rechallenge information is not required 10 fulfif Ihis definition

Possible

A Clinical event including laboratory tesl abnormality with a reasonable tesl sequence to adminislration of the drug bul which could also be explained by concurrent disease or other drugs or chemicals Information on drug withdrawal may be lacking or unclear

Unlikely

A clinical event including laboratory test abnormality with a temporal relationship 10 drug administration which makes a causal relationship improbable and in which other drugs chemicafs or underlying disease provide plausible expfanations

Conditionalunclassified A clinical event including laboratory test abnormality reported as an adverse reaction about which more data are essentiat for a proper assessment or the additional data are under examination

Unassessibfelunclassifiable

A report suggesting an adverse drug reaction which cannot be judged because information is insuHicient or contradictory and which cannot be supplemented or verified

Aderse r~actinl

20 eFluvox - ParoX u ro

OCitatOi iii DSertra 0- 15 6fluoxe ~ c ~ 0 ro L= 10 0 0 0

0 0

58 Q) co

(fJ

o F-shy1990 1991

Fig 1 Sales of selt reuptake inhibftors daily doses (000) 04 in 1991 15n 273 in 1996 anc citalopram fiuoxe 150mg tor liuvoxa

bull other potent bull time interv3

appearance Only repan

unkllown dech Ilot stopped 1

negative decha Total drug s

computerised s total amount 0

illacy and can terillS or in tt (ODDs) The 1 dose of a drug I adults for SSf ately severe d( sold per 1000 i although gross drug in the pOI are 20mg for ( tine 50mg for amineJ71

Results

Sales statist figure I The te

~ Adis Internolionalli I Adis InternOhOflol limiled All nghts reserveC Drug SOfely 1999 Mor 20 (3)
















uded


IS obtained

oatient


erechallcnge











0 r 10 0 0 0

0 0

5e ltfl Q)

iii Cf)

O~~~~~~==~~~~--- 1990 1991 1992 1993 1994 1995 1996 1997

Year








Results














150 6 Fluoxetine

~

a 100 a ci z

50

O~~~-amp--~--~~~~=-~ 1990 1991 1992 1993 1994 1995 1996 1997

Year



J - (

J

- (

( 1 pound

-0 Q)

0 o ()

(1J Q) a (1J o ~ 5 c o (ij -~

m E Q)

-= l- shy

280 Spigset




Neurological 132 (206) 22 (239) 71 (207) 161 (260) 30 (182) 416 (224)

Mental 121 (189) 19 (207) 67 (196) 113(182) 42 (255) 362 (195)


Dermatological 83 (129) 16 (174) 32 (93) 56 (90) 26 (158) 213 (114)

General 67 (105) 9 (98) 34 (99) 62 (100) 11 (67) 183 (98)

Other 134 (209) 14 (152) 48 (140) 123 (198) 33 (200) 352 (189)

Total 641 (100) 92 (100) 343 (100) 620 (99_9) 165 (1001) 1861 (100)




































Reaction

Anxiety

Confusion

Hallucinations

Sleep disturbances

Hypomaniamania

Depersonalisation

Amnesia

Nightmares

Aggression

Insomnia

Psychosis


Agilation

Personality change

Euphoria



hypomaniamania we

of 175 ODDs while t




less

Gostrointestinof RE

Gastrointestinal ad















Owner
Highlight

--



82) 416 (224) ~5 5) 362 (195) - 39) 336 (180) 58) 213 (114)

7) 183 (98) 00) 352 (189) 100_1) 1861 (100) ual drug




















General Reactions



(

-c Q-c C lt u


Owner
Highlight
Owner
Highlight

282 Spigscl




C1l


Parotitis~gt

14 64

14 75

11 40

8 63

7 71

4 50

49 (19-86)

49 (24-87)

54 (28-84)

48(17-90)

53 (30-78)

47 (28-74)

61 (30-75)

63 (55-88)

55 (46-81)

78 (75-84)


(range)



5 days (0 days-4wk)

4wk (3 days-9mo)

7 days (1 day-5mo)


4 days (1 day-1mo)

7 days (2 days-1mo)











Urticaria 42

Pruritus 40

Angioedema 10

Photosensitivity 5

lt


73 52 (18-88) 5 days (1 day-3y)

74 38 (14-77) 2wk (2 days-5mo)

76 49 (27-83) 3wk (1 day-15mo)

90 37 (24-77) 13 days (1 day-2mo)









Discussion



Reaction

Fatigue

Hyperhidrosis

Oedema

BOdyweight gainb

Syncope

Pain

Fever

Malaise

Faintness

Somnolence

Anorexia



3

283 Sligsrl





5 days (0 days-4wk)

4wk (3 days-9mo)

7 days (1 day-5mo)


4 days (1 day- lmo)

7 days (2 days-lmo)













2wk (2 days-5mo)

3wk (1 day-15mo)

13 days (1 day-2mo)

2mo (3 days-2y)






Discussion







(




(l













0 Q)

6 a o




Oedema 33 72 48 (29-82)




Fever 7 100 42 (34-48)

Malaise 5 40 49 (41 -43)


Somnolence 4 100 64 (50-81)

Anorexia 3 67 44 (28-75)

Chills 3 67 53 (43-65)





7 days (0 days-3mo)

9 days (0 days-4mo)

8 days (0 days-3mo)


5 days (1 day-3mo)

1 day (1 day-5mo)

3wk (3 days-6wk)

2wk (2 days-2mo)

7 days (0 days-4mo)




Q)

Ol ro 0

stn



1-shy

---i T CD

3 ()

~ ~ 0 gt

3 ihmiddot -0 ()

lt0 CD () U)

()

0 -0

CD Cl

(3 3 3 CD ()

Q CD l amiddot J

8shy3 [ CD


cr lt )

3 a I


D l

r f)

J )

~ shyT

234 Spigset









Endocrinological




Metabolic






Respiratory


Musculoskelelal







Visual





Other















1_- ---- shy

SpissCI



7wk (3wk-5mo)

7wk (4wk-3mo)

7 days (1 day-6mo)


2 days (1 day-3wk)

2 days (1 day-2mo)

4mo (2mo-11mo)

4wk (3wk-2mo)

9mo (3mo-9mo)

2wk (2 days -1 5y)

5wk (7 days-4mo)

2wk (0 days-4mo)

Not reported


6wk (4wk-2mo)

6wk (3 days-7mo)

9 days (1 day-1 mol

9 days (1 day-3wk)

3 days (0 days-3wk)

4 days (O days-2wk)

3mo (5 days-4mo)

10 days (1 day-4mo)

1mo (8 days-l1 mol

1 day (1 day-1 day)


10 days (1 day-6wk)

8mo (4wk-2y)

NOl reported




















286 SJligser c _________________ ______________________________________________________















)













Acknowledgell



database search













-1shy
























galactorrhoea















)n should be high






ahilily BMJ I ~1)1 30( (~ 1 -7


























D Q)

















uded


IS obtained

oatient


erechallcnge











0 r 10 0 0 0

0 0

5e ltfl Q)

iii Cf)

O~~~~~~==~~~~--- 1990 1991 1992 1993 1994 1995 1996 1997

Year








Results














150 6 Fluoxetine

~

a 100 a ci z

50

O~~~-amp--~--~~~~=-~ 1990 1991 1992 1993 1994 1995 1996 1997

Year



J - (

J

- (

( 1 pound

-0 Q)

0 o ()

(1J Q) a (1J o ~ 5 c o (ij -~

m E Q)

-= l- shy

280 Spigset




Neurological 132 (206) 22 (239) 71 (207) 161 (260) 30 (182) 416 (224)

Mental 121 (189) 19 (207) 67 (196) 113(182) 42 (255) 362 (195)


Dermatological 83 (129) 16 (174) 32 (93) 56 (90) 26 (158) 213 (114)

General 67 (105) 9 (98) 34 (99) 62 (100) 11 (67) 183 (98)

Other 134 (209) 14 (152) 48 (140) 123 (198) 33 (200) 352 (189)

Total 641 (100) 92 (100) 343 (100) 620 (99_9) 165 (1001) 1861 (100)




































Reaction

Anxiety

Confusion

Hallucinations

Sleep disturbances

Hypomaniamania

Depersonalisation

Amnesia

Nightmares

Aggression

Insomnia

Psychosis


Agilation

Personality change

Euphoria



hypomaniamania we

of 175 ODDs while t




less

Gostrointestinof RE

Gastrointestinal ad















Owner
Highlight

--



82) 416 (224) ~5 5) 362 (195) - 39) 336 (180) 58) 213 (114)

7) 183 (98) 00) 352 (189) 100_1) 1861 (100) ual drug




















General Reactions



(

-c Q-c C lt u


Owner
Highlight
Owner
Highlight

282 Spigscl




C1l


Parotitis~gt

14 64

14 75

11 40

8 63

7 71

4 50

49 (19-86)

49 (24-87)

54 (28-84)

48(17-90)

53 (30-78)

47 (28-74)

61 (30-75)

63 (55-88)

55 (46-81)

78 (75-84)


(range)



5 days (0 days-4wk)

4wk (3 days-9mo)

7 days (1 day-5mo)


4 days (1 day-1mo)

7 days (2 days-1mo)











Urticaria 42

Pruritus 40

Angioedema 10

Photosensitivity 5

lt


73 52 (18-88) 5 days (1 day-3y)

74 38 (14-77) 2wk (2 days-5mo)

76 49 (27-83) 3wk (1 day-15mo)

90 37 (24-77) 13 days (1 day-2mo)









Discussion



Reaction

Fatigue

Hyperhidrosis

Oedema

BOdyweight gainb

Syncope

Pain

Fever

Malaise

Faintness

Somnolence

Anorexia



3

283 Sligsrl





5 days (0 days-4wk)

4wk (3 days-9mo)

7 days (1 day-5mo)


4 days (1 day- lmo)

7 days (2 days-lmo)













2wk (2 days-5mo)

3wk (1 day-15mo)

13 days (1 day-2mo)

2mo (3 days-2y)






Discussion







(




(l













0 Q)

6 a o




Oedema 33 72 48 (29-82)




Fever 7 100 42 (34-48)

Malaise 5 40 49 (41 -43)


Somnolence 4 100 64 (50-81)

Anorexia 3 67 44 (28-75)

Chills 3 67 53 (43-65)





7 days (0 days-3mo)

9 days (0 days-4mo)

8 days (0 days-3mo)


5 days (1 day-3mo)

1 day (1 day-5mo)

3wk (3 days-6wk)

2wk (2 days-2mo)

7 days (0 days-4mo)




Q)

Ol ro 0

stn



1-shy

---i T CD

3 ()

~ ~ 0 gt

3 ihmiddot -0 ()

lt0 CD () U)

()

0 -0

CD Cl

(3 3 3 CD ()

Q CD l amiddot J

8shy3 [ CD


cr lt )

3 a I


D l

r f)

J )

~ shyT

234 Spigset









Endocrinological




Metabolic






Respiratory


Musculoskelelal







Visual





Other















1_- ---- shy

SpissCI



7wk (3wk-5mo)

7wk (4wk-3mo)

7 days (1 day-6mo)


2 days (1 day-3wk)

2 days (1 day-2mo)

4mo (2mo-11mo)

4wk (3wk-2mo)

9mo (3mo-9mo)

2wk (2 days -1 5y)

5wk (7 days-4mo)

2wk (0 days-4mo)

Not reported


6wk (4wk-2mo)

6wk (3 days-7mo)

9 days (1 day-1 mol

9 days (1 day-3wk)

3 days (0 days-3wk)

4 days (O days-2wk)

3mo (5 days-4mo)

10 days (1 day-4mo)

1mo (8 days-l1 mol

1 day (1 day-1 day)


10 days (1 day-6wk)

8mo (4wk-2y)

NOl reported




















286 SJligser c _________________ ______________________________________________________















)













Acknowledgell



database search













-1shy
























galactorrhoea















)n should be high






ahilily BMJ I ~1)1 30( (~ 1 -7


























D Q)


280 Spigset




Neurological 132 (206) 22 (239) 71 (207) 161 (260) 30 (182) 416 (224)

Mental 121 (189) 19 (207) 67 (196) 113(182) 42 (255) 362 (195)


Dermatological 83 (129) 16 (174) 32 (93) 56 (90) 26 (158) 213 (114)

General 67 (105) 9 (98) 34 (99) 62 (100) 11 (67) 183 (98)

Other 134 (209) 14 (152) 48 (140) 123 (198) 33 (200) 352 (189)

Total 641 (100) 92 (100) 343 (100) 620 (99_9) 165 (1001) 1861 (100)




































Reaction

Anxiety

Confusion

Hallucinations

Sleep disturbances

Hypomaniamania

Depersonalisation

Amnesia

Nightmares

Aggression

Insomnia

Psychosis


Agilation

Personality change

Euphoria



hypomaniamania we

of 175 ODDs while t




less

Gostrointestinof RE

Gastrointestinal ad















Owner
Highlight

--



82) 416 (224) ~5 5) 362 (195) - 39) 336 (180) 58) 213 (114)

7) 183 (98) 00) 352 (189) 100_1) 1861 (100) ual drug




















General Reactions



(

-c Q-c C lt u


Owner
Highlight
Owner
Highlight

282 Spigscl




C1l


Parotitis~gt

14 64

14 75

11 40

8 63

7 71

4 50

49 (19-86)

49 (24-87)

54 (28-84)

48(17-90)

53 (30-78)

47 (28-74)

61 (30-75)

63 (55-88)

55 (46-81)

78 (75-84)


(range)



5 days (0 days-4wk)

4wk (3 days-9mo)

7 days (1 day-5mo)


4 days (1 day-1mo)

7 days (2 days-1mo)











Urticaria 42

Pruritus 40

Angioedema 10

Photosensitivity 5

lt


73 52 (18-88) 5 days (1 day-3y)

74 38 (14-77) 2wk (2 days-5mo)

76 49 (27-83) 3wk (1 day-15mo)

90 37 (24-77) 13 days (1 day-2mo)









Discussion



Reaction

Fatigue

Hyperhidrosis

Oedema

BOdyweight gainb

Syncope

Pain

Fever

Malaise

Faintness

Somnolence

Anorexia



3

283 Sligsrl





5 days (0 days-4wk)

4wk (3 days-9mo)

7 days (1 day-5mo)


4 days (1 day- lmo)

7 days (2 days-lmo)













2wk (2 days-5mo)

3wk (1 day-15mo)

13 days (1 day-2mo)

2mo (3 days-2y)






Discussion







(




(l













0 Q)

6 a o




Oedema 33 72 48 (29-82)




Fever 7 100 42 (34-48)

Malaise 5 40 49 (41 -43)


Somnolence 4 100 64 (50-81)

Anorexia 3 67 44 (28-75)

Chills 3 67 53 (43-65)





7 days (0 days-3mo)

9 days (0 days-4mo)

8 days (0 days-3mo)


5 days (1 day-3mo)

1 day (1 day-5mo)

3wk (3 days-6wk)

2wk (2 days-2mo)

7 days (0 days-4mo)




Q)

Ol ro 0

stn



1-shy

---i T CD

3 ()

~ ~ 0 gt

3 ihmiddot -0 ()

lt0 CD () U)

()

0 -0

CD Cl

(3 3 3 CD ()

Q CD l amiddot J

8shy3 [ CD


cr lt )

3 a I


D l

r f)

J )

~ shyT

234 Spigset









Endocrinological




Metabolic






Respiratory


Musculoskelelal







Visual





Other















1_- ---- shy

SpissCI



7wk (3wk-5mo)

7wk (4wk-3mo)

7 days (1 day-6mo)


2 days (1 day-3wk)

2 days (1 day-2mo)

4mo (2mo-11mo)

4wk (3wk-2mo)

9mo (3mo-9mo)

2wk (2 days -1 5y)

5wk (7 days-4mo)

2wk (0 days-4mo)

Not reported


6wk (4wk-2mo)

6wk (3 days-7mo)

9 days (1 day-1 mol

9 days (1 day-3wk)

3 days (0 days-3wk)

4 days (O days-2wk)

3mo (5 days-4mo)

10 days (1 day-4mo)

1mo (8 days-l1 mol

1 day (1 day-1 day)


10 days (1 day-6wk)

8mo (4wk-2y)

NOl reported




















286 SJligser c _________________ ______________________________________________________















)













Acknowledgell



database search













-1shy
























galactorrhoea















)n should be high






ahilily BMJ I ~1)1 30( (~ 1 -7


























D Q)


--



82) 416 (224) ~5 5) 362 (195) - 39) 336 (180) 58) 213 (114)

7) 183 (98) 00) 352 (189) 100_1) 1861 (100) ual drug




















General Reactions



(

-c Q-c C lt u


Owner
Highlight
Owner
Highlight

282 Spigscl




C1l


Parotitis~gt

14 64

14 75

11 40

8 63

7 71

4 50

49 (19-86)

49 (24-87)

54 (28-84)

48(17-90)

53 (30-78)

47 (28-74)

61 (30-75)

63 (55-88)

55 (46-81)

78 (75-84)


(range)



5 days (0 days-4wk)

4wk (3 days-9mo)

7 days (1 day-5mo)


4 days (1 day-1mo)

7 days (2 days-1mo)











Urticaria 42

Pruritus 40

Angioedema 10

Photosensitivity 5

lt


73 52 (18-88) 5 days (1 day-3y)

74 38 (14-77) 2wk (2 days-5mo)

76 49 (27-83) 3wk (1 day-15mo)

90 37 (24-77) 13 days (1 day-2mo)









Discussion



Reaction

Fatigue

Hyperhidrosis

Oedema

BOdyweight gainb

Syncope

Pain

Fever

Malaise

Faintness

Somnolence

Anorexia



3

283 Sligsrl





5 days (0 days-4wk)

4wk (3 days-9mo)

7 days (1 day-5mo)


4 days (1 day- lmo)

7 days (2 days-lmo)













2wk (2 days-5mo)

3wk (1 day-15mo)

13 days (1 day-2mo)

2mo (3 days-2y)






Discussion







(




(l













0 Q)

6 a o




Oedema 33 72 48 (29-82)




Fever 7 100 42 (34-48)

Malaise 5 40 49 (41 -43)


Somnolence 4 100 64 (50-81)

Anorexia 3 67 44 (28-75)

Chills 3 67 53 (43-65)





7 days (0 days-3mo)

9 days (0 days-4mo)

8 days (0 days-3mo)


5 days (1 day-3mo)

1 day (1 day-5mo)

3wk (3 days-6wk)

2wk (2 days-2mo)

7 days (0 days-4mo)




Q)

Ol ro 0

stn



1-shy

---i T CD

3 ()

~ ~ 0 gt

3 ihmiddot -0 ()

lt0 CD () U)

()

0 -0

CD Cl

(3 3 3 CD ()

Q CD l amiddot J

8shy3 [ CD


cr lt )

3 a I


D l

r f)

J )

~ shyT

234 Spigset









Endocrinological




Metabolic






Respiratory


Musculoskelelal







Visual





Other















1_- ---- shy

SpissCI



7wk (3wk-5mo)

7wk (4wk-3mo)

7 days (1 day-6mo)


2 days (1 day-3wk)

2 days (1 day-2mo)

4mo (2mo-11mo)

4wk (3wk-2mo)

9mo (3mo-9mo)

2wk (2 days -1 5y)

5wk (7 days-4mo)

2wk (0 days-4mo)

Not reported


6wk (4wk-2mo)

6wk (3 days-7mo)

9 days (1 day-1 mol

9 days (1 day-3wk)

3 days (0 days-3wk)

4 days (O days-2wk)

3mo (5 days-4mo)

10 days (1 day-4mo)

1mo (8 days-l1 mol

1 day (1 day-1 day)


10 days (1 day-6wk)

8mo (4wk-2y)

NOl reported




















286 SJligser c _________________ ______________________________________________________















)













Acknowledgell



database search













-1shy
























galactorrhoea















)n should be high






ahilily BMJ I ~1)1 30( (~ 1 -7


























D Q)


282 Spigscl




C1l


Parotitis~gt

14 64

14 75

11 40

8 63

7 71

4 50

49 (19-86)

49 (24-87)

54 (28-84)

48(17-90)

53 (30-78)

47 (28-74)

61 (30-75)

63 (55-88)

55 (46-81)

78 (75-84)


(range)



5 days (0 days-4wk)

4wk (3 days-9mo)

7 days (1 day-5mo)


4 days (1 day-1mo)

7 days (2 days-1mo)











Urticaria 42

Pruritus 40

Angioedema 10

Photosensitivity 5

lt


73 52 (18-88) 5 days (1 day-3y)

74 38 (14-77) 2wk (2 days-5mo)

76 49 (27-83) 3wk (1 day-15mo)

90 37 (24-77) 13 days (1 day-2mo)









Discussion



Reaction

Fatigue

Hyperhidrosis

Oedema

BOdyweight gainb

Syncope

Pain

Fever

Malaise

Faintness

Somnolence

Anorexia



3

283 Sligsrl





5 days (0 days-4wk)

4wk (3 days-9mo)

7 days (1 day-5mo)


4 days (1 day- lmo)

7 days (2 days-lmo)













2wk (2 days-5mo)

3wk (1 day-15mo)

13 days (1 day-2mo)

2mo (3 days-2y)






Discussion







(




(l













0 Q)

6 a o




Oedema 33 72 48 (29-82)




Fever 7 100 42 (34-48)

Malaise 5 40 49 (41 -43)


Somnolence 4 100 64 (50-81)

Anorexia 3 67 44 (28-75)

Chills 3 67 53 (43-65)





7 days (0 days-3mo)

9 days (0 days-4mo)

8 days (0 days-3mo)


5 days (1 day-3mo)

1 day (1 day-5mo)

3wk (3 days-6wk)

2wk (2 days-2mo)

7 days (0 days-4mo)




Q)

Ol ro 0

stn



1-shy

---i T CD

3 ()

~ ~ 0 gt

3 ihmiddot -0 ()

lt0 CD () U)

()

0 -0

CD Cl

(3 3 3 CD ()

Q CD l amiddot J

8shy3 [ CD


cr lt )

3 a I


D l

r f)

J )

~ shyT

234 Spigset









Endocrinological




Metabolic






Respiratory


Musculoskelelal







Visual





Other















1_- ---- shy

SpissCI



7wk (3wk-5mo)

7wk (4wk-3mo)

7 days (1 day-6mo)


2 days (1 day-3wk)

2 days (1 day-2mo)

4mo (2mo-11mo)

4wk (3wk-2mo)

9mo (3mo-9mo)

2wk (2 days -1 5y)

5wk (7 days-4mo)

2wk (0 days-4mo)

Not reported


6wk (4wk-2mo)

6wk (3 days-7mo)

9 days (1 day-1 mol

9 days (1 day-3wk)

3 days (0 days-3wk)

4 days (O days-2wk)

3mo (5 days-4mo)

10 days (1 day-4mo)

1mo (8 days-l1 mol

1 day (1 day-1 day)


10 days (1 day-6wk)

8mo (4wk-2y)

NOl reported




















286 SJligser c _________________ ______________________________________________________















)













Acknowledgell



database search













-1shy
























galactorrhoea















)n should be high






ahilily BMJ I ~1)1 30( (~ 1 -7


























D Q)


283 Sligsrl





5 days (0 days-4wk)

4wk (3 days-9mo)

7 days (1 day-5mo)


4 days (1 day- lmo)

7 days (2 days-lmo)













2wk (2 days-5mo)

3wk (1 day-15mo)

13 days (1 day-2mo)

2mo (3 days-2y)






Discussion







(




(l













0 Q)

6 a o




Oedema 33 72 48 (29-82)




Fever 7 100 42 (34-48)

Malaise 5 40 49 (41 -43)


Somnolence 4 100 64 (50-81)

Anorexia 3 67 44 (28-75)

Chills 3 67 53 (43-65)





7 days (0 days-3mo)

9 days (0 days-4mo)

8 days (0 days-3mo)


5 days (1 day-3mo)

1 day (1 day-5mo)

3wk (3 days-6wk)

2wk (2 days-2mo)

7 days (0 days-4mo)




Q)

Ol ro 0

stn



1-shy

---i T CD

3 ()

~ ~ 0 gt

3 ihmiddot -0 ()

lt0 CD () U)

()

0 -0

CD Cl

(3 3 3 CD ()

Q CD l amiddot J

8shy3 [ CD


cr lt )

3 a I


D l

r f)

J )

~ shyT

234 Spigset









Endocrinological




Metabolic






Respiratory


Musculoskelelal







Visual





Other















1_- ---- shy

SpissCI



7wk (3wk-5mo)

7wk (4wk-3mo)

7 days (1 day-6mo)


2 days (1 day-3wk)

2 days (1 day-2mo)

4mo (2mo-11mo)

4wk (3wk-2mo)

9mo (3mo-9mo)

2wk (2 days -1 5y)

5wk (7 days-4mo)

2wk (0 days-4mo)

Not reported


6wk (4wk-2mo)

6wk (3 days-7mo)

9 days (1 day-1 mol

9 days (1 day-3wk)

3 days (0 days-3wk)

4 days (O days-2wk)

3mo (5 days-4mo)

10 days (1 day-4mo)

1mo (8 days-l1 mol

1 day (1 day-1 day)


10 days (1 day-6wk)

8mo (4wk-2y)

NOl reported




















286 SJligser c _________________ ______________________________________________________















)













Acknowledgell



database search













-1shy
























galactorrhoea















)n should be high






ahilily BMJ I ~1)1 30( (~ 1 -7


























D Q)


---i T CD

3 ()

~ ~ 0 gt

3 ihmiddot -0 ()

lt0 CD () U)

()

0 -0

CD Cl

(3 3 3 CD ()

Q CD l amiddot J

8shy3 [ CD


cr lt )

3 a I


D l

r f)

J )

~ shyT

234 Spigset









Endocrinological




Metabolic






Respiratory


Musculoskelelal







Visual





Other















1_- ---- shy

SpissCI



7wk (3wk-5mo)

7wk (4wk-3mo)

7 days (1 day-6mo)


2 days (1 day-3wk)

2 days (1 day-2mo)

4mo (2mo-11mo)

4wk (3wk-2mo)

9mo (3mo-9mo)

2wk (2 days -1 5y)

5wk (7 days-4mo)

2wk (0 days-4mo)

Not reported


6wk (4wk-2mo)

6wk (3 days-7mo)

9 days (1 day-1 mol

9 days (1 day-3wk)

3 days (0 days-3wk)

4 days (O days-2wk)

3mo (5 days-4mo)

10 days (1 day-4mo)

1mo (8 days-l1 mol

1 day (1 day-1 day)


10 days (1 day-6wk)

8mo (4wk-2y)

NOl reported




















286 SJligser c _________________ ______________________________________________________















)













Acknowledgell



database search













-1shy
























galactorrhoea















)n should be high






ahilily BMJ I ~1)1 30( (~ 1 -7


























D Q)


SpissCI



7wk (3wk-5mo)

7wk (4wk-3mo)

7 days (1 day-6mo)


2 days (1 day-3wk)

2 days (1 day-2mo)

4mo (2mo-11mo)

4wk (3wk-2mo)

9mo (3mo-9mo)

2wk (2 days -1 5y)

5wk (7 days-4mo)

2wk (0 days-4mo)

Not reported


6wk (4wk-2mo)

6wk (3 days-7mo)

9 days (1 day-1 mol

9 days (1 day-3wk)

3 days (0 days-3wk)

4 days (O days-2wk)

3mo (5 days-4mo)

10 days (1 day-4mo)

1mo (8 days-l1 mol

1 day (1 day-1 day)


10 days (1 day-6wk)

8mo (4wk-2y)

NOl reported




















286 SJligser c _________________ ______________________________________________________















)













Acknowledgell



database search













-1shy
























galactorrhoea















)n should be high






ahilily BMJ I ~1)1 30( (~ 1 -7


























D Q)


286 SJligser c _________________ ______________________________________________________















)













Acknowledgell



database search













-1shy
























galactorrhoea















)n should be high






ahilily BMJ I ~1)1 30( (~ 1 -7


























D Q)

























galactorrhoea















)n should be high






ahilily BMJ I ~1)1 30( (~ 1 -7


























D Q)


adverse reactions of selective ., serotonin reuptake...

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