Parecoxib Sodium

**NDA 21-294**

**Medical Officer Review**

**Submission Date:** September 11, 2000

**Received Date:** September 12, 2000

**Review Date:** December 1, 2000

**Drug Name:** Xaptek

**Generic Name:** parecoxib sodium

Chemical Name: **sodium salt of N-{\[4-(5-methyl-3-phenylisoxazol
4-yl)phenyl\]sulfonyl}propanamide**

**Applicant:** G.D. Searle & Co.

**Related Reviews:** Statistics, Cardio-Renal, Gastrointestinal,
Biopharm, Chemistry, Pharmacology, Medical (valdecoxib)

**Pharmacologic category:** COX-2 inhibitor (parenteral)

**Proposed Indication:** Management of pain (postoperative and
preemptive)

Opioid Sparing

**Dosage forms and route:** For injection, 20 and 40 mg

**Submission type:** Original NDA

Materials Reviewed: **Primary documents- N93-00-07-815**

N93-00-07-816

N93-00-07-804

I93-00-06-035

Orig NDA \# 21-294

HFD-550/Div File

HFD-550/PM/Schmidt

HFD-550/Pharm/Yang
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

HFD-550/Chem/Bhavnagri (James Witter, M.D., Ph.D. Medical Officer)

HFD-550/Biopharm/Bashaw

HFD-550/Statistics/Lin

HFD-550/MO/Witter/Goldkind

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####### Parecoxib Executive Summary {#parecoxib-executive-summary .unnumbered}

**Significant Issues**

-   Parecoxib is a new molecular entity and represents the first
    parenteral "COX-2 selective" agent to seek approval in the U.S.

-   Although the single dose data in several surgical situations have
    established that parecoxib sodium at 40 mg is efficacious compared
    to placebo, this is not the case for single doses of 20 mg.

-   Multiple dose data with parecoxib sodium are limited and do not
    allow for characterization of the safe and effective dose, or dosing
    interval after the first dose.

-   The proposed labeling claims for management of postoperative pain or
    for the preemptive treatment of pain or for opioid sparing with
    parecoxib sodium are not supported by the data available in this NDA
    either due to insufficient data or lack of replication of results.

-   Safety data from the CABG trial suggest that certain subgroups of
    patients may be at increased risks for serious adverse events.
    Furthermore, these data can not exclude the possibility of an
    important safety liability associated with parecoxib sodium,
    particularly with repeated doses, over placebo.

    **Highlights**

-   Parecoxib sodium is a parenteral prodrug of the orally available
    compound valdecoxib which is under concurrent review. This dual
    development has impacted, and confounded, the ability to make clear
    distinctions in terms of the safety and efficacy associated with
    parecoxib sodium.

-   Most (approximately two thirds) of the data on safety and efficacy
    in the original NDA were obtained from patients or subjects exposed
    to single doses of parecoxib sodium. While such data is fundamental
    to supporting the efficacy and safety of parecoxib sodium, it is
    insufficient to fully characterize the safety and efficacy of this
    compound.

-   It is unclear, from the currently available data, whether the
    efficacy associated with parecoxib sodium in a surgical setting is
    sufficient to balance the observed adverse events. However, owing to
    the nature of the surgical setting or use of medications both during
    and after the surgery, interpretation of adverse events is not
    always straightforward. There are no data regarding the use of
    parecoxib sodium in an emergency or trauma-like setting.

    **BACKGROUND AND OVERVIEW:**

In acutely painful conditions, parenteral administration of analgesic
medication can provide a rapid and sustained onset of analgesia,
especially in patients unable to ingest or tolerate oral medication.
Opioids and non-steroidal anti-inflammatory drugs (NSAIDs) are

commonly used parenteral analgesics for the management of acute pain.
However, their use can be limited by a wide spectrum of adverse effects.
These adverse effects can actually slow the postoperative rehabilitation
process and compound the risk inherent in any surgical procedure. These
adverse outcomes may be particularly true for elderly patients, patients
with a history of peptic ulcer disease, patients in whom respiratory
depression should be avoided, patients with an increased susceptibility
to perioperative bleeding, and patients with compromised renal function.

Parenteral opioids are the mainstay of acute postoperative pain
management in the inpatient setting. However, a number of frequent
adverse effects associated with their use have been identified. These
include: respiratory depression, nausea, vomiting, sedation,

urinary retention, constipation, decreased gastrointestinal (GI)
motility, and paralytic

ileus. These adverse effects often impede postoperative rehabilitation
and limit their use in the ambulatory surgical setting. Failure to
provide adequate management of pain, either due to inadequate analgesic
efficacy or sub-optimal treatment due to concerns about potential
adverse effects, can contribute substantially to reduced quality of life
among patients experiencing acute pain. Due to the growing number of
outpatient surgical procedures, additional symptoms such as **somnolence
and dizziness** that frequently accompany the use of opioids may further
limit these agents as a treatment for postoperative analgesia,
particularly in an outpatient setting.

The current standard of care for analgesia in the perioperative setting
consists of opioids,

with adjunctive use of NSAIDs ("multimodal analgesia"). In less severe
cases, NSAIDs alone are sufficient to provide effective postoperative
analgesia. The selection of multimodal drug therapy (including opioids
and NSAIDs) for the management of acute pain is based on a number of
principles, including the analgesic efficacy of centrally acting
opioids, the peripheral anti-inflammatory and analgesic effects of
NSAIDs, and the synergy that can be observed between these two modes of
treatment. Although both opioids and NSAIDs are effective analgesics,
neither are without safety and tolerability concerns that may become
exaggerated in an already compromised postsurgical patient population.

Toradol  (ketorolac tromethamine) is currently the only approved
parenteral NSAID for use in the United States. It is effective and may
be used as an adjunct to opioids for the management of postoperative
pain. However, the use of ketorolac is associated with a number of
adverse effects characteristic of NSAIDs, including upper GI ulceration
and bleeding (particularly in the elderly), reduction in renal function,
hemostatic impairment (decrease in platelet aggregation and increase in
duration of bleeding), and bronchospasm. Owing to concerns about safety,
the use of ketorolac has been limited to five days and cannot be
administered preoperatively.

Parecoxib sodium (SC-69124A; C~19~H~17~N~2~O~4~SNa) is a water-soluble
inactive prodrug of

valdecoxib (SC-65872), a highly selective inhibitor of cyclooxygenase-2
(COX-2).

Parecoxib sodium was developed as a parenteral analgesic for the
management of acute pain. It is chemically designated as the sodium salt
of N-{\[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl\]sulfonyl}propanamide.
Parecoxib sodium is rapidly (T~1/2~=15-30 min) and essentially
completely converted via enzymatic hydrolysis to the pharmacologically
active moiety valdecoxib
\[4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonamide\] and propionic
acid. This enzymatic conversion occurs primarily in the liver. The
terminal half-life (T~1/2)~ of valdecoxib is approximately 8 hours.
Following intravenous (IV) administration of parecoxib, peak (T~max~)
plasma levels of valdecoxib are achieved in approximately 30 minutes;
for intramuscular (IM) injection, peak plasma levels are achieved in
approximately 1 hour.

Parecoxib sodium is supplied as a sterile, preservative-free,
lyophilized powder equivalent to 20 mg or 40 mg parecoxib in single-use
vials. Inactive ingredients include dibasic sodium phosphate
heptahydrate, and phosphoric acid and/or sodium hydroxide (which might
be added to adjust the pH to 8.0). Parecoxib sodium is designed to be
reconstituted with 1 mL (20 mg vials) or 2 mL (40 mg vials) sterile
saline for injection (0.9% sodium chloride).

Based on the in vitro inhibition of recombinant human COX-1 (IC~50~=140
μm) and

COX-2 (IC~50~=0.005 μm), valdecoxib (the active moiety of parecoxib
sodium) exhibits

approximately 28,000-fold selectivity for COX-2 versus COX-1. On the
basis of the its COX-2 specificity of valdecoxib, it was hypothesized
that parecoxib would provide a superior therapeutic index compared to
currently approved conventional ketorolac and mild opioids and yield
significant benefits for patients who require relief of acute pain.

According to the Sponsor, as a novel COX-2 specific parenteral agent,
parecoxib has been developed to have an improved safety profile
(particularly with respect to the absence of respiratory depression,
lack of sedative effects, absence of effects on platelet function, and
absence of UGI ulceration). The demonstration that a compound has
analgesic efficacy for moderate to severe pain along with improved
safety relative to currently available alternatives would represent a
valuable addition to the therapeutic armamentarium for acute pain
management. Parecoxib was designed to meet an unmet medical need of an
efficacious anti-inflammatory parenteral analgesic that would reduce or
eliminate the deleterious side effects that accompany opioid analgesics
or conventional NSAIDs such as ketorolac tromethamine.

The goal of the **nonclinical pharmacology** program emphasized models
in which pain and inflammation were mediated primarily by prostaglandin
production via COX-2. The efficacy of parecoxib in animal models of
inflammation and pain was consistent with its conversion to valdecoxib
in vivo. In dose-response comparisons, parecoxib and valdecoxib
exhibited identical efficacy. In models of surgery-induced nociception,
the efficacy of IV parecoxib appeared comparable to that of ketorolac
tromethamine.

The safety pharmacology studies of parecoxib included neurobehavioral
assessments in the rat, hemodynamic assessments in the dog, renal
assessments in the rat and dog, and cardiopulmonary assessments in the
guinea pig. The adverse effects of parecoxib seen in these studies
suggested this agent would not be associated with adverse
pharmacological effects at clinically relevant exposures. Parecoxib was
also evaluated for its potential to produce acute lethality, multidose
toxicity in rat and dog, GI toxicity in the rat and dog, reproductive
toxicity in rat and rabbit, and in vitro and in vivo mutagenicity.
Results from these studies showed that parecoxib is not expected to pose
any increased risk in humans for lethality, multidose toxicity, GI
toxicity, or mutagenicity.

Studies included in the NDA that discussed efficacy included fourteen
double-blind, placebo controlled trials, conducted in patients
experiencing pain associated with oral surgery, gynecologic surgery,
orthopedic surgery, or coronary artery bypass graft (CABG) surgery. All
36 studies involving parecoxib that were included in this NDA are
briefly summarized in **Table 1.**

###### Integrated Summary of Safety

This ISS is not intended to be the only review of the safety of
parecoxib although it does attempt to integrate all relevant safety
information; this relates to the nature of the compound and how the
review of this NDA was divided. Therefore, the safety review of the this
NDA has been addressed as follows and the interested reader should also
see these other reviews:

Mark Avigan, M.D. UGI Safety Review

Anne Farrell, M.D. Platelet Safety Review

Douglas Throckmorton, M.D. Renal and CV Safety Review

The intent of the following sections is to look for trends suggesting an
increased incidence of a given adverse event, based on multiple line of
(indirect) evidence. This is, of course, the nature of a safety review.

> ***Reviewer's comment: In order to obtain a more robust picture of the
> safety of parecoxib, certain of the trials that included valdecoxib
> will also be reviewed.***

**[Study 035-Coronary Artery Bypass Graft (CABG):]{.underline}**

> ***Reviewer's comment: Owing to the unique role that the CABG trial
> has in this NDA, this trial will be reviewed separately.***

Study 035 was designed to evaluate the general safety and analgesic
efficacy of parecoxib

and valdecoxib in patients who had undergone a first-time, isolated,
coronary artery bypass graft (CABG) via median sternotomy. Patients
(N=462) were randomized to receive placebo (N=151) or active (N=311)
treatment, which consisted of IV or IM parecoxib 40 mg every 12 hours
for at least 72 hours, followed by oral valdecoxib 40 mg every 12 hours,
for a minimum total of 14 days. Both placebo and active treatment groups
received standard of care medication in addition to study medication,
with supplementary pain medication (morphine during the IV phase and
codeine 30 mg/acetaminophen 300 mg \[Tylenol #3 ® \] or, at ex-US sites,
codeine 30 mg/paracetamol 500 mg \[Tylox ® , Gelonida ® \]) available
throughout the trial. **Per the study protocol, all patients were
required to be taking low dose aspirin (\<325 mg daily) during the
study. Over 90% of the patients were in compliance with this
requirement.**

Patients who participated in the CABG study were as follows for the
placebo and the parecoxib/valdecoxib treatment groups, respectively:

-   angina, 92.7 and 90.7%

-   hypertension, 77.5 and 71.4%

-   congestive heart failure, 3.9 and 4.5%

-   atherosclerotic cardiovascular disease, 83.4 and 85.5%

-   cerebrovascular disease (transient ischemic attacks and
    cerebrovascular accidents), 4.6 and 5.8%

-   diabetes mellitus, 19.9 and 22.8%

-   hyperlipidemia, 62.9 to 64.6%

> ***Reviewer's comment: The treatment groups appear to be balanced with
> regards to these risk factors and co-morbid conditions.***

Evaluation of safety was the primary objective of this study. Due to the
complexity of post-operative medical-surgical care and the potential for
the occurrence of a large number events which are routine post-CABG
surgical occurrences, a 5-member independent committee was established
to review the adverse data on a selected number of \"Clinically
Relevant\" adverse events (CRAEs). CRAE members did not participate as
investigators in this trial. A "Parecoxib 035 -CABG study algorithm" was
be used as a guide in forwarding case materials to the CRO safety
specialist. These CRAEs were defined as follows:

-   **Death**

-   All cause death following randomization within 30 days of last dose
    of study drug

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-   **Cardiovascular Events**

-   **myocardial infarction. New onset (post-randomization) myocardial
    infarction diagnosed by finding at least two of the following four
    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

-   **severe myocardial ischemia**

-   an acute event characterized by the onset of ischemic ECG changes in
    an

> ECG done for a specific clinical event, which resolve over time
> without reaching the
>
> above definitions of myocardial infarction

-   **cerebrovascular accident (CVA, TIA, or hemorrhage)**

-   a new onset central neurologic event of either focal or global
    nature, with unequivocal

> physical or cognitive findings, which may be accompanied by a
> confirmatory diagnostic test (angiography, MRI, brain scan).

-   **peripheral arterial occlusion**

-   a new clinical event characterized by clearly reduced pulses or with
    evidence of regional ischemia, accompanied by a confirmatory
    arterial vascular study (invasive or non-invasive). In the absence
    of a positive diagnostic test, the suspicion must be sufficiently
    compelling to require specific medical treatment (aggressive
    anti-coagulation) or surgical intervention.

-   **deep vein thrombosis**

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-   a syndrome consisting of increased unilateral or bilateral leg
    swelling, warmth and

> edema, with confirmatory documentation based on a positive diagnostic
> test (venous
>
> ultrasonagraphy, angiography, magnetic resonance imaging, radionuclide
> scan or
>
> impedance plethysmography). In the absence of a positive diagnostic
> test, the suspicion
>
> must be sufficiently compelling to require full dose anti-coagulation.

-   **pulmonary embolism**

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-   an event consisting of chest pain or dyspnea and/or hypoxemia with
    confirmatory

> angiography or ventilation-perfusion scanning (high probability V/Q
> scan or moderate probability V/Q scan with compelling clinical
> picture).

-   **Pericarditis**

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-   a clinical event consisting of an evolving, non-ischemic pattern of
    PR, ST segment and

T-wave changes without evolution of a new Q waves, without accompanying
significant myocardial enzyme elevation. Clinical symptoms consisting of
chest pain, a rub, or fever may or may not be present. Imaging studies,
if performed, show no evidence of new wall motion abnormalities,
myocardial ischemia or infarction. Therapeutic intervention (e.g.,
NSAIDs or steroids), in the absence or additional information, does not
establish the diagnosis.

-   **Congestive Heart Failure (new onset or exaberation)**

-   due to the complexity of identifying the precise etiology of new
    onset or exacerbation of congestive heart failure in a clinical
    trial setting wherein study volunteers are

> receiving parenteral fluid admistration during the time of study drug
> use, the
>
> adjudication of this adverse event occurrence was divided into two
> time frameworks:
>
> a\) During the post-operative phase of parenteral fluid administration
> and for 96 hours
>
> following discontinuation of parenteral fluid administration; b)
> commencing at a point 96 hours following discontinuation of parenteral
> fluid administration and through to the end of study. This "time
> framework" division of the study was intended to provide an
> opportunity to assess the occurrence of primary cardio-pulmonary
> destabilization as a cause of heart failure versus a study drug effect
> upon the kidney producing salt and water retention with subsequent
> congestive heart failure. The diagnosis of new onset or worsening of
> congestive heart failure was made by standard clinical assessment of
> relevant medical history, physical, radiological examination and
> hemodynamic monitoring, together with blood chemical evaluation and
> confirmation of myocardial function impairment by one or more standard
> cardiac imaging techniques (such as echocardiography).

-   **Renal Failure/Dysfunction**

-   Reduced Renal Perfusion/Filtration

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-   in the absence of acute hypovolemia due to a nonrenal cause, other
    causes of reduced

renal perfusion, obstructive uropathy, or other documented alternative
cause of intrinsic renal disease, the presence of any one of the
following would be defined as reduced renal perfusion/filtration event:

-   An increase of serum creatinine \>30% if baseline creatinine \>0.9
    mg/dL (or \>1.2 mg/dL if baseline creatinine \<0.9 mg/dL) and
    verified by a second determination

-   BUN \> 200% from baseline or, with a baseline value in the upper
    limit of normal an absolute value \>50 mg/dL and verified by a
    second determination

-   An absolute serum creatinine \>1.7 mg/dL [and]{.underline} BUN \>45
    mg/dL verified by second determination

-   Acute renal failure of recent onset as shown by hospital evaluation

-   Systemic fluid, electrolyte, and metabolic abnormalities

-   In the absence of other obvious causes, the presence of the
    following would be defined as a fluid, electrolyte and metabolic
    abnormality:

-   Serum potassium \>6.0 mEq/L (verified)

-   Serum sodium \<130 mEq/L (verified)

-   Serum bicarbonate \<20 mEq/L and chloride \>110 mEq/L and other
    evidence of tubular dysfunction (elevated urinary amino acid
    excretion or elevated urinary beta-microglobulin excretion or
    inappropriately high urine pH or abnormal serum potassium)

-   New onset, sustained urinary dipstick proteinuria (3+ or greater
    magnitude (verified by a second determination)

-   New onset or worsening of edema of distal extremities or generalized
    edema as evidenced by either of the following:

-   weight gain of \>2 kg and an increase in 1+ on a semi-quantitative
    clinical assessment of edema (1+ to 4+ scale) verified by a second
    determination

-   any report of edema with evidence of a clinical consequence (an
    increase of systolic blood pressure \> 20 mg Hg or an increase of
    diastolic blood pressure \> 10 mg Hg on tow consecutive daily
    determinations or two-consecutive visits; initiation or increase in
    daily dose of diuretic or antihypertensive drugs to treat edema;
    discontinuation of study drug to treat the edema.

-   Interference with blood pressure regulation

-   In the absence of alternative medicinal, volumetric on other
    clinical interventions or evidence of medical noncompliance, dietary
    indiscretion with respect to salt intake, superimposed alternative
    cause for secondary hypertension, or a concurrent condition
    necessitating use or change in diuretics/antihypertensives, the
    presence of any one of the following would be defined as a renal
    event of the NSAID-induced interference with blood pressure
    regulation type:

-   An increase of systolic blood pressure ≥ 20 mm Hg and ≥ 140 mm Hg or
    an increase of diastolic blood pressure ≥10 mm Hg and ≥ 90 mm Hg on
    two consecutive daily determinations

-   Any increase in systolic or diastolic blood pressure accompanied by
    the initiation of antihypertensive medication

-   Any increase in systolic or diastolic blood pressure accompanied by
    the escalation of antihypertensive drug therapy (e.g., increase in
    dose, addition of a new agent, substitution of a more potent agent)

-   Glomerular or Tubulo-interstitial Disease

-   A condition which resolves all or in part upon discontinuation of
    drug and which occurs in the absence of other causes of glomerular
    or tubulo-interstitial disease is defined as a glomerular or
    tubulo-interstitial renal event by the presence of the following:

-   Proteinuria \>3+ or greater verified by a second determination

-   Active urinary sediment (hematuria, excess tubular epithelial cells,
    or pyuria)

-   Histopathologic or imaging evidence of glomerular or
    tubulointerstitial disease

-   Evidence of renal dysfunction as manifested by one of the following:

-   An increase of serum creatinine \>30% if baseline creatinine \> 0.9
    mg/dL (or ≥ 1.2 mg/dL if baseline creatinine ≤ 0.9 mg/dL) and
    verified by a second determination

-   An increase of BUN \>200% from baseline or, with the baseline value
    in the upper limit of normal, an absolute value =50 mg/dL and
    verified by a second determination

-   A serum creatinine ≥ 1.7 mg/dL and BUN  ≥ 45 mg/dL verified by
    second determination.

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-   **Gastrointestinal Event (bleeding, perforation or obstruction)
    consisting of the following nine categories:**

-   UGI Bleeding (one of seven traditional clinical presentations)**:**

-   Hematemesis with a gastric or duodenal ulcer or large erosion proven
    by endoscopy or a UGI barium x-ray

-   A gastric or duodenal ulcer or large erosion proven by endoscopy
    with evidence of active bleeding or stigmata of a hemorrhage
    (visible vessel or attached clot to base of an ulcer)

-   Melena with a gastric or duodenal ulcer or large erosion proven by
    endoscopy or UGI barium x-ray

-   Hemoccult positive stools with a gastric or duodenal ulcer or large
    erosion proven by endoscopy or UGI barium x-ray and with bleeding as
    evidenced by a fall in hematocrit of \> 5% or a reduction of
    hemoglobin of ≥ 1.5 g/dL from baseline

-   Hemoccult positive stools with a gastric or duodenal ulcer or large
    erosion proven by endoscopy or UGI barium x-ray and with bleeding as
    evidenced by orthostasis (changes to postural vital signs; increase
    in pulse rate of \>20 beats/min and/or a decrease in systolic blood
    pressure of \>20 mm Hg and/or diastolic blood pressure of \>10 mm
    Hg)

-   Hemoccult positive stools with a gastric or duodenal ulcer or large
    erosion proven by endoscopy or UGI barium x-ray and with bleeding as
    evidenced by a need for blood transfusion of two or more units

-   Hemoccult positive stools with a gastric or duodenal ulcer or large
    erosion proven by endoscopy or UGI barium x-ray and with bleeding as
    evidenced by blood in the stomach as determined by endoscopy or
    nasogastric aspiration. A separate analysis assigning suspected UGI
    bleeding events to one of the following alternate categories will
    also be done:

-   Hematemesis with a gastric or duodenal ulcer or large erosion proven
    by endoscopy or a UGI baruim x-ray, and

-   a drop in hemoglobin \>2 g/dL with adequate hydration or if urgent
    transfusion required, final hemoglobin (approximately 12-24 hours
    after the last urgent transfusion) \< pre-bleed hemoglobin (within
    assay variability) or

-   hypotension (defined as less than 90/60) or orthostatic hypotension

-   A gastric or duodenal ulcer or large erosion proven by endoscopy
    with evidence of active bleeding or stigmata of recent hemorrhage
    (visible vessel or attached clot to base of an ulcer) and

-   a drop in hemoglobin \>2 g/dL with adequate hydration or if urgent
    transfusion required, final hemoglobin (approximately 12-24 hours
    after the last urgent transfusion) \< pre-bleed hemoglobin (within
    assay variability) or

-   hypotension (defined as less than 90/60) or orthostatic hypotension

-   Melena with a gastric or duodenal ulcer or large erosion proven by
    endoscopy or a UGI baruim x-ray; and

-   a drop in hemoglobin \>2 g/dL with adequate hydration or if urgent
    transfusion required, final hemoglobin (approximately 12-24 hours
    after the last urgent transfusion) \< pre-bleed hemoglobin (within
    assay variability); or

-   hypotension (defined as less than 90/60) or orthostatiic hypotension

-   Hemoccult positive stools with a gastric or duodenal ulcer or large
    erosion proven by endoscopy or a UGI baruim x-ray, and

-   hypotension (defined as less than 90/60) or orthostatic hypotension

-   UGI Perforation

-   An opening in the wall of the stomach or duodenum requiring surgery,
    or laparoscopic repair but only if the evidence is unequivocal (free
    air, peritoneal irritation signs, etc.)

-   Gastric Outlet Obstruction

-   Opinion of clinician with endoscopic or UGI barium x-ray
    documentation. Endoscopic evidence would include tight edematous
    pylorus with an ulcer in the pyloric channel, inability to pass the
    endoscope tip into the duodenal bulb or descending duodenum, or
    retained fluid/food in the stomach. UGI barium x-ray evidence of
    obstruction would include; (1) a dilated stomach, (2) a slowly
    emptying stomach in a patient with clinical evidence of outlet
    obstruction and in some instances with an ulcer seen in the channel
    or duodenal bulb or (3) severe narrowing and edema obstructing the
    outlet of the stomach. Ulcers documented by endoscopy or UGI barium
    x-ray and with no evidence of GI bleeding will be summarized
    separately as will other symptomatic GI complaints.

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-   **Major non-GI bleed (requiring transfusion)**

-   New onset post-randomization bleeding due to a non-GI source (single
    or multi-site) accompanied by either transfusion of 2 or more units
    of PRBCs, or a Hgb drop of 3 gm/dL or greater, (or 9 hematocrit
    points) which is unrelated to the sequelae of hemodilution.

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-   **Infection (requiring institution of antibiotics)**

-   A documented or suspected infectious process (based on a documented
    constellation of signs and symptoms, with suspected source),
    requiring new antibiotic or antiviral therapy or a change in
    pre-existing antibiotic regimen.

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-   **Pulmonary complications (non-infectious)**

-   atelectasis or decline in respiratory function, requiring
    intervention consisting of non-routine post-operative respiratory
    care (e.g., bronchoscopy, reintubation, or non intubation
    ventilatory modalities)

-   development of new, persistent (beyond 72 hours) non-LLL,
    symptomatic non-infectious infiltrates

-   pleural effusion requiring drainage or which compromise pulmonary
    function as manifested by dyspnea or other discrete symptoms of
    respiratory compromise or which requires anti-inflammatory therapy

-   ARDs or other forms non-cardiac pulmonary edema

-   pneumothorax or persistent air leak

The \"Events Committee\" reviewed all AEs (blinded to treatment
assignment) submitted by investigators which potentially meet any of the
above categories. The committee verified that the AE meet pre-defined
definitions, and made a judgment whether the event was \"probably,
possibly or remotely related\" or \"not related\" to study drug
treatment and the date of onset of the event.

> ***Reviewer's comment: As noted above, a 4-member (external)
> Gastrointestinal Events Committee (GEC) and Renal Events Committee
> (REC) were also established for this study. Of note, no events in the
> valdecoxib "long-term" safety study (91-048) were adjudicated by the
> GEC to be clinically significant.***

**Table 66** summarizes the duration of exposure to either parecoxib or
valdecoxib in study 035. As noted earlier, patients were given parecoxib
for the first 3 days after surgery (IV dosing period) and they were then
switched to oral valdecoxib. Also noted earlier, most of the patients in
this trial were male (85%), Caucasian (93%) with an approximate mean age
of 60 years.

**^Table\ 66:\ Duration\ of\ Exposure:\ CABG\ Surgery\ Trial\ (035)^**1

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

1.  From Table T.3.3, N93-00-07-816.

**[Incidences of Clinically Relevant Adverse Events
(CRAEs)]{.underline}**

**Table 67** summarizes the clinically relevant adverse events as
defined and adjudicated by the events committee discussed above. During
the IV dosing period, 11.6% of parecoxib /valdecoxib patients and 9.3%
of placebo patients had a CRAE; these incidences were comparable to each
other. During this time period, the most commonly occurring individual
CRAEs were renal failure/dysfunction, infection requiring antibiotics,
and pulmonary complications. Although not statistically significantly
different, the number of deaths, myocardial infarctions, cerebrovascular
accidents, pulmonary embolisms, along with renal and pulmonary
complications were numerically more frequent for parecoxib during the IV
dosing period. During the entire study period, 25.7% of
parecoxib/valdecoxib patients and 15.2% of placebo patients had a CRAE;
this difference was statistically significant. All events listed, with
the exception of myocardial infarctions and major non-GI bleeds, were
numerically more frequent for parecoxib/valdecoxib during the entire
study period.

**Table 67: Incidence of Clinically Relevant Adverse Events (CRAEs)-
Study 035^1,2^**

+------------------+------------+-----------+------------+------------+
| #########        | # Placebo  |           | ######     |            |
|                  |            |           | ### Pareco |            |
| ######### Event  | *          |           | xib/Valdec |            |
|                  | *(N=151)** |           | oxib 40 mg |            |
|                  |            |           |            |            |
|                  |            |           | *          |            |
|                  |            |           | *(N=311)** |            |
+------------------+------------+-----------+------------+------------+
|                  | IV Dosing  | Entire    | IV Dosing  | Entire     |
|                  | Period     | Study     | Period     | Study      |
+------------------+------------+-----------+------------+------------+
| Any Event (%)    | 14 (9.3)   | 23 (15.2) | 36 (11.6)  | 80         |
|                  |            |           |            | (25.7)\*   |
+------------------+------------+-----------+------------+------------+
| Death            | 0.0        | 0.0       | 2 (0.6)    | 4 (1.3)    |
|                  |            |           |            |            |
| Myocardial       | 0.0        | 1 (0.7)   | 1 (0.3)    | 1 (0.3)    |
| infarction       |            |           |            |            |
|                  | 0.0        | 1 (0.7)   | 5 (1.6)    | 9 (2.9)    |
| Cerebrovascular  |            |           |            |            |
| accident         | 0.0        | 0.0       | 0.0        | 3 (1.0)    |
|                  |            |           |            |            |
| Deep vein        | 0.0        | 0.0       | 1 (0.3)    | 2 (0.6)    |
| thrombosis       |            |           |            |            |
|                  | 0.0        | 1 (0.7)   | 0.0        | 4 (1.3)    |
| Pulmonary        |            |           |            |            |
| embolism         | 0.0        | 1 (0.7)   | 2 (0.6)    | 4 (1.3)    |
|                  |            |           |            |            |
| Congestive heart | 6 (4.0)    | 7 (4.6)   | 21 (6.8)   | 29 (9.3)   |
| disease          |            |           |            |            |
|                  | 0.0        | 0.0       | 0.0        | 4 (1.3)    |
| Pericarditis     |            |           |            |            |
|                  | 2 (1.3)    | 2 (1.3)   | 0.0        | 0.0        |
| Renal            |            |           |            |            |
| fai              | 6 (4.0)    | 11 (7.3)  | 3 (1.0)    | 29 (9.3)   |
| lure/dysfunction |            |           |            |            |
|                  | 2 (1.3)    | 4 (2.6)   | 6 (1.9)    | 19 (6.1)   |
| GI event         |            |           |            |            |
|                  |            |           |            |            |
| Major non-GI     |            |           |            |            |
| bleed            |            |           |            |            |
|                  |            |           |            |            |
| Infection        |            |           |            |            |
|                  |            |           |            |            |
| Pulmonary        |            |           |            |            |
| complication     |            |           |            |            |
+------------------+------------+-----------+------------+------------+

1.  Derived from Table 9g and Table T5.7.1, N93-00-07-816. Numbers in ()
    are percentages.

2.  \* p-value by Fischer's exact test = 0.012. There were no other
    statistically significant results noted by the sponsor.

> ***Reviewer's comment: Of a total of 13 myocardial infarctions (Figure
> 8b, I93-00-06-035), 11 events (2-placebo, 9-parecoxib/valdecoxib) were
> sent to the Events committee for adjudication. Only 2 events (patient
> 1128-placebo; patient 0130-parecoxib/valdecoxib) were adjudicated as
> meeting the predefined criteria for a CRAE as noted in the table
> above. Of the nine remaining events (1-placebo,
> 8-parecoxib/valdecoxib) all were felt to either have occurred prior to
> drug or did not meet the criteria. One event that was felt not to meet
> criteria in the parecoxib/valdecoxib group was a death (patient 1136,
> see appendix of this review for summary). Owing to the uncertainty of
> timing of myocardial infarctions in the perioperative setting, review
> of the other cases suggests a possibility of a relationship with study
> drug, especially if such an event can occur within the first few doses
> of parecoxib.***

**Risk Factors for Clinically Relevant Adverse Events**

A number of risk factors including age (with 65 and 70 years as cut
points), gender, BMI, baseline serum creatinine or creatinine clearance,
diabetes, CHF, CVD, hypertension, smoking status, time to extubation,
use or time on heart pump, pre-operative NSAIDs, pre-operative or
concurrent aspirin/salicylate or their interactions were evaluated (data
not shown, Table T5.7.3; N93-00-07-816). Comparisons within group and
subgroups was by Fisher's exact test, while interactions were compared
by Breslow-Day testing were stratified by risk factor.

Within the parecoxib/valdecoxib treatment group, patients with **body
mass index (BMI)**

≥30 kg/m^2^ (p=0.014) or with a positive history of **cerebrovascular
disease** (p=0.008) were more likely to have a CRAE than patients
without a previous cerebrovascular disease or with BMI \<30 kg/m^2^.
Among placebo patients, those who were **current smokers** were
significantly more likely to have a CRAE (p=0.011) than were other
patients in the placebo group.

When the incidence of CRAEs was analyzed for the interaction of risk
factor and treatment group, history of cerebrovascular disease (p=0.038)
and being a current smoker (p=0.007) were identified. History of
cardiovascular disease was associated with a higher incidence of CRAEs
than was a negative history of cardiovascular disease (52 v. 24%,
respectively) for parecoxib/valdecoxib, while the reverse was noted for
placebo (0 v. 16%, respectively). Current smokers had a higher incidence
of CRAEs than did other patients in the placebo group, while current
smokers had a slightly lower incidence of CRAEs than did other patients
in the parecoxib/valdecoxib group.

A stepwise logistic regression analysis of potential risk factors
revealed within the parecoxib/valdecoxib group, age ≥65 years (OR: 2.14;
CI: 1.11, 4.08), BMI ≥ 30 (OR: 1.85; CI: 1.07, 3.21), and prior CVD (OR:
2.95; CI: 1.16, 7.58) were predictive variables associated with risks
for CRAE. However, the analysis also suggested that age ≥ 70 years was
protective (OR: 0.55; CI: 0.22, 1.33). That patients between 65 and 69
years of age are at greater risk of a CRAE, but patients at least 70
years of age are at a reduced risk, suggests some instability of the
model.

Other variables associated with an increased risk for CRAEs noted when
the analysis involved all patients included history of **diabetes,
preoperative aspirin therapy and baseline creatinine ≥106 umol/L** (OR:
6.54; CI: 2.03 - 21.11).

#### Comparative studies for CABG:

In an attempt to put the results of study 035 into context with respect
to current standards of care and outcome, comparative outcome data from
two other studies of CABG surgery patients were included in the NDA.

The first of these two studies, EPI 2, is a prospective, international,
multicenter, observational study of patients undergoing CABG and/or
valve surgery with or without concurrent cardiac or non-cardiac
procedures. The study is being conducted by the

Ischemia Research and Education Foundation, in conjunction with the
Multicenter Study of Perioperative Ischemia, which is a consortium of
approximately 300 investigators and 160 academic centers that, since
November 1996, have enrolled more than 5,000 patients at 69 centers. The
present database was locked at the end of June 2000. This study includes
consenting adult patients (between 18 and 75 years, inclusive)
undergoing an isolated, primary CABG via median sternotomy with a NYHA
Class I - III classification or had a cardiac ejection fraction of at
least 35%, and who **had preoperative aspirin treatment** (325 mg/day)
maintained throughout the study.

The second source of comparative data is the Society for Thoracic
Surgery (STS) database, compiled and maintained by the Society for
Thoracic Surgery. Previous published results from this database included
patients undergoing a primary, isolated CABG procedure between 1990 and
1994, followed by standard care postoperatively. STS data used for
comparison in the present report included results through 1997.

A comparison of the incidences of CRAEs among the three databases is
shown in **Table 68**. Since both the EPI 2 and STS databases ended
adverse event collection at the time of hospital discharge, the data
from study 035 includes only events occurring before hospital discharge.
Also, the column of EPI 2 data labeled "Matched Patients" contains only
patients who would have satisfied the inclusion/exclusion criteria for
Study 035 and were treated at sites included in Study 035. Recognizing
the limitations of comparisons between trials, the EPI 2 and STS
databases help to add perspective to the data obtained in trial 035.

**^Table\ 68:\ Comparative\ Outcome\ Data\ from\ Two\ Observational\ Databases1^**

+------------------+-------+---------+------------+---------+--------+
| **Adverse Events | **    |         | **EPI 2**  |         | *      |
| to Hospital**    | Study |         |            |         | *STS** |
|                  | 035** |         |            |         |        |
| **Discharge**    |       |         |            |         |        |
+------------------+-------+---------+------------+---------+--------+
|                  | Pl    | Par     | Patients   | All     | All    |
|                  | acebo | ecoxib/ | Matched    | P       | Pa     |
|                  |       |         |            | atients | tients |
|                  | N =   | Val     | to 035     |         |        |
|                  | 151   | decoxib | Sites &    | N =     | N =    |
|                  |       |         |            | 3449    | 1      |
|                  | n (%) | N = 311 | Entry      |         | 61,018 |
|                  |       |         | Criteria   | n       |        |
|                  |       | n (%)   |            | (%)\*\* | n (%)  |
|                  |       |         | N = 547    |         |        |
|                  |       |         |            |         |        |
|                  |       |         | N (%)\*\*  |         |        |
+------------------+-------+---------+------------+---------+--------+
| Death            | 0 (0) | 3 (1.0) | 3 (0.6)    | 103     | 2972   |
|                  |       |         |            | (3.0)   | (1.7)‡ |
| MI               | 0 (0) | 1 (0.3) | 9 (1.7)    |         |        |
|                  |       |         |            | 146     | 1771   |
| CVA accident     | 1     | 8 (2.6) | 18 (3.2)   | (4.2)   | (1.1)  |
| (+TIA)           | (0.7) |         |            |         |        |
|                  |       | 3 (1.0) | 0 (0)      | 245     | 3703   |
| Deep vein        | 0 (0) |         |            | (7.1)   | (2.3)  |
| thrombosis       |       | 1 (0.3) | \-\--      |         |        |
|                  | 0 (0) |         |            | 4 (0.1) | \-\--  |
| Pulmonary        |       | 13      | 81 (15.0)  |         |        |
| embolism         | 9     | (4.2)   |            | \-\--   | 524    |
|                  | (6.0) |         | 15 (3)     |         | (0.3)  |
| Infection        |       | 7 (2.2) |            | 586     |        |
|                  | 3     |         | 100 (41)   | (17.0)  | \-\--  |
| Surgical wound   | (2.0) | 27      |            |         |        |
| infection\*\*\*  |       | (8.7)   | 4 (0.7)    | 140 (4) | 4214   |
|                  | 6     |         |            |         | (2.6)  |
| Renal            | (4.0) | 8 (2.6) | 4 (0.7)    | 1009    |        |
| dysfunction†     |       |         |            | (50)    | \-\--  |
|                  | 3     | 3 (1.0) |            |         |        |
| Major renal      | (2.0) |         |            | 97      | 5063   |
| CRAE††           |       |         |            | (2.8)   | (3.1)  |
|                  | 0 (0) |         |            |         |        |
| GI event†††      |       |         |            | 50      | 3939   |
|                  |       |         |            | (1.5)   | (2.5)  |
+------------------+-------+---------+------------+---------+--------+

1.  \*\* Percentages calculated based on number of patients with
    available data for a given event. \*\*\* Surgical wound infection is
    a subset of all reported infections. ‡ N = 174,806 for death rate in
    STS. † Includes both renal failure and renal dysfunction in the 035
    database. †† Serum creatinine \> 2.0 mg/dL and increase of \> 0.7
    mg/dL from Baseline. ††† Includes bleeds, perforations, and
    obstructions for study 035, and bleeds for EPI 2 database.

**[Adverse Events-Study 035:]{.underline}**

Selected adverse events occurring in study 035 are presented in **Table
69.** The overall incidence of adverse events (over 80%) in each
treatment group, likely reflects the population studied and the surgical
procedure and post-operative course. The incidence of adverse events was
generally similar during the IV dosing period and the entire study
period. However, some of these apparent similarities, as well as some of
the differences and trends are of interest.

For example, some of the most common adverse events were constipation,
nausea and vomiting. The lack of any difference in the placebo versus
the "add-on" group of parecoxib/ valdecoxib to this "standard of care",
**suggests that any opioid-sparing effects of these agents is not
apparent at a clinical level** i.e. less of the events commonly ascribed
to opioids. The results with somnolence, pruritis and respiratory
depression would tend to support this lack of an obvious beneficial
clinical effect on sparing opioid-related events.

Among other commonly reported **gastrointestinal adverse events**
(ulceration, hemorrhage, hemoccult positivity SGOT/SGPT increases), the
trends suggest more of these events in the parecoxib/valdecoxib group as
compared to the placebo group. Of note, post-operative anemia was more
common in the parecoxib/valdecoxib group as compared to placebo.

The **cardiovascular and renal events** noted tend to have somewhat
mixed results. While there were significantly lower incidences of
tachycardia, there were significantly more episodes of supraventricular
tachycardia and hypotension in the parecoxib/valdecoxib group; however,
this hypotension did not seem to reflected in episodes of syncope,
dizziness or vertigo. On the other hand, events such as hypertension,
myocardial infarction, cerebrovascular disorder, hypokalemia, BUN
increases, oliguria, and acute renal failure were generally numerically
higher in the parecoxib/valdecoxib group.

**Pulmonary events** such as pleural effusion, bronchospasm, pneumonia,
and upper respiratory tract infections were significantly less frequent
in the parecoxib/valdecoxib group compared to the placebo group; the
latter effects did not seem to persist until the end of the study.
Episodes of pulmonary embolism or atelectasis did not differ between the
treatment groups. Although there were significantly fewer events listed
as fever, this did not seem to translate into higher infection rates
(data not shown).

Adverse events that increased by at least five percentage points between
the IV dosing period and the entire study included peripheral edema,
dizziness, constipation, nausea, somnolence, pleural effusion along with
fatigue and insomnia (latter two, data not shown).

Most adverse events were mild or moderate in severity (Appendices
4.7.1-4.8.2, N93-00-07-816, data not shown). During the IV dosing
period, 10.9% (34/311) and 13.2% (20/151) of patients in the
parecoxib/valdecoxib and placebo groups, respectively, had a severe
adverse event. During the entire study period, 20.3% (63/311) and 17.2%
(26/151) of patients who received parecoxib/valdecoxib and placebo,
respectively, experienced a severe adverse event.

**Table 69: Incidence of Selected Adverse Events- Study 035^1,2^**

+------------------+------------+-----------+------------+------------+
| #########        | # Placebo  |           | ######     |            |
|                  |            |           | ### Pareco |            |
| ######### Event  | *          |           | xib/Valdec |            |
|                  | *(N=151)** |           | oxib 40 mg |            |
|                  |            |           |            |            |
|                  |            |           | *          |            |
|                  |            |           | *(N=311)** |            |
+------------------+------------+-----------+------------+------------+
|                  | IV Dosing  | Entire    | IV Dosing  | Entire     |
|                  | Period     | Study     | Period     | Study      |
+------------------+------------+-----------+------------+------------+
| Any Event (%)    | 127 (84.1) | 135       | 251 (80.7) | 277 (89.1) |
|                  |            | (89.4)    |            |            |
+------------------+------------+-----------+------------+------------+
| Gastrointestinal |            |           |            |            |
+------------------+------------+-----------+------------+------------+
| Duodenal ulcer   | \-         | 0         | \-         | 2 (0.6)    |
| (perforated)     |            |           |            |            |
|                  | \-         | 0         | \-         | 1 (0.3)    |
| Gastric Ulcer    |            |           |            |            |
|                  | 0          | 0         | 1 (0.3)    | 3 (1.0)    |
| GI hemorrhage    |            |           |            |            |
|                  | 1 (0.7)    | 1 (0.7)   | 3 (1.0)    | 4 (1.3)    |
| Hematemesis      |            |           |            |            |
|                  | 0          | 0         | 1 (0.3)    | 2 (0.6)    |
| Hemoccult        |            |           |            |            |
| positivity       | 2 (1.3)    | 3 (2.0)   | 5 (1.6)    | 11 (3.5)   |
|                  |            |           |            |            |
| SGOT increased   | 0          | 4 (2.6)   | 4 (1.3)    | 12 (3.9)   |
|                  |            |           |            |            |
| SGPT increased   | 35 (23.2)  | 56 (37.1) | 75 (24.1)  | 116 (37.3) |
|                  |            |           |            |            |
| Constipation     | 50 (33.1)  | 58 (38.4) | 116 (37.3) | 137 (44.0) |
|                  |            |           |            |            |
| Nausea           | 13 (8.6)   | 17 (11.3) | 33 (10.6)  | 43 (13.8)  |
|                  |            |           |            |            |
| Vomiting         | 3 (2.0)    | 6 (4.0)   | 9 (2.9)    | 19 (6.1)   |
|                  |            |           |            |            |
| Dyspepsia        | 3 (2.0)    | 5 (3.3)   | 6 (1.9)    | 12 (3.9)   |
|                  |            |           |            |            |
| Abdominal Pain   |            |           |            |            |
+------------------+------------+-----------+------------+------------+
| Card             |            |           |            |            |
| iovascular/Renal |            |           |            |            |
+------------------+------------+-----------+------------+------------+
| Hyperte          | 1 (0.7)    | 2 (1.3)   | 6 (1.9)    | 7 (2.3)    |
| nsion-aggravated |            |           |            |            |
|                  | 9 (6.0)    | 9 (6.0)   | 37         | 39         |
| Hypotension      |            |           | (11.9)\*   | (12.5)\*   |
|                  | 0          | 1 (0.7)   |            |            |
| Syncope          |            |           | 3 (1.0)    | 5 (1.6)    |
|                  | 9 (6.0)    | 27 (17.9) |            |            |
| Dizziness        |            |           | 13 (4.2)   | 37 (11.9)  |
|                  | \-         | 0         |            |            |
| Vertigo          |            |           | \-         | 1 (0.3)    |
|                  | 6 (4.0)    | 7 (4.6)   |            |            |
| Edema            |            |           | 7 (2.3)    | 9 (2.9)    |
|                  | 14 (9.3)   | 21 (13.9) |            |            |
| Generalized      |            |           | 35 (11.3)  | 51 (16.4)  |
|                  | 21 (13.9)  | 22 (14.6) |            |            |
| Peripheral       |            |           | 15 (4.8)\* | 22 (7.1)\* |
|                  | 0          | 0         |            |            |
| Tachycardia      |            |           | 9 (2.9)\*  | 10 (3.2)\* |
|                  | 29 (19.2)  | 30 (19.9) |            |            |
| Supraventricular |            |           | 43 (13.8)  | 49 (15.8)  |
| tachycardia      | 5 (3.3)    | 6 (4.0)   |            |            |
|                  |            |           | 20 (6.4)   | 22 (7.1)   |
| Atrial           | 1 (0.7)    | 1 (0.7)   |            |            |
| fibrillation     |            |           | 8 (2.6)    | 10 (3.2)   |
|                  | 3 (2.0)    | 3 (2.0)   |            |            |
| Hypokalemia      |            |           | 1 (0.3)    | 2 (0.6)    |
|                  | 0          | 1 (0.7)   |            |            |
| BUN increased    |            |           | 6 (1.9)    | 6 (1.9)    |
|                  | 15 (9.9)   | 15 (9.9)  |            |            |
| Angina Pectoris  |            |           | 44 (14.1)  | 45 (14.5)  |
|                  | 0          | 0         |            |            |
| Myocardial       |            |           | 2 (0.6)    | 2 (0.6)    |
| Infarction       | 2 (1.3)    | 2 (1.3)   |            |            |
|                  |            |           | 7 (2.3)    | 9 (2.9)    |
| Oliguria         | 1 (0.7)    | 1 (0.7)   |            |            |
|                  |            |           | 6 (1.9)    | 8 (2.6)    |
| Acute renal      | 1 (0.7)    | 1 (0.7)   |            |            |
| failure          |            |           | 0          | 0          |
|                  | 0          | 0         |            |            |
| Abnormal Renal   |            |           | 0          | 2 (0.6)    |
| Function         | 0          | 1 (0.7)   |            |            |
|                  |            |           | 6 (1.9)    | 7 (2.3)    |
| Cerebrovascular  | 1 (0.7)    | 1 (0.7)   |            |            |
| Disorder         |            |           | 1 (0.3)    | 4 (1.3)    |
|                  | 1 (0.7)    | 1 (0.7)   |            |            |
| Peripheral       |            |           | 0          | 0          |
| Ischemia         |            |           |            |            |
|                  |            |           |            |            |
| T                |            |           |            |            |
| hrombophlebitis, |            |           |            |            |
| deep             |            |           |            |            |
|                  |            |           |            |            |
| Pericarditis     |            |           |            |            |
|                  |            |           |            |            |
| Hematoma         |            |           |            |            |
|                  |            |           |            |            |
| Vasculitis       |            |           |            |            |
+------------------+------------+-----------+------------+------------+
| Pulmonar         |            |           |            |            |
| y/Post-operative |            |           |            |            |
+------------------+------------+-----------+------------+------------+
| Fever            | 29 (19.2)  | 32 (21.3) | 11 (3.5)\* | 13 (4.2)\* |
|                  |            |           |            |            |
| Pulmonary        | 0          | 0         | 2 (0.6)    | 2 (0.6)    |
| Embolism         |            |           |            |            |
|                  | 11 (7.3)   | 14 (9.3)  | 12 (3.9)   | 16 (5.1)   |
| Atelectasis      |            |           |            |            |
|                  | 10 (6.6)   | 10 (6.6)  | 5 (1.6)\*  | 6 (1.9)\*  |
| Bronchospasm     |            |           |            |            |
|                  | 18 (11.9)  | 26 (17.2) | 16 (5.1)\* | 23 (7.4)\* |
| Pleural Effusion |            |           |            |            |
|                  | 4 (2.6)    | 4 (2.6)   | 1 (0.3)\*  | 4 (1.3)    |
| Pneumonia        |            |           |            |            |
|                  | 2 (1.3)    | 2 (1.3)   | 6 (1.9)    | 6 (1.9)    |
| Respiratory      |            |           |            |            |
| Depression       | 5 (3.3)    | 5 (3.3)   | 0\*        | 3 (1.0)    |
|                  |            |           |            |            |
| URTI             | 5 (3.3)    | 7 (4.6)   | 2 (0.6)\*  | 6 (1.9)    |
|                  |            |           |            |            |
| Post-op          | 0          | 0         | 4 (1.3)    | 5 (1/6)    |
| incisional pain  |            |           |            |            |
|                  | 5 (3.3)    | 8 (5.3)   | 22 (7.1)   | 28 (9.0)   |
| Thrombocytopenia |            |           |            |            |
|                  | 6 (4.0)    | 19 (12.6) | 13 (4.2)   | 36 (11.6)  |
| Post-op anemia   |            |           |            |            |
|                  | 2 (1.3)    | 2 (1.3)   | 4 (1.3)    | 8 (2.6)    |
| Somnolence       |            |           |            |            |
|                  | 9 (6.0)    | 10 (6.6)  | 13 (4.2)   | 16 (5.1)   |
| Headache         |            |           |            |            |
|                  |            |           |            |            |
| Confusion        |            |           |            |            |
+------------------+------------+-----------+------------+------------+
| Skin             |            |           |            |            |
+------------------+------------+-----------+------------+------------+
| Rash             | 2 (1.3)    | 4 (2.6)   | 1 (0.3)    | 2 (0.6)    |
|                  |            |           |            |            |
| Pruritis         | 3 (2.0)    | 4 (2.6)   | 4 (1.3)    | 6 (1.9)    |
+------------------+------------+-----------+------------+------------+

1.  Derived and revised from Table T5.3.1, N93-00-07-816.

2.  \* indicates statistically significantly different at p \< 0.05.

#### Incidence of Adverse Events Causing Withdrawal

The incidences of adverse events causing withdrawal are shown in **Table
70.** During the entire study period, 13.2% of patients in the placebo
group and 16.7% of patients in the parecoxib/valdecoxib group withdrew
from the study due to an adverse event. Of these, 10.6% and 10.3% of
patients in the placebo and parecoxib/valdecoxib treatment groups,
respectively, withdrew during the IV dosing period. Statistical
comparisons did not reveal any significant differences in the overall or
individual event rates between treatment groups.

**Table 70: Incidence of Adverse Events Causing Withdrawal ≥ 1%- Study
035^1,2^**

+------------------+------------+-----------+------------+------------+
| #########        | # Placebo  |           | ######     |            |
|                  |            |           | ### Pareco |            |
| ######### Event  | *          |           | xib/Valdec |            |
|                  | *(N=151)** |           | oxib 40 mg |            |
|                  |            |           |            |            |
|                  |            |           | *          |            |
|                  |            |           | *(N=311)** |            |
+------------------+------------+-----------+------------+------------+
|                  | IV Dosing  | Entire    | IV Dosing  | Entire     |
|                  | Period     | Study     | Period     | Study      |
+------------------+------------+-----------+------------+------------+
| Any Event (%)    | 16 (10.6)  | 20 (13.2) | 32 (10.3)  | 52 (16.7)  |
+------------------+------------+-----------+------------+------------+
| Gastrointestinal |            |           |            |            |
+------------------+------------+-----------+------------+------------+
| Nausea           | 2.0        | 2.0       | 1.6        | 2.6        |
|                  |            |           |            |            |
| Vomiting         | 1.3        | 2.0       | 1.0        | 1.6        |
+------------------+------------+-----------+------------+------------+
| Card             |            |           |            |            |
| iovascular/Renal |            |           |            |            |
+------------------+------------+-----------+------------+------------+
| Hypotension      | 0          | 0         | 0.6        | 1.0        |
|                  |            |           |            |            |
| Cerebrovascular  | 0.7        | 0.7       | 1.0        | 1.0        |
| Disorder         |            |           |            |            |
|                  | 1.3        | 1.3       | 0          | 0.6        |
| Dizziness        |            |           |            |            |
|                  | 0          | 0         | 1.0        | 1.0        |
| BUN increased    |            |           |            |            |
|                  | 1.3        | 1.3       | 1.9        | 1.9        |
| Creatinine       |            |           |            |            |
| increased        | 0          | 0         | 1.0        | 1.3        |
|                  |            |           |            |            |
| Pericarditis     | 0.7        | 0.7       | 1.3        | 1.3        |
|                  |            |           |            |            |
| Renal function   |            |           |            |            |
| abnormal         |            |           |            |            |
+------------------+------------+-----------+------------+------------+
| Pulmonar         |            |           |            |            |
| y/Post-operative |            |           |            |            |
+------------------+------------+-----------+------------+------------+
| Pneumonia        | 1.3        | 1.3       | 0          | 0          |
+------------------+------------+-----------+------------+------------+

1.  Derived and revised from Table T5.4, N93-00-07-816. Data are
    expressed as percentage of total.

2.  There were no P-values (by Fisher's exact test) ≤ 0.05 for any
    differences between the treatment groups.

**Table 71: Incidence of Extreme Vital Signs- Study 035^1,2^**

+------------------+------------+-----------+------------+------------+
| ######### Event  | # Placebo  |           | ######     |            |
|                  |            |           | ### Pareco |            |
|                  |            |           | xib/Valdec |            |
|                  |            |           | oxib 40 mg |            |
+------------------+------------+-----------+------------+------------+
|                  | IV Dosing  | PO Dosing | IV Dosing  | PO Dosing  |
|                  | Period     | Period    | Period     | Period     |
+------------------+------------+-----------+------------+------------+
| Blood pressure   |            |           |            |            |
| (change from     |            |           |            |            |
| baseline)        |            |           |            |            |
+------------------+------------+-----------+------------+------------+
| Systolic         | 27/142     | 9/97      | 50/290     | 16/187     |
|                  | (19.0)     | (9.3)     | (17.2)     | (8.6)      |
| 15% decrease     |            |           |            |            |
|                  | 29/142     | 17/97     | 56/290     | 29/187     |
| 15% increase     | (20.4)     | (17.5)    | (19.3)     | (15.5)     |
|                  |            |           |            |            |
| Diastolic        | 19/142     | 11/97     | 36/290     | 20/186     |
|                  | (13.4)     | (11.3)    | (12.4)     | (10.8)     |
| 15% decrease     |            |           |            |            |
|                  | 58/142     | 23/97     | 106/290    | 34/186     |
| 15% increase     | (40.8)     | (23.7)    | (36.6)     | (18.3)     |
+------------------+------------+-----------+------------+------------+
| Pulse (change    |            |           |            |            |
| from baseline)   |            |           |            |            |
+------------------+------------+-----------+------------+------------+
| 15% decrease     | 31/142     | 18/98     | 95/290     | 27/187     |
|                  | (21.8)     | (18.4)    | (32.8)\*   | (14.4)     |
| 15% increase     |            |           |            |            |
|                  | 30/142     | 12/98     | 34/290     | 25/187     |
|                  | (21.1)     | (12.2)    | (11.7)\*   | (13.4)     |
+------------------+------------+-----------+------------+------------+
| Temperature      |            |           |            |            |
+------------------+------------+-----------+------------+------------+
| \> 39.7 ^o^C     | 3/142      | 0/120     | 4/297      | 2/245      |
|                  | (2.1)      |           | (1.3)      | (0.8)      |
+------------------+------------+-----------+------------+------------+

1.  Derived and revised from Table 9j, N93-00-07-816.

2.  Data are expressed as number of patients with extreme value/number
    of patients tested. \* statistically significant from placebo P
    ≤0.05.

#### 

#### Serious Adverse Events

Serious adverse events that occurred in two or more patients in either
treatment group during the IV dosing period and the entire study are
summarized in **Table 72.** A total of 146 serious adverse events were
reported in 74 patients (118 events in 59 patients and 28 events in 15
patients who received parecoxib/valdecoxib or placebo, respectively).
These serious events represent 19.0% and 9.9% (entire study) or 6.8% and
6.6% (IV dosing) of patients receiving parecoxib/valdecoxib and placebo,
respectively. With the lone exceptions of pneumonia (IV period only) and
atrial arrhythmia (entire study), there were as many, but usually more,
events in the parecoxib/valdecoxib as compared to the placebo-treated
group.

This trend towards more serious adverse events in the
parecoxib/valdecoxib group includes gastrointestinal events,
thromboembolic and other cardiovascular events, renal events, and
infectious episodes.

**Table 72: Incidence of Serious Adverse Events- Study 035^1^**

+------------------+------------+-----------+------------+------------+
| #########        | # Placebo  |           | ######     |            |
|                  |            |           | ### Pareco |            |
| ######### Event  | *          |           | xib/Valdec |            |
|                  | *(N=151)** |           | oxib 40 mg |            |
|                  |            |           |            |            |
|                  |            |           | *          |            |
|                  |            |           | *(N=311)** |            |
+------------------+------------+-----------+------------+------------+
|                  | IV Dosing  | Entire    | IV Dosing  | Entire     |
|                  | Period     | Study     | Period     | Study      |
+------------------+------------+-----------+------------+------------+
| Total number of  | 10 (6.6%)  | 15 (9.9%) | 21 (6.8)   | 59 (19.0)  |
| patients (%)     |            |           |            |            |
|                  | 18         | 28        | 39         | 118        |
| Total number of  |            |           |            |            |
| events           |            |           |            |            |
+------------------+------------+-----------+------------+------------+
| Gastrointestinal |            |           |            |            |
+------------------+------------+-----------+------------+------------+
| Duodenal ulcer   | 0          | 0         | 0          | 2          |
| (perforated)     |            |           |            |            |
|                  | 0          | 0         | 1          | 3          |
| GI hemorrhage    |            |           |            |            |
|                  | 0          | 0         | 0          | 2          |
| Vomiting         |            |           |            |            |
+------------------+------------+-----------+------------+------------+
| Card             |            |           |            |            |
| iovascular/Renal |            |           |            |            |
+------------------+------------+-----------+------------+------------+
| Cerebrovascular  | 1          | 1         | 6          | 9          |
| disorder         |            |           |            |            |
|                  | 0          | 0         | 0          | 3          |
| Thrombophlebitis |            |           |            |            |
|                  | 0          | 0         | 1          | 2          |
| Hypotension      |            |           |            |            |
|                  | 0          | 0         | 2          | 2          |
| Chest pain (non  |            |           |            |            |
| cardiac)         | 1          | 2         | 1          | 3          |
|                  |            |           |            |            |
| Cardiac failure  | 1          | 2         | 1          | 1          |
|                  |            |           |            |            |
| Atrial           | 1          | 1         | 1          | 2          |
| arrhythmia       |            |           |            |            |
|                  | 0          | 0         | 1          | 3          |
| Atrial           |            |           |            |            |
| fibrillation     | 0          | 1         | 4          | 5          |
|                  |            |           |            |            |
| Creatinine       | 0          | 0         | 3          | 3          |
| increase         |            |           |            |            |
|                  |            |           |            |            |
| Myocardial       |            |           |            |            |
| infarction       |            |           |            |            |
|                  |            |           |            |            |
| Renal function   |            |           |            |            |
| abnormal         |            |           |            |            |
+------------------+------------+-----------+------------+------------+
| Pulmonar         |            |           |            |            |
| y/Post-operative |            |           |            |            |
+------------------+------------+-----------+------------+------------+
| Sternal (deep)   | 0          | 0         | 0          | 2          |
| wound infection  |            |           |            |            |
|                  | 0          | 0         | 0          | 7          |
| Sternal wound    |            |           |            |            |
| infection        | 0          | 0         | 0          | 2          |
|                  |            |           |            |            |
| Infection (non   | 0          | 0         | 0          | 2          |
| sternal)         |            |           |            |            |
|                  | 0          | 0         | 2          | 3          |
| Sternal wound    |            |           |            |            |
| drainage         | 0          | 1         | 0          | 2          |
|                  |            |           |            |            |
| Sternal wound    | 0          | 0         | 1          | 2          |
| dehiscence       |            |           |            |            |
|                  | 0          | 0         | 0          | 2          |
| Sternal          |            |           |            |            |
| instability      | 0          | 0         | 1          | 2          |
|                  |            |           |            |            |
| Bacterial        | 0          | 0         | 2          | 2          |
| infection        |            |           |            |            |
|                  | 1          | 1         | 1          | 7          |
| Sepsis           |            |           |            |            |
|                  | 3          | 3         | 1          | 4          |
| Post-op anemia   |            |           |            |            |
|                  |            |           |            |            |
| Hypoxia          |            |           |            |            |
|                  |            |           |            |            |
| Pleural effusion |            |           |            |            |
|                  |            |           |            |            |
| Pneumonia        |            |           |            |            |
+------------------+------------+-----------+------------+------------+

1.  Derived and revised from Table T5.5, N93-00-07-816. Data are
    expressed as number of patients. Only those groups with ≥ 2 patients
    in any treatment group are included.

#### 

#### Deaths

Four deaths occurred among patients receiving the parecoxib/valdecoxib
treatment regimen; there were no deaths among the placebo group.
Narratives of these deaths can be found in the appendix of this review.
A 58-year-old male patient (035-CA0203-0145), who received four doses of
IV parecoxib, died on Day 15 (counting first dose day as Day 1) from a
duodenal ulcer. A 69-year-old female patient (035-GE0402-1136), who
received seven doses of IV parecoxib and thirteen doses of valdecoxib,
expired on Day 19 due to a probable myocardial infarction. A 67-year-old
male patient (035-UK0303-0938), who received six doses of IV parecoxib
and six doses of oral valdecoxib, died on Day 12 from

septicemia, sternal wound infection, and bronchopneumonia. A 62-year-old
male (035-

US0127-0231), who received seven doses of IV parecoxib, expired on Day 6
from massive left cerebellar infarct with brainstem compression (listed
as "impression") and herniation.

**Summary of Safety Results for Analgesia Study, CABG Surgery Model**

-   Most patients (\>80%) in either treatment group were exposed for \>
    7 days.

-   The overall incidence of adverse events (over 80%) in each treatment
    group, likely reflects the population studied and the surgical
    procedure and post-operative course. The incidence of adverse events
    was generally similar during the IV dosing period and the entire
    study period. However, some of these apparent similarities, as well
    as some of the differences and trends are of interest.

-   During the IV dosing period, 10.9% (34/311) and 13.2% (20/151) of
    patients in the parecoxib/valdecoxib and placebo groups,
    respectively, had a severe adverse event. During the entire study
    period, 20.3% (63/311) and 17.2% (26/151) of patients who received
    parecoxib/valdecoxib and placebo, respectively, experienced a severe
    adverse event.

-   During the IV dosing period, 11.6% of parecoxib /valdecoxib patients
    and 9.3% of placebo patients had a clinically relevant adverse
    event; these incidences were comparable to each other. Although not
    statistically significantly different, the number of deaths,
    myocardial infarctions, cerebrovascular accidents, pulmonary
    embolisms, along with renal and pulmonary complications were
    numerically more frequent for parecoxib during the IV dosing period.

-   During the entire study period, 25.7% of parecoxib/valdecoxib
    patients and 15.2% of placebo patients had a clinically relevant
    adverse event; this difference was statistically significant. All
    events, with the exception of myocardial infarctions and major
    non-GI bleeds, were also numerically more frequent for
    parecoxib/valdecoxib during the entire study period.

-   Differential risk factors for developing clinically relevant adverse
    events in the parecoxib/valdecoxib group included prior history of
    cerebrovascular disease and body mass index of ≥ 30 kg/m^2^ and
    history of cardiovascular disease while current cigarette smoking
    was a risk factor for placebo patients. For both groups, by logistic
    regression analysis, history of diabetes, preoperative aspirin
    therapy and baseline creatinine \>106 umol/L also increased risk:
    the latter was the most predictive risk factor for developing an
    event.

```{=html}
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-   Although the adverse event rates in study 035 were within the
    expected background rates noted in other CABG trials, high-risk
    patients, such as those identified above may have a higher risk of
    adverse events with parecoxib/valdecoxib.

-   Trends with commonly reported gastrointestinal adverse events
    (ulceration, hemorrhage, hemoccult positivity SGOT/SGPT increases,
    post-op anemia) suggest more of these events in the
    parecoxib/valdecoxib group as compared to the placebo group.

-   The cardiovascular and renal events noted tend to have somewhat
    mixed results. While there were significantly lower incidences of
    tachycardia, there were statistically significantly more episodes of
    supraventricular tachycardia and hypotension in the
    parecoxib/valdecoxib group; however, this hypotension did not seem
    to reflected in episodes of syncope, dizziness or vertigo. On the
    other hand, events such as hypertension, myocardial infarction,
    cerebrovascular disorder, hypokalemia, BUN increases, oliguria, and
    acute renal failure were generally numerically higher in the
    parecoxib/valdecoxib group.

-   Pulmonary events such as pleural effusion, bronchospasm, pneumonia,
    and upper respiratory tract infections were significantly less
    frequent in the parecoxib/valdecoxib group compared to the placebo
    group; the latter effects did not seem to persist until the end of
    the study.

-   During the entire study period, 13.2% of patients in the placebo
    group and 16.7% of patients in the parecoxib/valdecoxib group
    withdrew from the study due to an adverse event. Of these, 10.6% and
    10.3% of patients in the placebo and parecoxib/valdecoxib treatment
    groups, respectively, withdrew during the IV dosing period.

-   Although laboratory data were generally similar between groups,
    decreases of hemoglobin and/or hematocrit tended to occur more often
    in the parecoxib/valdecoxib treated groups. Postoperative anemia was
    higher for patients \<65 years than ≥65 years receiving
    parecoxib/valdecoxib.

-   During the IV dosing period, a statistically significantly higher
    proportion of patients in the parecoxib/valdecoxib group had extreme
    low pulse than in the placebo group, and a statistically
    significantly lower proportion of patients in the parecoxib
    /valdecoxib group than patients in the placebo group had extreme
    high pulse.

-   Serious adverse events occurred in 19.0% and 9.9% (entire study) or
    6.8% and 6.6% (IV dosing) of patients receiving parecoxib/valdecoxib
    and placebo, respectively. With the lone exceptions of pneumonia (IV
    period only) and atrial arrhythmia (entire study), there were as
    many, but usually more, events in the parecoxib/valdecoxib as
    compared to the placebo-treated group. This trend towards more
    serious adverse events in the parecoxib/valdecoxib group includes
    gastrointestinal events, thromboembolic and other cardiovascular
    events, renal events, and infectious episodes.

-   Four deaths occurred among patients receiving the
    parecoxib/valdecoxib treatment regimen; there were no deaths among
    the placebo group. Causes of death included duodenal ulcer, probable
    myocardial infarction, septicemia, and cerebellar infarct with
    brainstem compression and herniation.

-   Any opioid-sparing effects by the addition of parecoxib/valdecoxib
    is not apparent by comparing the pattern of adverse events (i.e.
    constipation, nausea, vomiting, somnolence, pruritis, respiratory
    depression) to the standard of care/placebo group. Events commonly
    ascribed to opioids tended to be more, not less, common in the
    parecoxib/valdecoxib group.

**Renal Effects:**

Mechanism-based (i.e., based on COX-2 inhibition) disturbance of renal
function was observed in rat and dog models of volume-contraction. In
**animal models** based on an

activated renin-angiotensin axis, valdecoxib **decreased renal blood
flow**, as well as the

**rates of glomerular filtration** and urine formation, **and the
urinary excretion of prostanoids**. These effects occurred **at plasma
concentrations of valdecoxib that are within its window of
COX-2-selective action.** These results suggest that caution should be
exercised if parecoxib or valdecoxib is used clinically in patients with
high renin states (e.g., volume depletion, congestive heart failure).

Reviewer's comment: Readers interested in more detailed analysis of the
renal effects of parecoxib/valdecoxib should read the review of Dr.
Douglas Throckmorton.

**Placebo-Controlled Multiple Dose Studies vs. Ketorolac:**

During the platelet studies in healthy volunteers (studies 015, 017, and
027) discussed earlier, certain renal parameters were measured (as
secondary variables). These parameters included urinary excretion rates
for **11-dehydro-TxB~2~** (derived partly from platelets), prostaglandin
excretion (**PGE2 and 6-keto-PGF~1α~** ;  number of methodologic as well
as biologic variables can affect urinary prostaglandin measurements in
humans) and **fractional sodium excretion**. No statistical analyses
were conducted for the prostaglandin data, as the studies were not
powered to detect differences between treatment groups.

Treatment with parecoxib (up to 40 mg BID) resulted in small numerical
changes in median values of urinary 11-dehydro- TxB~2~ excretion
(studies 015 and 017, day 1 or 8) while ketorolac 15 or 30 mg QID
reduced it to approximately half the baseline rate (day 1 and 5).
Treatment with parecoxib (10 or 40 mg BID) tended to reduce urinary PGE2
excretion but the effect was of lower magnitude than that observed after
treatment with ketorolac 15 or 30 mg BID. Treatment with parecoxib (10-
40 mg BID) reduced urinary 6-keto- PGF~1α~  excretion on both the first
and final dose days, but the effects were not as great as was observed
for treatment with ketorolac 15 or 30 mg QID. Fractional sodium
excretion was transiently reduced by statistically significant margins
on the first day of treatment with parecoxib (10-40 mg BID). Reductions
of 0.220% to 0.270% in parecoxib groups, compared to reductions of no
more than 0.091% with placebo. These reductions were significantly less
severe than those observed for ketorolac 15 or 30 mg QID (mean
reductions of 0.360% to 0.568%). In all cases, fractional sodium
excretion rates returned to normal (not significantly different from
baseline) by the last dose day.

> ***Reviewer's comment: These findings support the conclusion that
> COX-2 influences renal function.***

**Adverse Events Related to Renal Function:**

> Adverse events, potentially related to renal function, were
> consolidated as \"renal adverse events\" for review; this included
> urinary system disorders of the W.H.O.a.r.t. body system
> classifications as well as adverse events from other body systems
> (e.g., edema, hypertension). The results (Tables T11.1.1, Tables 4.5.2
> --4, Tables T8.3.1-2, Tables T7.3.1-2, T11.2.1, Table T11.4.2, Table
> T11.5.2; N93-00-07-816) are summarized as follows:

-   In the general surgery trials, there were few renal adverse events
    in any treatment group

> (2.4% was the highest incidence rate; peripheral edema with NSAIDs).
> The most common renal adverse events were **hypertension and
> peripheral edema**. There was no obvious pattern of increased
> incidence across treatments. None of the renal adverse event rates
> were statistically significantly different between treatment groups.

-   In the pharmacological differentiation studies (011, 015, 016, 017,
    026, 027 and 030) with healthy young or elderly subjects, there was
    a dose-dependent increase in the **incidence of peripheral edema
    associated with parecoxib** (parecoxib 20 mg BID 1.8%, parecoxib 40
    mg BID 3.9%). The combined incidence for parecoxib (3.1%) was
    statistically significantly higher than for placebo (p=0.023) but
    not NSAIDs (0.9%). These episodes of edema occurred in both young
    and elderly subjects. Two subjects receiving parecoxib 20 mg BID
    (both in Study 017) had simultaneous adverse events consisting of
    creatinine, BUN, and weight increases, consistent with transient
    renal insufficiency; these patients had no prior histories of edema.

-   Renal adverse events in the valdecoxib (highest dose only 20 mg QD)
    longer-term safety study occurred at a generally low rate (highest
    incidence of 3.4% for peripheral edema, valdecoxib 10 mg) and did
    not suggest any obvious dose-dependent increase. The incidences of
    the most common renal adverse events, hypertension, peripheral
    edema, BUN and creatinine increases, were not statistically
    significantly different between treatment groups.

-   Among CABG surgery patients with a **history of diabetes mellitus**,
    the risk difference (RD) for **peripheral edema** was 19.7 (higher
    risk for patients receiving parecoxib or valdecoxib than for
    patients receiving placebo). The RD for patients without a history
    of diabetes was -1.9 (slightly higher risk for patients receiving
    placebo). The difference in these RDs (21.7) was statistically
    significant (p=0.008). In patients with a history of
    **hypertension** , the RD for **oliguria** was 0.7 (slightly higher
    risk for patients receiving parecoxib/valdecoxib than for patients
    receiving placebo). The RD for patients without a history of
    hypertension was 16.9 (higher risk for patients receiving parecoxib
    or valdecoxib. The difference in these RDs (-16.2) was statistically
    significant (p=0.018).

In the **CABG surgery trial**, where patients were treated for longer
periods of time, renal

adverse events were more common than in the general surgery trials
(**Table 83**). The most commonly reported adverse events were
**peripheral edema and oliguria**. Although there were no statistically
significant differences between the two groups, **trends** suggested
more events for parecoxib/valdecoxib compared to placebo-treated
patients.

^**Table\ 83:\ Renal\ Adverse\ Events**\ ≥**1%\ -CABG\ Surgery\ Trial1**^

+------------------+------------+------------+------------+-----------+
| ######## Event   | *          |            | **         |           |
|                  | *Placebo** |            | Parecoxib/ |           |
|                  |            |            | Valdecoxib |           |
|                  | (N=151)    |            | 40 mg**    |           |
|                  |            |            |            |           |
|                  |            |            | (N=311)    |           |
+------------------+------------+------------+------------+-----------+
|                  | IV Dosing  | Entire     | IV Dosing  | Entire    |
|                  | Period     | Study      | Period     | Study     |
+------------------+------------+------------+------------+-----------+
| BUN increased    | 0.7        | 0.7        | 2.6        | 3.2       |
|                  |            |            |            |           |
| Creatinine       | 4.0        | 4.0        | 3.9        | 5.8       |
| increased        |            |            |            |           |
|                  | 4.0        | 4.6        | 2.3        | 2.9       |
| Edema            |            |            |            |           |
| generalized      | 9.3        | 13.9       | 11.3       | 16.4      |
|                  |            |            |            |           |
| Edema peripheral | 0.7        | 0.7        | 1.0        | 1.6       |
|                  |            |            |            |           |
| Hyperkalemia     | 0          | 0          | 1.3        | 1.3       |
|                  |            |            |            |           |
| Hypertension     | 0.7        | 1.3        | 1.9        | 2.3       |
|                  |            |            |            |           |
| Hypertension     | 9.9        | 9.9        | 14.1       | 14.5      |
| aggravated       |            |            |            |           |
|                  | 1.3        | 1.3        | 2.3        | 2.9       |
| Oliguria         |            |            |            |           |
|                  |            |            |            |           |
| Renal function   |            |            |            |           |
| abnormal         |            |            |            |           |
+------------------+------------+------------+------------+-----------+

1.  Derived from Table T11.1.2, N93-00-07-816. Data represent
    percentages of patients.

Serious and Clinically Relevant Adverse Events Related to Renal
Function:

Of the 17 serious renal adverse events noted in this NDA, 14 occurred in
patients who received any dose of parecoxib or valdecoxib. The majority
of the cases (11 of the 14 cases) were from the CABG surgery trial and
most (10 of the 14 cases) did not result in withdrawal from study
participation. Reasons included aggravated hypertension (3 cases),
peripheral edema (1 case), fluid overload (1 case), urinary retention or
infection (2 cases), acute renal failure (1 case), abnormal renal
function (3 cases) and increases of creatinine (3 cases). Although the
events from the CABG trial (which included all three cases of creatinine
increases) are multifactorial in etiology, it was felt that patient
US0131-0273 (a 61-year-old man who developed oliguria and hypotension
with a systolic pressure 59 mm/Hg on the first treatment day following
CABG surgery), was attributable to parecoxib.

> ***Reviewer's comment: Although difficult to interpret without other
> treatment arms, it is of interest to note that most of the serious
> renal events, in a patient population likely to receive it, occurred
> with parecoxib/valdecoxib vs. placebo.***

As noted earlier, clinically relevant adverse renal events were
adjudicated by an outside committee (CRAEC). For changes in BUN and
creatinine, a separate set of criteria deemed to be more appropriate for
CABG surgery patients defined major clinically relevant renal adverse
events as those events associated with a serum creatinine value \> 2.0
mg/dL and an increase of \> 0.7 mg/dL from baseline. Using these
criteria, 8 (2.6%) parecoxib/valdecoxib and 4 (2.6%) placebo patients
had major renal events in study 035. Of these major renal events, 7 were
detected by laboratory tests and required no treatment, and 3 were first
noted as oliguria. Seven of these events resulted in discontinuation of
study medication. All but 1 **patient** (035-CA0203-0145, who **died**
of respiratory arrest **eight days after oliguria onset**; see Appendix:
Narrative of Deaths: Parecoxib Trials) recovered from these events.

In the valdecoxib longer-term OA trial, the CRAEC adjudicated renal
events for 33 patients

as being clinically significant: 1 (0.5%) in the placebo group; 6 (2.9%)
in the valdecoxib

10 mg QD dose group; 4 (1.8%) in the valdecoxib 20 mg QD dose group; 14
(6.8%) in

the ibuprofen 800 mg TID dose group; and 8 (3.8%) in the diclofenac
sodium 75 mg BID

dose group. Of the 33 patients with clinically significant renal events,
two patients were

withdrawn due to treatment-emergent adverse events.

**Cardiovascular Effects:**

In the nonclinical cardiovascular safety studies, oral valdecoxib and IV
parecoxib did not appear to have significant effects on arterial
pressure, heart rate or hemodynamics. In conscious dogs, detailed study
of the ECG intervals including the QT intervals, gave normal results.

**Conduction Abnormalities, Arrhythmias and ECG Findings**

Twelve-lead electrocardiograms (ECGs) were performed at pre- and
post-treatment visits in five phase I/II studies (001, 002, 008, 009,
and 012); ECGs were normal for all but 20 of

188 (10.6%) subjects; the exceptions were not considered to be
clinically significant. An in-depth analysis of the QT interval was
conducted in subjects (study 91-056) who received a single 20 mg dose of
valdecoxib on Days 1, 8, 15 and 22; this study was designed as a
bioequivalence study to compare two valdecoxib tablet formulations
(Phase III versus commercial). Subjects underwent 12-lead ECG
assessments on each dosing day at predose and approximately 3 and 24
hours postdose. On each of the individual dosing days, none of the mean
predose or postdose QT intervals were \>400 msec, and the changes in
mean

postdose QT intervals were ≤ 5% of the predose values. QT intervals,
corrected for heart rate (QTc) using Bazett's methodology, mean QTc
intervals were not prolonged following valdecoxib administration (mean
decreases of ≤ 4% \[-15.8 msec\] from predose were observed in both
formulation groups). Eight subjects (7 males, 1 female) had postdose QT
or QTc intervals \> 430 msec or postdose increases in QT or QTc \> 30
msec. The majority of these events were single, transient occurrences;
one of these individual changes in QT or QTc were considered clinically
meaningful.

> ***Reviewer's comment: Although the Sponsor noted that a single dose
> of valdecoxib 20 mg did not have a clinically significant effect on QT
> or QTc intervals (or on any of the remaining ECG parameters), further
> study with more clinically relevant doses and in patients would be
> more appropriate to answer these questions.***

The incidences of heart rate and rhythm disorders reported as adverse
events or withdrawals in the **general surgery trials** (Table T4.5.1
and Table 15.c, N93-00-07-816) suggested no significant
treatment-related effects associated with the use of parecoxib.

The results for the **CABG trial** are noted in **Table 84**. Here,
there was a higher incidence of atrial fibrillation and significantly
more episodes of tachycardia in placebo-treated patients while
ventricular arrhythmia and a significantly higher incidence of
supraventricular tachycardia were noted in patients treated with
parecoxib/valdecoxib compared to patients treated with placebo. Patients
were withdrawn from the CABG surgery study as a result of cardiac
conduction abnormalities or arrhythmias. Five patients (1.6%) receiving
parecoxib/valdecoxib experienced a serious adverse event related to
heart or rhythm disorders as compared to four (2.6%) placebo-treated
patients; parecoxib did not seem associated with any particular type of
arrhythmia or conduction disturbance. Subgroup analyses in the CABG
study by age, history of hypertension, cardiovascular atherosclerotic
disease and cerebrovascular disease did not reveal a significant risk
difference for heart rate or rhythm-related adverse events (Tables
T5.6.1-2, T21.2.1-2, T23.2.2, T23.4.2, and T23.6.2; N93-00-07-816).

**^Table\ 84:\ Heart\ Rate\ and\ Rhythm\ Disorders,\ CABG\ Surgery\ Study1^**

+---------------------+-----------+-----------+-----------+----------+
|                     | IV Dosing |           | Entire    |          |
|                     | Period    |           | Study     |          |
+---------------------+-----------+-----------+-----------+----------+
| Event               | Placebo   | Parecoxib | Placebo   | Pa       |
|                     |           |           |           | recoxib/ |
|                     | (N=151)   | (N=311)   | (N=151)   |          |
|                     |           |           |           | Va       |
|                     |           |           |           | ldecoxib |
|                     |           |           |           |          |
|                     |           |           |           | (N=311)  |
+---------------------+-----------+-----------+-----------+----------+
| Arrhythmia          | 2.0       | 2.3       | 4.0       | 2.6      |
|                     |           |           |           |          |
| Arrhythmia atrial   | 2.0       | 1.0       | 3.3       | 1.0      |
|                     |           |           |           |          |
| Arrhythmia nodal    | 0.7       | 0         | 0.7       | 0        |
|                     |           |           |           |          |
| Arrhythmia          | 0.7       | 2.6       | 1.3       | 2.6      |
| ventricular         |           |           |           |          |
|                     | 0.7       | 0.3       | 0.7       | 0.3      |
| AV block            |           |           |           |          |
|                     | 0.7       | 1.9       | 2.0       | 1.9      |
| Bradycardia         |           |           |           |          |
|                     | 0         | 0         | 0         | 0.3      |
| Bundle branch block |           |           |           |          |
|                     | 0         | 1.0       | 0         | 1.0      |
| Extrasystoles       |           |           |           |          |
|                     | 19.2      | 13.8      | 19.9      | 15.8     |
| Fibrillation atrial |           |           |           |          |
|                     | 1.3       | 1.6       | 1.3       | 1.6      |
| Palpitation         |           |           |           |          |
|                     | 13.9      | 4.8       | 14.6      | 7.1      |
| Tachycardia         |           |           |           |          |
|                     | 0         | 2.9       | 0         | 3.2      |
| Tachycardia         |           |           |           |          |
| supraventricular    | 1.3       | 0.6       | 2.0       | 1.0      |
|                     |           |           |           |          |
| Tachycardia         |           |           |           |          |
| ventricular         |           |           |           |          |
+---------------------+-----------+-----------+-----------+----------+

1.  Derived from Table T5.3.1, N93-00-07-816. Numbers represent
    percentages. By Fischer's exact test, the following were
    significantly different: tachycardia (P=0.001 and 0.017, IV and
    oral, respectively), supraventricular tachycardia (p=0.034 and 0.035
    , IV and oral, respectively).

Vaso-Occlusive Adverse Events:

In the **general surgery trials**, no treatment-related differences were
apparent to suggest that parecoxib was associated with an increased
incidence of vaso-occlusive adverse events in patients participating in
the general surgery studies. One patient (0.3%) treated with parecoxib
20 mg and two patients (1.2%) treated with NSAIDs experienced myocardial
infarctions. Two patients, one (0.3%) receiving parecoxib 20 mg and one
(0.3%) receiving a dose of 40 mg experienced a cerebrovascular disorder;
2 NSAID-treated patients (1.2%) experienced a cerebrovascular disorder.
One placebo-treated patient was withdrawn from the general surgery
studies due to peripheral ischemia (Table T4.7.1, N93-00-07-816).

In the **CABG trial** (see separate review of this trial), although
there were no statistically significant differences detected between the
treatment groups with regards to adverse events, there were higher
incidences rate of **myocardial infarctions** (1.9% vs 0.7%) and
**cerebrovascular disorders** (2.6% vs 0.7%) in patients receiving
parecoxib/valdecoxib when compared to placebo-treated patients.
Myocardial infarction or cerebrovascular disorders led to withdrawal of
two patients treated with placebo and three patients who received
parecoxib/valdecoxib. Subgroup analyses of adverse events dichotomized
by age (\<65 years and \>65 years) did not show a statistically
significant excess of myocardial vaso-occlusive adverse events
(myocardial infarction, myocardial ischemia or angina pectoris) with
parecoxib/valdecoxib treatment in elderly patients participating in the
CABG surgery trial (Table T5.6.1, N93-00-07-816).

Reviewer's comment: No myocardial infarctions were observed in the
valdecoxib OA study in any treatment group and no cerebrovascular
disorders were noted in the valdecoxib-treated patients.

**Serious vaso-occlusive adverse events** that occurred in any study
included in this NDA are summarized in **Table 85**. In the **general
surgery** trials, 4 serious adverse events

(3 cases of pulmonary embolism, 1 thrombophlebitis deep) occurred in
morphine-treated patients; four events (2 myocardial infarctions, 2
cerebrovascular disorders) in ketorolac-treated patients; and 6 events
(3 cases of thrombophlebitis deep, 1 myocardial infarction and 2
cerebrovascular disorders) in parecoxib-treated patients.

> ***Reviewer's comment: Most of the exposure to parecoxib or valdecoxib
> in these general surgery trials was single dose.***

In the **CABG surgery** study, 9 patients (2.9%) experienced
cerebrovascular disorders, 5 patients (1.6%) experienced myocardial
infarctions, 3 patients (1.0%) experienced thrombophlebitis deep, and 1
patient (0.3%) experienced urgent revascularization in the
parecoxib/valdecoxib-treated group. This compares with 2 similar events
in the placebo-treated patients: 1 patient (0.7%) with myocardial
infarction and 1 patient (0.7%) with cerebrovascular disorder.

**^Table\ 85:\ Serious\ Adverse\ Events\ Related\ to\ Vaso-Occlusive\ Events1^**

+-----------------------+-------+--------------------------------------+
| **Event**             | **St  | **Treatment (number of events)**     |
|                       | udy** |                                      |
+-----------------------+-------+--------------------------------------+
| Thrombophlebitis,     | 018   | Parecoxib (3)                        |
| deep                  |       |                                      |
|                       | 020   | Morphine (1)                         |
|                       |       |                                      |
|                       | 035   | Parecoxib (1)                        |
|                       |       |                                      |
|                       |       | Valdecoxib (3)\*                     |
+-----------------------+-------+--------------------------------------+
| Cerebrovascular       | 018   | Ketorolac (1)                        |
| disorder              |       |                                      |
|                       | 020   | Ketorolac (1)                        |
|                       |       |                                      |
|                       | 035   | Parecoxib (1)                        |
|                       |       |                                      |
|                       | 037   | Parecoxib (6)                        |
|                       |       |                                      |
|                       |       | Valdecoxib (3)                       |
|                       |       |                                      |
|                       |       | Placebo (1)                          |
|                       |       |                                      |
|                       |       | Parecoxib (1)                        |
+-----------------------+-------+--------------------------------------+
| Pulmonary embolism    | 018   | Morphine (1)                         |
|                       |       |                                      |
|                       | 019   | Morphine (1)                         |
|                       |       |                                      |
|                       | 020   | Morphine (1)                         |
|                       |       |                                      |
|                       | 035   | Valdecoxib (1)\*                     |
|                       |       |                                      |
|                       |       | Parecoxib (1)                        |
+-----------------------+-------+--------------------------------------+
| Myocardial infarction | 018   | Ketorolac (1)                        |
|                       |       |                                      |
|                       | 020   | Ketorolac (1)                        |
|                       |       |                                      |
|                       | 035   | Parecoxib (4)                        |
|                       |       |                                      |
|                       | 037   | Valdecoxib (1)                       |
|                       |       |                                      |
|                       |       | Placebo (1)                          |
|                       |       |                                      |
|                       |       | Parecoxib (1)                        |
+-----------------------+-------+--------------------------------------+
| Angina pectoris       | 035   | Placebo (1)                          |
|                       |       |                                      |
|                       | 9     | Ibuprofen (1)                        |
|                       | 1-048 |                                      |
+-----------------------+-------+--------------------------------------+
| Urgent                | 035   | Valdecoxib (1)                       |
| revascularization     |       |                                      |
+-----------------------+-------+--------------------------------------+
| Cardiac tamponade     | 035   | Valdecoxib (1)                       |
+-----------------------+-------+--------------------------------------+
| Pericardial effusion  | 035   | Valdecoxib (1)                       |
+-----------------------+-------+--------------------------------------+
| Coronary artery       | 9     | Diclofenac (2)                       |
| disorder              | 1-048 |                                      |
+-----------------------+-------+--------------------------------------+
| Hemopericardium       | 9     | Ibuprofen (1)                        |
|                       | 1-048 |                                      |
+-----------------------+-------+--------------------------------------+

1.  Derived from Appendix 2.1.1 and Appendix 2.2; N93-00-07-816.
    Valdecoxib is 10 or 20 mg. Parecoxib is 20 or 40 mg. There was one
    patient (\*) who had both a pulmonary embolism and DVT.

> ***Reviewer's comment: It is of interest to note that in the CABG
> study (035), 21 of the 23 patients listed having serious
> "vaso-occlusive" events had received either parecoxib or valdecoxib.
> If a composite endpoint of MI, CVA, PE and DVT were created, 18 of 311
> patients (5.5%) versus 3 of 151 patients (2.0%) would be included in
> the parecoxib/valdecoxib and placebo groups, respectively. Of the
> cerebrovascular disorders, all events appeared to be related to
> ischemia or embolism; only one case in the parecoxib group appears to
> have had a hemorrhagic component to it. Eleven of the patients in the
> parecoxib/valdecoxib group were ≥ 65 years, nine of these having
> cerebrovascular events.***

**Hemodynamic Adverse Events and Blood Pressure:**

In the **general surgery trials**, no significant differences in these
adverse events were seen between parecoxib and the NSAID groups,
however, a significantly higher incidence of supine systolic and
diastolic blood pressure reductions greater than 15% was observed for
the parecoxib than the placebo group. Small, albeit significant, mean
reductions in supine systolic blood pressure were also evident for
parecoxib when compared to placebo over the first 4 hours after
treatment (Table 4.19.1 and T4.22.2, N93-00-07-816).

In the **CABG surgery** study, there were statistically significantly
higher incidences of **hypotension** during both the IV dosing period
and the entire study period for patients receiving parecoxib/valdecoxib,
compared to patients receiving placebo. Subgroup analyses by history of
hypertension showed a statistically significant risk difference for the
event of hypotension. There were no statistically significant
differences in the other events of hypertension or cardiac failure.

There were few events of serious adverse events of hypertension,
hypotension, and cardiac failure in the general surgery studies. In the
CABG surgery study, there were two events that the Investigator
attribution as "uncertain" while 4 events were not attributed to either
parecoxib or valdecoxib (Appendix 2.1.1 and 2.2; N93-00-07-816).

## "Risk-Benefit" analysis of Parecoxib:

Any type of risk or benefit needs to be talked about in context. In this
NDA, there would seem to be several levels for such discussion. This
section will attempt to look at both the big picture, as well as its key
components. This particular discussion is complicated by the fact that
parecoxib in an "inactive" parenteral prodrug of an orally "active"
agent valdecoxib, which is the subject of another concurrent NDA review.
Therefore, lines are "fuzzy" in terms of where the efficacy associated
with parecoxib ends and that of valdecoxib begins; the same is true for
issues surrounding safety. Also complicating this discussion are the
multiple claims for efficacy that the Sponsor is seeking which include
not only the "usual" treatment of established pain, but also prevention
or preemptive treatment of pain as well as language in the label as to
how parecoxib has an "opioid-sparing" effect.

The overriding (and arguably most conservative) principle for what
follows is that the efficacy associated with parecoxib derives solely
from the trials in which it had an important role whereas the safety
associated with parecoxib is better appreciated by including data also
involving the use of valdecoxib. The limiting aspect of most NDA
applications is a robust assessment of the safety of the compound of
interest; parecoxib appears to be no exception.

Of the 36 trials noted in this NDA, nine were considered "pivotal" and
one was considered "supportive" toward the proposed labeling claims. The
nine pivotal trials included studies 014 and 025 (oral surgery), 018 and
020 (post-orthopedic surgery), 019 and 021 (post-gynecologic surgery),
022 and 037 (pre-operative surgery) and the CABG trial 035
(opioid-sparing). The supportive trial was 029, this also evaluated
opioid-sparing in a post-gynecologic surgical setting. Most of the
experience (approximately 64%) with parecoxib, in terms of both efficacy
and safety, derives from single-dose experiences (Table 65). This
single-dose exposure includes all the studies listed above with the
exception of 020, 021 (limited multiple dose component, discussed
below), study 029 (included 3 doses) and study 035; the latter being the
most robust assessment of the safety of parecoxib in a surgical setting.

Safety discussion:

**Consideration of "safety" in a post-surgical setting, particularly as
included in this NDA, is difficult for a variety of reasons. For
example, patients enrolled in oral surgery trials do not have the same
risk factors such as age, co-morbidities or medications as those
enrolled in a CABG trial. Even when patients can be balanced for risk
factors in any individual trial, surgical manipulations in a hip or knee
replacement procedure, abdominal hysterectomy and CABG settings
undoubtedly do not uniformly impact important parameters that factor
into an assessment of safety such as pain pathways, cytokines and
proinflammatory mediator release, or the development of a risk such as a
hypercoagulable state. Therefore, the intrinsic heterogeneity of
surgical procedures and patients makes adequate risk assessment
difficult in a "controlled" surgical setting where patients are screened
for predefined inclusion and exclusion criteria. An even more difficult
"extrapolation" of the relative safety of parecoxib in this NDA would be
to subjects (or patients) who then become patients due to some type of**
trauma or emergency**. This "all comers" approach to safety in people at
all levels of risk is a** special area of concern for a compound such as
parecoxib**. Acute clinical situations such as these often engender an
abnormal or unstable cardiovascular status confounded by numerous
factors (fluid imbalances, increased catecholamine secretion, etc.)
whose impact may not be adequately addressed by the types of trials
included in this NDA.**

**Yet another layer of complication is the fact that data on** the
safety of single doses of parecoxib can not predict that of a multiple
dose experience**. Consequently, much of the safety data noted in this
NDA will underestimate the true risk. However, the most robust data on
the safety of parecoxib in terms of dose and duration of use came from
the CABG trial. For this section, therefore, the safety profile of
parecoxib in the CABG trial will discussed separately from the other
surgical studies.**

[Overall safety (excludes CABG)]{.underline}

The safety results from the **general surgery trials** of patients who
were treated briefly (most single dose) either postoperatively or
preoperatively with one or more doses (20 to 40 mg) of parecoxib need to
be interpreted with caution. By comparison to results with placebo, the
major **safety concerns may relate more to the surgery and associated
medical management care than the treatments evaluated** (i.e. parecoxib,
morphine, ketorolac). There are **suggestions of trends that parecoxib
is associated with more hypotensive episodes, lower blood pressures, and
more anemia** than the other treatment groups. However, the frequency
and character of severe or serious adverse events does not suggest these
trends are clinically important. The adverse events most frequently
observed with parecoxib were headache, fever, nausea, vomiting, and
pruritus; however, the incidences of these complaints in placebo-treated
patients were generally similar. No obvious unusual laboratory findings
or vital sign changes were seen with parecoxib administration.

Similarly, the incidence and pattern of adverse events in patients
undergoing **dental extraction** likely represent effects of surgery and
anesthesia rather than the effects of treatment with parecoxib or the
comparators (Tramadol may be the exception). Across all treatment
groups, the most common types of adverse events were nausea, dizziness,
headache, vomiting, and injection site ecchymosis. The incidences of
nausea and vomiting associated with parecoxib were lower than those
associated with NSAIDs or placebo. No specific adverse event was
observed significantly more frequently with parecoxib than with either
placebo or NSAIDs. In these studies, **there were no obvious
dose-related increases in adverse events associated with parecoxib.**

The short-term, **pharmacological, pharmacokinetic and drug interaction
trials** provided early information on the safety of parecoxib
administered to mostly healthy (exception of study 012 in patients with
hepatic impairment) young and elderly people (over 100 subjects received
parecoxib 40 mg BID). In this setting, parecoxib appeared to be
generally well tolerated. Adverse events consisted of those not
unexpected in these types of trials (dizziness, headache, nausea)
although there were **suggestions that peripheral edema, increases of
ALT and AST, and changes in blood pressure may be areas of concern**. No
consistent pattern in the incidence of specific adverse events was
apparent in these studies. There were no deaths or serious adverse
events in this study and only a few withdrawals (urticaria and weight
increase).

**Exposure to valdecoxib 10 or 20 mg** for up to 12 weeks in OA patients
did not result in the emergence of any obviously clinically important
adverse events when compared to the other treatments; it appeared to be
generally safe and well tolerated. However, it is **difficult to
extrapolate these results**, obtained in patients who are generally
healthy to patients undergoing a surgical procedure; the same limitation
would seem to apply to the doses since higher doses would generally be
required in the latter situations. Nonetheless, the results observed for
events such as rashes, bronchospasm, GI events, liver function tests,
effects of formed blood elements, and renal function do not suggest
important concerns at these doses. No meaningful age, gender, racial, or
demographic interactions were apparent. Also, no drug interactions were
apparent.

**There were only two deaths in all these trials**, one in the general
surgery studies (single dose of parecoxib with death nine days later)
and the other in the OA study (patient received ibuprofen).

**[Coronary Artery Bypass Graft (CABG) trial:]{.underline}**

Although this trial was the most robust test of the overall safety of
parecoxib, it could be argued that even here the safety results in these
"healthy CABG" patients may have underestimated the true risk that may
occur with more widespread use of parecoxib. Examples of this oxymoron
may well include most of the exclusion criteria before the surgery (like
emergency CABG, occurrence of MI within 48 hours, CVA or TIA within 6
months, etc.) as well as many of the criteria for inclusion before
surgery or those applied to the intra- or postoperative period (see
description of CABG trial earlier in this review).

In addition to the fact that this is a single trial, it also lacks any
positive control for comparison of safety (or efficacy). In the
postsurgical setting, where patients may be unable to tolerate oral
medications, the only parenteral comparator NSAID available for use in
the United States is ketorolac tromethamine **(Toradol).** Owing to
concerns about the high rate of serious GI complications and other
adverse effects, ketorolac has been withdrawn from some markets (France
and Germany) while its use is limited in others (U.S.-5 continuous days;
U.K -2 days). Lacking data even in the "controlled" situation of this
clinical trial, **no valid comparisons are possible between parecoxib
and ketorolac**, only to the "placebo" standard of care. Unfortunately,
therefore, no useful extrapolations of safety comparisons can be made
between these same two compounds in any other surgical or emergency
situation.

**The adverse event profile of parecoxib was generally worse than that
of placebo** in this trial. For example, looking at the overall
incidence of adverse events (over 80%) in the two treatment groups,
while many likely reflect the surgical procedure and intra- and
post-operative course, some trends seemed to emerge such as **more
severe adverse events associated with parecoxib /valdecoxib over the
course of the study.** During the IV dosing period, there were
numerically more parecoxib /valdecoxib patients with "clinically
relevant" adverse events. Although not statistically significantly
different, the number of deaths, myocardial infarctions, cerebrovascular
accidents, pulmonary embolisms, along with renal and pulmonary
complications were also numerically more frequent for parecoxib during
this IV dosing period than placebo. In fact, **during the entire study
period,** **the incidence of these "clinically relevant" adverse events
associated with parecoxib/valdecoxib was statistically significantly
different than placebo**. Once again, although individual events were
not significantly different between the two groups, with few exceptions
adverse events were numerically more frequent for parecoxib/valdecoxib
than placebo. Similarly, during the entire study period, more patients
in the parecoxib/valdecoxib versus the placebo group withdrew from the
study due to an adverse event. And perhaps most importantly of all,
since the causes were similar in nature to what was noted with the
adverse events (i.e. duodenal ulcer, myocardial infarction, infectious
complications, cerebrovascular accident), **all four deaths occurred
among patients receiving the parecoxib/valdecoxib** treatment regimen;
there were no deaths among the placebo group.

The Sponsor has argued that certain high-risk patients, such as those
with a prior history of cerebrovascular disease or a body mass index of
≥ 30 kg/m^2^ or elevated baseline creatinine levels, may have a higher
risk of adverse events with parecoxib/valdecoxib. The implication may be
that such patients can be identified prospectively and hence avoided or
managed differently. It is noteworthy that the vast majority of patients
enrolled in this trial were on aspirin to prevent myocardial infarctions
and other thromboembolic-type phenomenon. Regarding myocardial
infarctions, the incidence of these types of events was different
between events adjudicated and considered "clinically relevant" compared
to those listed as serious adverse events. It is of interest that one of
the events for parecoxib listed as not being clinically relevant by the
committee resulted in the death of that patient from a myocardial
infarction. Nonetheless, taken as a composite type endpoint to include
events such myocardial infarctions, cerebrovascular accidents, deep
venous thrombosis and pulmonary embolism (Table 67 or 69, for example),
there were consistently more of these types of thromboembolic outcomes
in the parecoxib/valdecoxib versus the placebo groups. **If it is true
that certain adverse events, even when prophylaxed against (in this case
aspirin) still can occur in short-term, perioperative settings, then it
is even more worrisome to consider what the pattern and frequency of
adverse events may be in situations where risks are not addressed or can
not be altered.**

It is also worrisome to consider the breath of organ systems adversely
impacted by parecoxib and valdecoxib compared to the standard of care in
this trial. For example, GI events such as duodenal or gastric ulcer or
hemorrhage or hemoccult positivity only occurred in patients receiving
parecoxib/valdecoxib. Similarly, sternal wound infections, drainage and
dehiscence were also only noted in the parecoxib/valdecoxib group. Some
of the events, such as hypotension, were not only unique to parecoxib
but were also statistically significantly different than placebo.
Furthermore, increases of SGOT or SGOT, supraventricular tachycardia,
hypokalemia, increases of BUN, acute renal failure, oliguria, hematoma,
thrombocytopenia and post-operative anemia were also numerically more
frequent with parecoxib/valdecoxib as compared to placebo. Whether these
trends can be ascribed only to drug and/or mechanism-related causes, or
also reflect some other more technical aspect of this trial such as the
unequal randomization in this trial, remain elusive.

While it may be true that certain adverse events, such as atelectasis,
pleural effusion and pneumonia were more common in the placebo group in
this trial, these results do not support any conclusion that
parecoxib/valdecoxib had significant opioid sparing qualities. If
adverse events typically associated with opioids include outcomes such
as constipation, nausea, vomiting, somnolence, pruritis and respiratory
depression (Table 69), these events were no less common in the
parecoxib/valdecoxib groups than the standard of care groups; in fact,
these events were often more common. Further study of prospectively
defined endpoints, such as time to discharge from intensive care units
or from the hospital may be necessary to fully appreciate the clinical
importance of any numeric or statistically significant differences in
opioid use.

**[Safety conclusions:]{.underline}**

Most of the data on the safety of parecoxib, and its metabolite
valdecoxib, in this NDA resulted from single dose, or limited multiple
dose administration. In these surgical settings with such limited
exposure, it is not possible to adequately address the necessary
conclusions regarding the overall safety profile of parecoxib. To
conclude from such limited experience that parecoxib "was generally well
tolerated" could be argued to be a requirement for further, more in
depth study of this or any other drug; this is particularly true for any
drug contending to have an improved safety profile over extant
therapies.

Without robust head-to-head comparisons with currently available
therapies, useful inferences are impossible. In the CABG trial, the
comparisons that can be made to the standard of care/placebo group note
trends, and in some cases, statistically significant differences to
suggest that parecoxib has consistent and important adverse events
associated with its use. That these differences appear evident in the
population studied, for the durations studied and in the face of certain
compounds meant to prevent their occurrence brings substantial concern
to the overall safety of parecoxib. Further study will be important to
add to an understanding of the true safety liability of this potentially
important new analgesic.

If it is argued that the dose (40 mg BID) of parecoxib (and valdecoxib)
used in the CABG trial is too high, and this high dose contributed to a
less favorable safety profile for parecoxib, then the lack of data on
the safety of multiple doses of parecoxib in any acute or surgical
setting becomes more important owing to the observation that doses of
parecoxib lower than 40 mg did not seem to consistently demonstrate
efficacy in trials included in this NDA. If parecoxib has both a narrow
efficacy and safety window, this emphasizes the importance of continued
study to adequately define these windows.

**Overall Conclusions**:

-   Parecoxib sodium, at single doses of 40 mg, is consistently
    efficacious (with respect to onset, magnitude, and duration of
    analgesia) in the management of acute pain; 20 mg is not
    consistently efficacious as a single-dose analgesic.

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-   Multiple dose data with parecoxib sodium are limited and do not
    allow for characterization of the safe and effective dose, or dosing
    interval after the first dose.

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-   IV and IM parecoxib sodium appear to provide comparable analgesic
    efficacy when administered at the same dose although most of the
    data in this NDA derives from IV.

-   Parecoxib sodium did no consistently reduce opioid consumption.

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-   The safety of parecoxib sodium has not been adequately addressed.
    Most (approximately two thirds) of the data on safety and efficacy
    in the original NDA was obtained from patients or subjects exposed
    to single doses of parecoxib sodium. While such data is fundamental
    to supporting the efficacy and safety of parecoxib sodium, it is
    insufficient to fully characterize the safety and efficacy of this
    compound.

-   Safety data from the CABG trial suggest that certain subgroups of
    patients may be at increased risks for serious adverse events.
    Furthermore, these data can not exclude the possibility of an
    important safety liability associated with parecoxib sodium,
    particularly with repeated doses, over placebo.

-   The proposed labeling claims for management of postoperative pain or
    for the preemptive treatment of pain or for opioid sparing with
    parecoxib sodium are not supported by the data available in this NDA
    either due to insufficient data or lack of replication of results.

#### Regulatory discussion 

Parecoxib represents the first "COX-2 selective" agent to be submitted
for parenteral use as an analgesic. The Sponsor has proposed labeling
which includes the following:

**"Xaptek is indicated for the prevention and treatment of moderate to
severe pain in adults. In addition, for surgical pain requiring
analgesia at the opioid level, Xaptek significantly reduces opioid
consumption. "**

Data from the clinical trials included in this NDA are inadequate to
support any of the claims including treatment, prevention of pain or
opioid sparing either due to insufficient data or to lack of replication
of results. Furthermore, data on the safety of parecoxib suggest that it
has important clinical differences from placebo that need to be studied
in more detail, and in a variety of other settings, to help understand
whether the efficacy benefits are overshadowed by safety risks.
Consequently, with reference to 21 CFR 314.125 (b) (4) (5), it is
recommended that the data in this NDA support the conclusion that
parecoxib is not approvable.