Selective COX-2 Inhibitors: Good or Bad Guys?
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Transcript of 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