# Presentation: 682723

## COX-2 CV Safetyvaldecoxib-parecoxib

- James Witter MD, PhD
- DAAODP/ODE V
- February 16, 2005

## Bextra (valdecoxib)

- Original NDA (January 15, 2001)
- 60 studies
- Phase 1-2: 31 studies
- Arthritis (OA/RA): 10 studies
- Included open-label exposure
- Post-surgical analgesia: 19 studies
- CABG 035
- Original approval did not contain sulfonamide warning
- Addressed by subsequent label changes and DHCP letters

## Valdecoxib -  OA and RA Exposure (pt-yrs)

|  | Valdecoxib (mg) |  |  |  |  |  | NSAID | Placebo |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  | ≤ 5 | 10  | 20  | 40  | 80  | Total | Naproxen
Diclofenac
Ibuprofen |  |
| Double-blind | 107 | 323 | 397 | 316 | 142 | 1285 | 580 | 161 |
| Open-label
(120 day update) | - | 308 | 787 | 736 | 233 | 2064 | - | - |
| TOTAL | 107 | 631 | 1184 | 1052 | 375 | 3349 | 580 | 161 |

- From Medical Officer review: November 7, 2001

## Valdecoxib - Deaths

- Total of 22 deaths in NDA
- 17 occurred during double-blind studies
- 4 in CABG trials (discussed in parecoxib data)
- 2 were CV related
- 8 in patients receiving valdecoxib
- 4 were CV related
- 3 in patients receiving NSAIDs
- 2 were CV related
- 2 non-CV deaths occurred in cancer pain trial
- 5 during open-label studies
- 3 were CV related

## Valdecoxib - CV Mortality

| Population | # Deaths | Pt-yrs Exposure | Mortality Rate |
| --- | --- | --- | --- |
| Controlled Arthritis Trials |  |  |  |
| Placebo
valdecoxib (+ CABG)
valdecoxib (- CABG)
NSAID | 0
6
4
2 | 161
1285
1143
580 | 0.00%
0.47%
0.35%
0.35% |
| Open-label Arthritis Trial  |  |  |  |
| All Known Cardiac Deaths | 3 | 2064 | 0.14% |

## Valdecoxib - CV SafetySpecial Analysis

- Rates of Serious Thromboembolic CV Adverse Events Calculated for High- and At-risk Patients:
-   High-risk patients:
- - angina, myocardial infarction, coronary artery disease and cerebrovascular accident
-   At-risk patients:
- - hypertension, hyperlipidemia or smoking
-   FDA-defined endpoints:
- - MI, myocardial ischemia, unstable angina, cardiac arrest, sudden cardiac death, CVA/TIA, PE, venous thrombosis, embolism, peripheral gangrene and peripheral ischemia

## Valdecoxib - CV safetyHigh Risk Patients

|  | Placebo | Valdecoxib (mg) |  |  |  | NSAIDs |
| --- | --- | --- | --- | --- | --- | --- |
|  |  | 10  | 20 | 40  | 80 |  |
| n 
(pt-yrs) | 106 
(13) | 174 
(49) | 144 
(47) | 93 
(23) | 42 
(12) | 248
(71) |
| # Events | 2 | 3 | 1 | 1 | 1 | 6 |
| Incidence (%) | 1.9 | 1.7 | 0.7 | 1.1 | 2.4 | 2.4 |
| Events/100 pt-yrs | 15.4 | 6.1 | 2.1 | 4.3 | 8.3 | 8.5 |

- From Medical Officer review (Nov. 7, 2001)
- All valdecoxib groups: incidence = 1.3%; events/100 pt-yrs = 4.6%

## Valdecoxib - CV safetyAt Risk Patients

|  | Placebo | Valdecoxib (mg) |  |  |  | NSAIDs |
| --- | --- | --- | --- | --- | --- | --- |
|  |  | 10  | 20 | 40  | 80 |  |
| n 
(pt-yrs) | 503 
(73) | 665 
(198) | 773 
(262) | 646 
(187) | 258 
(93) | 1144
(357) |
| No. Events | 0 | 1 | 4 | 3 | 1 | 7 |
| Incidence (%) | 0 | 0.2 | 0.5 | 0.5 | 0.4 | 0.6 |
| Events/100 pt-yrs | 0 | 0.5 | 1.5 | 1.6 | 1.1 | 2.0 |

- From Medical Officer review (Nov. 7, 2001)
- All valdecoxib groups: incidence = 0.4%; events/100 pt-yrs = 1.2%

## CV Adverse Events - Study 0476-month (OA/RA)

| Adverse Event | Naproxen
500 mg BID
(N = 415) | Valdecoxib
20 mg BID
(N = 399) | Valdecoxib
40 mg BID
(N= 403) |
| --- | --- | --- | --- |
| Completed week 26 | 180 (43%) | 207 (52%) | 204 (51%) |
| Edema
Worsened BP
Unstable angina
Angina Pectoris
Cardiac failure
Arrhythmia
Palpitations
Thrombosis
Cerebrovascular disorder | 6 (1.4%)
13 (3.2%)
0
2 (0.5%)
0
0
2 (0.5%)
0
0 | 9 (2.2%)
24 (5.8%)
1 (0.3%)
2 (0.5%)
0
1 (0.3%)
2 (0.5%)
0
1 (0.3%) | 3 (0.7%)
31 (7.7%)*
0
3 (0.8%)
2 (0.5%)
4 (1.0%)
2 (0.5%)
1 (0.2%)
1 (0.3%) |

**Table 2.3b.2 and 7.0.1: 6/25/01 consult.  Labeled doses for OA/RA = 10 mg QD**.
**P < 0.05**

## Parecoxib

- IV/IM

## Toradol IV/IM Label - PDR

| Incidence (%) of Clinically Serious GI bleeding after 5 days |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- |
| 

Age of patient |  | Total daily dose (mg) |  |  |  |
|  |  | ≤ 60  | > 60-90  | > 90-120  | >120  |
| Without history of PUB |  |  |  |  |  |
| < 65 years | 0.4` |  | 0.4 | 0.9 | 4.6 |
| ≥ 65 years | 1.2 |  | 2.8 | 2.2 | 7.7 |
| With history of PUB |  |  |  |  |  |
| < 65 years | 2.1 |  | 4.6 | 7.8 | 15.4 |
| ≥ 65 years | 4.7 |  | 3.7 | 2.8 | 25.0 |

## Parecoxib

- Parenteral precursor to valdecoxib
- T1/2 = 15-30 minutes
- Allows exposure to different patient population with different risk factors
-  Intended to address the issues
- multi-modal analgesia
- COX-2 role in pain
- pre-emptive analgesia
- opioid sparing
- Certain studies conducted with valdecoxib
- CABG studies

## Parecoxib

- Original NDA (September 11, 2000)
- 36 studies
- Phase 1-2: 14 studies
- GI-renal-platelet: 7 studies
- Post-surgical analgesia: 8 studies
- Pre-operative analgesia: 4 studies
- Opioid-sparing analgesia: 2 studies
*CABG-035*
- Long-term safety (with valdecoxib): 1 study

## Parecoxib - CABG I (035)

- First time via median sternotomy
- 2:1 randomization
- 311 parecoxib
- 151 placebo (standard-of-care; PCA/opioids)
- Study with 2 phases
- parecoxib IV/IM 40 mg q12 hrs for 72 hours
- valdecoxib 40 mg orally q 12 hrs to day 14
- ASA (≤ 325 mg) during study**  **

## Safety Assessment-CABG I

- Complex (patients, procedures, co-meds)
- Blinded committees established to:
- verify AE meet criteria established
- addressed date and attribution to include:
- CRAEs (clinically relevant adverse events)
- No active controls in CABG trials
- Are NSAIDs appropriate?

## CABG (035) - Exposure

| Days | Placebo  | Parecoxib/Valdecoxib  
40 mg Q12H |
| --- | --- | --- |
| 1-4
5-7
>7
Total |  22 (15%)
   6 (4%)
123 (81 %)
151 (100 %) | 40 (13 %)
15 (5 %)
256 (82 %)
311 (100 %) |

- Data from Medical Officer review  (December 1, 2000)

## CRAEs - CABG (035) 

- Death
- All cause death following randomization within 30 days of last dose of study drug
- Cardiovascular Events
- myocardial infarction.
- severe myocardial ischemia
- cerebrovascular accident (CVA, TIA, or hemorrhage)
- peripheral arterial occlusion
- deep vein thrombosis
- pulmonary embolism
- Pericarditis
- Congestive Heart Failure (new onset or exacerbation)
- Renal Failure/Dysfunction
- Gastrointestinal Event
- Major non-GI bleed (requiring transfusion)
- Infection (requiring institution of antibiotics)
- Pulmonary complications (non-infectious)

## Myocardial Infarction - CRAE (035)diagnosed by 2 of following criteria

- Prolonged (>20 min) typical chest pain not relieved by rest and/or nitrates
- Enzyme level elevation, either by:
- CK-MB >5% of total CPK
- CK greater than 2x normal
- LDH subtype 1>LDH subtype 2
- troponin >0.2 micrograms/ml
- New wall motion abnormalities
- Serial ECG (at least two) showing changes from baseline or serially in ST-T and/or Q waves that are 0.03 seconds in width and/or > or + one third of the total QRS complex in two or more contiguous leads

## CRAEs - 035

| Event | Placebo
(N =151) |  | Parecoxib/Valdecoxib  40 mg BID
(N = 311) |  |
| --- | --- | --- | --- | --- |
|  | IV | Entire | IV | Entire |
| Any | 14 (9.3%) | 23 (15.2%) | 36 (11.6%) | 80 (25.7%)* |
| Death

MI
CVA
DVT
PE
CHF
Pericarditis

Renal failure
GI event
Major non-GI bleed
Infection
Pulmonary | 0

0
0
0
0
0
0

6 (4.0%)
0
2 (1.3%)
6 (4.0%)
2 (1.3%) | 0

1 (0.7%)
1 (0.7%)
0
0
1 (0.7%)
1 (0.7%)

7 (4.6%)
0
2 (1.3%)
11 (7.3%)
4 (2.6%) | 2 (0.6%)

1 (0.3%)
5 (1.6%)
0
1 (0.3%)
0
2 (0.6%)

21 (6.8%)
0
0
3 (1.0%)
6 (1.9%) | 4 (1.3%)

1 (0.3%)
9 (2.9%)
3 (1.0%)
2 (0.6%)
4 (1.3%)
4 (1.3%)

29 (9.3%)
4 (1.3%)
0
29 (9.3%)
19 (6.1%) |

- * P = 0.012 (Fischer’s)

## MI - CABG (035)

- Of 13 possible MI, 11 sent to committee:
- 9 events (parecoxib)
- 2 events (placebo)
- Of these, 2 MIs believed met CRAE definition
- 1 parecoxib
- 1 placebo
- One rejected event in parecoxib group resulted in death (probable MI) of patient
- Difficulty of adjudication
- Timing of drug vs. event

## Parecoxib - Deaths

- 58 y/o male- 4 doses (IV):
- died on day 15 of duodenal ulcer
- 69 y/o female-20 doses (IV/PO):
- died on day 19 of probable MI
- 67 y/o male-12 doses (IV/PO):
- died day 12 septicemia, pneumonia
-  62 y/o male-7 doses (IV):
- died day 5 of infarct-left cerebellum

## CABG II (Study 071)

- 50% dose reduction
- dosing on day 1
- timing of events (IV vs. PO)

## CRAEs - 071 (entire study)

| Event | Plc/Plc
(N = 548) | Plc/Valde
(N = 544) | Pare/Valde
(N = 544) |
| --- | --- | --- | --- |
| Any Event (%) | 22 (4.0%) | 40 (7.4%)* | 40 (7.4)* |
| Deaths | 1 (0.2%) | 3 (0.6%) | 4 (0.8%) |
| CV-Thromboembolic
MI/arrest/ischemia/cardiac death
CVA
DVT
PE
Renal failure/dysfunction

GI event
Wound complication/infection | 3 (0.5%)
0
2 (0.4%)
1 (0.2%)
1 (0.2%)
3 (0.5%)

2 (0.4%)
16 (2.9%) | 6 (1.1%)
2 (0.4%)
2 (0.4%)
0
2 (0.4%)
4 (0.7%)

4 (0.7%)
27 (5.0%) | 11 (2.0%)*
4 (0.7%)
5 (0.9%)
0
2 (0.4%)
7 (1.3%)

6 (1.1%)
20 (3.7%) |

- * p < 0.05; information included in valdecoxib label

## Deaths - 071

- Placebo
- Intestinal perforation
- Placebo/valdecoxib
- Cardiac arrest
- Pneumonia
- Cardiac failure
- Parecoxib/valdecoxib
- Cardiac arrest
- PE
- MI
- VF

## General Surgery (study 069)

- -40 mg LD, then 20 mg BID
- -General Surgery Patients including orthopedic, GI, GYN, thoracic, other

## CRAEs - 069 (Entire Study)

| Event | Placebo
(n=525) | Pare/Valdecoxib
(n=525) |
| --- | --- | --- |
| Any Event (%) | 17 (3.2) |  14 (2.7) |
| Death [CV-related] | 4 (0.8) | 3 (0.6) |
| CV-Thromboembolic

MI/arrest/cardiac death
CVA
DVT
PE

Renal failure/dysfunction
GI event
Wound complication/infection | 5 (1.0)

1 (0.2)
1 (0.2)
2 (0.4)
1 (0.2)

0
1 (0.2)
1 (0.2) | 5 (1.0)

3 (0.6)
0
1 (0.2)
1 (0.2)

1 (0.2)
1 (0.2)
1 (0.2) |

- Data included in valdecoxib label

## Deaths - 069

- Placebo
- Cardiac failure
- Carcinoma
- Mesenteric vein thrombosis
- Cardiac arrest
- Parecoxib/valdecoxib
- GI hemorrhage
- MI
- PE

## Is Safety Related to COX selectivity?

- COX-1

- COX-2

- CV

- GI

## Safety: Selectivity or Drug ?

- Diclofenac       COX-2

## Endoscopic Ulceration RA (6 month)

|  | Celecoxib 
200 mg BID
(N = 326) | Diclofenac 
75 mg SR BID
(N = 329) |
| --- | --- | --- |
| Crude Gastroduodenal Ulcer Rate (ITT) | 3.8%* 
(8/212) | 15.1% 
(33/218) |

- * p < 0.001 (CMH); included in original label.**  **

## CLASS - GI outcomes

- Compared to diclofenac, celecoxib did not demonstrate statistical superiority for any prospectively defined, adjudicated endpoint including:
- Primary endpoint  (complicated ulcers)
- Including non-ASA users
- Expanded endpoint of complicated and symptomatic ulcers
- Including non-ASA users

## CLASS - Hepatic Events

| Event | Celecoxib | Diclofenac | Ibuprofen |
| --- | --- | --- | --- |
| Any | 1.8 | 6.9* | 0.6 |
| X-ULN
3X AST ± 3X ALT
3X ALT ± 3X AP
3X ALT ± 1.8X TB | 
0.4
0.4
0.4 | 
3.7*
3.3*
3.4* | 
0.7
0.6
0.6 |
| Withdrawals | 0.3 | 3.5* | 0.3 |

- * p < 0.05

## Safety Data - NSAIDs vs COX-2

- Think about the data we have
- Worry about the data we don’t have
- Absence of evidence, is not evidence of absence