Selective COX-2 Inhibitors: Good or Bad Guys?

Selective COX-2 Selective COX-2 Inhibitors: Good or Bad Inhibitors: Good or Bad

Guys?Guys?

Nimmaanrat S, MD, FRCAT, Nimmaanrat S, MD, FRCAT, MMedPM (University of MMedPM (University of

Sydney)Sydney)

Basic Basic ScienceScience

Pharmacology of Pharmacology of Selective COX-2 Inhibitors Selective COX-2 Inhibitors

(COXIBs)(COXIBs) Early 1990, cyclo-oxygenase (COX) Early 1990, cyclo-oxygenase (COX)

existed in 2 distinct isoforms existed in 2 distinct isoforms While COX-1 and COX-2 are While COX-1 and COX-2 are

structurally similarstructurally similar COX-2 contains a side pocketCOX-2 contains a side pocket

Pharmacology of Pharmacology of Selective COX-2 Inhibitors Selective COX-2 Inhibitors

(COXIBs)(COXIBs)

Pharmacology of Pharmacology of Selective COX-2 Inhibitors (COXIBs)Selective COX-2 Inhibitors (COXIBs)

Pharmacology of Pharmacology of Selective COX-2 Inhibitors Selective COX-2 Inhibitors

(COXIBs)(COXIBs) Ratio of affinities to COX-1 and COX-2 Ratio of affinities to COX-1 and COX-2

determines how “selective” determines how “selective” a compound a compound isis

NSAIDs inhibit COX-1 and COX-2 with NSAIDs inhibit COX-1 and COX-2 with different ratiosdifferent ratios

Differences in selectivity lead to some Differences in selectivity lead to some variability in variability in Clinical action Clinical action Safety profilesSafety profiles

Classification and Classification and Basic Differences of COXIBsBasic Differences of COXIBs ClassificationClassification DrugDrug SelectivitySelectivity Chemical Chemical

structurestructure

First First generationgeneration

CelecoxibCelecoxibRofecoxibRofecoxib

3030272272

SulfonamideSulfonamideSulfoneSulfone

Second Second generationgeneration

ValdecoxibValdecoxibEtoricoxibEtoricoxib

LumiracoxibLumiracoxib

6161344344433433

SulfonamideSulfonamideSulfoneSulfonePhenylacetic Phenylacetic acid derivativeacid derivative

COX-1 vs COX-COX-1 vs COX-22

Cyclo-oxygenase I (COX-Cyclo-oxygenase I (COX-1)1)

Constitutive enzymeConstitutive enzyme ““House keeping” enzymeHouse keeping” enzyme Expresses ubiquitouslyExpresses ubiquitously Mediates physiological responsesMediates physiological responses

Cyclo-oxygenase I (COX-Cyclo-oxygenase I (COX-1)1)

Only isoenzyme found in plateletsOnly isoenzyme found in platelets Thromboxane AThromboxane A22 (TXA (TXA22) formation) formation

Also plays a role inAlso plays a role in Protection of GI mucosaProtection of GI mucosa Renal hemodynamicsRenal hemodynamics Platelet thrombogenesis Platelet thrombogenesis

Cyclo-oxygenase II (COX-Cyclo-oxygenase II (COX-22))

Highly expressed by cells Highly expressed by cells involved in inflammationinvolved in inflammation (eg. (eg. macrophage, monocytes, synoviocytes)macrophage, monocytes, synoviocytes)

Unregulated by bacterial Unregulated by bacterial lipopolysaccharides, cytokines, lipopolysaccharides, cytokines, growth factors, tumor promotersgrowth factors, tumor promoters

Cyclo-oxygenase II (COX-Cyclo-oxygenase II (COX-2)2)

““Inducible” formInducible” form Primarily responsible for Primarily responsible for

synthesis of prostanoids involved synthesis of prostanoids involved in acute and chronic in acute and chronic inflammatory states inflammatory states

COX-1 and COX-2COX-1 and COX-2 However, this distinction is somewhat However, this distinction is somewhat

simplifiedsimplified COX-2 also constitutively expressed under COX-2 also constitutively expressed under

physiological conditions in severe tissues physiological conditions in severe tissues Brain Brain Spinal cordSpinal cord KidneyKidney Vascular endotheliumVascular endothelium

COX-1 also be unregulated to a certain COX-1 also be unregulated to a certain degree in inflammationdegree in inflammation

Development of Development of COXIBsCOXIBs

Development of COXIBSDevelopment of COXIBS

Theoretically, selective inhibition Theoretically, selective inhibition of COX-2 would provideof COX-2 would provide Anti-inflammatory effectsAnti-inflammatory effects Without disrupting gastric Without disrupting gastric

cytoprotection and platelet cytoprotection and platelet functionfunction

Development of COXIBSDevelopment of COXIBS

Hypothesis: selective inhibition Hypothesis: selective inhibition of COX-2 will haveof COX-2 will have Therapeutic actions similar to Therapeutic actions similar to

NSAIDsNSAIDs Without GI side effectsWithout GI side effects

Thromboxane AThromboxane A22 (TXA (TXA22) ) & &

Prostacyclin (PGIProstacyclin (PGI22))

Thromboxane AThromboxane A2 2 (TXA(TXA22)) Synthesized by COX-1 in plateletSynthesized by COX-1 in platelet

VasoconstrictionVasoconstriction Smooth muscle proliferationSmooth muscle proliferation Platelet aggregationPlatelet aggregation

Prostacyclin (PGIProstacyclin (PGI22))

In contrast, PGIIn contrast, PGI22, a product of , a product of arachidonic acid (AA) from COX-2 in arachidonic acid (AA) from COX-2 in vessel walls plays important role in vessel walls plays important role in homeostatic defense mechanism homeostatic defense mechanism that promotesthat promotes VasodilatationVasodilatation Inhibition of platelet functionInhibition of platelet function

NSAIDS and COXIBsNSAIDS and COXIBs NSAIDs block both COX-1 and COX-2 NSAIDs block both COX-1 and COX-2

production to a similar extentproduction to a similar extent In contrast, COXIBs inhibits PGIIn contrast, COXIBs inhibits PGI22 production production Thus, COXIBs may create an imbalance Thus, COXIBs may create an imbalance

between TXAbetween TXA22 and PGI and PGI22 This might be the dominant mechanism This might be the dominant mechanism

that can lead to increased risk of that can lead to increased risk of thrombosisthrombosis

Therapeutic Therapeutic UseUse

Therapeutic UseTherapeutic Use Postoperative painPostoperative pain Osteoarthritis (OA)Osteoarthritis (OA) Rheumatoid arthritis (RA)Rheumatoid arthritis (RA) Acute gouty arthritisAcute gouty arthritis Chemoprevention Chemoprevention

Its role in carcinogenesis, apoptosis and Its role in carcinogenesis, apoptosis and angiogenesisangiogenesis

Celecoxib approved for Rx of familial Celecoxib approved for Rx of familial adenomatous polyp (FAP)adenomatous polyp (FAP)

Therapeutic UseTherapeutic Use

Clinical Clinical SafetySafety

Gastrointestinal Gastrointestinal (GI) Tract(GI) Tract

Gastrointestinal (GI) TractGastrointestinal (GI) Tract Common reported adverse events Common reported adverse events

(AEs) were related to GI tract(AEs) were related to GI tract DyspepsiaDyspepsia DiarrheaDiarrhea NauseaNausea Abdominal painAbdominal pain FlatulenceFlatulence

Gastrointestinal (GI) TractGastrointestinal (GI) Tract Upper GI complications have also Upper GI complications have also

occurred in pts treated with occurred in pts treated with COXIBsCOXIBs PerforationPerforation UlcersUlcers BleedingsBleedings PUBsPUBs

Gastrointestinal (GI) TractGastrointestinal (GI) Tract Many large RCTsMany large RCTs

COXIBs caused COXIBs caused fewer GI AEs fewer GI AEs compared to NSAIDscompared to NSAIDs

However, most, if However, most, if not all, of the GI not all, of the GI benefits will be lost benefits will be lost in pts who take in pts who take low-low-dose aspirindose aspirin

Comparison of Upper Gastrointestinal Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and Naproxen in Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis:Patients with Rheumatoid Arthritis:

Vioxx Gastrointestinal Outcome Vioxx Gastrointestinal Outcome ResearchResearch

(VIGOR) study Group(VIGOR) study Group

VIGOR StudyVIGOR Study 11stst large scale large scale

trialtrial Significantly Significantly

fewer clinically fewer clinically important important upper GI events upper GI events (POBs) with (POBs) with rofecoxib rofecoxib compared compared to naproxento naproxen

Gastrointestinal Toxicity Gastrointestinal Toxicityww -ith Celecoxib vs Nonsteroidal Anti in -ith Celecoxib vs Nonsteroidal Anti in

flammatory Drugs for Osteoarthritis a flammatory Drugs for Osteoarthritis a nd Rheumatoid Arthritis nd Rheumatoid Arthritis: the : the CLASSCLASS

Study: Study: A Randomized Controlled Trial A Randomized Controlled Trial

Celecoxib Long-term Arthritis Safety Celecoxib Long-term Arthritis Safety StudyStudy

CLASS StudyCLASS Study Celecoxib (greater dose Celecoxib (greater dose

- 400 mg bid): a lower - 400 mg bid): a lower incidence of incidence of symptomatic ulcers and symptomatic ulcers and ulcers complications ulcers complications combined combined (diclofenac, (diclofenac, ibuprofen)ibuprofen)

No GI benefit if pts took No GI benefit if pts took low-dose aspirin low-dose aspirin concomitantlyconcomitantly

Celecoxib versus Naproxen and Celecoxib versus Naproxen and diclofenac in Osteoarthritis diclofenac in Osteoarthritis

Patients:Patients:Successive Celecoxib Efficacy Successive Celecoxib Efficacy

and Safety Study I (SUCCESS-I) and Safety Study I (SUCCESS-I)

SUCCESS - ISUCCESS - I

Successive Celecoxib Efficacy and Successive Celecoxib Efficacy and Safety Study I (13,274 OA pts)Safety Study I (13,274 OA pts)

Celecoxib: significantly fewer serious Celecoxib: significantly fewer serious upper GI eventsupper GI events

No statistical significance in pts No statistical significance in pts taking aspirin concomitantly taking aspirin concomitantly

SUCCESS- ISUCCESS- I

Gastrointestinal Side Effects of Gastrointestinal Side Effects of Etoricoxib in Patients with Etoricoxib in Patients with

Osteoarthritis: Results of theOsteoarthritis: Results of the Etoricoxib versus Diclofenac Etoricoxib versus Diclofenac

Sodium Gastrointestinal Sodium Gastrointestinal Tolerability and Effectiveness Tolerability and Effectiveness

(EDGE) Trial(EDGE) Trial

EDGE TrialEDGE Trial Cumulative discontinuation rate Cumulative discontinuation rate

significantly lower with etoricoxib than significantly lower with etoricoxib than diclofenacdiclofenac

Assessment of Assessment of UU pper pper GG astrointestinal astrointestinal SSafaf ety of ety of EE toricoxib and toricoxib and DD iclofenac in iclofenac in PPatientatient

s with s with OO steoarthritis and steoarthritis and RR heumatoid heumatoid AArthrth ritis in the ritis in the Multinational Etoricoxib and Multinational Etoricoxib and

- Diclofenac Arthritis Long term (MEDA - Diclofenac Arthritis Long term (MEDA L) programme: a randomised compari L) programme: a randomised compari

sonson

MEDAL ProgrammeMEDAL Programme Largest RCT: 34,701 ptsLargest RCT: 34,701 pts Overall upper GI clinical events (POBs / Overall upper GI clinical events (POBs /

ulcers) and uncomplicated GI events ulcers) and uncomplicated GI events significantly less common with significantly less common with etoricoxib than diclofenacetoricoxib than diclofenac

Benefit maintained in pts taking PPI Benefit maintained in pts taking PPI (proton pump inhibitor) (proton pump inhibitor) or low-dose aspirinor low-dose aspirin

But no difference in complicated GI But no difference in complicated GI events events

High-risk PatientsHigh-risk Patients High-risk pts with history of NSAID-High-risk pts with history of NSAID-

related complicated peptic ulcersrelated complicated peptic ulcers Celecoxib as effective as NSAID plus PPICelecoxib as effective as NSAID plus PPI However, significant proportion of pts However, significant proportion of pts

still had recurrent ulcer complications still had recurrent ulcer complications over period of 24 wksover period of 24 wks

Gastroenterology 2004; 127: 1038-43.Gastroenterology 2004; 127: 1038-43. Am J Med 2005; 118: 1271-8.Am J Med 2005; 118: 1271-8.

High-risk PatientsHigh-risk Patients Celecoxib plus PPI more effective Celecoxib plus PPI more effective

than celecoxib alone for prevention than celecoxib alone for prevention of ulcer bleeding in very high-risk ptsof ulcer bleeding in very high-risk pts

13-month cumulative incidence of 13-month cumulative incidence of recurrent ulcer bleedingrecurrent ulcer bleeding 0% combined Rx0% combined Rx 8.9% celecoxib8.9% celecoxib

Lancet 2007; 369: 1621-6.Lancet 2007; 369: 1621-6.

High-risk PatientsHigh-risk Patients

Addition of PPI to celecoxib conferred Addition of PPI to celecoxib conferred extra GI protection for pts aged 75 extra GI protection for pts aged 75 yrs or olderyrs or older

But did not seem to be necessary for But did not seem to be necessary for pts aged 66-74 pts aged 66-74

Arthritis Rheum 2007; 57:748-55.Arthritis Rheum 2007; 57:748-55.

GI AEs: ConclusionsGI AEs: Conclusions Pts with risk factors are in need for Pts with risk factors are in need for

“gastroprotective” PPI irrespective of the “gastroprotective” PPI irrespective of the COX-2 selectivity of applied NSAIDCOX-2 selectivity of applied NSAID Age > 70Age > 70 Past ulcerationsPast ulcerations Multiple NSAIDs / aspirin taken esp. high Multiple NSAIDs / aspirin taken esp. high

dosedose AnticoagulantAnticoagulant SteroidSteroid Positive for Positive for Helicobacter pyloriHelicobacter pylori

Cardiovascular Cardiovascular (CV) System(CV) System

Cardiovascular (CV) Cardiovascular (CV) SystemSystem

First evidence that COXIBs might First evidence that COXIBs might increase CV risk emerged from increase CV risk emerged from VIGOR studyVIGOR study

Rofecoxib group: 5-fold increase in Rofecoxib group: 5-fold increase in thromboembolic events (primarily thromboembolic events (primarily

acute MIacute MI) )

Cardiovascular Events Associated Cardiovascular Events Associated with Rofecoxib in a Colorectal with Rofecoxib in a Colorectal

Adenoma Chemoprevention Trial: Adenoma Chemoprevention Trial:

Adenomatous Polyp Prevention Adenomatous Polyp Prevention on Vioxx (APPROVe)on Vioxx (APPROVe)

Cardiovascular (CV) Cardiovascular (CV) SystemSystem

3 yr period of study in 2,586 pts with 3 yr period of study in 2,586 pts with history of colorectal adenomashistory of colorectal adenomas

Rofecoxib 25 mg OD / placeboRofecoxib 25 mg OD / placebo Rofecoxib pts had greater risk of Rofecoxib pts had greater risk of

developing thrombotic eventsdeveloping thrombotic events Relative Risk (RR) 1.92Relative Risk (RR) 1.92 95% CI 1.19-3.1195% CI 1.19-3.11

Withdrawal of rofecoxibWithdrawal of rofecoxib

Cumulative Incidence of Cumulative Incidence of Confirmed Thrombotic EventsConfirmed Thrombotic Events

Cardiovascular (CV) Cardiovascular (CV) SystemSystem

High-risk pts with CABGHigh-risk pts with CABG 3-fold increased risk of CV events in 3-fold increased risk of CV events in

pts initially received iv parecoxib pts initially received iv parecoxib followed by oral valdecoxibfollowed by oral valdecoxib

J Thorac Cardiovasc Surg 2003; 125: 1481-92.J Thorac Cardiovasc Surg 2003; 125: 1481-92. N Engl J Med 2005; 352: 1081-91.N Engl J Med 2005; 352: 1081-91.

In addition, case reports of severe skin In addition, case reports of severe skin reactions -> valdecoxib was withdrawnreactions -> valdecoxib was withdrawn

Cardiovascular (CV) Cardiovascular (CV) SystemSystem

CLASS study (intake of low-dose CLASS study (intake of low-dose aspirin allowed)aspirin allowed)

Incidence of serious CV events not Incidence of serious CV events not significantly different between significantly different between celecoxib and NSAID (ibuprofen / celecoxib and NSAID (ibuprofen / diclofenac)diclofenac)

Cardiovascular (CV) Cardiovascular (CV) SystemSystem

Celecoxib for the prevention of Celecoxib for the prevention of colorectal adenomatous polyps: colorectal adenomatous polyps: Prevention of Spontaneous Prevention of Spontaneous Adenomatous Polyps Adenomatous Polyps (PreSAP)(PreSAP) Trial Trial

1,561 pts with prior adenomatous 1,561 pts with prior adenomatous polypspolyps

No significant difference in CV risk No significant difference in CV risk between celecoxib between celecoxib (400 mg/day)(400 mg/day) vs placebo vs placebo

Cardiovascular (CV) Cardiovascular (CV) SystemSystem

Celecoxib for the prevention of Celecoxib for the prevention of sporadic colorectal adenoma: Adenoma sporadic colorectal adenoma: Adenoma Prevention with Celecoxib Prevention with Celecoxib (APC)(APC)

Celecoxib 200 / 400 mg bid vs placeboCelecoxib 200 / 400 mg bid vs placebo Low-dose celecoxib 2.3 XLow-dose celecoxib 2.3 X High-dose celecoxib 3.4 X High-dose celecoxib 3.4 X Early termination of trialEarly termination of trial

The Effects of Cyclooxygenase-2 The Effects of Cyclooxygenase-2 Inhibitors and Nonsteroidal Anti-Inhibitors and Nonsteroidal Anti-

inflammatory Therapy on inflammatory Therapy on 24-hour Blood Pressure in Patients with 24-hour Blood Pressure in Patients with

Hypertension, Osteoarthritis, and Type 2 Hypertension, Osteoarthritis, and Type 2 Diabetes Mellitus: Diabetes Mellitus: Celecoxib Rofecoxib Celecoxib Rofecoxib Efficacy and Safety in Comorbidities Efficacy and Safety in Comorbidities

Evaluation Trial (CRESCENT)Evaluation Trial (CRESCENT)

CRESCENTCRESCENT 24-hr SBP (after 6 wks 24-hr SBP (after 6 wks

of Rx)of Rx) HT, type 2 DM, OAHT, type 2 DM, OA Celecoxib / rofecoxib / Celecoxib / rofecoxib /

naproxennaproxen Rofecoxib: significant Rofecoxib: significant

increased SBPincreased SBP But not by celecoxib But not by celecoxib

or naproxenor naproxen Use of 3 drugs may Use of 3 drugs may

result in different rates result in different rates of CV eventsof CV events

EDGE StudyEDGE Study No significant differences between No significant differences between

EtoricoxibEtoricoxib DiclofenacDiclofenac

Same was true in pts taking aspirinSame was true in pts taking aspirin But in pts on etoricoxib, the non-But in pts on etoricoxib, the non-

aspirin group had more MIsaspirin group had more MIs

MEDAL Programme MEDAL Programme Cardiovascular OutcomesCardiovascular Outcomes

Composite of major Composite of major thrombotic CV thrombotic CV events (at 18 events (at 18 months) similar months) similar with etoricoxib and with etoricoxib and diclofenacdiclofenac

Diclofenac (RR 1.4)Diclofenac (RR 1.4)

Cardiovascular (CV) Cardiovascular (CV) SystemSystem

Nested case-control study in 486,378 Nested case-control study in 486,378 ptspts

Elevated risk of acute MI was a Elevated risk of acute MI was a ““class effect”class effect” of COXIBs of COXIBs All COXIBs associated with higher MI All COXIBs associated with higher MI

risks compared to placebo / NSAIDsrisks compared to placebo / NSAIDs

Cardiovascular (CV) Cardiovascular (CV) SystemSystem

Health-register data suggested that Health-register data suggested that increased mortality in pts with increased mortality in pts with previous MI caused byprevious MI caused by COXIBs in all dosagesCOXIBs in all dosages NSAIDs in high dosages NSAIDs in high dosages

Cardiovascular (CV) Cardiovascular (CV) SystemSystem

Meta-analyses of 17 case-control and Meta-analyses of 17 case-control and 6 cohort studies calculated RR factors6 cohort studies calculated RR factors Rofecoxib (<25 mg/day) 1.33Rofecoxib (<25 mg/day) 1.33 Rofecoxib (>25 mg/day) 2.19Rofecoxib (>25 mg/day) 2.19 Celecoxib 1.06Celecoxib 1.06 Diclofenac 1.4Diclofenac 1.4 Naproxen 0.97Naproxen 0.97 Piroxicam 1.06Piroxicam 1.06 Ibuprofen 1.07Ibuprofen 1.07

CV System - ConclusionsCV System - Conclusions Data from large-scale clinical trial Data from large-scale clinical trial

and epidemiologic studies and epidemiologic studies COXIBs and NSAIDs (except COXIBs and NSAIDs (except

naproxen) as a group can potentially naproxen) as a group can potentially increase the risk of CV events increase the risk of CV events

And apparently there is a dose-And apparently there is a dose-dependent gradient among the dependent gradient among the various COXIBs and NSAIDsvarious COXIBs and NSAIDs

Recommendations for the Use of NSAIDs Recommendations for the Use of NSAIDs according to Gastrointestinal and according to Gastrointestinal and

Cardiovascular RisksCardiovascular RisksCV riskCV risk

GI riskGI risk

LowLow Moderate Moderate HighHighLowLow NSAIDNSAID NSAID + PPI NSAID + PPI

/ / misoprostolmisoprostolor COXIBor COXIB

COXIB + PPICOXIB + PPI

HighHigh NSAID + PPI NSAID + PPI / / misoprostolmisoprostol

NSAID + PPI NSAID + PPI / / misoprostol misoprostol

Avoid Avoid NSAID or NSAID or

COXIBCOXIB

Recommendations for the Use of NSAIDs Recommendations for the Use of NSAIDs according to Gastrointestinal and according to Gastrointestinal and

Cardiovascular RisksCardiovascular Risks a a Gastrointestinal risk is arbitrarily defined as low (no risk fac Gastrointestinal risk is arbitrarily defined as low (no risk fac

tors), moderate (presence one or two risk factors), or high (m tors), moderate (presence one or two risk factors), or high (m ore than two risk factors, previous ulcer complications, or co ore than two risk factors, previous ulcer complications, or co

ncomitant use of corticosteroids or anticoagulants). All patie ncomitant use of corticosteroids or anticoagulants). All patie nts with a history of ulcers who require NSAIDs should be tes nts with a history of ulcers who require NSAIDs should be tes ted for ted for H. pylori H. pylori and if infection is present, eradication therap and if infection is present, eradication therap

y should be given. y should be given.

b b High cardiovascular risk is arbitrarily defined as the require High cardiovascular risk is arbitrarily defined as the require - ment for low dose aspirin for primary cardiovascular event p - ment for low dose aspirin for primary cardiovascular event p

- revention (calculated 1 0 year cardiovascular risk >1 0 % - revention (calculated 1 0 year cardiovascular risk >1 0 % ) orsecondar y pr event i on of ser i ous car di ovascul ar even ) orsecondar y pr event i on of ser i ous car di ovascul ar even

ts.ts.

c c Naproxen is the preferred NSAID in patients with a high car Naproxen is the preferred NSAID in patients with a high car - diovascular risk. Abbreviation: COX2 , cyclo oxygenase 2 . - diovascular risk. Abbreviation: COX2 , cyclo oxygenase 2 .

KidneyKidney

KidneyKidney COX-2 also constitutively expressed COX-2 also constitutively expressed in kidneyin kidney Is regulated in response to alterations Is regulated in response to alterations

in intravascular volume in intravascular volume COXIBs may transiently COXIBs may transiently

Decrease urinary NaDecrease urinary Na++ excretion excretion Can induce mild to moderate BP elevationCan induce mild to moderate BP elevation

COXIBs and NSAIDs COXIBs and NSAIDs Similar effects for kidney damageSimilar effects for kidney damage

Renal insufficiencyRenal insufficiency NaNa++ retention with HT retention with HT Peripheral edemaPeripheral edema HyperkalemiaHyperkalemia Papillary necrosisPapillary necrosis

KidneyKidney

Other Adverse Other Adverse Events (AEs)Events (AEs)

Other (Common) Adverse Other (Common) Adverse EventsEvents

DizzinessDizziness

HeadacheHeadache

Flu-like symptomsFlu-like symptoms

FatigueFatigue

AnxietyAnxiety

InsomniaInsomnia

Other Adverse EventsOther Adverse Events As a sulfonamide, celecoxib can cause As a sulfonamide, celecoxib can cause

cutaneous adverse reactions without cutaneous adverse reactions without warning even in pts with no history of warning even in pts with no history of sulfonamide allergysulfonamide allergy RashRash UrticariaUrticaria Photoallergic dermatitisPhotoallergic dermatitis Serious and potentially fetal AEsSerious and potentially fetal AEs

Exfoliative dermatitisExfoliative dermatitis Steven Johnson syndromeSteven Johnson syndrome Toxic epidermal necrolysisToxic epidermal necrolysis

Other Adverse EventsOther Adverse Events Etoricoxib 30-90 mg/day for up to 1 yr, Etoricoxib 30-90 mg/day for up to 1 yr,

the most frequently reported lab AEsthe most frequently reported lab AEs Increased level of SGOTIncreased level of SGOT Increased level of SGPTIncreased level of SGPT 1-2.1%1-2.1%

Hepatic dysfunction presents a Hepatic dysfunction presents a contraindicationcontraindication

During long-term Rx with COXIBs, LFTs During long-term Rx with COXIBs, LFTs should be regularly monitoredshould be regularly monitored

Other Adverse EventsOther Adverse Events

Lumiracoxib withdrawn due to Lumiracoxib withdrawn due to severe liver damagesevere liver damage

ConclusionsConclusions

ConclusionsConclusions CV risks of COXIBs apparently increase CV risks of COXIBs apparently increase

with with dosedose and and durationduration of exposure of exposure If COXIBs indicatedIf COXIBs indicated

The lowest effective doseThe lowest effective dose For a limited timeFor a limited time

BPBP as well as as well as renalrenal and and hepatic hepatic functionfunction advisably monitored advisably monitored

ConclusionsConclusions

COXIBs should not be prescribed in COXIBs should not be prescribed in pts withpts with Ischemic heart diseaseIschemic heart disease Cerebrovascular disorders (stroke)Cerebrovascular disorders (stroke) Peripheral arterial diseasePeripheral arterial disease

Thank You

SN