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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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slide1
FDA Advisory Committee Meeting

16 February 2005

Cardiovascular Safety of Valdecoxib and Parecoxib

&

Risk-Benefit Assessment

valdecoxib background
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 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
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
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
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
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
CV Death, MI and Stroke:Valdecoxib vs NSAIDs

n (events per 100 patient-years)

cv death mi and stroke valdecoxib vs nsaids1
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

cv death mi and stroke valdecoxib vs pbo nsaids combined individually
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
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
Incidence of Cardiorenal Events

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

Combined analysis of RCTs

valdecoxib and serious skin reactions
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
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
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: Water Soluble Prodrug of Valdecoxib

Parecoxib sodium

Valdecoxib

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

medical need for parecoxib
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
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
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
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 design cabg surgery study 035
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
Adjudicated Thromboembolic CV Events: CABG Surgery Study 035

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

study design cabg surgery study 071
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
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 events cabg surgery study 071
Adjudicated Thromboembolic CV EventsCABG Surgery Study 071

Significantly different from placebo; p<0.05

-- p > 0.20

n (percent of patients)

adjudicated thromboembolic cv events cabg surgery study 0711
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 0712
Adjudicated Thromboembolic CV Events:CABG Surgery Study 071

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

cabg surgery
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 design general surgery study 069
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
Adjudicated Thromboembolic CV Events:General Surgery Study 069

n (percentage of patients with an event)

slide31
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 events combined parecoxib general surgery studies
Thromboembolic CV EventsCombined Parecoxib General Surgery Studies

n (percentage of patients with an event)

daily summed pain intensity scores a general surgery study 069
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

slide34
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
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
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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