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FDA Advisory Committee Meeting. 16 February 2005. Cardiovascular Safety of Valdecoxib and Parecoxib & Risk-Benefit Assessment. Valdecoxib - Background. Valdecoxib approved for OA and RA in Nov ‘01 Approved dose = 10 mg once daily

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16 February 2005

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FDA Advisory Committee Meeting

16 February 2005

Cardiovascular Safety of Valdecoxib and Parecoxib

&

Risk-Benefit Assessment


Valdecoxib - Background

  • Valdecoxib approved for OA and RA in Nov ‘01

  • Approved dose = 10 mg once daily

  • >15,000 individuals studied in the registration program = celecoxib

  • Since the approval:

    • Acute pain and chronic pain conditions


Valdecoxib Overall Conclusions

  • Valdecoxib remains a viable treatment alternative for OA and RA

  • Valdecoxib provides improved GI safety compared to NSAIDs

  • Valdecoxib CV safety database is small at present, however, emerging CV safety profile of valdecoxib is similar to NSAIDs for up to 6 months.

    • CV signal in CABG surgery setting does not extrapolate to the arthritis population.


Clinical Effects of Valdecoxib in OA

Efficacy

Upper GI Safety

B

H

11

Placebo (n=205)

20

F

B

J

P

J

Valdecoxib 5 mg QD (n=201)

H

Valdecoxib 10 mg QD (n=205)

10

15

F

Valdecoxib 20 mg QD (n=201)

P

Naproxen 500 mg BID (n=204)

Patients with Ulcer (%)

WOMAC Pain Scorea

9

*

B

**

10

B

B

8

J

H

P

H

F

H

5

J

J

P

F

P

F

7

0

0

0

2

6

12

Pbo

5

10

20

500

Weeks

Valdecoxib

(mg qd)

Naproxen

(mg bid)

a. 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

** Significantly different from placebo, valdecoxib 5 mg and 10 mg; p < 0.05

Kivitz et al. J Family Practice 2002:51;530-537


Incidence of Ulcer Complications

Pre-defined analysis of 8 RCTs (12-26 wks) & 3 open label studies up to 1 yr

2.5

*

1.95

11/563

2.0

1.5

Events/100 pt yrs)

0.68

8/1183

1.0

0.39

7/1791

0.5

0

0/146

0

Valdecoxib 5-80 mg (n=4362)

Valdecoxib10-80 mg (n=2871)

Placebo

(n=973)

NSAIDs(n=2099)

Controlled Trials

Open-Label

* Significantly different from other treatments; p< 0.05

Goldstein et al. Alimentary Pharmacol Ther 2004;20:527-538


Sources of CV Data for Valdecoxib

  • More limited CV safety database than celecoxib

    • Randomized controlled trials in arthritis

    • Short-term acute pain studies alone or in combination with parecoxib

    • No completed epidemiology studies – 3 ongoing


Cardiovascular Safety of Valdecoxib: Meta-analysis

  • 19 randomized controlled trials and a total of 12,254 treated patients (>84% OA/RA)

    • 7,061 valdecoxib-treated patients

    • 2,235 placebo-treated patients

    • 2,958 patients treated with active comparators

  • Study duration: 2 wks – 12 months

    • 11 studies  3 month duration

  • Valdecoxib doses; 1 – 80 mg daily

Valdecoxib exposure

> 3 months – 2714 (50%) of patients

> 6 months – 1176 (22%) of patients

> 1 yr – 211 (4%) of patients


CV Death, MI and Stroke:Valdecoxib vs NSAIDs

n (events per 100 patient-years)


CV Death, MI and Stroke:Valdecoxib vs NSAIDs

Relative Risk (95%CI)

0.49 (0.21, 1.13)

CV death, MI, or stroke

0.53 (0.13, 2.24)

CV death

0.39 (0.11, 1.37)

MI

Stroke

0.43 (0.09, 2.05)

0.3

3.0

0.1

1.0

10.0

Favors NSAIDs

Favors valdecoxib

Valdecoxib daily dose > 10 mg


Relative Risk (95%CI)

vs. Placebo

vs. NSAID

vs. Naproxen

vs. Diclofenac

0.38 (0.13, 1.09)

vs. Ibuprofen

No events

3.0

0.3

0.1

1.0

10.0

Favors comparator

Favors valdecoxib

CV Death, MI and Stroke:Valdecoxib vs Pbo, NSAIDs Combined & Individually

1.26 (0.35, 4.46)

0.49 (0.21, 1.13)

0.73 (0.18, 2.99)

Valdecoxib daily dose > 10 mg


CV Death, MI and Stroke:Valdecoxib vs NSAIDs: By Dose

Relative Risk (95%CI)

0.49 (0.21, 1.13)

 10 mg

0.27 (0.07, 1.04)

10 mg

0.38 (0.13, 1.17)

20 mg

1.36 (0.31, 5.94)

40 mg

No events

80 mg

0.3

3.0

0.1

1.0

10.0

Favors NSAIDs

Favors valdecoxib

Valdecoxib daily dose > 10 mg


Incidence of Cardiorenal Events

n (percent of patients) NS = not significant (p>0.05)

Combined analysis of RCTs


Spontaneous reports of serious skin reactions received approximately 6 months after launch in the US

Rate appears to be higher than celecoxib or rofecoxib

Black Box warning added November 2004

Valdecoxib and Serious Skin Reactions


Risk-Benefit of Valdecoxib in Arthritis - Conclusions

  • Efficacy similar to NSAIDs

  • Emerging data to establish:

    • GI safety benefit superior to NSAIDs

    • CV safety profile comparable to NSAIDs

  • Added warnings allow physicians to choose appropriately based on the evidence of rare although severe skin reactions.


Future Plans for Valdecoxib

  • As with celecoxib, longer term studies are planned to evaluate the GI safety and CV safety of valdecoxib in arthritis patients.


Parecoxib Sodium: Water Soluble Prodrug of Valdecoxib

Parecoxib sodium

Valdecoxib

Water Solubility ~23 mg/ml ~0.08 mg/ml


Medical Need for Parecoxib

  • Inadequate postoperative pain control is one of the most important factors in:

    • prolonging hospitalization

    • progression from acute pain to chronic pain

  • Postoperative analgesia traditionally provided by opioids

    • associated with complications (eg, ventilatory depression, nausea/vomiting, ileus)

    • inadequate analgesia upon movement

  • Multimodal analgesia (eg, drugs from 2 or more classes)

    • Earlier oral intake, ambulation, hospital discharge

Parecoxib is intended to provide significant analgesia, sparing opioids without GI/bleeding risks of parenteral NSAIDs.

White. Anesth Analg 2002;94:577-585


Post-Operative Pain and Function Following Ambulatory Surgery

Patients treated with Standard of Care Opioids

Laparoscopy (n=59)

120

40

B

Hernia (n=41)

H

35

N=3729

100

H

B

30

80

25

B

60

20

Functional Score

Percent of Patients

B

15

*

40

H

*

10

H

20

B

Mean + Std Dev

p<0.05 vs pre

*

5

H

*

*

0

0

None

Mild

Moderate

Severe

Pre-Surgery

1 day

4 days

7 days

Time (post-surgery)

Pain Status (day after surgery)

Swan et al. Anesth Analg 1998;86:739-45

Chung et al. Anesth Analg 1997;85:808-16


Background

  • Parecoxib was approved for short-term post-surgical pain in Europe March 2002

    • > 1 million patients treated

  • Parecoxib NDA under review in US for management of acute pain


Parecoxib Clinical Registration Program

  • 64 studies completed

  • 26 analgesia studies completed*

  • 10,086 patients randomized

    • 3,415 patients treated with placebo

    • 5,516 patients treated with parecoxib

    • 1,155 patients treated with active comparator**

  • 1,670 patients treated for >3 days with parecoxib

  • 1,183 patients treated for >10 days with parecoxib/valdecoxib

* general surgery, oral and bunion surgery, renal colic trials

** morphine, ketorolac, ibuprofen, tramadol, valdecoxib


Study DesignCABG Surgery Study 035

Day 3

Day 1

Day 14

Parecoxib 40 mg IV Q12h ® Valdecoxib 40 mg PO Q12h (N=311)

Surgery*

Extubate, baseline exam & labs; Randomize

Placebo IV Q12h ® Placebo PO Q12h (N=151)

Both treatment groups receive: PRN Supplemental Analgesia (PCA morphine à oral APAP+codeine)

All patients received aspirin (80-325 mg daily)

*89% cardiopulmonary bypass/11% off-pump cases


Adjudicated Thromboembolic CV Events: CABG Surgery Study 035

* p<0.05 vs placebo; (n) percentage of patients with an event


Study DesignCABG Surgery Study 071

Day 3

Day 1

Day 10

Parecoxib 40 mg IV loading dose + 20 mg IV Q12h ® Valdecoxib 20 mg PO Q12h (N=544)

Surgery*

Placebo IV Q12h ® Valdecoxib 20 mg PO Q12h (N=544)

Randomize (Post-Op Day 1)

Placebo IV Q12h ® Placebo PO Q12h (N=548)

Both treatment groups receive: PRN Supplemental Analgesia (PCA morphine à oral APAP+codeine)

All patients received aspirin (75-325 mg daily)

*all cases were cardiopulmonary bypass


Adjudicated Thromboembolic CV Events

  • Myocardial events:

    • MI, severe myocardial ischemia,

    • cardiac arrest, or sudden cardiac death

  • Cerebrovascular events:

    • Acute ischemic or hemorrhagic stroke, hemorrhagic infarction or TIA

  • Peripheral vascular events:

    • Vascular thrombosis (venous or arterial)

  • Pulmonary embolism


Adjudicated Thromboembolic CV EventsCABG Surgery Study 071

Significantly different from placebo; p<0.05

-- p > 0.20

n (percent of patients)


IV

Study Medication Discontinued

3.0

ORAL

2.5

2.0

1.5

1.0

0.5

0

0

2

4

6

8

10

12

14

16

18

20

22

24

26

28

30

32

34

36

38

40

42

Adjudicated Thromboembolic CV EventsCABG Surgery Study 071

Time to Event Analysis

Treatment

Log rank test

pbo/pbo vs pbo/valde, p=0.311

pbo/pbo vs pare/valde, p=0.030

Parecoxib/Valdecoxib (n=544)

H

H

H

Percent of Patients

H

H

Valdecoxib only (n=544)

J

H

J

H

J

Placebo (n=548)

J

B

H

J

B

H

J

B

H

B

J

H

Days


Adjudicated Thromboembolic CV Events:CABG Surgery Study 071

* p<0.05 vs placebo; n (percentage of patients with an event)


CABG Surgery

  • Limited data to evaluate the effects of NSAIDs in this setting

  • Mechanism for increased CV risk with parecoxib/ valdecoxib is not known:

    • CBP results in activation of platelets, leukocytes and endothelial cells

    • Aortic cross-clamping; ischemia reperfusion injury and emboli

    • Complex time course of changes in PGI2/TXA2

    • High degree of platelet aspirin resistance

These factors are largely confined to the CABG surgery setting

Wan et al. Chest 1997;112:676-92Faymonville et al. J Thorac Cardiovasc Surg 1986;91:858-66Zimmerman et al. Circulation 2003;108:542-7


Study DesignGeneral Surgery Study 069

Day 3

Day 1

Day 10

Parecoxib 40 mg IV loading dose + 20 mg IV/IM Q12h ® Valdecoxib 20 mg PO Q12h (N=525)

Surgery

Randomize (within 6 hr of surgery)

Placebo IV Q12h ® Placebo PO Q12h (N=525)

Both treatment groups receive: PRN Supplemental Analgesia (PCA morphine à oral APAP+codeine)


Adjudicated Thromboembolic CV Events:General Surgery Study 069

n (percentage of patients with an event)


ORAL

Study Medication Discontinued

3.0

2.5

2.0

1.5

1.0

0.5

0

0

2

4

6

8

10

12

14

16

18

20

22

24

26

28

30

32

34

36

38

40

42

Adjudicated Thromboembolic CV EventsGeneral Surgery Study 069

Time to Event Analysis

Treatment

Log rank test

placebo vs parecoxib/valdecoxib, p=0.999

IV/IM

Placebo (N=525)

B

H

Parecoxib/Valdecoxib (N=525)

Percent of Patients

B

H

B

H

B

H

B

H

B

H

H

B

Days


Thromboembolic CV EventsCombined Parecoxib General Surgery Studies

n (percentage of patients with an event)


Daily Summed Pain Intensity Scoresa General Surgery Study 069

35

Placebo (n=525)

Parecoxib / Valdecoxib (n=525)

30

25

*

Mean Scorea

20

*

*

*

15

*

*

*

10

*

*

Less

Pain

5

0

2

3

4

5

6

7

8

9

10

Days

* Significantly different from placebo; p<0.05

a. Scale ranges from 0 to 72. Larger number indicates more pain


p<0.001

-35%, p<0.001

0.6

75

0.59

66.2

0.39

0.4

50

43.2

Morphine Equivalents (mg)

Morphine Equivalents (mg/hr)

0.2

25

p=0.085

0.11

0.08

0

0

IV Phase

PO Phase

Supplemental Opioid UseGeneral Surgery Study 069

Placebo (n=519)

Parecoxib / Valdecoxib (n=520)

Combined IV/PO


Modified Brief Pain Inventory - Function:General Surgery Study 069

3.5

Placebo (N=525)

3.0

Parecoxib / Valdecoxib (N=525)

2.5

*

2.0

Mean Scorea

1.5

*

*

*

1.0

*

*

improved

function

*

*

*

0.5

0

2

3

4

5

6

7

8

9

10

Days

* Significantly different from placebo; p<0.05

a. Scale ranges from 0 to 11. Larger number indicates greater interference with function

Composite score: general activity, walking, sleeping, deep breathing, coughing, concentration, mood, relations with others


Risk-Benefit of Parecoxib - Conclusions

  • Parecoxib offers unique benefits over existing parenteral analgesic medications and a favorable risk benefit ratio in surgical settings other than CABG/ revascularization

    • Parecoxib administered in controlled settings under physician observation

    • CV risk found only in CABG surgery setting; not observed in other surgical settings

      • other revascularization procedures not assessed


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