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P R E S C R I P T I O N - E V E N T M O N I T O R I N G A N D T H E C O X I B S

2

2 . 1

S A F E T Y P R O F I L E O F R O F E C O X I B A S U S E D I N G E N E R A L P R A C T I C E I N

E N G L A N D : R E S U L T S O F A P R E S C R I P T I O N - E V E N T

M O N I T O R I N G S T U D Y

Deborah Layton

Jane Riley

Lynda V. Wilton

Saad A.W. Shakir

Drug Safety Research Unit, Bursledon Hall, Blundell Lane, Southampton, UK

Br J Clin Pharmacol 2002; 55: 166-174

Reproduced with kind permission from Blackwell Science Ltd

3 8 | C H A P T E R 2 . 1 P E M A N D T H E C O X I B S | 3 9

I n t r o d u c t i o n

In June 1999, rofecoxib (Vioxx®), a cyclo-oxygenase (COX)-2 selective inhibitor,

was launched in the UK, licensed for the symptomatic relief of osteoarthritis. [1] The

benefit of selectivity is seen as maximum anti-inflammatory activity by potent inhibition

of the COX-2 isoenzyme, with minimal clinically significant effects on COX-1 isoenzyme

activity, thus improving the gastrointestinal (GI) adverse event profile. [2,3] Published

studies have shown that rofecoxib has equivalent efficacy to other non-steroidal anti-

inflammatory drugs (NSAIDs) and is associated with a reduced incidence of peptic

ulcers, perforations and GI bleeding compared to placebo and other non-selective

NSAIDs. [4-8] However, limitations of these published trials include the exclusion of

high-risk subgroups with current or recently active GI disease, and/or restrictions in

those receiving concomitant gastroprotective agents such as H2 antagonists.

The Drug Safety Research Unit (DSRU) provides an additional postmarketing drug

surveillance scheme which monitors the safety of newly marketed drugs during their

immediate postmarketing period in England, using the non-interventional observational

cohort technique of Prescription-Event Monitoring (PEM). [9] PEM systematically

collects data on patients prescribed a drug in primary care clinical practice, including

high-risk groups who may previously have been excluded from controlled clinical trials,

and are also likely to be exposed to the newly marketed drug because of the nature of their

disease. This paper reports the results of an observational cohort study undertaken to

examine the safety of rofecoxib as used by primary care physicians (GPs) in England.

M e t h o d s

Patients were identified by means of dispensed British National Health Service

(NHS) prescription data supplied in confidence by the Prescription Pricing Authority

(PPA) in England, between July and November 1999. A simple questionnaire (‘Green

Form’) was sent to the prescribing GP approximately 9 months after notification by the

PPA of the date of the first dispensed prescription (for each individual patient). This

interim period allows for prescribing patterns to establish for the newly licensed drug,

collection of prescription data by the PPA to achieve the anticipated cohort size, and

enables longitudinal monitoring of patients prescribed and dispensed the drug.

In PEM, the Green Form requests information on patient age, indication, dose,

effectiveness, duration of treatment (start and stop dates), reasons for stopping and any

A b s t r a c t

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) induced gastrointestinal (GI) toxicity is associated with inhibition of the cyclo-oxygenase (COX)-1 isoenzyme. COX-2 isoenzyme specific inhibitors are new agents considered to lack the liability for GI symptoms associated with COX-1 inhibition. Rofecoxib was the first COX-2 specific inhibitor to be marketed in the United Kingdom (UK), in June 1999.

Objectives: To monitor the safety of rofecoxib prescribed in the primary care setting in England using Prescription-Event Monitoring (PEM).

Methods: A postmarketing surveillance study using the observational cohort technique of PEM. Questionnaires requesting clinical event data were sent to prescribing physicians between February and November 2000, and the data analysed for all events.

Results: There were 15 268 patients identified, mean age 62 years, 67% female. The commonest specified indication was osteoarthritis (24%). Dyspepsia and nausea were the most frequently reported adverse events. A history of dyspeptic or upper gastrointestinal (GI) conditions, recent use of other non-steroidal anti-inflammatory drugs (NSAIDs), use of selected concomitant gastroirritant drugs (NSAIDs, aspirin, anticoagulants, antiplatelet drugs), or gastroprotective drugs (misoprostol, antacids, proton-pump inhibitors, histamine2 antagonists), and age (>65 years) modified the risk of having minor GI events. During treatment or within one month of stopping, 110 serious GI events were reported (including 76 upper GI bleeds/peptic ulcers, one perforated colon); 101 thromboembolic events, three reports of acute renal failure, one each of Stevens-Johnson syndrome, severe anaphylaxis and angio-oedema.

Conclusions: Doctors should continue to prescribe NSAIDs including COX-2 selective inhibitors with caution.


to test the hypothesis that the rate did not change over time. Where the arithmetic

difference between ID1 and ID2 was above 0 at the level of p = 0.01, this was considered

to be a signal of a possible ADR, especially for predictable (Type A) reactions.

IDs for all events were stratified according to the responses to the additional

questions posed on the Green Form. Crude IDs were calculated separately for the most

frequently reported GI events (dyspepsia, nausea/vomiting, diarrhoea, abdominal pain,

unspecified GI events, constipation, abdominal distension, upper GI haemorrhage, GI

haemorrhage, rectal haemorrhage, peptic ulcer), and indicators of bleeding (anaemia

and iron deficiency anaemia) according to positive and negative response to the

additional questions, or age (>65 years vs ≤64 years). The ID ratios were then calculated

and examined using univariate (Mantel-Haenszel) methods. In order to account for

multiple testing, comparisons were modified using the Bonferroni’s correction. [10] A

Microsoft SQL query was used to retrieve data from the DSRU PEM database, followed

by analysis using Excel, Access and STATA 7.0.

All records and computer data are stored at the DSRU to maximise patient

confidentiality. PEM is conducted in accordance with international ethical

guidelines. [11-13]

Sample sizeThe ability to detect an ADR is dependent upon the expected incidence rate of

that ADR for those exposed, the background rate of those unexposed and number of

patients available. A sample size of 10 000 patients should allow for the detection of at

least three cases of an ADR if it occurred with an incident rate of between 1 in 1000

and 1 in 2000 patients, assuming that it was very rare as a background event. Power, 1-ß,

given as 0.80. [14]

R e s u l t s

Of forms posted, 40% (16 861/42 303) were returned. Of these, 1593 (10.4%)

were void [reasons: patient or doctor moved (n=809); blank forms (n=550); no record of

treatment in notes (n=178); rofecoxib prescribed but not taken (n=49); duplicate Green

Form (n=6); wrong drug dispensed (n=1)]. Thus, useful information was available for

15 268 patients. Overall, the mean age was 62.2 ± 14.6 years; 10 289 (67.4%) patients

were females.

significant health-related events that may have occurred to the patient since the day the

drug was started, including events considered an adverse drug reaction (ADR). Reported

events are coded using the DSRU event dictionary, a hierarchical dictionary arranged by

system-organ class with selective ‘lower’ terms grouped together under broader ‘higher’

terms. Those questionnaires returned with no information (clinical or other) provided

are classified as ‘void’ and excluded from the study cohort and subsequent analysis, as

there is no means of determining whether forms not completed indicated no reported

events.

For this PEM study, the questionnaires also included three additional questions

regarding potential risk factors for GI conditions; past medical history of dyspeptic

symptoms or other upper GI conditions; whether any NSAIDs had been prescribed in

the 3 months prior to rofecoxib and whether any gastroprotective or irritant drugs were

prescribed during treatment with rofecoxib (NSAIDs, aspirin, misoprostol, antacids,

proton pump inhibitors (PPIs)/H2 antagonists, anticoagulants, antiplatelet agents).

Each individual Green Form was reviewed by a DSRU research fellow and the

circumstances of each event assessed. All pregnancies, any events of interest of particular

concern with this drug and not mentioned in the Summary of Product Characteristics

(SPC) [1] or considered medically important and where additional information was

required, were followed up by sending additional questionnaires to the prescribing GP.

Individual case reports were assessed for causality by a clinical research fellow at the

DSRU, using four basic considerations (temporality, pharmacological plausibility, clinical

and pathological characteristics of the event, exclusion of other possible causes) and five

categories (probable, possible, unlikely, awaiting further information or not assessable).

If no reply was received, one further reminder was sent. In the case of deaths, if the

cause was not specified, a copy of the death certificate was requested from the Office of

National Statistics.

Statistical analysisIncidence densities (IDs) were calculated for all reported events during treatment

within specified time periods and expressed as the number of first reports of an event

per 1000 patient months of treatment. IDs for events occurring in the first month of

treatment (ID1), during months 2-6 of treatment (ID2) and for events occurring during

the overall treatment period (IDA) were calculated either for patients for whom the date

of stopping the drug was known, or in those who continued to take the drug until the

end of the study period. The difference between the two rates (ID1 – ID2) was calculated


bleeding, 11 events possibly associated with a thromboembolic event [cerebrovascular

accident (CVA), myocardial infarction (MI), aphasia, dysphasia, slurred speech], three

reports of acute renal failure, one each of anaphylaxis and angioneurotic oedema.

Table 1. Incidence densities (ID) for events, ranked in order of number of events in month 1 (where ID1-ID2 >0)

Higher Term Description N1

N2

ID1

ID2

ID1 - ID

2CI min CI max N

AID

A

Incidence risk (%)

No. of ADRs

Dyspepsia 394 332 33.6 10.2 23.4 18.8 28.0 835 13.0 5.47 50

Nausea, vomiting 179 116 15.3 3.6 11.7 8.6 14.8 326 5.1 2.14 51

Diarrhoea 160 109 13.6 3.3 10.3 7.4 13.2 300 4.7 1.96 37

Pain abdomen 160 145 13.6 4.4 9.2 6.3 12.1 358 5.6 2.34 32

Oedema 86 79 7.3 2.4 4.9 2.8 7.1 198 3.1 1.30 7

Dizziness 78 54 6.6 1.7 5.0 3.0 7.0 152 2.4 1.00 25

Intolerance 69 24 5.9 0.7 5.2 3.3 7.0 99 1.5 0.65 4

Headache, migraine 69 66 5.9 2.0 3.9 1.9 5.8 161 2.5 1.05 13

Gastrointestinal unspecified

61 54 5.2 1.7 3.6 1.7 5.4 129 2.0 0.84 35

Malaise, lassitude 59 54 5.0 1.7 3.4 1.6 5.2 136 2.1 0.89 21

Pruritus 50 47 4.3 1.4 2.8 1.2 4.5 114 1.8 0.75 11

Rash 40 59 3.4 1.8 1.6 0.1 3.1 123 1.9 0.81 11

Dyspnoea 35 39 3.0 1.2 1.8 0.4 3.2 89 1.4 0.58 4

Constipation 28 27 2.4 0.8 1.6 0.3 2.8 70 1.1 0.46 2

Unspecified side effects 27 18 2.3 0.6 1.8 0.6 2.9 51 0.8 0.33 47

Insomnia 24 19 2.0 0.6 1.5 0.3 2.6 50 0.8 0.33 6

Drowsiness, sedation 21 11 1.8 0.3 1.5 0.4 2.5 35 0.5 0.23 11

N1 , total number of reports of each event during the first month of treatment; N2 , total number of reports of each event during treatment in months 2-6; ID1 , incidence density for each event during the first month of treatment; ID2 , incidence density for each event during treatment months 2-6; ID1-ID2 , arithmetic difference between ID1 and ID2; 99% CI , 99% confidence intervals for ID1-ID2 ; NA , total number of reports of each event during the total treatment period; IDA incidence density for each event for the total treatment period; Incidence risk (%) as proportion of events reported by study cohort (n=15 268); CI: confidence interval, ADR: adverse drug reaction

In total, 2557 (17.9%) out of 14 308 events reported during treatment were associated

with the GI system. A summary of events associated with GI bleeding, and anaemia is

presented in Table 2. Twenty-one out of 90 events assessed as ‘possibly/probably associated’

occurred within the first month of exposure, of which eight had been prescribed other

NSAIDs in the 3 months prior to rofecoxib, suggesting the possibility of a carry-over effect.

The major specified indication was osteoarthritis (23.7%, n=3621). The indication

was not specified for 38.1% (n=5810), and the remaining 38.2% (n=5837) were for

other (predominantly musculoskeletal) indications. Of 10 977 (71.8%) Green Forms

that included a GP opinion about effectiveness, 7447 (68%) reported rofecoxib as being

effective.

An event was coded as an ADR if the GP specified that the event was attributable

to the drug; 491 events in 360 (2.4%, n=15 268) patients were reported as ADRs with 62

(12.6%) of these events documented as reported by the prescriber to the Committee on

Safety of Medicines (CSM). Suspected ADRs included dyspepsia (five reports), nausea

(five), dizziness (four), melaena (two), cardiac failure (two) and acute renal failure (one).

The clinical events reported most frequently (for which ID1 - ID2 was significantly

greater than 0 at the p=0.01 level) are shown in Table 1, ranked in descending order

according to the number of events reported in the first month. Commonly occurring listed

events [1](≥1 in 100 patients) were, in descending order of ID1 per 1000 patient months:

‘dyspepsia’, ‘nausea/vomiting’, ‘diarrhoea’, ‘abdominal pain’, ‘oedema’, ‘dizziness’ and

‘headache/migraine’. Listed events occurring less frequently (<1 in 100 patients but

>1 in 1000 patients) were ‘malaise/lassitude’, ‘rash’, ‘dyspnoea’, ‘constipation’, and

‘insomnia’. The event ‘ drowsiness/sedation’ was not listed in the SPC, and ‘pruritus’

was reported less frequently than listed.

Events of interest which did not occur in sufficient numbers to generate a signal

using the ID1-ID2 statistic included: haemorrhage of upper GI tract (ID1 1.4, n1=16);

cardiac failure (ID1 1.6, n1=19); asthma/wheezing (ID1 1.4, n1=16); inflammatory disease

of the colon (ID1 1.0, n1=12); and anaemia (ID1 1.0, n1=12).

Other events of interest included reports affecting the renal system [acute renal

failure (all three reports ‘possibly’ related to rofecoxib) and abnormal renal function

tests (9/24 reports ‘possibly’ related)]; and the hepatic system [pancreatitis (five reports

unlikely related), jaundice (one report unlikely), and abnormal liver function tests (4/20

reports ‘possibly’ related)]. One case each of anaphylaxis requiring urgent hospital

treatment, Stevens Johnson Syndrome, and angioneurotic oedema were reported, and

all three cases assessed as ‘possibly’ related. Nine out of 13 reports of oedema of the face

were also assessed as possibly related to rofecoxib.

GPs recorded 7430 reasons for stopping rofecoxib for 6653 patients. The commonest

reasons given were not effective (n=2817) and condition improved (n=1222). A total

of 1499 (20.2%) reports of dyspepsia and other GI symptoms were given as reasons

for stopping. Other reasons of interest included: 41 upper GI bleeding, 10 lower GI


Table 3 Rate per 1000 patient months exposure and relative risks† (95% confidence interval) for selected gastrointestinal (GI) events and anaemia according to response to additional questions‡.

Event Number of events Rate Relative risk (95% CI) χ2 P-value*

Past history of dyspeptic symptoms and other upper GI conditions

Dyspepsia

Yes 611 18.19 2.69 (2.21-3.26) <0.0001

No 123 6.77 1

Pain abdomen

Yes 242 7.20 1.87 (1.43-2.44) <0.0001

No 70 3.85 1

Gi unspecified

Yes 93 2.77 4.19 (2.30-7.65) <0.0001

No 12 0.66 1

NSAIDs had been prescribed in the 3 months prior to rofecoxib.

Dyspepsia

Yes 373 12.48 0.79 (0.68-0.91) 0.0015

No 360 15.80 1

Nausea, vomiting

Yes 137 4.58 0.68 (0.54-0.86) 0.001

No 153 6.71 1

Use of concomitant gastroprotective drugs (misoprostol, antacids, proton-pump Inhibitors /H2 antagonists)

Dyspepsia

Yes 329 23.34 2.44 (2.09-2.85) <0.0001

No 317 9.56 1

Pain Abdomen

Yes 125 8.87 1.84 (1.46-2.33) <0.0001

No 160 4.83 1

Age:>65 years, compared to ≤64 years

Diarrhoea

>65 years 199 5.31 1.42 (1.12 - 1.80) 0.003

≤64 years 105 3.73 1

Haemorrhage GI

>65 years 1 0.03 0.04 (0.01 - 0.33) 0.002

≤64 years 17 0.60 1

*Bonferroni’s correction for 12 tests comparing event rates of 12 selected events of interest per additional questions: adjusted P-value for statistical significance, p<0.004;†Calculated using Poisson regression.‡Use of concomitant drugs leading to increased risk of bleeding (NSAIDs, aspirin, anticoagulants, antiplatelet drugs); none of selected events achieved statistical significance after introducing Bonferroni’s correction.

Of the 26 follow-up reports of rectal bleeding reviewed, seven cases who had a

history of diverticulitis were assessed as ‘possibly’ related, six out of seven cases who

Tab

le 2

. R

epor

ts of

gas

troin

testin

al (G

I) ev

ents

and

anae

mia

follo

wed

-up

and

caus

ality

ass

essm

ent.

Even

tN

umbe

r of

all

even

ts

Num

ber

repo

rted

*Fo

llow

-up

resp

onse

Sex

Med

ian

age

(IQR)

year

s

Past

his

tory

of

dys

eptic

sy

mpt

oms

or o

ther

up

per G

I co

nditi

ons

NSA

ID

pres

crib

ed

with

in 3

m

onth

s pr

ior t

o st

artin

g ro

feco

xib

Conc

omitt

ant

Med

icat

ion

Asse

ssed

as

‘pos

sibl

y’ o

r ‘p

roba

bly’

re

late

dM

ale

Fem

ale

Gas

tro-

irrita

nt‡

Gas

tro-

prot

ectiv

e§

Pept

ic u

lcer

atio

n10

576

57/7

6 (7

5%)

1827

77 (6

0,79

)37

2215

1845

Low

er G

I ble

ed48

3326

/33

(79%

)11

1169

(66,

77)

71

73

22

Anae

mia

9874

34/4

8 (7

1%)†

616

74 (6

1,80

)18

108

922

Perf

orat

ed c

olon

31

1/1

(100

%)

10

711

00

11

*Dur

ing

treat

men

t or

with

in a

mon

th o

f sto

ppin

g;†

Tw

enty

-six

not

sele

cted

for

follo

w-u

p: s

econ

dary

to

othe

r di

seas

e (1

9),

GI

blee

d (5

), de

aths

(2)

and

no

furth

er

info

rmat

ion

avai

labl

e;‡ G

astro

irrita

nt d

rugs

: as

pirin

, an

ticoa

gula

nts

and

antip

latel

et dr

ugs;§

Gas

tropr

otec

tive

drug

s: m

isopr

osto

l, an

tacid

s, pr

oton

-pum

p in

hibi

tors/

hista

min

e 2 ant

agon

ists


(8/41) satisfied the Joint British Societies criteria for the use of aspirin for secondary

cardiovascular prophylaxis (history of ischaemic heart disease (IHD), MI, CVA, TIA,

angioplasty or coronary artery bypass graft). [15] Causality assessment for cardiovascular

events was not carried out because these events are heavily confounded by previous

history of cardiovascular disease. Where the prescribing physician gave an opinion of

relation of these events to treatment, only one report (for TIA) was thought attributable

to rofecoxib use.

Table 4. Thromboembolic (TE) lower term events followed up

Event Total no. of all

events

Total no. reported *

Follow-up response

Sex Follow-up Risk factors

present for TE (>1)†‡

On con-comitant

anti-coagulant‡

Female Male Age, Median

(IQR) years

Cerebrovascular accident

56 40 25/35 (71%)§ 18 7 78 (71,86) 21 12

Transient ischaemic attack

30 24 22/24 (92%)¶ 17 4 75 (66,79) 17 12

Myocardial infarction

37 24 17/19 (84%)** 7 9 70 (64,75) 10 8

Deep vein thrombosis

17 9 9/9 (100%)†† 7 2 67 (63,75) 7 3

Pulmonary embolism

7 3 3/3 (100%) 0 3 55 (54,57) 3 0

Retinal vein thrombosis

2 1 0/1 (0%) - - - -

* During treatment or within 1 month of stopping. †Risk factors: past medical history ischaemic heart disease, diabetes, hypertension, cigarette smoker, obesity, recent surgery, peripheral vascular disease, polymyalgia rheumatica, atrial fibrillation, previous TE event. ‡Where follow-up received. §Five not selected for follow-up: pre-existing disease (3) and fatalities (2) no further information available, 1 one follow-up was a non-Event. ¶One follow-up was a non-Event. ** Five not selected for follow-up: pre-existing disease (2), and fatalities (3) no further information available. ††One patient duplicate Green Forms. IQR,: Interquartile range.

PregnanciesOf 1071 women aged 15 - 45 years in the cohort, nine pregnancies were reported,

two were planned and treatment stopped before the women become pregnant. The

seven pregnant women exposed to rofecoxib during the first trimester resulted in five live

births, one spontaneous miscarriage and one termination. Other than an undescended

testis, there were no abnormalities found.

had a history of rectal bleeding were ‘possibly’ related, and three out of four cases who

had a history of inflammatory bowel disease were considered ‘possibly’ related. There

were 19 reports of inflammatory bowel disease reported during treatment (colitis (n=10),

ulcerative colitis (n=4), Crohn’s disease (n=5)), diverticulitis (n=7), and 27 reports of

irritable bowel syndrome (IBS). On examinations, all ten reports of colitis, two reports of

ulcerative colitis and five reports of Crohn’s disease were exacerbations of pre-existing

disease.

Table 3 shows crude rates per 1000 person-years according to response to the

additional questions plus age (>65 years, ≤64 years), and rate ratios which achieve

statistical significance after adjustment for multiple significance testing. A past history

of dyspeptic symptoms or other upper GI conditions, and use of concomitant

gastroprotective drugs were each associated with a significantly increased relative risk

of dyspepsia and abdominal pain, which is consistent with channelling of patients at

high risk of these upper GI events. Conversely, a recent prescription of NSAIDs prior

to rofecoxib was associated with a decreased relative risk of dyspepsia. Cross tabulation

of use of NSAIDs prior to rofecoxib with use of either H2 antagonists (χ2 p<0.1) or

misoprostol (both χ2 p<0.1) suggests a link between use of gastroprotective agents and

prior use of NSAIDs in this cohort, which may explain the relative reduction in rate of

upper GI events (dyspepsia) where NSAIDS were reported to have been used within 3

months prior to rofecoxib. Furthermore, the significant relative reduction in rate of GI

haemorrhage for those aged >65 years, compared to those aged ≤64 years may be a

result of raised suspicion of such symptoms in this age group.

Other events of interestIn view of the concern regarding the possible differential effects of NSAIDs

on cardiovascular risk, a summary of those lower term events associated with

thromboembolism (TE) [including MI, CVA, transient ischaemic attack (TIA), retinal

vein thrombosis, deep vein thrombosis (DVT) and pulmonary embolism (PE)] is presented

in Table 4. In total, 101 events were reported during treatment or within a month of

stopping treatment.

Seventy-six replies out of 91 acute thromboembolic events followed-up were received

(84% response). Of these reports, 54 (71%) occurred in patients aged >65 years, 58 (76%)

reports occurred in patients with one or more risk factors for thromboembolism and

coronary heart disease, and 35 (46%) reports occurred in patients taking concomitant

aspirin or other anticoagulant agents. Among those not taking such medication, 20%


general practice use of rofecoxib regardless of age, past medical history or concomitant

medication. The large cohort of 15 268 patients enabled a considerable amount of

clinical information to be gathered. Furthermore, by asking GPs to supply ‘event’ data

without causality assessments, the study design was capable of identifying signals which

none of the participating GPs suspected to have been due to an adverse drug reaction.

The methodology of PEM does not lend itself to identifying the background prevalence

of events of interest in the population of England, but to identifying possible signals

of events of public health interest which then require further evaluation by means of

internal comparisons with other suitable PEM drug cohorts, or for example external

comparisons using demographic data of the population as a whole. Other sources

available in the UK for monitoring the safety of marketed medicines include the General

Practice Research database (GPRD), and the Medicines Monitoring Unit (MEMO)

record-linked databases. [16] Differences in data collection prevent comparisons with

these external databases. For example, because of the size of the population covered by

GPRD there is usually paucity of data regarding recently introduced products.

In PEM studies, a period of at least 6 months is typically used between notification

of a prescription being issued and the sending of Green Forms. This allows the patient

time to have the prescription dispensed, take the medication and report events that might

occur. As PEM uses record-based data of events deemed of significance to report to the

GP, recall bias is likely to be minimal. Regarding the 9-month observation time reported

for this study, this is a longer interval than normal, due to a combination of technical

difficulties that occurred at the PPA and the DSRU at the time of the study. However,

rather than resulting in an underestimate, one could argue that the longer observation

period would allow for the detection of possible latent events.

Achieving high response rates is an important issue in any postmarketing

surveillance study. This PEM study had a lower than the average response rate (normally

59%). Whilst the Green Form response rate for rofecoxib was 40% (after voids 35%), the

response rate is still substantial compared with the proportion of suspected adverse drug

reactions which are reported in spontaneous ADR reporting schemes. [17;18] For data

collection systems that are dependent on a third party, such as PEM, response bias is

likely. [19] We do not know if the responders were representative of all prescribers. The

fall in GP response rates to postal surveys [19;20] and PEM has been reported elsewhere

as attributable to increased workload. [21;22] Other methods of improving response to

questionnaires such as reminders [23] and providing feedback [24] are being considered

for PEM.

DeathsIn total, 299 deaths occurred during the study observation period, cause of death

was not ascertained for 13 patients. The underlying cause of death was cardiovascular

for 103 cases, cancer for 109 cases, and non cardiovascular for 74. For cardiovascular

deaths, 11 occurred within the first month of starting treatment; five were recorded as

a MI, two from a CVA and one each resulting from a PE. Insufficient information was

available to undertake a causality assessment in these patients.

Four patients died from serious upper GI adverse events: duodenal ulcer, duodenal

ulcer haemorrhage, GI haemorrhage and a perforated peptic ulcer. Additional follow-up

information (lifetime medical records) was received only for three patients. All three were

elderly (age range 69-83 years) and none were reported to be taking rofecoxib at time of

death (treatment had been stopped between 1 to 4 months prior to death). One patient

was on another NSAID at the time of death, one was on low-dose aspirin and the

third was on both. There were three deaths resulting from large bowel perforation (two

from a perforated colon and one from a perforated diverticulum). Additional follow-up

information was received for one patient only, which indicated that this patient had

discontinued rofecoxib 7 months prior to death.

D i s c u s s i o n

This PEM study provides a descriptive analysis of a population prescribed

rofecoxib under primary care conditions in England, a summary of the events reported

during use and possible signals of interest. The demographic data of this cohort were

consistent with that expected for an NSAID (51% ≥60 years, 67% females). Although

only licensed for use in osteoarthritis during the time of the study, rofecoxib was also

prescribed for a range of acute and chronic (predominantly musculoskeletal) conditions.

The most frequently reported adverse events in this PEM study were those GI events

commonly associated with treatment with other traditional non-selective NSAIDS, and

which occurred with a similar incidence to that mentioned in the SPC for rofecoxib. [1]

Our study also examined important risk factors for adverse GI events, and the results

suggested channelling of patients already at high risk of GI events.

PEM uses a non-interventional observational cohort design that does not interfere in

the prescribing decisions of the GPs, or specify strict inclusion criteria that occur within

controlled clinical trials. Thus a strength of this study is that it provides information on the


associated with use of NSAIDs, which may explain the relative reduction in rate of such

events. When the individual case histories of the reports of more serious GI events were

examined, at least 60% of those reports assessed as ‘possibly/probably related’ were in

patients with a past history of dyspepsia/upper GI disorder and in patients ≥65 years.

The product information states that patients with a past history of perforations, ulcers or

bleeds or age ≥65 years are at higher risk of developing a perforation, ulcer or bleed. [1]

These results could suggest channelling of patients at high risk of GI events. However,

it is expected that GPs would prescribe COX-2 selective drugs to these patients, in the

belief that these agents are less likely to cause such complications. Indeed, many GPs

would view such patients as prime candidates for a therapeutic trial of a new drug such

as this.

Regarding the relationship of the risk of GI events to the duration of exposure

to NSAIDs, epidemiological studies have suggested that the risk of GI complications

is highest in the first month of NSAID use. The meta-analysis by Gabriel et al.,[30]

reported an odds ratio of 8.0 [95% confidence interval (CI) 6.4,10.1] for <1 month of

NSAID use, 3.3 (95% CI 2.3, 4.8) for 1-3 months use, and 1.9 (95% CI 1.2, 3.1) for >3

months use. Conversely, other prospective trials, such as the VIGOR study, failed to

show such a change in risk over time either for clinical upper GI events or complicated

upper GI events. [7] Symptoms of acute gastric injury (such as mucosal erythema,

superficial erosions or haemorrhages) have been reported with a frequency of 60-100%

of patients on NSAID therapy, but complicated events such as gastric or duodenal ulcers

occur with a frequency of between 5 to 30% after 1 month of chronic NSAID therapy

or more. [31] In PEM, time-dependent treatment effects can be evaluated by comparing

the incidence of events reported within the first month of treatment to the subsequent

5 months. While drug-related adverse events often occur within the first few weeks of

treatment, and a study examining the immediate post-exposure period (weeks) could

identify such events, the events in our study are dependent on third-party reporting

and those events deemed less serious by the patient may not be reported immediately.

Furthermore, a strength of PEM is that the follow-up period allows for the collection of

event data which may signal delayed adverse reactions. [32]

Regarding lower GI tract adverse events, there is a link between non-selective

NSAIDs and exacerbation of inflammatory bowel disease (IBD); however, the evidence

implicating COX-2-specific inhibitors is weak. [33] Rofecoxib is contraindicated in

patients with a known history of IBD. [1] In this PEM study several reports of lower

GI tract events were in patients with a known history of such disorders. Inflammatory

Selection bias should be considered as we do not know at present the characteristics

of patients of doctors who do not respond and whether these patients experience similar

rates of adverse events when compared with patients of doctors who do respond to

Green Form questionnaires. Although one would wish to compare the characteristics

(such as age, sex and geographical distribution) of responders to non-responders, at

present this information is not routinely provided by the PPA. Furthermore, since data

collection in PEM is systematic, prospective and independent of individual studies,

limited information is available on other risk factors, e.g. smoking, alcohol use, and

concomitant medication. This study is limited to experience in primary care, excludes

information on patients prescribed rofecoxib in secondary care, and it is not possible to

estimate the degree of patient compliance.

Reports from clinical trials of rofecoxib in treatment of osteoarthritis indicate that

rofecoxib is associated with a lower incidence of treatment discontinuations due to GI

adverse events and ‘nuisance’-type symptoms than treatment with non-selective NSAIDS

[7;25] and reported to be associated with a significantly lower incidence of upper GI

tract bleeding events than treatment with NSAIDS. [5] In our study the most commonly

reported adverse events or reasons for stopping were ‘nuisance’ GI symptoms, such as

dyspepsia, nausea and pain in the abdomen.

Upper GI symptoms are not good predictors of the development of upper GI

events, and that dyspepsia is extremely common in patients not taking NSAIDs.

Nevertheless epidemiological studies show a significant increase in clinical upper GI

events with NSAID use (aspirin and non-aspirin NSAIDs) of between two- and six-fold

compared to nonusers, [26] and this increased risk may persist after discontinuation

of NSAID. [27] Dyspepsia has been proposed as a risk factor for NSAID-associated

complications. [28;29] In our study, a past history of dyspeptic symptoms or other GI

conditions, and use of an NSAID within 3 months prior to starting treatment, were

identified as an important risk factors. Stratification of all data by age and response to

the additional questions regarding these and other risk factors showed that people aged

>65 years, a past history of upper GI disorder; a recent prescription of NSAIDs prior

to rofecoxib and concomitant use of gastroprotective agents modified the risk of having

some minor GI symptoms. Those reported to have a past history of dyspeptic symptoms

and other GI conditions, and/or reporting use of concomitant gastroprotective drugs

were more likely to get upper GI events during treatment than those who did not. The

decreased relative rate of GI symptoms in those using NSAIDS within 3 months prior

to starting treatment was unexpected, but in this study use of gastroprotective drugs was


serious upper and lower GI events, as well as cases of thromboembolic events and renal

failure, did occur. Further longer-term comparative studies with non-selective NSAIDs

are needed to fully assess the risk-benefit impact of the COX-2 inhibitors in ‘real-world’

settings. Until such data are available, doctors should continue to prescribe all NSAIDs

with caution. In its guidance the National Institute for Clinical Excellence (NICE) restricts

the use of COX-2 inhibitors to arthritis patients who are at higher risk of developing

serious GI problems. [41] They also advise that they should not generally be prescribed

in preference to standard NSAIDs in patients with cardiovascular disease.

R e f e r e n c e s

(1) MSD. Summary of Product Characteristics: Vioxx.® 1999. (2) McKenna F. COX-2: separating myth from reality. Scand J Rheumatol Suppl 1999;

109:19-29.(3) Kam PC, See AU. Cyclo-oxygenase isoenzymes: physiological and pharmacological role.

Anaesthesia 2000; 55(5):442-449.(4) Laine L, Harper S, Simon T, Bath R, Johanson J, Schwartz H et al. A randomized trial

comparing the effect of rofecoxib, a cyclo-oxygenase 2-specific inhibitor, with that of ibuprofen on the gastroduodenal mucosa of patients with osteoarthritis.Rofecoxib Osteoarthritis Endoscopy Study Group. Gastroenterology 1999; 117(4):776-783.

(5) Langman MJ, Jensen DM, Watson DJ, Harper SE, Zhao PL, Quan H et al. Adverse upper gastrointestinal effects of rofecoxib compared with NSAIDs. JAMA 1999; 282(20):1929-1933.

(6) Cannon GW, Caldwell JR, Holt P, McLean B, Seidenberg B, Bolognese J et al. Rofecoxib, a specific inhibitor of cyclo-oxygenase 2, with clinical efficacy comparable with that of diclofenac sodium: results of a one- year, randomized, clinical trial in patients with osteoarthritis of the knee and hip. Rofecoxib Phase III Protocol 035 Study Group. Arthritis Rheum 2000; 43(5):978-987.

(7) Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000; 343(21):1520-8, 2.

(8) Hawkey C, Laine L, Simon T, Beaulieu A, Maldonado-Cocco J, Acevedo E et al. Comparison of the effect of rofecoxib (a cyclo-oxygenase 2 inhibitor), ibuprofen, and placebo on the gastroduodenal mucosa of patients with osteoarthritis: a randomized, double-blind, placebo-controlled trial. The Rofecoxib Osteoarthritis Endoscopy Multinational Study Group. Arthritis Rheum 2000; 43(2):370-377.

(9) Mann RD. Prescription-Event Monitoring--recent progress and future horizons. Br J Clin Pharmacol 1998; 46(3):195-201.

diseases of the colon were not highlighted as potential signals using the ID1-ID2 statistic,

but further investigation of this issue is warranted.

Thromboembolic events reported during this study became of interest as a result

of the concern that COX-2 selective inhibitors may contribute to an increased risk of

platelet-mediated adverse vascular events. [7,34,35] Rofecoxib does not appear to inhibit

platelet aggregation (mediated by COX-1) or prolong bleeding time. [36] It is plausible

that selective inhibition of COX-2 isoenzyme may not protect the cardiovascular

system to the same extent as aspirin, [37] or some non-selective NSAIDs. [38,39]

PEM is a dynamic process and not all events of interest can be identified in advance

of starting any study. This issue regarding possible change in cardiovascular risk was

reported subsequent to the completion of this PEM study. [34] The case histories of

thromboembolic events in this PEM study showed that 71% of the patients were >65

years, 76% had risk factors for IHD or thromboembolism and 46% were on concomitant

aspirin. There is no evidence from the PEM data currently available to suggest that any

deaths were attributable to rofecoxib. The DSRU is investigating this issue.

The Medicines Control Agency (MCA)/CSM spontaneous reporting system

provides one of the major sources of data in the process of pharmacovigilance in the

UK. Up to July 2000, most suspected ADRs submitted to the MCA/CSM for rofecoxib

were for non-serious GI symptoms (nausea, dyspepsia and abdominal pain). [40] There

were also 68 reports of upper GI bleeding, perforations and ulcerations (five fatal), and

177 cardiovascular system reports, mainly oedema (n=101) or hypertension (n=31). More

serious reports included 15 of cardiac failure and nine MIs (three fatal). Most of these

patients had risk factors for cardiac disease. The nature of events for which reports of

suspected ADRs were submitted to the MCA/CSM and adverse events reported in this

PEM study is similar. However, there is a distinct difference in the data collected, in that

spontaneous reports assume a causal relationship. Whilst the strength of spontaneous

reporting schemes is to identify potential signals of rare adverse reactions, limitations

include problems estimating population exposure to calculate incidence rates. Thus

this PEM study provides complimentary data regarding incidence rates of commonly

reported events.

Assessment of drug safety involves processing all the available information from

preclinical studies, pre- and postmarketing clinical trials, spontaneous adverse reaction

reporting, epidemiological studies and evaluation of prescription and outcome data

collected systematically. Rofecoxib was the first ‘coxib’ studied using PEM. The vast

majority of adverse events reported in this study were minor GI symptoms. However,


(27) Talley NJ, Evans JM, Fleming KC, Harmsen WS, Zinsmeister AR, Melton LJ, III. Non-steroidal anti-inflammatory drugs and dyspepsia in the elderly. Dig Dis Sci 1995; 40(6):1345-1350.

(28) Hansen JM, Hallas J, Lauritsen JM, Bytzer P. Non-steroidal anti-inflammatory drugs and ulcer complications: a risk factor analysis for clinical decision-making. Scand J Gastroenterol 1996; 31(2):126-130.

(29) MacDonald TM, Morant SV, Robinson GC, Shield MJ, McGilchrist MM, Murray FE et al. Association of upper gastrointestinal toxicity of non-steroidal anti-inflammatory drugs with continued exposure: cohort study. BMJ 1997; 315(7119):1333-1337.

(30) Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious gastrointestinal complications related to use of non steroidal anti-inflammatory drugs. A meta-analysis. Ann Intern Med 1991; 115(10):787-796.

(31) Raskin JB. Gastrointestinal effects of non-steroidal anti-inflammatory therapy. Am J Med 1999; 106(5B):3S-12S.

(32) Wilton LV, Stephens MD, Mann RD. Visual field defect associated with vigabatrin: observational cohort study. BMJ 1999; 319(7218):1165-1166.

(33) Lipsky PE, Brooks P, Crofford LJ, DuBois R, Graham D, Simon LS et al. Unresolved issues in the role of cyclo-oxygenase-2 in normal physiologic processes and disease. Arch Intern Med 2000; 160(7):913-920.

(34) Food and Drug Administration advisory committee. cardiovascular safety review of rofecoxib. [online] Available at URL: http:/www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_06_cardio.pdf . 2001. Date accessed Sept 8 2001.

(35) Daniels B, Seidenberg B. Cardiovascular safety profile of rofecoxib in controlled clinical trials. Arthritis Rheum 1999; 42(Suppl S143).

(36) Van Hecken A, Schwartz JI, Depre M, De L, I, Dallob A, Tanaka W et al. Comparative inhibitory activity of rofecoxib, meloxicam, diclofenac, ibuprofen, and naproxen on COX-2 versus COX-1 in healthy volunteers. J Clin Pharmacol 2000; 40(10):1109-1120.

(37) The physicians’ health study: aspirin for the primary prevention of myocardial infarction. N Engl J Med 1988; 318(14):924-926.

(38) Brochier ML. Evaluation of flurbiprofen for prevention of reinfarction and reocclusion after successful thrombolysis or angioplasty in acute myocardial infarction. The Flurbiprofen French Trial. Eur Heart J 1993; 14(7):951-957.

(39) Boers M. NSAIDS and selective COX-2 inhibitors: competition between gastroprotection and cardioprotection. Lancet 2001; 357(9264):1222-1223.

(40) CSM/MCA. In focus... Rofecoxib (Vioxx®). Current Problems in Pharmacovigilance 2000; 26:13.

(41) National Institute of Clinical Excellence. Guidance on use of cyclo-oxygenase (COXII) selective inhibitors celecoxib, rofecoxib, meloxicam and etodoloac for osteoarthritis and rheumatoid arthritis. 2001 Technology Appraisal No.27. Department of Health, London.

(10) Campbell M, Daly L, Machin D. Special topics. In: Altman D, Machin D, Bryant T, Gardner MJ, editors. Statistics with Confidence. Bristol: BMJ Books, 2000.

(11) Legemaate J. The CIOMS guidelines for biomedical research involving human subjects. Eur J Health Law 1994; 1(2):161-165.

(12) Royal College of Physicians of London. Guidelines on the practice of Ethical Committees in Medical Research involving Human Subjects. 1996.

(13) Anonymous. Multi-Centre Research Ethics Committees Guidance Notes. Examples of enquiries and surveys in the public interest where no reference to a Research Ethics Committee is necessary. Appendix C. [online]. Available at URL: http://www.corec.org.uk/wordDocs/Guidenotes.doc. Date accessed 2000 19 Oct.

(14) Machin D, Campbell M, Fayers P, et al. Sample Size Tables for Clinical Studies. Table 7.1. Blackwell Science Ltd., Oxford. 1997.

(15) Joint British recommendations on prevention of coronary heart disease in clinical practice. British Cardiac Society, British Hyperlipidaemia Association, British Hypertension Society, endorsed by the British Diabetic Association. Heart 1998; 80 Suppl 2:S1-29.

(16) Strom B. Chapter 2. Study designs available for Pharmacoepidemiology Studies. In: Strom B, editor. Pharmacoepidemiology. John Wiley & Sons Ltd., Chichester. 2000: 17-29.

(17) Martin RM, Kapoor KV, Wilton LV, Mann RD. Under-reporting of suspected adverse drug reactions to newly marketed (“black triangle”) drugs in general practice: observational study. BMJ 1998; 317(7151):119-120.

(18) Heeley E, Riley J, Layton D, Wilton LV, Shakir SA. Prescription-Event Monitoring and reporting of adverse drug reactions. Lancet 2001; 358(9296):1872-1873.

(19) Templeton L, Deehan A, Taylor C, Drummond C, Strang J. Surveying general practitioners: does a low response rate matter? Br J Gen Pract 1997; 47(415):91-94.

(20) McAvoy BR, Kaner EF. General practice postal surveys: a questionnaire too far? BMJ 1996; 313(7059):732-733.

(21) Deehan A, Templeton L, Taylor C, Drummond C, Strang J. The effect of cash and other financial inducements on the response rate of general practitioners in a national postal study. Br J Gen Pract 1997; 47(415):87-90.

(22) Key C, Layton D, Shakir SA. Results of a postal survey of the reasons for non-response by doctors in a Prescription-Event Monitoring study of drug safety. Pharmacoepidemiol Drug Saf 2002; 11(2):143-148.

(23) Wensing M, Mainz J, Kramme O, Jung HP, Ribacke M. Effect of mailed reminders on the response rate in surveys among patients in general practice. J Clin Epidemiol 1999; 52(6):585-587.

(24) Whitfield M. Giving feedback to questionnaire responders--an essential task? Br J Gen Pract 1997; 47(417):241-243.

(25) Watson DJ, Harper SE, Zhao PL, Quan H, Bolognese JA, Simon TJ. Gastrointestinal tolerability of the selective cyclo-oxygenase-2 (COX-2) inhibitor rofecoxib compared with non-selective COX-1 and COX-2 inhibitors in osteoarthritis. Arch Intern Med 2000; 160(19):2998-3003.

(26) Laine L. Approaches to non-steroidal anti-inflammatory drug use in the high-risk patient. Gastroenterology 2001; 120(3):594-606.

5 6 | C H A P T E R 2 . 1

2 . 2

S A F E T Y P R O F I L E O F C E L E C O X I B A S U S E D I N G E N E R A L P R A C T I C E

I N E N G L A N D : R E S U L T S O F A P R E S C R I P T I O N - E V E N T

M O N I T O R I N G S T U D Y

Deborah Layton 1,2

Lynda V Wilton 1,2

Saad A.W. Shakir 1,2

1 Drug Safety Research Unit, Bursledon Hall, Blundell Lane, Southampton, UK 2 University of Portsmouth, UK

Eur J Clin Pharmacol 2004; 60: 489-501

Reproduced with kind permission from Springer-Verlag


I n t r o d u c t i o n

Celecoxib, launched in May 2000, was the second of the selective cyclo-oxygenase

(COX)-2 specific inhibitor sub-classes of non-steroidal anti-inflammatory drugs (NSAIDs;

‘coxibs’) to reach the UK market. It was the first coxib available world-wide, being

indicated at launch for symptomatic treatment of osteoarthritis (OA) and rheumatoid

arthritis (RA). [1] The COX-2 hypothesis proposed that, at comparable COX-2

inhibiting doses, highly selective COX-2 inhibitors would be as effective as non-selective

NSAIDs, but cause fewer gastrointestinal (GI) adverse effects. [2;3] Clinical studies have

shown celecoxib as superior to placebo in the relief of pain and inflammation in patients

with OA and of symptoms of RA. [4-8]

The Drug Safety Research Unit (DSRU) provides a postmarketing drug surveillance

scheme which monitors the safety of newly marketed drugs in England in cohorts that

are frequently of over 10 000 patients, using the non-interventional observational cohort

technique of Prescription-Event Monitoring (PEM). [9] This design uses a systematic

approach to data collection, [9;10] in accordance with international guidelines for

record-based research. [11-13] Data is collected on patients prescribed a drug in “real

world” clinical practice, including groups at high risk of adverse events who may have

been excluded from controlled trials, and are also likely to be exposed to the newly

marketed drug because of the nature of their disease. The DSRU has also carried out a

PEM study of rofecoxib. [14] This paper describes a PEM study undertaken to examine

the safety of celecoxib as used by primary care physicians (GPs) in England.

M e t h o d s

Exposure data were obtained from dispensed British National Health Service

(NHS) prescriptions for celecoxib issued by GPs between May and December 2000,

which were collected by the Prescription Pricing Authority in England. Demographic

and outcome data (event reports) for each patient were obtained by sending simple

questionnaires (‘Green Forms’) to the prescribing GP at least 6 months after the date

of the first prescription. These questionnaires requested information on patient age,

indication for prescribing, dose, effectiveness, duration of treatment (start and stop dates),

reasons for stopping and any significant health related events the patient experienced

since starting the drug. Events were considered to be an adverse drug reaction (ADR) if

the GP specified that the event was attributable to the drug. Events attributed to other

A b s t r a c t

Background: Highly specific cyclo-oxygenase (COX) 2 isoenzyme inhibitors were developed to minimise the risk of gastrointestinal (GI) adverse effects. Celecoxib was the second of these agents to be marketed in the UK.

Objectives: To monitor the safety of celecoxib prescribed in the primary care setting in England using Prescription-Event Monitoring (PEM).

Methods: A postmarketing surveillance study using the observational cohort technique of PEM. Patients were identified from dispensed British National Health Service prescription data supplied in confidence by the Prescription Pricing Authority for celecoxib between May and December 2000. Simple questionnaires were sent to the prescribing general practitioner at least six months after the date of the first dispensed prescription for each individual patient. Event incidence densities (IDs) [the number of 1st reports per 1000 patient-months of exposure (pme)] were calculated. ID differences for events reported in month 1 (ID1) and months 2-6 (ID2) were examined for temporal changes in event rate. Information on suspected adverse drug reactions (ADRs), reasons for stopping treatment, outcome of pregnancies and cause of death was also requested. Data was gathered on potential gastrointestinal (GI) risk factors [recent use of other non-steroidal anti-inflammatory drugs (NSAIDs), past history of upper GI disorders and concomitant gastro-irritant agents or anti-ulcer drugs]. Crude IDs per 1000 pme and ID ratios were calculated according to potential risk factors, and age (>65 years, ≤64 years).

Results: The cohort comprised of 17 458 patients [median age 62 years (IQR 51,73); 68.3% female]. The most common specified indication was osteoarthritis (28.1%, n=4905). Not effective was the event with the highest ID1 (139.9 per 1000 pme). The clinical events with the highest ID1 were dyspepsia (25.4 per 1000 pme) followed by abdominal pain (10.6). These were also given frequently as reasons for stopping (551 and 174 out of 9126 reports). Of 436 events in 325 patients (1.9% of total cohort) that were reported as ADRs, the most frequent were events within the alimentary system (186 reports). Uncommon events reported during treatment (not necessarily as ADRs) included allergy (0.10%, n=17), anaphylaxis (0.01%, n=2), angioneurotic oedema (0.02%, n=3), and bronchospasm (0.05%, n=9). There were 103 reports of events associated with thromboembolism and 111 reports of serious GI events [90 GI bleeds (upper and lower); 21 peptic ulcers] received during treatment or within 1 month of stopping. A past history of dyspeptic/other upper GI conditions and use of concomitant gastro-protective drugs were each associated with a significantly increased risk of dyspepsia and abdominal pain.

Conclusion: Frequently reported adverse events were those GI events commonly associated with treatment with other NSAIDS. Stratification by identified risk factors suggested that channelling of high-risk patients is likely. Serious upper and lower GI events, and thromboembolic events did occur during this study, although the incidence was low (<1%). Doctors should continue to prescribe NSAIDs, including COX-2 specific inhibitors, with caution.


during the overall treatment period (IDA) were calculated for patients for whom either the

date of stopping the drug was known, or who continued to take the drug until the end of

the study period. In PEM, the difference between the two rates (ID1–ID2) is calculated

to test the hypothesis that the rate does not change over time. A 99% confidence limit

around the point estimate of the difference that does not include the null value (zero)

suggests that the rate of events in month 1 is significantly different to the rate of events

in months 2-6. A positive rate difference may signal that the event is associated with

starting treatment with the drug. [16]

Further statistical analysis involved comparison of the incidence rates of frequently

reported GI events, indicators of bleeding and GI investigations for the cohort,

according to positive and negative responses to the Green Form additional questions,

or age (>65 years versus ≤64 years). Crude IDA values per 1000 pme were calculated

separately for dyspepsia, nausea/vomiting, diarrhoea, abdominal pain, unspecified GI

events, constipation, abdominal distension, upper GI haemorrhage, GI haemorrhage,

rectal haemorrhage, peptic ulcer, anaemia, iron deficiency anaemia, gastroscopy and

endoscopy, for patients reported to have a past history of dyspeptic/other upper GI

conditions, or reported to have been prescribed any NSAIDs in the 3 months prior to

celecoxib, or those reported not to have either risk factor; for patients reported to be

using either concomitant gastro-protective drugs, or gastro-irritants drugs, or neither;

and for patients aged >65 years or ≤64 years. The IDA ratios were then calculated

and examined using univariate (Mantel-Haenszel) methods. The null hypothesis of no

relative difference in IDA was tested using Fisher’s Exact test. In order to account for

multiple testing, comparisons were modified using the Bonferroni’s correction. [17]

A Microsoft SQL query was used to retrieve data from the DSRU PEM database,

followed by analysis using Excel, Access and STATA 7.0. (Stata Corporation, College

Station, Texas, US.)

Sample sizeThe ability to detect an ADR is dependent upon the expected incidence rate of

that ADR for those exposed, the background rate of those unexposed and number of

patients available. PEM studies aim to recruit a cohort size of at least 10 000 patients

and this allows one to be 95% certain that any events not observed occur less often than

1 in 3333 cases. [18] A sample size of 10 000 patients should allow for the detection

of at least three cases of an ADR, with 85% power, if it occurred with an incidence

risk of at least 1 in 2000 patients where information on background risk is unavailable.

medication were examined in order to detect possible interactions between celecoxib

and specific drugs. Events were coded using the DSRU event dictionary, a hierarchical

dictionary with ‘doctor’ summary terms grouped under selective ‘lower’ terms, which

are themselves grouped together under broader ‘higher’ terms, arranged by system-

organ class (SOC). Green forms returned with no useful information were classified as

‘void’ and excluded from the study and subsequent analysis, as there was no means of

determining whether forms not completed indicated no reported events.

To address the issue of ‘channelling’, additional questions were included on the

Green Form requesting information on potential risk factors for GI events; whether the

patient had a history of dyspeptic/other upper GI symptoms, whether any NSAIDs

had been prescribed in the 3 months prior to starting celecoxib or whether any gastro-

protective drugs [misoprostol, antacids, proton-pump inhibitors (PPIs)/H2 antagonists]

or gastro-irritant drugs (NSAIDs, aspirin, anticoagulants/antiplatelet agents) were

prescribed during treatment with celecoxib.

Each Green Form returned was reviewed by a DSRU research fellow and the context

of each event assessed. All pregnancies, any events of medical interest not mentioned in

the Summary of Product Characteristics (SPC) at launch, [1] or considered medically

important and where additional information was required, were followed-up by sending

additional questionnaires to the prescribing GP. Individual case reports were assessed

for causality according to DSRU procedure, using four basic considerations (temporality,

pharmacological plausibility, clinical and pathological characteristics of the event,

exclusion of other possible causes) and classified according to one of five categories

(probable, possible, unlikely, awaiting further information or not assessable). [15] If no

reply was received, one further reminder was sent. All reported deaths for which a cause

was not specified were followed up to try to establish the cause of death.

All records and computer data are stored at the DSRU to maximise patient

confidentiality, by irreversible anonymisation of patient identifiable data supplied by

the PPA after the Green Form questionnaires have been sent, and the use of unique

identifier codes supplied to the DSRU by the GP for any subsequent correspondence.

Statistical analysisIncidence densities (IDs) were calculated for all reported events during treatment

within specified time periods and expressed as the number of first reports of an event

per 1000 patient months of exposure (pme). IDs for events occurring in the first month

of treatment (ID1), during months two to six of treatment (ID2) and for events occurring


included 62 reports of oedema [lower terms: oedema (n=29), facial oedema and swollen

ankles (n=14 each), fluid retention (n=4) and swollen limb (n=1)], 30 reports of chest pain/

tight chest, 8 reports each of hypertension and ischemic heart disease (IHD) [including 4

reports of lower term: myocardial infarction (MI)], 3 reports of cardiac failure (n=1 each

of lower terms cardiac failure, congestive cardiac failure and left ventricular failure) and

2 reports each of deep vein thrombosis and cerebrovascular accident (CVA).

Adverse drug reactions and drug-drug interactionsOf the 436 events that were also reported by the GPs as ADRs to celecoxib for

325 (2%) patients, the most frequently reported ADR was GI unspecified* (Table 1). Of

the events recorded as ADRs, 18 (4.1%) were also documented as having been reported

to the Committee of Safety of Medicines (CSM). In 4 patients, 4 ADRs to celecoxib

were also reported as drug interactions; an anaphylactic-type reaction with starflower

oil, an interaction with methotrexate leading to fatigue, a brief allergic response with

Salazopyrin® , and one as a drug interaction ( no details provided). In addition to these

4, another 100 ADRs were also reported to other drugs in 82 patients, of which 55

occurred whilst on concurrent treatment with celecoxib, including Salazopyrin® (n=5),

angiotensin converting enzyme (ACE) inhibitors (n=5), diuretics (n=4), anti-hypertensives

(n=2) and methotrexate (n=1). In addition, 10 of these 55 were reported to drugs known

to be cytochrome P450 (CYP) 2C9 substrates [amiodarone (n=2), atorvastatin (n=3),

diclofenac (n=1), amitriptyline (n=2) and fluoxetine (n=2)] whilst on concurrent treatment

with celecoxib. None of these was documented as having been reported to the CSM.

Events ‘Not effective’ and ‘condition improved’ were the most common higher term events

reported overall [incidence 20.7% (n=3609) and 9.3% (n=1620), respectively] and in

the first month of treatment (ID1 139.9 and 52.4 per 1000 pme, respectively). Common

undesirable events (>1%) listed in the SPC and also reported during treatment in this

PEM study included dyspepsia, abdominal pain, diarrhoea and rash (Table 1). These

were also the most frequently reported clinical events in month 1 and were associated

with starting treatment, along with ‘unspecified GI side effects’ (not listed in SPC). Other

common listed undesirable events oedema and dizziness were reported less frequently

than 1% in this PEM study, but were also associated with starting treatment (Table 1).

Vomiting is listed as an uncommon (incidence 0.1%-1%) event in the UK SPC.

In this PEM study, the event ‘nausea/vomiting’ was uncommon and associated with

[19] Assuming a background incidence of 1 in 1000, a cohort of 10 000 will enable the

detection of a doubling of this incidence risk to 1 in 500 with 80% power. [20]

R e s u l t s

Of forms posted, 44.1% (19 246 /43 688) were returned. Of these, 1788 (9.3%)

were classified as void [e.g. blank forms returned (n=616)] and useful information was

available for 17 458 patients. Where recorded, the median age was 62 years [interquartile

range (IQR) 53, 75], and 11 928 (68.3%) patients were females.

The major specified indication was OA (28.1% of total cohort, n=4905). The five

other most frequently specified indications reported on the Green Form were: joint

pain (10.6%, n=1854), back pain (7.8%, n=1368), arthritis (7.7%, n=1349), RA (6.5%,

n=1128) and neck pain (1.6%, n=274). The indication was not specified for 3853 (22.1%)

of the patients. Of 14 727 Green Forms, where information on starting dose for patients

was provided, the proportions prescribed 100mg, 200mg, 300mg and 400mg daily were

13.7% (n=2023), 80.6% (n=11 868), 0.2% (n=25) and 5.4% (n=803), respectively. Eight

patients were prescribed between 600mg to 800mg daily, and no reports were received

of prescriptions for more than the maximum recommended daily dose (800mg), as

stated in the SPC. Of 12 195 (69.9%) Green Forms that included a GP opinion about

effectiveness, 7967 (65.3%) reported celecoxib as being effective.

Treatment withdrawalAfter six months, of 15 527 patients for whom it was recorded that either treatment

was continuing or that the date of stopping celecoxib was given, 61.4% (n=9541)

had stopped treatment. GPs recorded 9126 reasons for stopping celecoxib for 8397

(48.1%) patients in total, the most frequently reported reason was ‘not effective’ (39.3%,

n=3590)

The most commonly reported clinical reasons for stopping were events associated

with the alimentary SOC, including dyspepsia and abdominal pain (Table 1). Events

reported less frequently as reasons for stopping within the alimentary SOC included:

GI haemorrhage (n=15), upper GI haemorrhage (n=16), peptic ulcer (n=11), rectal

haemorrhage (n=9), inflammatory diseases of the colon (n=5) and haemorrhagic

diarrhoea (n=2).

Clinical events given as reasons for stopping within the cardiovascular (CV) SOC


rarely or very rarely during treatment: allergy (n=17, three ‘possibly’ related), anaphylaxis

(n=2, neither ‘possibly’ related), angioneurotic oedema (n=3, two ‘possibly’ related),

Stevens Johnson syndrome (n=1, ‘possibly’ related), erythema nodosum (n=1, ‘possibly’

related), exfoliative dermatitis (n=1, unassessable) and bronchospasm (lower term, n=9,

one ‘possibly’ related). Of 36 reports of cardiac failure received during treatment, 17

were for congestive cardiac failure (two ‘possibly’ related). There were 17 reports of

abnormal liver function tests (one ‘possibly’ related), one report each of obstructive

jaundice, pleural effusion and nephritis (none ‘possibly’ related) and acute renal failure

(not assessed as insufficient information). The event ‘confusion’ was rare (0.03%, n=13),

whilst psychiatric events not mentioned in the SPC included hallucinations (n=5) and

thought disorders (n=3). Other events not listed in the SPC included lower terms: pruritis

(0.6%, n=108), and chest pain (0.5%, n=80).

Table 2. Reports of gastrointestinal (GI) bleeds and peptic ulcers followed-up and causality assessment

Higher level term

Total no. events (during)a

Follow-up response

Information of follow-up responders b

Sex Age (years)

Past history of upper GI problems

NSAIDs <3 months prior to starting celecoxib

Concomitant Medication Assessed as

‘possibly’ relatedM F GB GP

GI haemorrhage

25 (19)

12/15 (75%)

3 9 86 (64,88)

6/8 5/7 2/7 6/8 2/12

Rectal haemorrhage

56 (39)

24/28 (86%)

6 18 61 (56,75)

13/21 15/20 6/17 10/15 3/24

Upper GI haemorrhage c

42 (32)

18/25 (72%)

6 12 76 (64,81)

11/14 4/13 8/14 9/13 6/18

Peptic Ulcer d 30 (21)

13/15 (93%)

3 10 67 (51,74)

9/12 7/12 1/8 8/10 3/13

Total153(111)

67/83e (81%)

18 49 70 (57,79)

39/55 (71%)

31/52 (60%)

17/46 (37%)

13/46 (28%)

14/67

(21%)

a, total no. of events during treatment and within 1 month of stopping; b, where information available from follow-up and Green Form questionnaires: IQR interquartile range; GB drug leading to risk of bleeding-aspirin, anticoagulants and antiplatelet drugs; GP gastro protective drugs - misoprostol, antacids, proton-pump inhibitors/histamine2 antagonists; c, includes lower level term haematemesis, Mallory-Weiss syndrome, melaena, ulcer duodenal haemorrhage, ulcer gastric haemorrhage; d, includes lower level terms ulcer duodenal, ulcer duodenal perforated, ulcer gastric, ulcer peptic; e, 70 events not selected for follow-up. Reasons: off treatment (40), details included with related event (5), duplicate (3), pre-existing disease (8), other cause (4), investigations normal (3), delayed onset (1), unconfirmed diagnosis (1), no further information available (5).

starting treatment. Other listed uncommon clinical events of interest such as anaemia

(0.2%, n=39), cough (0.6%, n=97), anxiety (0.3%, n=48), hypertension (0.4%, n=62),

visual disturbance (0.1%, n=19) and insomnia (0.3%, n=45) were reported during but

not associated with starting treatment.

Table 1. Incidence densities (ID per 1000 patient months) of clinical events associated with starting treatment with celecoxib (lower 99% CI of ID1-ID2>0), ranked by number of events in month 1. Labelled events in Summary of Product Characteristics at launch are in bold.

Higher Term Description N1

N2

ID1

ID2

ID2-6

99% CI NA (%) No. ADRs Reason for stopping

Dyspepsia 354 332 25.4 9.1 16.3 12.5, 20.0 816 (4.7) 43 551

Pain abdomen 148 125 10.6 3.4 7.2 4.8, 9.6 314 (1.8) 24 174

Nausea, vomiting 147 110 10.5 3.0 7.5 5.2, 9.9 286(1.6) 28 161

Diarrhoea 127 95 9.1 2.6 6.5 4.3, 8.7 251(1.4) 23 144

Rash 105 76 7.5 2.1 5.4 3.4,7.4 215 (1.2) 12 128

GI unspecified* 97 55 7.0 1.5 5.4 3.5, 7.3 169 (1.0) 44 148

Intolerance 82 37 5.9 1.0 4.9 3.1,6.6 132 (0.8) 8 124

Oedema 67 60 4.8 1.7 3.2 1.5, 4.8 160 (0.9) 15 62

Dizziness 67 46 4.8 1.3 3.5 2.0, 5.1 135 (0.8) 12 69

Headache, migraine 49 65 3.5 1.8 1.7 0.3, 3.1 134 (0.8) 13 48

Malaise, lassitude 44 46 3.2 1.3 1.9 0.6, 3.2 113 (0.6) 14 49

Unspecified** side effects 37 29 2.7 0.8 1.9 0.7, 3.0 69 (0.4) 66 65

Asthma, wheezing 31 34 2.2 0.9 1.3 0.2, 2.4 82 (0.5) 7 33

Dyspnoea 31 32 2.2 0.9 1.3 0.2, 2.4 84 (0.5) 6 28

N1 total number of reports of each event during the first month of treatment, N2 total number of reports of each event during treatment in months 2-6, ID1 incidence density for each event during the first month of treatment, ID2 incidence density for each event during treatment months 2-6, ID1-ID2 arithmetic difference between ID1 and ID2, 99% CI 99% confidence intervals for ID1-ID2, NA (%) total number of reports of each event in the total treatment period (overall incidence), ADR events recorded as adverse drug reactions. *unspecified: no event term currently exists in DSRU dictionary; ** side effects not specified

Blood dyscrasias are listed as rare (<0.1%) and in this PEM study, there were six

reports of leucopenia received during treatment with celecoxib (one assessed as ‘possibly’

related). According to the SPC, reports of headache and nausea have been received

postmarketing of celecoxib, whilst allergic reactions, heart failure, MI, GI haemorrhage,

hepatitis, confusion, acute renal failure, bronchospasm and skin exfoliation are very rare

events (<0.0001%). In this study, headache/migraine occurred more frequently than

listed (0.8%, Table 1) and was associated with starting treatment. The following skin

disorders and allergic-type events (not necessarily reported as ADRs) were reported


Table 3. Incidence Densities (rates) per 1000 patient months exposure and relative ratesa for selected gastrointestinal (GI) events according to GI risk factors.

Event Number of events Rate Relative rateb (95% CI)Past history of dyspeptic symptoms/ upper GI conditions versus no historyDyspepsia

Yes 516 15.81 2.36 (1.98,2.83)No 170 6.69 1

Abdominal PainYes 193 5.92 2.03 (1.55,2.69)No 74 2.91 1

GI unspecifiedYes 106 3.25 2.85 (1.87,4.45)No 29 1.14 1

Nausea, VomitingYes 173 5.30 1.95 (1.47,2.62)No 69 2.72 1

EndoscopyYes 23 0.70 5.97 (1.80, 31.05)No 3 0.12 1

NSAIDs use <3 months prior to celecoxib treatment versus no NSAID use.Dyspepsia

Yes 342 10.15 0.75 (0.65,0.88)No 352 13.45 1


Use of concomitant gastro-irritant drugs c versus no drug use Haemorrhage GI upper

Yes 13 1.06 4.98 (1.85,14.74)No 7 0.21 1

GastroscopyYes 6 0.49 16.08 (1.95,740.07)No 1 0.03 1

Use of concomitant gastro-protective drugs d versus no drug useDyspepsia

Yes 401 19.84 2.59 (2.21,3.05)No 251 7.65 1


EndoscopyYes 23 1.14 9.33 (3.19,37.13)No 4 0.12 1

GastroscopyYes 13 0.64 21.10 (3.17, 898.50)No 1 0.03 1

AgePain Abdomen

>65 years 75 3.41 0.62 (0.46,0.83)≤64 years 124 5.49 1

a Calculated using Poisson regression; b Bonferroni’s correction: significant P values <0.004; c NSAIDs, aspirin, anticoagulants/antiplatelets; d Misoprostol, antacids, proton pump inhibitors/ histamine2 antagonists

GI adverse events There were 123 reports of GI bleeds (upper and lower) and 30 reports of peptic

ulcer received during the study (Table 2). Of the 67 individual case reports assessed, 14

(21%) were assessed as ‘possibly’ or ‘probably related’. For these 14 (where information

was specified) over 50% were aged 65 years or more, had a past history of dyspepsia/

upper GI disorder, had recently been prescribed an NSAID before starting treatment or

were also on concomitant drugs leading to an increased risk of bleeding.

Examination of crude IDA (per 1000 pme) and for selected GI events calculated

according to GI risk factors (Table 3 see next page) showed that a past history of upper

GI disorder and use of concomitant gastro protective drugs were each associated with

a significantly higher rate of dyspepsia, abdominal pain and endoscopy compared with

those reported not to have these risk factors, which is consistent with a channelling

effect. Patients reported to use concomitant gastro-irritant medication had a significantly

higher rate of haemorrhage GI upper and gastroscopy than patients not reported to use

such drugs. Conversely, patients aged 65 years or more had a significantly lower rate of

abdominal pain than those aged less than 64 years. Similarly, the recent use in patients

who took NSAIDs within the 3 months prior to starting celecoxib was associated with

lower rates of dyspepsia and abdominal pain than in patients who had no such history.

Cross tabulation of use of NSAIDs prior to celecoxib with use of either H2 antagonists

[df (1), χ2 p<0.0001] or misoprostol [df (1), χ2 p<0.0001] suggested a link between use of

these gastro-protective agents and prior use of NSAIDs, which may explain the relative

reduction in rate of upper GI events in patients for whom NSAIDs were reported to

have been used within 3 months prior to celecoxib.

Regarding lower GI tract adverse events, there were 25 reports of irritable bowel

syndrome and 37 reports of inflammatory bowel disease during treatment, including

colitis (n=5), ulcerative colitis (n=3) and Crohn’s disease (n=2). Both reports of

exacerbations of Crohn’s disease and one report of ulcerative colitis were assessed as

‘possibly’ related to use of celecoxib.


DeathsDuring the study period, 346 (2.0% of total cohort) deaths were reported, for which

the cause of death was established for 265 (76.6%). Of 84 deaths of CV origin, the

most frequently reported causes of death were MI (n=33), CVA (n=15), IHD (n=15) and

pulmonary embolus (n=1). Of 7 deaths within the alimentary SOC, 3 were reported as

due to GI perforations/bleeding and 1 to a peptic ulcer. Insufficient information was

available to ascertain whether celecoxib was taken at the time of death.

D i s c u s s i o n

This PEM study provides a descriptive and quantitative analysis of a cohort

prescribed celecoxib and events reported during use of this drug, plus alerts of possible

adverse events (‘signals’). The large cohort of 17 458 patients enabled collection of a

considerable quantity of clinical information associated with use of celecoxib under

primary care conditions in England, without the selection bias inherent in randomised

controlled trials. The demographic data for this PEM cohort were consistent with that

expected for NSAID users (59% ≥60 years; 68% females). [21] Although only licensed

for use in OA and RA during the time of this PEM study, GPs also prescribed celecoxib

for a range of acute and chronic (predominantly musculoskeletal) conditions. Frequently

reported adverse events were those GI events commonly associated with treatment with

other NSAIDS and included in the SPC. Our study also revealed channelling of patients

already at high risk of GI adverse events on to celecoxib.

The strengths and limitations of this study design have been described in detail

elsewhere. [9] PEM uses an observational cohort design that does not interfere with

the prescribing decisions of the GPs and provides information on the use of new drugs

in general practice conditions. [22] PEM relies on reporting of all events rather than

suspicions of ADRs and, because of the anticipated cohort size [18] has the potential

to detect signals of common, less common or rare adverse events that may be of public

health interest, which none of the participating GPs might initially suspect. PEM has

several quantitative approaches to generating signals, including calculation and ranking

of rates (IDs), making internal comparisons between different treatment periods

(ID1 - ID2) or patients with and without pre-specified risk factors for selected events,

looking at the most common reasons for stopping and events considered to be ADRs by

the reporting GP. While these quantitative approaches appear to yield objective estimates

Thromboembolic eventsThere were 103 reports of events associated with thromboembolism (TE) reported

during treatment or within 1 month of stopping (Table 4). Of 62 individual case reports

assessed, 78.1% (43/55 where age was specified) were over 65 years of age, 86.5%

were reported to have risk factors for TE/coronary heart disease and 54.0% were on

concomitant aspirin or other anticoagulant/antiplatelet agents. Despite the potential

for heavy confounding by previous history of CV disease, six of these TE events were

assessed as ‘possibly’ related to celecoxib use.

Table 4. Reports of Thromboembolic (TE) events followed-up and causality assessment

Higher level term

Total no. events

(during)a

Follow-up

response

Information of follow-up responders b

Sex Age years

Median (IQR)

Dose at start (mg) Median

(IQR)

Concomitant aspirin or anti-

coagulant use

>1 risk factors

present c

Assessed as

‘possibly’ related

M F

Cerebrovascular accident

50(33)

19/23 (83%)

11 8 78 (67,83)

200 (200,200)

10/19 15/15 3/19

Deep Vein Thrombosis

23 (12)

9/12 (75%)

4 5 73 (63,85)

200 (200,400)

3/8 8/8 0/9

Arterial embolism

2 (1)

1/1 (100%)

1 - 82 (-)

200 (-)

1/1 1/1 0/1

Myocardial infarction

63 (29)

19/21 (90%)

12 7 72 (66,74)

200 (200,200)

8/14 14/17 2/19

Pulmonary embolism

9 (6)

4/7 (57%)

4 - 36 (36,56)

200 (-)

1/4 1/4 0/4

Transient Ischemic attack

39 (22)

10/13 (77%)

7 3 83 (83,84)

200 (100,200)

4/4 6/7 1/10

Total186

(103) 62/77 d (81%)

39 23 76 (66,83)

200 (200,200)

27/50 (54%)

45/52 (87%)

6/62 (10%)

a, total no. of events during treatment and within 1 month of stopping; b, where information available from follow-up and Green Form questionnaires; c, reported risk factors: past medical history ischaemic heart disease, diabetes, hypertension, cigarette smoker, obesity, recent surgery, peripheral vascular disease, polymyalgia rheumatica, atrial fibrillation, previous TE event; IQR interquartile range; d, 109 events not selected for follow-up. reasons: off treatment (67), pre-existing disease (10), onset delay (14), other cause (3), duplicate miscode (1), not reason for stopping (2), no further information available (12)

Pregnancies Sixteen pregnancies were reported during the study period (n=16, median age 32 years

(range 29-33). Ten women were reported to have taken celecoxib during the first trimester, for

seven of whom pregnancy was given as a reason for stopping treatment. For these ten women,

six pregnancies resulted in live births and no congenital abnormalities were reported.


reported elsewhere that certain patient populations respond differently to individual

NSAIDs, and physicians often switch treatment between NSAIDs. [30;31]

In this PEM study, where information on stopping treatment was provided, just

under two-thirds of patients had stopped celecoxib by the end of the sixth month of

observation. At 6 months, the PEM discontinuation rate was higher than that reported

for the CLASS (celecoxib long-term arthritis safety study) trial that was constructed to

replicate clinical practice, [32] but this difference (61% versus 41%) is to be expected

for observational studies compared with randomised controlled trials. Furthermore, at

6 months, approximately one fifth (n=3295, 18.9%) of the total cohort had the event

‘not effective’ recorded as the reason for stopping, a lower proportion than that reported

from the CLASS trial, where 31.2% (503/1611) of patients in the celecoxib treatment

arm were reported to have had treatment failure due to lack of therapeutic efficacy at

6 months.

As for many NSAIDs, the GI safety of celecoxib has been studied by evaluating

the risk of endpoints such as endoscopically detectable ulcers, [7;33] or occurrence of

predefined ulcer complications. [34] These studies show that the risk of experiencing

such events is much less (up to 50%) compared to non-selective NSAIDs. [35]

Unfortunately such endpoints are not always predictors of more serious complications

or indicators of overall harm. Drug safety studies should also consider those events that

are less serious in nature but are sufficiently detrimental to the quality of life to patients

to result in treatment withdrawal. For example, dyspepsia has been proposed as a risk

factor for NSAID complications, [36] but the use of such an event as an endpoint is

also complicated by the fact that it is extremely common in patients not taking NSAIDs.

In this PEM study, the most frequently reported adverse events associated with start of

treatment and reasons for stopping were GI events commonly associated with treatment

with non-selective NSAIDS such as dyspepsia, abdominal pain, and diarrhoea, [37;38]

and these are mentioned as common undesirable adverse events in the SPC for

celecoxib. [1]

The SPC also notes in the special warnings that “upper GI perforations, ulcers

and bleeds have occurred in patients treated with celecoxib” and that “caution should

be taken in patients with a history of GI disease such as ulceration and inflammatory

conditions or in patients at special risk”. Published case reports of serious GI events such

as upper GI haemorrhage in patients prescribed celecoxib are rare. [39] In this PEM

study there were 111 reports of serious GI bleeds and ulcers during treatment. The

overall incidence of upper GI haemorrhage and GI haemorrhage during treatment was

of risk and hypotheses of safety signals, they cannot be taken as conclusive evidence of

such. Signal detection must not detract from, or be viewed as a substitute for individual

case or cluster analysis; further details of individual cases are necessary to confirm or

refute that a possible safety signal exists, as well as obtain useful information on possible

risk factors. [23] In PEM, clusters of reports are also evaluated by DSRU research

fellows using standardised causality assessments. Thus PEM utilises both quantitative

and qualitative approaches to drug safety.

Achieving high response rates is an important issue in any postmarketing surveillance

study. This PEM study had a response rate of 44%, (after voids 40%), which is lower

than average (56% for 85 PEM studies; 51% after voids). We acknowledge that selection

bias may be introduced by falling GP response rates, but this is not isolated to PEM

alone. [24-27] Other methods of improving response in PEM, such as reminders, [28]

are being considered but have yet to be fully evaluated. As in any observational study

dependent on third party reporting, outcome misclassification is possible, and under-

reporting is also likely. [29] Importantly PEM is at least as likely to detect events reported

as ADRs as with spontaneous reporting systems; evidence suggests that reporting in

PEM is much higher than spontaneous reporting for both serious and non-serious

ADRs. [22] In this study, of 436 events recorded as ADRs (considered attributable to use

of celecoxib by the GP), only 4% of these were reported to the CSM (where indicated

on the Green Form). Under-reporting of suspected ADRs to the regulatory authority

is a worrying observation, since prescribers are encouraged to report any suspected

reaction, no matter how trivial for newly licensed drugs under intensive surveillance

by the CSM. Other possible bias that should be considered in this study design is the

exclusion of patients receiving treatment using hospital-only prescriptions, and the level

of prescription adherence.

PEM studies do not provide formal assessments of efficacy; however it is useful to

ascertain a GP’s overall assessment of a patient’s response. This is a subjective indicator

and not a specific enquiry based on detailed clinical assessments. In this study, of GPs

expressing an opinion, 65% rated celecoxib as effective. A similar figure was reported

in the PEM study of rofecoxib (68%). [14] Nevertheless, the term ‘not effective’ was the

most frequently reported event during, and associated with the start of treatment. One

explanation may be related to a higher expectation of improved efficacy and tolerability

of the new drug by both the patient and prescriber; or possibly that patients being

prescribed the new drug are those who have failed to respond to other NSAIDs and

thus more likely to find the new agent ineffective by nature of their disease. It has been


to be a COX-2 inhibitor (meloxicam), a retrospective comparison of the incidence

rates of selected GI events between these two drugs revealed a significant difference

in the rate of symptomatic GI (acid/peptic) upper GI events and complicated upper

GI conditions (perforations and bleeding) in favour of celecoxib in the 9 months after

starting treatment [adjusted rate ratio (RR) 0.77 (95%CI 0.69,0.85) and 0.56 (95%CI

0.32,0.96) respectively]. [45] Examination of the time to event revealed no significant

difference between these two drugs in the time to occurrence of these events, with 50% of

symptomatic GI events occurring by the second month after starting treatment, whereas

50% of complicated upper GI conditions occurred by the third month. Another large

scale population-based observational study in elderly patients reported a lower short-

term risk of upper GI haemorrhage for selective COX- 2 inhibitors than with non-

selective NSAIDs. [42] Clearly changes in the risk of GI adverse events over time require

further investigation.

Regarding lower GI tract adverse events, there is a link between non-selective

NSAIDs and exacerbation of inflammatory bowel disease; however the evidence

implicating COX-2 specific inhibitors is weak. [14;49;50] The number of reports of

inflammatory bowel disease during treatment with celecoxib was small (n=37). Events

such as colitis or ulcerative colitis were not highlighted as potential signals using the

ID1-ID2 statistic; however, these events were recorded as reasons for stopping treatment

in five patients.

CV and renal safety is another area of concern for the COX-2 inhibitors. The COX

isoenzymes play an important role in vascular physiology, [51] and the maintenance

of renal haemodynamics, [52] yet the implications of COX isoenzyme inhibition on

CV risk remain unclear. The hypothesis that COX-2 inhibition may be associated with

an increased risk of TE events in susceptible individuals receiving COX-2 inhibitors

is pharmacologically plausible. [53-56] Despite accumulating published evidence on

this issue, one is still unable draw any conclusions regarding changes in CV TE risk

associated with use of COX-2 inhibitors as a class. [57] Celecoxib does not appear to

inhibit platelet aggregation (mediated by COX-1). [58] Analyses of large scale clinical

trials (designed to examine GI outcomes), provide no evidence of increased risk of CV

thrombotic events associated with celecoxib compared with conventional NSAIDs,

naproxen or placebo; [59;60] neither do the retrospective pharmacoepidemiological

studies conducted on large databases of systematically collected health data. [61;62]

In this PEM study, the incidence of CV TE events reported during treatment with

celecoxib, or within 1 month of stopping was low (0.6%, n=103). Examination of the TE

small (<0.2%), with no statistical evidence to suggest a possible association with start of

treatment using the ID1-ID2 statistic, probably because of the small numbers involved.

Epidemiological studies indicate that the risk of serious upper GI complications is

greater in certain patient groups, [40] and the safety of celecoxib and other coxibs has

been studied in some of these clinical situations. [41;42] For example, the CLASS study

showed that the risk of GI ulcer complications with celecoxib was greater when low-

dose aspirin users were included in the study. [32] Because of the proposed benefits of

the COX-2 inhibitors, it is very likely that these agents would be chosen for patients of

advanced age with multiple pathologies. By undertaking internal comparisons between

subsets of patients with and without pre-defined risk factors, this PEM study attempted

to identify such “at risk” patients. Our study demonstrated that there was a significantly

higher rate of GI adverse events in patients for whom a past history of GI conditions

were reported and also separately in patients using concomitant gastro-protective drugs

or concomitant gastro-irritant medication compared with patients not reported to have

these risk factors. These observations are consistent with the preferential prescribing

or ‘channelling’ of patients at high risk of upper GI events on to drugs associated with

reduced risk of GI events, as reported for the other COX-2 inhibitors. [14;43;44] The

recent use in patients who took NSAIDs within the 3 months prior to starting celecoxib

was associated with lower rates of dyspepsia and abdominal pain than in patients not

reported to have used these drugs. One explanation could be that some patients had

their treatment “switched” onto celecoxib by practitioners for potential efficacy reasons,

despite no tolerability problems with the original treatment. Another might be the

association between use of gastro-protective drugs and NSAIDs. Age (65 years or more)

was associated with a significantly lower rate of abdominal pain than in those aged 64

years or less, which may be a result of raised suspicion of such symptoms in this age

group. Regarding GI investigative procedures, patients with a past history of dyspeptic/

upper GI symptoms or use of gastro-protective drugs were also reported to have a higher

relative rate of endoscopy and/or gastroscopy than patients for whom these risk factors

were not reported. These results also suggest channelling of patients likely to be at higher

risk of GI events.

Undertaking comparisons between pharmacoepidemiological studies is complex,

but is helpful to gauge the clinical safety profile of drugs within a therapeutic class. The

DSRU have undertaken comparisons of selected adverse event rates among the COX-2

inhibitors using PEM data, and the results have been published elsewhere. [45-48] Using

data collected in this PEM study and from a PEM study of an NSAID also considered


may lead to bronchospasm; [68] however, small scale studies have reported that celecoxib

did not induce bronchospasm in patients with asthma, [69] and was tolerated well in

patients with a history of aspirin sensitivity. [70] The SPC for celecoxib recommends

caution in prescribing coxibs to these groups of patients as with any NSAID. In this

PEM study, asthma/wheezing and dyspnoea were uncommon but associated with

starting celecoxib treatment.

The utilisation of pharmacogenetic information in pharmacovigilance is attracting

much interest, as it may enable the early identification of individuals who are susceptible

to ADRs or drug interactions. The prescribing information reports that the metabolism

of celecoxib is primarily catalysed in the liver by CYP2C9, [1] which is one of the

most important drug metabolising enzymes in humans. There are many in vitro studies

that indicate that significant interactions may occur when celecoxib is administered

with drugs that inhibit CYP2C9. Potentially significant interactions with fluconazole

(increased celecoxib concentrations), lithium (increased lithium concentrations) and

warfarin (increased prothrombin time) have been identified in the literature. [71] In

this PEM study, events also reported as ADRs were reported in patients taking drugs

known to be CYP2C9 substrates concurrently with celecoxib. The clinical significance

of these possible interactions remains to be established. The SPC also recommends that

patients known to be CYP2C9 poor metabolisers should be treated with caution. [1]

Further studies are planned to examine whether patients prescribed celecoxib identified

as having particular genetic polymorphisms of CYP2C9 are more likely to experience

ADRs than others. In terms of adverse hepatic events, cases of serious hepatotoxicity,

[72;73] hepatitis and pancreatitis [74] associated with celecoxib have been reported

in the literature, but current evidence does not support a causal association between

celecoxib and cholestatic hepatitis. [75;76] In this PEM study, the incidence of hepatic

adverse events (abnormal liver function tests, obstructive jaundice and pancreatitis) was

low (<0.1%) during treatment with celecoxib.

Regarding hypersensitivity reactions, the SPC recommends that celecoxib is

contraindicated in patients with known sulphonamide hypersensitivity and that skin and

subcutaneous tissue disorders are very rare (<1 in 10 000). [1] The structure of celecoxib

does not contain moieties considered to be critical in the development of hypersensitivity

syndrome or severe skin reactions nor immunoglobulin E-mediated reactions. [77]

Nevertheless sulphonamide-like ADRs have been reported. [78-85] In this PEM study,

of allergic-type adverse events reported during treatment, ‘rash’ and ‘pruritis’ were

possible signals associated with starting celecoxib. Very rare serious skin events (Stevens

events followed-up showed that the majority of patients were over 65 years of age, had

risk factors for TE and/or on concomitant aspirin or other anticoagulant/antiplatelet

agents. There is no evidence from the PEM data currently available to suggest that any

CV deaths were attributable to celecoxib.

The results of a retrospective comparison of the rates of selected TE events

undertaken using the PEM data collected for celecoxib and meloxicam, [47] revealed

a statistically significant higher rate of cerebrovascular TE events for celecoxib than

for meloxicam [adjusted RR 1.66 (95%CI 1.10,2.51)], but no difference in the rate

of the CV TE events or peripheral venous thrombotic events, over the 270-day study

period. Furthermore, examination of the time to first event revealed a significance

difference between the two drugs for both the CV and the cerebrovascular TE event

groups. Further studies specifically designed to investigate the possibility of an excess of

adverse CV outcomes in users of some or all selective COX-2 inhibitors, controlling for

differences in baseline CV risk, including the use of aspirin. This is especially important

given that the protective effect of aspirin may be antagonised by celecoxib. [63]

Published studies suggest that the incidence of renal adverse effects of celecoxib

is low, similar to other NSAIDs. [64-66] Celecoxib is well tolerated by patients who

may be at risk of NSAID-induced renal toxicity, such as the elderly and those with

hypertension or pre-existing chronic heart disease. [65] The SPC recommends caution

in patients with a history of cardiac failure, left ventricular dysfunction or hypertension,

and in patients with pre-existing oedema. In this PEM study, oedema was identified as

a possible signal associated with starting celecoxib. Other CV/renal events of interest

reported during treatment with celecoxib included renal failure, congestive cardiac

failure and hypertension. Clinical studies also report that celecoxib does not have a

significant effect on the anti-hypertensive action of the ACE inhibitors or beta-blockers.

[64] Information on drug interactions is also provided in the SPC. In this PEM study,

11 possible celecoxib-drug interactions with ACE-inhibitors, diuretics and other anti-

hypertensives were identified. However, such NSAID anti-hypertensive interactions are

complex and depend on the specific NSAID, the anti-hypertensive agent used and the

renal function of the patient; thus, this issue requires further investigation.

The effect of COX-2 inhibition of the respiratory system is also of interest. COX-2

is expressed under basal conditions in macrophage- and mast cell-like cells in proximity

to bronchial epithelium. Inhibition of COX-2-mediated prostanoids, which regulate

pulmonary vascular tone, may divert arachiodonic acid to produce leukotrienes, which

cause bronchoconstriction. [67] In some patients with asthma, aspirin and NSAID use


then, practitioners in the UK should continue to follow the guidance from the National

Institute for Clinical Excellence (NICE), which restricts the use of COX-2 inhibitors to

arthritis patients who are at higher risk of developing serious GI problems and advises

that these drugs should not generally be prescribed in preference to standard NSAIDs in

patients with CV disease. [91]

A c k n o w l e d g m e n t s

We would like to record our keen appreciation of the co-operation of the general

practitioners and numerous other colleagues who have helped in this investigation. We

would also like to thank for their important participation: The Prescription Pricing

Authority, The Health Authorities of England and The Office for National Statistics.

The Drug Safety Research Unit is an independent charity (no. 327206), which works

in association with the University of Portsmouth. It receives unconditional donations

from pharmaceutical companies. The companies have no control on the conduct or the

publication of the studies conducted by the DSRU. The Unit has received such funds

from the manufacturer of celecoxib. SAS has received lecture fees and support to attend

scientific conferences from Pfizer.

R e f e r e n c e s

(1) Anonymous. Summary of Product Characteristics: Celebrex® (celecoxib) May. 2000.

Searle/Pfizer(2) FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclo-oxygenase-2. N Engl J

Med 2001 Aug 9; 345(6):433-42.3) Kam PC, See AU. Cyclo-oxygenase isoenzymes: physiological and pharmacological role.

Anaesthesia 2000 May; 55(5):442-9.(4) Ehrich EW, Dallob A, De L, I, Van Hecken A, Riendeau D, Yuan W, et al. Characterization

of rofecoxib as a cyclo-oxygenase-2 isoform inhibitor and demonstration of analgesia in the dental pain model. Clin Pharmacol Ther 1999 Mar;65(3):336-47.

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Johnson Syndrome, erythema nodosum and exfoliative dermatitis) were reported during

treatment, but were neither recorded as an ADR to celecoxib by the prescriber nor

reported to the CSM. Generalised allergic responses (anaphylaxis and angioneurotic

oedema) were also very rare. There was no information available in this study to confirm

whether these events occurred in patients with a sulphonamide allergy.

Other adverse events of interest include neuropsychiatric events and visual

disturbances. Neuropsychiatric-type events are known to occur with the non-selective

NSAIDs, and have been reported as adverse events associated with celecoxib. [86;87] In

this PEM study, a small number of psychiatric-type events (hallucinations and thought

disorders) were reported during treatment. In terms of visual disturbance, the SPC lists

“blurred vision” as an uncommon undesirable event, and cases of visual disturbance

with use of celecoxib have been reported in the literature, with a marked but temporary

loss of vision. [88;89] A biologically plausible mechanism exists in that prostaglandins

are also expressed in the vascular endothelium of retinal blood vessels; thus inhibition of

COX-2 may alter the regulation of retinal blood flow with potential changes in vision.

In this PEM study, the incidence of visual disturbance during treatment was low (0.1%)

and was not associated with starting treatment. However nine cases led to cessation of

treatment, of which four were recorded as an ADR to celecoxib. This signal requires

further research.

C o n c l u s i o n

This postmarketing surveillance study shows that celecoxib is fairly well tolerated

when used in general practice in England. Frequently reported adverse events were those

GI events commonly associated with treatment with other NSAIDs and included in the

prescribers’ information. The reported presence of selected GI risk factors increased the

risk of some minor GI symptoms, suggesting that channelling of high-risk patients is

likely. Serious upper and lower GI events, and thromboembolic events did occur during

this study, although the incidence was low (<1%).

Further longer-term comparative studies with non-selective NSAIDs are needed

to fully assess clinically meaningful differences of the COX-2 inhibitors in “real-world”

settings. The results of a safety review of all COX-2 inhibitor ‘substances’ (including

celecoxib) by the European Agency for the Evaluation of Medicinal Products Committee

for Proprietary Medicinal Products, initiated July 2002, [90] is expected in 2004. Until


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