Valde Clin Efficacy SAfety by mikeholy

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									    Valdecoxib Talk
           CSM Name
     Clinical Science Manager
           Pharmacia



1
Conventional NSAIDs: Historical Perspective
                        Arachidonic acid


                                  Cyclooxygenase (COX)
                                                          X    Conventional
                                                               NSAIDs


                           Prostanoids
                 ( Prostaglandins/thromboxane)

     Renal toxicity                           Inflammation,
    Impaired platelet                        pain, and fever
       function
                        Gastrointestinal
                           toxicity
2
Mechanism of Action of Anti-inflammatory Agents
                                   Arachidonic acid

                                      COX-2–targeted
                                         agents        X
                 COX-1                                        COX-2
                               X       Traditional     X
                                        NSAIDs


    Prostaglandins       Thromboxane                       Prostaglandins




        Protect           Supports                             Mediate
    gastroduodenal         platelet                        inflammation,
        mucosa            function                         pain, and fever

3
                 Two Forms of Cyclooxygenase (COX)

                       COX-1                                      COX-2

     Constitutive                                   Inducible (in most tissues)
     Synthesizes prostanoids                        Synthesizes prostanoids that
      that mediate homeostatic                        mediate inflammation, pain, and
      functions                                       fever
       Especially important in:                     Induced mainly at sites of
    –   Gastric mucosa                                inflammation by cytokines
    –   Kidney                                       Constitutive expression
    –   Platelets                                     primarily in:
    –   Vascular endothelium                        – Brain
                                                    – Kidney

4   DuBois RN, et al. FASEB J. 1998;12:1063–1073.
     COX-1 Active Site            COX-2 Active Site
       Flurbiprofen              Celecoxib Prototype




         Picot D, et al.        Kurumbail RG, et al.
    Nature 1994; 367: 243-49   Nature 1996; 384: 644-8
5
                           COX Inhibition Assays
                          Interpretation and Application
     Essential for:
      – Structure-activity relationships
      – Kinetic mechanism
      – Compound screening and advancement
     Results dependent on assay system and conditions
     In vitro assays may not predict in vivo profile
     Demonstration of selectivity in vivo is necessary
     “In the absence of definite clinical data, an agent cannot be assumed to be
      COX preferential or specific, regardless of its biochemical profile.”

6   The International COX-2 Study Group. J Rheumatol. 1998;25:2298–2303.
               An In Vivo Model of Selectivity
      Carrageenan-induced air pouch
      Inflammatory PGs
      (COX-2 derived)
                                   Inflamed
                                  air pouch

                                      Gastric
                                      mucosa


      Gastric mucosa
      Physiologic PGs
      (COX-1 derived)
                                                Dose
    PG = prostaglandin
                                                orally
7
            In Vitro and In Vivo Data for COX Inhibitors
                                            Enzyme IC50 (mM)    In vivo ED50 (mg/kg)

                                           COX-1       COX-2    COX-1*        COX-2†

     Indomethacin                           0.1          1        0.1          0.2
     Naproxen                               32          235       0.1          1.3
     Ibuprofen                              38          117       0.2          2.5
     Aspirin                                145         180       3.7          30
     Diclofenac                            0.03        0.01       0.3          0.8
     Etodolac                              > 100        54        0.2          5.1
     Nabumetone (6-MNA)                     82        > 1,000     14           22
     Piroxicam                              679         662       0.1          0.9
     Meloxicam                             1,300       1,700      0.7           1
     Celecoxib                              15         0.04     > 2,000         0.2
     Valdecoxib                             170        0.005     > 200         0.06

    *Gastric PGs; †Air pouch PGs
8   Data on file, Pharmacia Corporation.
                           Enzyme Inhibition Profiles of
                            COX-2-Selective Inhibitors

        Valdecoxib                              Celecoxib                       Naproxen
                      BB B                             B                  100    J
                                         100          B B                            B
      100 B B B B
          J                  B                J BB
            J                                 B             B                        JJ
                                           80                              80                               COX-1
       80                                       J                                                       B
                                                                B
              J                  B                                         60
       60                                  60                                         B                 J   COX-2
                                                  J                                       J
       40                                  40                              40
                  J

       20                            B     20         J                    20             B
                                                                                              BBB
                                                                                              J
                      J                                                                           B
                                                          JJ J      B                           JJJBJ
        0                 J JJ JJ           0               J       J B
                                                                      J     0



                      mM                                  mM                              mM
9   Data on file, Pharmacia Corporation.
                                            Conclusions
       • COX-2 inhibition reduces PG levels and is
         anti-inflammatory and analgesic
       • COX-2 is the therapeutic target for NSAIDs
       • COX-1 inhibition is not anti-inflammatory or analgesic
       • Risk of serious side effects associated with
         conventional NSAIDs is the result of COX-1 inhibition




10   Data on file, Pharmacia Corporation.
     COX-2 and Pain




11
            Role of Prostaglandins in Pain
                          A Working Hypothesis
           Peripheral                                      Central
       Trauma / inflammation                       Pathophysiologic conditions
           PLA2   IL-1b                             (eg hypoxia, ischemia) or
                                   IL-6?
                                                       inflammatory stimuli
     Release of arachidonic acid           PGES?
         induction of COX-2                            induction of COX-2
                                           IL-1b
                                                         Prostaglandins
          Prostaglandins
                                                      Central sensitization

           Sensitivity of
       peripheral nociceptors                       Abnormal pain sensitivity



                                    PAIN
12
             Effect of COX Inhibitors on Inflammation

                                              edema           hyperalgesia
                                   1.5                                               15




                                                                                          D paw withdrawal latency, sec
                                   1.2                                               12
                D paw volume, ml




                                   0.9                                               9


                                   0.6                                               6


                                   0.3                                               3


                                    0                                                0
                                         control   vehicle   SC-560*   celecoxib**

 * Highly selective inhibitor of COX-1; ** COX-2 specific inhibitor
13
     Smith CJ, et al. Proc Natl Acad Sci U S A. 1998;15:13313–13318.
                                   COX-2 in the CNS
         • Prostaglandins in the CNS important in central
           sensitization and hyperalgesia 1
         • Peripheral inflammation leads to central induction of
           COX-2 2
              – Occurs even with complete sensory nerve block 3
              – Humoral signal (IL-6?) may play a role in signal transduction
                across the blood-brain barrier 3
              – IL-1beta plays an important role centrally 3
              – Elevation of prostaglandins in CSF lead to hyperalgesia 3
              – Inhibition of IL-1beta synthesis or receptors reduce CSF levels
                of COX-2, PG and hyperalgesia 3
              – Inhibition of COX-2 centrally has similar effects 3,4

14   1. Taiwo et al Brain Res 1986; 2. Yang et al Pain 1996; 3. Samad et al Nature 2001
     4. Smith et al Proc Natl Acad Sci USA 1998
          Effect of COX-2 Inhibition on PGE2 Levels in the
              CSF Following Peripheral Inflammation
                                 1.4        Prophylactic        Treatment

                                 1.2

                                 1.9
                   PGE2, ng/ml




                                 0.8

                                 0.6

                                 0.4

                                 0.2

                                  0
                                       normal   vehicle      SC-560    celecoxib
 * Highly selective inhibitor of COX-1; ** COX-2 specific inhibitor
15
     Smith CJ, et al. Proc Natl Acad Sci U S A. 1998;15:13313–13318.
                                     Pain Sensitization

                              10
                                   Hyperalgesia

                              8                                         Normal
                                                                         Pain
             Pain Intensity




                                                                       Response
                              6                            Injury

                              4
                                   Allodynia

                              2


                              0

                                                  Stimulus Intensity

16   Gottschalk and Smith, Am Fam Physician 2001
                           Neuronal Plasticity and Pain
      • Neurons detecting and transmitting pain display ―plasticity‖
           – capacity to change function, chemical profile or structure
           – response to painful stimuli and inflammation
           – all contribute to altered sensitivity to pain
      • Three forms of ―neuronal plasticity‖
           – ―Activation‖:            rapid onset, substantial, readily reversible
                                      ―Autosensitization and Wind-up‖
           – ―Modulation‖:            follows repeated, intense stimuli, substantial,
                                      slowly reversible
                                      ―Peripheral and Central Sensitization‖
           – ―Modification‖: follows prolonged, intense stimuli or nerve
                             damage, very long-lasting
                             ―Persistent, pathological (neuropathic) pain‖

17   Woolf and Salter, Science 288: 1765-1768, 2000
 Arthritis Care: An Increasing Burden on Healthcare Resources


                                        Escalating Burden of Arthritis
                                                   57% increase1
                                                                   59.4             Arthritis prevalence
                                   60
                                                                                    Arthritis causing
         Millions of Cases in US




                                   50                                               activity limitation

                                   40   37.9

                                   30
                                                          66%2
                                   20
                                                        increase
                                                                             11.6
                                   10             7.0

                                    0
                                           1990                           2020*
                                                            Year
     *Projected
18   1. Lawrence, et al. Arthritis Rheum. 1998;41:778–799. 2. MMWR Morbid Mortal Wkly Rep. 1994;43:433–438.
 Arthritis Care: An Increasing Burden on Healthcare Resources


Upper GI Events Related to Conventional NSAID Use 1
              Morbidity, Mortality, and Costs in United States

       Condition               Number exposed                 Hospitalizations/y              Deaths

       Inflammatory                   5 million                       51,000                   7,700
       arthritis
       OA/other                       8 million                       56,000                   8,800

       Total                         13 million                       107,000                 16,500


              Total costs ($13,150 per hospitalization): $1.4 billion2


19   1. Singh. Am J Med. 1998;105(suppl 1B):31S–38S; 2. Kong, et al. Am J Managed Care. 1998;4:399–409.
                 Arthritis Care: An Increasing
               Burden on Healthcare Resources
                            Summary
     • Arthritis is the most common chronic musculoskeletal
       condition and cause of activity limitation in people aged
       > 65 years
     • Arthritis management places an enormous burden on
       healthcare resources throughout the world
     • NSAIDs: cornerstone of arthritis therapy
     • However, NSAID-associated upper GI events represent:
        – a significant burden on healthcare resources
        – a major factor in the hospitalization and premature
          death of patients with arthritis

20
                    Pain: The Fifth Vital Sign

     • Pain should be considered the ―fifth vital sign‖
     • Patients should be assessed for pain every time
       pulse, blood pressure, core temperature, and
       respiration are measured
     • Healthcare professionals should recognize a
       report of unrelieved pain as a ―red flag‖




21   American Pain Society Quality Improvement Committee. JAMA. 1995;1847–1880.
                               The Cost of Pain
         The annual cost of chronic pain is
         estimated to be $ 150 billion. It includes:

                          • Medical expenses
                          • Lost income
                          • Lowered productivity



22   American Society of Consultant Pharmacists. Symposium highlights, May 18, 1998
                       The Indirect Costs of Pain
            • Chronic pain diminishes quality of life
            • More than 50 million workdays are lost
              each year due to chronic pain
            • Daily nonmalignant pain in elderly
              person s has been associated with:
                 – impaired activities of daily living
                 – mood

     APF 1999
                 – decreased involvement in activities
23
     Won et al J Am Geriatr Soc 1999
                           Pain is Under-treated:
                          The Patient Perspective
                       1308 patients - 54 ECOG treatment sites




                 67%                         42%                 36%
      Had daily pain in prior             Had negative      Had pain severe
         week and took                  Pain Management       enough to
          analgesics daily                 Index score      impair function

24   Cleeland et al N Engl J Med 1994
                                Pain is Undertreated:
                              The Physician Perspective
                 90
                                                    Most patients are
                 80                                 undermedicated
% of physician




                 70                                 Pain control in my
                 60                                 practice is good
                                                    or very good
                 50
                                                    I would wait until
                 40                                 patient’s prognosis
                 30                                 is six months or less
                                                    before beginning
                 20                                 maximal analgesia
                 10
                  0



25           Von Roenn et al Ann Intern Med 1993
       Barriers to Effective Pain Management
        • Inadequate pain asessment
        • Patient reluctance to:
              – report pain
              – take opioids
        • Physician reluctance to prescribe opioids
        • Inadequate knowledge of pain management by
          healthcare providers and patients


26   Von Roenn et al Ann Intern Med 1993
                  JCAHO Revised Standards
                    The Patient’s Rights

                   • Patient’s Rights
                   • Assessment of Pain
                   • Care of Patients
                   • Rehabilitation
                   • Education of Patient and
                     family
                   • Continuum of Care


27   JCAHO 1999
           Valdecoxib

 Pharmacokinetics and Pharmacodynamics



28
       Valdecoxib Absorption and Distribution
      • Absorption
           – 83% bioavailable
           – no food effect on bioavailabilty

      • Distribution
           –   Valdecoxib 98% plasma protein- bound
           –   2% unbound with linear kinetic profile
           –   Active metabolite 87% protein-bound
           –   Protein binding is concentration-independent


29   Data on file, Pharmacia Corporation.
         Valdecoxib Metabolism and Excretion
             • Hepatic metabolism
                  – CYP 2C9 and 3A4
                  – One active metabolite: SC66095 present
                  at ~10% of the concentration of valdecoxib

             • Excretion
                  – 76% urine
                       • 20% valdecoxib-N-glucuronide
                       • 23% SC66095 glucuronide
                  – 18% fecal
                  – <1% unchanged drug in the urine
30   Data on file, Pharmacia Corporation.
               Metabolism of Valdecoxib in Man
                                                                                       Major
                                                                                     Glucuronide
                                                                (~70%)                (Alcohol)
                                                                                Urine ~23%; Feces ~0%
                                                                Non-P450
            Valdecoxib


                                                     N    O                         Glucuronide
                                                                  C H OH           (Sulfonamide)
                                                                     2
                                    (~80%)

                                      P450                               P450         Aryl
                                    3A4, 2C9                          ~9%         Hydroxylation

                                                         SO2NH2

         Urine <3%; Feces <2%                  Active Metabolite
                                                   Urine ~1%;
                                                   Feces <1%                            Major
         ~19%      Non-P450
                                                                                     Glucuronide
                                                                                      (Alcohol)
              Major
                                               Acid Metabolite                         Urine ~9%
           Glucuronide                             Urine ~1%
          (Sulfonamide)
      Urine ~19%; Feces 0%
31   Data on file, Pharmacia Corporation.
                                Valdecoxib Pharmacokinetics
                                             Valdecoxib

                                            COX-1 IC50 = 140 mM
                                             COX-2 IC50 = 5 nM
                                              Ratio = 28,000


                                               Active Metabolite


                                            Protein Binding ~98%


                                             Elimination = Hepatic
                                                Half Life ~8 hr


                                              CL/F ~100 ml/min
                                                 V/F ~80 L


                                                     Oral
32   Data on file, Pharmacia Corporation.
                Comparison of Three Specific Inhibitors of COX-2:
           Celecoxib                            Valdecoxib                  Rofecoxib


         COX-1 IC50 = 15 mM                    COX-1 IC50 = 140 mM          COX-1 IC50 = 15 mM
         COX-2 IC50 = 40 nM                     COX-2 IC50 = 5 nM           COX-2 IC50 = 18 nM
            Ratio = 375                          Ratio = 28,000                Ratio =1000


          Inactive Metabolites                    Active Metabolite            Active Metabolite


         Protein Binding ~98%                 Protein Binding ~98%          Protein Binding ~87%


         Elimination = Hepatic                  Elimination = Hepatic        Elimination =Hepatic
            Half Life ~12 hr                      Half Life ~8-11 hr           Half Life ~ 17 hr

           CL/F ~500 ml/min                      CL/F ~100 ml/min             CL/F ~ 120 ml/min
             V/F ~400 L                             V/F ~86 L                   V/F ~ 86-91 L


               Oral Only                    Oral and Injectable (Prodrug)         Oral Only
33   Data on file, Pharmacia Corporation.
                Valdecoxib
     Analgesic and Anti-Inflammatory Efficacy




36
               Valdecoxib Clinical NDA Program

      • Studies: 62 completed
      • Total Patients/Subjects: 17,498
      • Endoscopy: 4256 patients (on Valdecoxib)
      • Patient Years: 3080




37   Data on file, Pharmacia Corporation.
     Valdecoxib Efficacy in the Treatment of
                      Pain
             • Management of Acute Pain
             • Pre-Operative Administration
             • Opioid Sparing
             • Primary Dysmenorrhea




38
     Analgesic Efficacy was Measured in Terms of:
     Primary
     •   Pain relief (PR)
     •   Pain intensity difference categorical scale (PID categorical)
     •   Pain relief and intensity difference (PRID)
     •   Time to perceptible pain relief
     •   Time to onset of analgesia
     •   Subject’s global evaluation of study medication (assessed in select studies)
     Secondary
     •   Pain intensity difference visual analog scale (PID VAS)
     •   Peak pain intensity difference (PPID)
     •   Summed Pain Intensity Difference (SPID)
     •   Total Pain Relief (TOTPR)
     •   Summed Pain Relief and Intensity Difference (SPRID)
     •   Time to meaningful Pain Relief

39   Data on file, Pharmacia Corporation.
 Post-Oral Surgery

                                              Study Design
                                Single Dose                     Study A   Study B

                                        Placebo                  n=52      n=51
               Surgery                  Valdecoxib 20 mg         n=42      n=49
          Screen
Randomize        xx                     Valdecoxib 40 mg         n=50      n=50
      -14 d
                                        Oxycodone 10 mg/
                                        acetaminophen 1000 mg    n=51      n=51

                                       **** ************
                                     0h                                      24 h


                                        Evaluable (1h)



40   Data on file, Pharmacia Corporation.
    Post-Oral Surgery

                                     Time to Onset of Analgesia

                     >24
                             C        Study A                               B       Study B
                                                                >24
                      hr                                         hr
 Median Time (min)




                     120                                            120

                      90                                            90

                      60                                            60
                                      B                                                       A
                                                 AB       A                          A                 A
                      30                                             30

                       0                                             0
                                      20          40                                 20       40
                           Placebo        Valdecoxib    Oxy/APAP          Placebo    Valdecoxib     Oxy/APAP
                                             (mg)      10/1000 mg                       (mg)       10/1000 mg

          Treatment(s) with the same letter are not statistically significantly different
41       Data on file, Pharmacia Corporation.
   Post-Oral Surgery


              Time Specific Pain Intensity Difference
     Study A                                                                                         Study B
                                             Placebo                    Valdecoxib 40 mg
                                             Valdecoxib 20 mg           Oxy/APAP 10/1000 mg
                      All active treatments vs Placebo                      All active treatments vs Placebo
              2.5                                             2.5
 Mean Score




              2.0                                             2.0

              1.5                                             1.5

              1.0                                             1.0

              0.5                                             0.5

               0                                                0
                    0 2   4   6   8   10 12 14 16   22   24         0   2     4   6   8   10 12 14 16 22 24

                                  Hours                                               Hours
       * Categorical Scale
       PI Scale = 0 (no pain) - 3 (severe pain)
42    Data on file, Pharmacia Corporation.
              Conclusions: Post-Oral Surgery

• In replicate controlled trials:
       – Onset of analgesia of valdecoxib was within 30 min
       – Single 40 mg dose of valdecoxib was comparable to
         10/1000 mg oxycodone/acetaminophen in onset of
         analgesia
       – Valdecoxib had significantly greater magnitude and
         duration of effect



  43   Data on file, Pharmacia Corporation.
 Post-Abdominal Hysterectomy

                                            Study Design


                               Single Dose

                                                        Placebo (n=66)
               Surgery
          Screen                  Valdecoxib 40 mg (n=67)
Randomize        xx
      -14 d            Oxycodone 10 mg/acetaminophen 1000 mg (n=67)

                                      **** ************                  24 h
                                     0h
                                       Evaluable (1h)




44   Data on file, Pharmacia Corporation.
 Post-Abdominal Hysterectomy

                                       Time to Onset of Analgesia

                                       >24
                   Median Time (min)
                                        hr
                                        60

                                        45

                                        30     A              A
                                                                                       A
                                        15

                                         0
                                             Placebo     Valdecoxib            Oxy/APAP
                                                           40 mg               10/1000 mg
     Treatment(s) with the same letter are not statistically significantly different
45   Data on file, Pharmacia Corporation.
 Post-Abdominal Hysterectomy

                Time Specific Pain Intensity Difference*
                                                 Oxy/APAP vs Placebo
                                                     Valdecoxib vs Placebo
                           1.5                            Valdecoxib vs Oxy/APAP

                                                                         Placebo (n=66)
                                                                         Valdecoxib 40 mg (n=67)
              Mean Score




                           1.0                                           Oxy/APAP 10/1000mg (n=67)



                           0.5



                            0
                                 0   2   4   6      8    10   12    14 16 22       24
     * Categorical Scale
     Scale = 0 (no pain) - 3 (severe pain)
                                                        Hours
46   Data on file, Pharmacia Corporation.
 Post-Abdominal Hysterectomy

                       Patient’s Global Evaluation

                                                    28%           21%          44%         7%
                           Placebo

                                                            15% 17%            35%              33%
                         Oxy/APAP
                        10/1000 MG                                                                          *

                                                          26%     15% 18%            41%
                     VALDECOXIB
                             40 MG                                                                    **

                                   100   80    60    40     20     0    20     40     60    80        100

                                                    Percent of Patients Responding
                                  OVERALL RATING:          POOR         FAIR         GOOD         EXCELLENT




     * Statistically significant vs placebo at p< 0.001
     ** Statistically significant vs placebo at p<0.05
47   Data on file, Pharmacia Corporation.
 Post-Major surgery

                                            Study Design

                            Single Dose                              Multiple Dose
                     Valdecoxib 10mg        (n=45)        Valdecoxib 10 mg QID PRN           (n=25)

                     Valdecoxib 20 mg       (n=45)        Valdecoxib 20 mg QID PRN           (n=13)

                         Oxy/APAP           (n=42)                                           (n=27)
 Surgery                10/1000 mg
                                                        Oxy/APAP 10/1000 mg QID PRN


                     Ibuprofen 400 mg       (n=47)        Ibuprofen 400 mg QID PRN           (n=25)


                         Placebo            (n=47)   Randomized to active treatment groups


                  *
                0 h * * * Evaluable (1hr)
                        4 hr min-                                6 days
                        24 hr max

48   Data on file, Pharmacia Corporation.
 Post-Major Surgery


                               Patients with Onset of Analgesia

                               100
               % of Patients



                                75             *          *                    *

                                50

                                25

                                 0
                                               10         20      400       10/1000
                                     Placebo   Valdecoxib (mg)   Ibu (mg)   Oxy/APAP
                                                                              (mg)
     * Significantly different from placebo; p<0.05
49   Data on file, Pharmacia Corporation.
 Post-Major Surgery


                                            SPID Scores*
                                                  Placebo (n=47)
                                                  Valdecoxib 10 mg (n=47)
                              14                  Valdecoxib 20 mg (n=47)
                                                                               A
                              12                  Ibuprofen 400 mg (n=47)
                 Mean Score



                              10                  Oxy/APAP 10/1000 (n=44)

                               8             A                           AB
                                                                                   AB
                              6         A                                               BC
                                                  A    A
                              4    B

                              2
                                                                   C
                              0
                              -2             12                               24
                                                  Hours Post-dose
     * Categorical Scale
     Treatment(s) with the same letter are not statistically significantly different
50   Data on file, Pharmacia Corporation.
 Post-Major Surgery


         Percent of Patients with Effective Relief
                     over 24 Hours
                               100
               % of Patients



                               75

                               50
                                                          26%
                               25                          *
                                               10%                 11%
                                       2%                                     3%
                                0
                                               10         20       400       10/1000
                                     Placebo   Valdecoxib (mg)   Ibuprofen   Oxy/APAP
                                                                    (mg)       (mg)
     * Significantly different from placebo; p<0.05
51   Data on file, Pharmacia Corporation.
       Conclusions: Post-Surgical Studies

             • Valdecoxib 20 mg or 40 mg vs Tylox:
                  – provided significantly greater pain relief
                    over 24 hours
                  – A lower percentage of patients with 24 hr
                    pain relief was seen with either dose in
                    general surgery compared to oral surgery




52   Data on file, Pharmacia Corporation.
     Valdecoxib Efficacy in the Treatment of
                      Pain
             • Management of Acute Pain
             • Pre-Operative Administration
             • Opioid Sparing
             • Primary Dysmenorrhea




53
 Pre-Operative Oral Surgery


      Study Design
                                                  Administer   Surgery    Time to
             Randomize
                                                    Drug                  Rescue
                                                                         Medication
                               Placebo (n=57)
                                                        60-75 min
                        Valdecoxib 10 mg (n=56)

       Screen           Valdecoxib 20 mg (n=57)

                        Valdecoxib 40 mg (n=57)
-14 d
                        Valdecoxib 80 mg (n=57)




54   Data on file, Pharmacia Corporation.
      Pre-Operative Valdecoxib for Oral Surgery Pain
                                   Dosing       Time to Rescue Medication           Placebo (n=57)
                                                                                    Valdecoxib 10 mg (n=56)
                                    100     J
                                            H
                                            F
                                            B
                                                                                    Valdecoxib 20 mg (n=57)
                                     90             J
             Percent of Patients


                                                                                    Valdecoxib 40 mg (n=57)
                                     80
                                                                                    Valdecoxib 80 mg (n=57)
                                     70
                                     60
                                     50
                                     40
                                     30
                                     20
                                     10
                                      0
                                            0   2       4   6   8    10 12 14 16 18 20 22 24
                                                                    Time (Hrs)
55   Data on file, Pharmacia Corporation.
 Pre-Operative Oral Surgery


                      Time to Rescue Medication
                                       % of Patients
                                         Who Took        Median Time      95%-CI
        Treatment                    Rescue Medication      (H:M)          (H:M)
        Valdecoxib 10 mg                    67           09:04 (C)     07:18 to 14:35
        Valdecoxib 20 mg                    57           13:06 (BC)    09:16 to >24:00
        Valdecoxib 40 mg                    32           >24:00 (A)    >24:00
        Valdecoxib 80 mg                    41           >24:00 (AB)   13:57 to >24:00
        Placebo                             95           02:59 (D)     02:46 to 03:30




56   Data on file, Pharmacia Corporation.
  Pre-Operative Oral Surgery
                       Patient’s Global Evaluation
                                   Excellent
                                   Good
Valdecoxib 80 mg                   Fair
                                   Poor

Valdecoxib 40 mg

Valdecoxib 20 mg


              Placebo

                        100      80       60   40    20   0   20    40   60   80   100

                                                    % of Patients
 57   Data on file, Pharmacia Corporation.
  Pre-Operative Bunionectomy

                                             Study Design

                                                   Administer      Surgery       Time to
            Randomize
                                                     Drug                        Rescue
                                                                                Medication
                              Placebo (n=55)
                                                                45-75   30-90
                    Valdecoxib 20 mg PO (n=56)
                                                                 min     min
      Screen
                    Valdecoxib 40 mg PO (n=57)

-14 d               Valdecoxib 80 mg PO (n=55)




      Pain assessments at 30 minutes and every 2 hours post closure of surgery
      through 24 hours while the patient is awake.
 58   Data on file, Pharmacia Corporation.
 Pre-Operative Bunionectomy

            Percent of Patients Remaining in Study
                                   Dosing        Rescue Medication

                                   100
                                                                              Placebo (n=55)
                                    90
             Percent of Patients

                                                                              Valdecoxib 20 mg (n=56)
                                    80                                        Valdecoxib 40 mg (n=57)
                                    70                                        Valdecoxib 80 mg (n=56)
                                    60
                                    50
                                    40
                                    30
                                    20
                                    10
                                     0
                                         0   2   4   6    8    10 12 14 16 18 20 22 24

                                                              Time (Hrs)
59   Data on file, Pharmacia Corporation.
 Pre-Operative Bunionectomy

                      Time to Rescue Medication

                                            % of Patients
                                             Who Took
                                              Rescue
         Treatment                          Medication        Median Time (H:M)
         Valdecoxib 20 mg                        88                   7:04 (A)
         Valdecoxib 40 mg                        79                   8:44 (A)
         Valdecoxib 80 mg                        71                   8:05 (A)
         Placebo                                100                   3:24 (B)


     Treatment(s) with the same letter are not statistically significantly different
60   Data on file, Pharmacia Corporation.
 Pre-Operative Bunionectomy

                        Patient Global Evaluation
                                                                                 Excellent
                                                                                 Good
Valdecoxib 80 mg
                                                                                 Fair
                                                                                 Poor
Valdecoxib 40 mg


Valdecoxib 20 mg


              Placebo

                      100      80      60   40    20   0   20    40   60   80   100

                                                 % of Patients

61   Data on file, Pharmacia Corporation.
       Conclusions: Pre-Operative Dosing
           • Single doses of valdecoxib within 60 minutes
             prior to surgery significantly delayed the
             development of post-operative pain in
             patients undergoing oral and bunionectomy
             surgery
           • A significant percentage of patients rated
             valdecoxib as excellent in the Patient Global
             Evaluation




62   Data on file, Pharmacia Corporation.
     Valdecoxib Efficacy in the Treatment of
                      Pain
             • Management of Acute Pain
             • Pre-Operative Administration
             • Opioid Sparing
             • Primary Dysmenorrhea




63
 Opioid Sparing Analgesia—Total Knee Replacement

                                             Study Design


                                                 Valdecoxib 20 mg q 12 hrs (n=70)
                         Surgery
                         (<6 hrs)                Valdecoxib 40 mg q 12 hrs (n=69)

                                                      Placebo q 12 hrs (n=70)
       Screen
      -14 days
                                              † * * †
                                            * * †† * *      *
                                                            †    *          *       *
                                            0h




64   Data on file, Pharmacia Corporation.
 Opioid Sparing Analgesia—Total Knee Replacement

                           Cumulative Amount of Morphine
                               Consumed Over Time
                                                            All treatments vs
                               100                                Placebo
        Quantity of Morphine
          Consumed (mg)



                               80

                               60

                               40                                  Placebo (n=63)
                                                                   Valdecoxib 20 mg (n=60)
                               20                                  Valdecoxib 40 mg (n=63)


                                0
                                 0   4   8   12 16 20 24 28    32 36            48
                                                    Hours
65   Data on file, Pharmacia Corporation.
 Opioid Sparing Analgesia—Total Knee Replacement

                          Patient’s Global Evaluation
                                      Excellent
                                      Good
                                      Fair
Valdecoxib 40 mg                                                                      *
                                      Poor


Valdecoxib 20 mg                                                                      **


               Placebo


                        100      80         60    40   20    0 20      40   60   80   100
                                                       % of Patients
     * Significantly different from placebo; p =0.001
     ** Significantly different from placebo; p =0.042
66   Data on file, Pharmacia Corporation.
 Opioid Sparing Analgesia—Total Hip Replacement


                                       Study Design

                     1st Dose of                                 Placebo (n=64)
                  Study Medication
         Baseline                Surgery                    Valdecoxib 20 mg BID (n=67)

                                                            Valdecoxib 40 mg BID (n=71)
                                                      0h
                              1-3 Hrs
          <14 Days                          <4 Hrs                   48 Hrs
                            presurgery




     Note: PCA begins 30 minutes after the end of surgery
67   Data on file, Pharmacia Corporation.
 Opioid Sparing Analgesia—Total Hip Replacement
                      Cumulative Amount of Morphine
                          Consumed Over Time
                                                    Valdecoxib 20 and 40 mg vs Placebo
                                     50
              Quantity of Morphine



                                     40
                Consumed (mg)




                                     30

                                     20                                             Placebo (n=64)
                                                                                    Valdecoxib 20 mg BID (n=67)
                                     10                                             Valdecoxib 40 mg BID (n=71)

                                     0
                                          0   4   8 12 16 20 24 28 32 36 40 44 48
                                                               Hours
68   Data on file, Pharmacia Corporation.
 Opioid Sparing Analgesia—Total Hip Replacement


                            Patient’s Global Evaluation
                                            Excellent
                                            Good
       Valdecoxib 40 mg
                                            Fair
                                                                                        *
                                            Poor

       Valdecoxib 20 mg                                                                 *


                   Placebo



                            -100 -80         -60 -40    -20   0   20   40   60   80   100

                                                   % of Patients
     * Significantly different from placebo; p<0.001
69   Data on file, Pharmacia Corporation.
                    Conclusions: Opioid-Sparing


 • In replicate controlled hip or knee replacement
   trials:
        – Doses of 20 BID and 40 mg BID significantly
          reduced opioid consumption
        – Patient satisfaction was higher with valdecoxib
          + morphine than with morphine alone



70   Data on file, Pharmacia Corporation.
     Valdecoxib Efficacy in the Treatment of
                      Pain
             • Management of Acute Pain
             • Pre-Operative Administration
             • Opioid Sparing
             • Primary Dysmenorrhea




71
                                            Study Design

                                                      Placebo

                                              Valdecoxib 20 mg BID PRN
                  Screen
                                              Valdecoxib 40 mg BID PRN
     - 30 days                                naproxen 550 mg BID PRN

                                    **** ************
                                   Day 1                                 Day 3




72   Data on file, Pharmacia Corporation.
 Primary Dysmenorrhea

        Time-Specific Pain Intensity Difference*

                                          Anaprox 550 mg vs Placebo
                                 Valdecoxib 20 mg vs Placebo
                                          Valdecoxib 40 mg vs Placebo
                       2.0                                                        Placebo (n=83)
          Mean Score




                                                            *                *    Valdecoxib 20 mg (n=83)
                       1.5
                                                                                  Valdecoxib 40 mg (n=84)
                       1.0                                                        naproxen 550 mg (n=81)

                       0.5

                        0
                             0   2        4        6        8           10   12
                                           Hours
     * Pain Intensity (PI) Scale = 0 (no pain) - 3 (severe pain)
     * valdecoxib 40 mg significantly different from valdecoxib 20 mg; P<0.05
73   Data on file, Pharmacia Corporation.
Conclusions: Primary Dysmenorrhea Trials

        Valdecoxib 40 mg in replicate controlled trials:
        • Provides analgesic efficacy comparable to
          naproxen 550 mg
        • Has onset of analgesia within one hour




74   Data on file, Pharmacia Corporation.
     Valdecoxib Efficacy in
      the Management of
           Arthritis

     • Osteoarthritis
     • Rheumatoid Arthritis




75
 Phase III OA—Hip OA and Knee OA


      Study Design                                               Placebo
                                                            Valdecoxib 5 mg QD
         Symptomatic Osteoarthritis                         Valdecoxib 10 mg QD
                                                            Valdecoxib 20 mg QD*
                                                            Naproxen 500 mg BID

                                      Pretreatment   Wk 2        Wk 6              Wk 12




     * Valdecoxib 20 mg QD only in Knee OA Study
76   Data on file, Pharmacia Corporation.
 Phase III OA Studies--Knee OA and Hip OA
                                             WOMAC OA Pain Index
                            Knee OA                                                              Hip OA
                                    Placebo (n=205)                                             Placebo (n=117)
                                    Valdecoxib 5 mg QD (n=201)                                  Valdecoxib 5 mg QD (n=120)
                   11                                                          11
                                    Valdecoxib 10 mg QD (n=205)                                 Valdecoxib 10 mg QD (n=111)
                                    Valdecoxib 20 mg QD (n=201)                                 Naproxen 500 mg BID (n=118)
                   10                                                          10       *
                                    Naproxen 500 mg BID (n=204)
      Mean Score




                                                                  Mean Score
                                                                                                    *
                                                                                                                      *
                             *
                   9                                                            9
                                         †
                                                          ‡                             J

                    8       J                                                   8
                            F            J
                                                          J
                    7                                                           7

                   0                                                           0
                        0       2        6                12                        0       2        6               12
                                    Weeks                                                       Weeks
Scale = 0 (best) - 20 (worst)
* Placebo significantly different from all treatments; P < 0.05
† Placebo significantly different from all treatments except valdecoxib 5 mg; P < 0.05
‡ Placebo significantly different from valdecoxib 20 mg and naproxen; P < 0.05
77   Data on file, Pharmacia Corporation.
 Phase III OA Studies--Knee OA and Hip OA
                                 WOMAC OA Composite Index
                            Knee OA                                                                Hip OA
                                          Placebo (n=205)                                         Placebo (n=117)
                                          Valdecoxib 5 mg QD (n=201)                              Valdecoxib 5 mg QD (n=120)
                   55                                                                55
                                          Valdecoxib 10 mg QD (n=205)                             Valdecoxib 10 mg QD (n=111)
                                          Valdecoxib 20 mg QD (n=201)                             Naproxen 500 mg BID (n=118)
                   50                     Naproxen 500 mg BID (n=204)                50
      Mean Score




                                                                        Mean Score
                                                                                                       *
                                                                                              *                         *


                   45        *                                                       45
                                      †                ‡

                   40                                                                40

                   35                                                                35
                   0                                                                 0
                        0    2     6                  12                                  0   2        6               12
                                 Weeks                                                            Weeks
Scale = 0 (best) - 96 (worst)
* Placebo significantly different from all treatments; P < 0.05
† Placebo significantly different from all treatments except valdecoxib 5 mg; P < 0.05
‡ Placebo significantly different from valdecoxib 20 mg and naproxen; P < 0.05
78   Data on file, Pharmacia Corporation.
     Conclusions: Valdecoxib in Osteoarthritis

                • Doses of 10 and 20 mg
                      – Efficacious in OA
                      – Comparable efficacy to naproxen
                        500 mg BID




79   Data on file, Pharmacia Corporation.
     Valdecoxib Efficacy in
      the Management of
           Arthritis
     • Osteoarthritis
     • Rheumatoid Arthritis




80
 RA Safety and Efficacy Study – I and J


      Study Design                                   Placebo (n=222)

                                               Valdecoxib 10 mg QD (n=209)

                        RA Flare               Valdecoxib 20 mg QD (n=212)
                                               Valdecoxib 40 mg QD (n=221)
                                               Naproxen 500 mg BID (n=225)

                                       Baseline Week 2   Week 6          Week 12




81   Data on file, Pharmacia Corporation.
 RA Safety and Efficacy Studies

                                       ACR-20 at Week 12
                                 Study I                                          Study J

                     60                                        60
                                                                                                B
                     50         B      B                       50                 B      B
                                               B      B                   B
     % of Patients




                     40                                        40
                          A                                         A
                     30                                        30

                     20                                        20

                     10                                        10

                     0                                         0
                          0     10     20      40     500           0    10       20     40     500

                          Valdecoxib (mg QD)        Naproxen        Valdecoxib (mg QD)        Naproxen
                                                    (mg BID)                                  (mg BID)
       Treatment(s) with the same letter are not statistically significantly different
82   Data on file, Pharmacia Corporation.
 RA Safety and Efficacy Studies
                         Physician’s Global Assessment of
                                  Disease Activity
                                  Study I                                                    Study J
                                  Placebo (n=222)                                          Placebo (n=220)
                   4.0            Valdecoxib 10 mg QD (n=209)                4.0           Valdecoxib 10 mg QD (n=226)
                                  Valdecoxib 20 mg QD (n=212)                              Valdecoxib 20 mg QD (n=219)
                                  Valdecoxib 40 mg QD (n=221)                              Valdecoxib 40 mg QD (n=209)
      Mean Score




                                                                Mean Score
                                  Naproxen 500 mg BID (n=225)                              Naproxen 500 mg BID (n=219)
                   3.5                                                       3.5
                              *         *              *                               *         *
                                                                                                                   *
                   3.0                                                       3.0


                   2.5                                                       2.5       †                       †

                    0                                                         0
                          0   2       6               12                           0   2       6                12
                                   Weeks                                                    Weeks
     Scale = 1 (very good) - 5 (very poor)
     * Significantly different than all other treatments; P < 0.05
     † Significantly different than valdecoxib 10 mg; P < 0.05
83   Data on file, Pharmacia Corporation.
      Conclusions: Valdecoxib in Rheumatoid
                     Arthritis

• Doses of 10, 20 and 40 mg QD
       – Efficacious in RA
       – Comparable efficacy to naproxen 500 mg BID
       – There was no additional benefit of valdecoxib
         40 mg compared to valdecoxib 20 mg



84   Data on file, Pharmacia Corporation.
           Valdecoxib

     COX-2 Specific Inhibitor Safety




85
     Valdecoxib: Safety Profile

      Cox-II safety profile
      • hemostasis
      • gastric safety
      Renal profile
      Cardiac profile
      Hepatic profile
      Tolerability


86
Platelet Aggregation

                                            Study Design
                                                        Placebo BID

Healthy Young (18-55yrs) and
 Elderly (65-95yrs) Subjects                      Valdecoxib 40 mg BID


                                                          NSAIDs

                                       Baseline Day 1                    Day 8




87   Data on file, Pharmacia Corporation.
Platelet effects – young adults
        Platelet Aggregation With Arachidonate
                                                Placebo (n=16)                        Naproxen 500 mg BID (n=15)
               Percent (Mean ± SE)   100        Valdecoxib 40 mg BID (n=15)           Diclofenac 75 mg BID (n=16)

                                      80
                                                                        *        *
                                                                    *                               *
                                      60                                                  *

                                      40                  *

                                      20                                                            *
                                                      *   *         *   *        *        *
                                      0
                                           Base- 0   2    4    6    8 Pre- 0     2        4    6    8
                                           line hr   hr   hr   hr   hr Dose hr   hr       hr   hr   hr

                                            0             1                           8
                                                                    Day
     * Change from baseline significantly different from all other treatments; p< 0.05
88   Leese et al. EULAR 2001
     Platelet Aggregation Response to Arachidonate
                 Day 8, Elderly Subjects
                   100
                     90
                     80
                     70
                                                                         Baseline
                     60                                                  - 30 min
                     50                                                  2 hours
                     40                                                  4 hours
                                                                         8 hours
                     30
                                                                   *
                     20
                                                               *
                     10
                      0
                               Placebo         Valdecoxib    Ibuprofen
                                                40 mg BID   800 mg BID
     *Significantly different from placebo, P<0.05
89   Leese et al. EULAR 2001
General Surgery Trials
        Incidence of Bleeding-related Adverse
                        Events
                                            Placebo Valdecoxib* Tylox      NSAID
         Adverse Event                       (n=378)  (n=578)   (n=250)   (n=203)
      Any Bleeding-Related
       Event               1.3                          0.3      0.8       1.0
      Anemia                                  0.5       0.2      0.0       0.0


      Ecchymosis                              0.5       0.2      0.4       0.0

      Withdrawals                             0.0       0.0      0.0       0.0

     * doses   of 20-40 mg daily combined
90   Data on file, Pharmacia Corporation.
     Valdecoxib: Safety Profile

      Cox-II safety profile
      • hemostasis
      • gastric safety
      Renal profile
      Cardiac profile
      Hepatic profile
      Tolerability


91
3-Month Endoscopy Trials - OA


                                Incidence of Gastroduodenal Ulcers
                           20                                          20
 Patients with Ulcer (%)




                           15                             B            15
                                                                 C
                                                                                                                   B
                           10                                          10
                                                                                  AB                       AB
                           5      A        A      A                     5                 A       A

                           0                                                0
                                Placebo    10    20     800     75              Placebo   5       10       20     500
                                          Valdecoxib Ibuprofen Diclofenac                     Valdecoxib        Naproxen
                                           (mg BID)   (mg TID) (mg BID)                        (mg BID)         (mg BID)

             * Treatment(s) with the same letter are not statistically significantly different
92          Data on file, Pharmacia Corporation.
     NA and International Arthritis Trials

                         Incidence of Ulcer Complications
                       2.5
                                                                     *
                                                                   1.96%
                       2.0                                        11/562
      Incidence* (%)




                       1.5

                       1.0                       0.68%
                                                 8/1183
                                                                                       0.39%
                       0.5                                                             7/1791
                                0%
                              0/146
                        0
                             Placebo           Valdecoxib         NSAIDs             Valdecoxib
                                            Controlled Trials                        Open-Label
     * Significantly different from other treatments; P < 0.05; * events/patient years of exposure x 100
93   Data on file, Pharmacia Corporation.
 NA and International Arthritis Trials
                        Incidence of Ulcer Complications/
                               Symptomatic Ulcers
                                                                 *
                                                              12.28%
                                                              69/562
                       12
      Incidence* (%)




                       8

                                             3.04%
                       4                     36/1183
                              1.37%                                              0.95%
                              2/146                                             17/1791
                       0
                            Placebo         Valdecoxib        NSAIDs            Valdecoxib
                                        Controlled Trials                       Open-Label
     * Significantly different from other treatments; P < 0.05; * events/patient years of exposure x 100
94   Data on file, Pharmacia Corporation.
 NA and International Arthritis Trials
                         Incidence of Ulcer Complications/
                       Symptomatic Ulcers: Non-Aspirin Users
                                                                B
                                                              11.43%
                         12                                   55/481
      Incidence* (%)




                         8
                                               A
                                              2.53%
                         4       A                                               A
                                             26/1029
                                0.79%                                          0.54%
                                1/127                                          8/1472
                         0
                              Placebo       Valdecoxib       NSAIDs           Valdecoxib
                                        Controlled Trials                     Open-Label
     * events/patient years of exposure x 100
     Treatment(s) with the same letter are not statistically significantly different
95   Data on file, Pharmacia Corporation.
      6 Month Renal and UGI Safety 6 Month Study

      Study Design
                                            Valdecoxib 20 mg BID (n=399)
                      OA/RA                 Valdecoxib 40 mg BID (n=403)

                                            Naproxen 500 mg BID (n=415)

                         Pre-               Wk    Wk     Wk    Wk          Wk   Wk
                      Treatment             2      6     10    14          20   26
 Arthritis Assessments X                    X     X       X     X           X    X
 UGI Endoscopy            X                                     X
 Renal Function Tests     X                  X                  X               X




96   Data on file, Pharmacia Corporation.
      6 Month Renal and UGI Safety Study
             Incidence of Gastroduodenal Ulcers:
                     OA and RA Patients
                Patients with Ulcer (%)
                                          25                                   *

                                          20

                                          15

                                          10

                                          5

                                          0
                                                 20            40            500
                                               (n=253)       (n=258)        (n=273)
                                                Valdecoxib (mg BID)    Naproxen (mg BID)
* Significantly different from other treatments; P < 0.006
97   Data on file, Pharmacia Corporation.
     Valdecoxib: Safety Profile

      Cox-II safety profile
      • hemostasis
      • gastric safety
      Renal profile
      Cardiac profile
      Hepatic profile
      Tolerability


98
      Controlled Arthritis Trials: Valdecoxib 10-20 mg TDD

        Incidence of Renal Adverse Events (%)
               compared to all NSAIDS
                                            Placebo    Valdecoxib    NSAIDs
      Event                                 (n=1142)    (n=2296)    (n=1347)

      Hypertension             0.6                        1.3         1.5
      Aggravated Hypertension 0.1                         0.5         0.2
      Generalized Edema        0.0                        0.4        <0.1
      Peripheral Edema         0.7                        2.4         2.2
      BUN Increased           <0.1                        0.3         0.8
      Creatinine Increased     0.3                        0.3         0.9
      Weight Increased        <0.1                        0.4         0.7

99   Data on file, Pharmacia Corporation.
    Controlled Arthritis Trials Valdecoxib 40 mg TDD
       Incidence of Renal Adverse Events (%)
              compared to all NSAIDs
                                             Placebo   Valdecoxib   NSAIDs
    Event                                    (n=442)     (n=430)    (n=444)

    Hypertension                               0.5        2.8        1.6
    Aggravated Hypertension                    0.2        0.9        0.7
    Peripheral Edema                           0.5        2.3        2.9
    Acidosis                                     0        0.2          0
    Increased Creatinine                       1.8        0.9        0.2
    BUN Increased                              0.2        0.7        0.9
    Weight Increased                             0          0        0.2

100 Data on file,   Pharmacia Corporation.
  General Surgery Trials

          Renal Adverse Events > 3% in any
                  Treatment Group
                                   Valdecoxib      Oxycodone/   Ibuprofen
                                                  Acetaminophen

                                         40 mg      10/1000 mg    400 mg
                                        (n=300)       (n=250)     (n=203)
 Hypertension                            1.2 %        0.8 %       3.4 %




101   Data on file, Pharmacia Corporation.
      Valdecoxib: Safety Profile

       Cox-II safety profile
       • hemostasis
       • gastric safety
       Renal profile
       Cardiac profile
       Hepatic profile
       Tolerability


102
 Controlled Arthritis Trials

            Cardiovascular Adverse Events
                                       Placebo                Valdecoxib              NSAIDs

                                                    10 mg       20 mg       40 mg
                                       (n=1142)    (n=1284)   (n=1012)     (n=430)    (n=1347)
                                         % (n)      % (n)       % (n)       % (n)       % (n)

  Coronary Artery Disorder              0.2% (2)   0.2% (2)   0.2% (2)     0.2% (1)   0.3% (4)


  Cerebrovascular Disorder              0.2% (2)   0.0% (0)   <0.1% (1)    0.5% (2)   0.2% (3)


  Myocardial Infarction                <0.1% (1)   0.2% (2)   <0.1% (1)    0.2% (1)   <0.1% (1)




103   Data on file, Pharmacia Corporation.
Arthritis and General Surgery Trials

        Valdecoxib Cardiovascular Safety
                   Summary
      • The incidence of coronary artery disorder, cerebrovascular
        disorder, and myocardial infarction is similar in patients
        receiving valdecoxib, placebo, or conventional NSAIDs.




104
      Valdecoxib: Safety Profile

       Cox-II safety profile
       • hemostasis
       • gastric safety
       Renal profile
       Cardiac profile
       Hepatic profile
       Tolerability


105
      Controlled North American Arthritis Trials

               Hepatic Adverse Events:
        AST(SGOT)/ALT(SGPT) Increased 3.0 x ULN
                                     1.2                                   C
                                     1.0
                     % of Patients


                                     0.8
                                     0.6

                                     0.4                  AB
                                              A
                                     0.2

                                      0
                                           Placebo    Valdecoxib       NSAIDs
                                           (n=1093)    (n=3444)       (n=1302)

  Treatment(s) with the same letter are not statistically significantly different
106   Data on file, Pharmacia Corporation.
      Valdecoxib: Safety Profile

       Cox-II safety profile
       • hemostasis
       • gastric safety
       Renal profile
       Cardiac profile
       Hepatic profile
       Tolerability


107
General Surgery Trials

                          Common Adverse Events
                                        Valdecoxib Valdecoxib Oxy/APAP
                                        Placebo     20 mg       40 mg           10/1000
       Adverse Event                     (n=378)      (n=257)         (n=330)   (n=250)
       Any Event                             51.3       47.5           47.9       77.6*†
       Nausea                                21.2       16.3           15.2        28.4†
       Vomiting                              10.1        8.9            6.1       16.4
       Abdominal Pain                         4.5         5.4           2.7        7.6
       Constipation                           4.0         2.7           5.8       10.4
       Dizziness                              3.4         2.7           3.9       10.8*†
       Headache                               5.3         6.6           5.2        7.6
       Somnolence                             2.9         2.3           3.3       14.4*†
      * Significantly different from placebo; P < 0.05
      † Significantly different from valdecoxib, 20-40 mg; P < 0.05
108   Data on file, Pharmacia Corporation.
Controlled Arthritis Trials

                     Common Adverse Events (%)
                                                  Valdecoxib (mg QD)
                                 Placebo        10                   20       NSAIDs
         Event                   (n=1142)     (n=1284)            (n=1012)    (n=1347)
         All Events                49.7          54.6*                57.0*    62.7*†
         Dyspepsia                  5.7          7.7*                 7.4*     12.0*†
         Abdominal Pain             5.8           6.2                 6.6      10.1*†
         Nausea                     5.9           6.9                 6.2       7.9*†
         Headache                   7.5           5.2                 8.1       5.2*
         URTI                       6.1           6.0                 5.7       5.8
         Diarrhea                   4.1           5.4                 5.6       6.2*



      * Significantly different from placebo; P < 0.05
      † Significantly different from valdecoxib, 10-20 mg; P < 0.05
109   Data on file, Pharmacia Corporation.
 Controlled Arthritis Trials


        Incidence of Selected Adverse Events in
      Patients with History of Sulfonamide Allergy*
                                             Sulfa Allergy            No Sulfa Allergy
                                      NSAID            Valde      NSAID              Valde
      Adverse Event                   (n=121)         (n=294)     (n=1226)          (n=3250)
      Rash                               2.5           3.1           1.1               1.5
      Pruritus                           0.8           2.0           0.9               1.0
      Urticaria                          0.0           0.7           0.3               0.4
      Bronchospasm                       0.8           0.3           0.5               0.5
      Allergic Reaction                  0.0           0.3           0.2               0.1
      Eosinophilia                       0.0           0.0          <0.1              <0.1

  * Patients who received either valdecoxib 10 - 20 mg QD in an active-controlled trial
110   Data on file, Pharmacia Corporation.
 Controlled Arthritis Trials


        Incidence of Selected Adverse Events in
      Patients with History of Sulfonamide Allergy*
                                             Sulfa Allergy           No Sulfa Allergy
                                      Placebo          Valde     Placebo           Valde
      Adverse Event                   (n=77)          (n=294)    (n=1065)         (n=3250)
      Rash                               0.0           3.1          1.0               1.5
      Pruritus                           1.3           2.0          0.5               1.0
      Urticaria                          0.0           0.7         <0.1               0.4
      Bronchospasm                       0.0           0.3          0.4               0.5
      Allergic Reaction                  0.0           0.3          0.2               0.1
      Eosinophilia                       0.0           0.0          0.0              <0.1

 * Patients who received either valdecoxib 10 - 20 mg QD in an active-controlled trial
111   Data on file, Pharmacia Corporation.
      Comparison with Conventional NSAIDS

      • Sulfonamide-sensitive patients were included in
        clinical trials
      • Compared to placebo, an increased incidence of
        rash was seen in both valdecoxib and NSAID
        arms in sulfonamide-sensitive patients




112   Data on file, Pharmacia Corporation.
         Valdecoxib Conclusions: Tolerability in
           Post-surgical and Arthritis Patients

                   • Doses 20 mg and 40 mg were safe and
                     well tolerated
                   • Incidence of adverse events is
                        – similar to placebo
                        – significantly lower than with NSAIDs and
                          Oxy/APAP 10/1000 mg



113   Data on file, Pharmacia Corporation.
                Valdecoxib Drug Interactions
                         Summary

           Need to monitor the following therapies:
                – Lithium
                – Warfarin
           Increased plasma levels of valdecoxib with:
                – Fluconazole
                – Ketoconazole
           On-going studies:
                – Omeprazole
                – Phenytoin
114   Data on file, Pharmacia Corporation.
                  Valdecoxib Drug Interactions
                           Summary
  Valdecoxib has no significant effect on:
         – Methotrexate
         – Glyburide
         – Midazolam
         – Fentanyl (with parecoxib*)
         – Propofol (with parecoxib*)
         – Dextromethorphan (increased 3-fold but not clinicallly
           significant)

       * Parecoxib is a prodrug of valdecoxib

115   Data on file, Pharmacia Corporation.
           Study design, Warfarin Coadministration
                      with Valdecoxib


  Warfarin dose adjusted to                  Stable Warfarin   Valdecoxib 40 mg BID +
  target PT time                             Dose              Warfarin

                                                 3 days
                                                                                   Day 7: Blood
                                                                                   sampled over
                                                                                     24 hours
                        Days –10 to 0                                 Days 1-7




116   Data on file, Pharmacia Corporation.
            Conclusion: Serum Warfarin is not significantly
                        altered by Valdecoxib
                                                         Warfarin QD Alone (Day 0, N=24)
                                                         Warfarin QD + Valdecoxib 40 mg BID, (Day 7, N=23)

                                           250                                                                               250
         S-Warfarin Plasma Conc. (ng/mL)




                                                                                           R-Warfarin Plasma Conc. (ng/mL)
                                           200                                                                               200


                                           150                                                                               150


                                           100                                                                               100


                                            50                                                                                50


                                            0                                                                                 0
                                                 0   4    8   12   16   20    24                                                   0   4    8   12   16   20   24
                                                           Time (hr)                                                                         Time (hr)
                                                         S-enantiomer                                                                      R-enantiomer

117   Data on file, Pharmacia Corporation.
         Warfarin + Valdecoxib Coadministration
        Causes Little Change in Prothrombin Times

      Parameter                       Ratio† 90% CI            p-value    % change

                                             S enantiomer
      AUC0-24 (ng/mL·hr)              1.12      (1.04, 1.21)   0.0192     +10%
      Cmax (ng/mL)                    1.10      (1.02, 1.20)   0.0497     +12%


                                             R enantiomer
      AUC0-24 (ng/mL·hr)              1.15      (1.08, 1.23)   0.0015     +14%
      Cmax (ng/mL)                    1.14      (1.06, 1.22)   0.0043     +15%

      † Ratio of least squares means: (warfarin+ valdecoxib) / (warfarin + placebo)


118   Data on file, Pharmacia Corporation.
      Coadministration of Lithium and Valdecoxib Increases
        Lithium Serum Levels and Decreases Clearance

                               1.6
                                     1.34       1.33
        Ratio +/- Valdecoxib



                               1.4
                               1.2
                                 1                           0.75         0.7
                               0.8
                               0.6
                               0.4
                               0.2
                                 0
                                     AUC       Cmax          CL/F       CL renal
                                            Pharmacokinetic parameter

120   Data on file, Pharmacia Corporation.

								
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