+-----------------+----------------------------------------------------+
| MEMORANDUM      | DEPARTMENT OF HEALTH AND HUMAN SERVICES            |
|                 |                                                    |
|                 | PUBLIC HEALTH SERVICE                              |
|                 |                                                    |
|                 | FOOD AND DRUG ADMINISTRATION                       |
|                 |                                                    |
|                 | CENTER FOR DRUG EVALUATION AND RESEARCH            |
+-----------------+----------------------------------------------------+

DATE: December 29, 2000

FROM: Joyce Weaver, Pharm.D., Safety Evaluator

Division of Drug Risk Evaluation I, HFD-430

THROUGH: Julie Beitz, M.D., Director ***Signed 12-29-00 by***

Division of Drug Risk Evaluation I, HFD-430

TO: Jonca Bull, M.D., Acting Division Director

> Division of Antiinflammatory and Ophthalmic Drug Products, HFD-550

SUBJECT: OPDRA Postmarketing Safety Review

Drugs: Etodolac (Lodine NDA 18-922, NDA 20-584)

Celecoxib (Celebrex NDA 20-998)

Rofecoxib (Vioxx NDA 21-042, NDA 21-052)

Reaction: US Deaths related to Gastrointestinal bleeding,

> obstruction, perforation, or stenosis

INTRODUCTION/ EXECUTIVE SUMMARY

Our objective was to summarize serious gastrointestinal events reported
in postmarketing for celecoxib and rofecoxib relating to
gastrointestinal bleeding, obstruction, perforation, or stenosis. A
summary of similar events for the nonselective nonsteroidal
anti-inflammatory drug, etodolac was also performed. We concentrated on
the most serious gastrointestinal events, those resulting in death.

We evaluated 82 US deaths related to gastrointestinal bleeding,
obstruction, perforation, or stenosis in the AERS database. All cases
were temporally related to therapy with etodolac (9), celecoxib (36), or
rofecoxib (37). Generally, the cases occurred in high-risk elderly
patients. In 5 of the etodolac cases, 30 of the celecoxib cases, and 26
of the rofecoxib cases, the patients were at increased risk of bleeding
or having a poor outcome with a bleed. The patients were at increased
risk because of past medical history, a recent major systemic medical
event, or concomitant therapy with aspirin or another antiplatelet drug,
corticosteroids, warfarin, or another NSAID. Many patients had more than
one risk factor. Eleven of the patients taking celecoxib had a past
history of peptic ulcer disease, and 6 patients had experienced
gastrointestinal bleeding in the past. Four patients taking rofecoxib
had a past history of peptic ulcer disease, and one patient had
experienced gastrointestinal bleeding in the past. Thirteen patients
each taking celecoxib and rofecoxib were taking aspirin and/or warfarin
concomitantly.

We conclude that the labeling for celecoxib and rofecoxib reflect the
risk of fatal gastrointestinal bleeding, obstruction, perforation, and
stenosis observed in the postmarketing experience.

DRUG INFORMATION/LABELING

Etodolac is a nonsteroidal anti-inflammatory drug indicated for acute
and long-term use in the management of signs and symptoms of
osteoarthritis and rheumatoid arthritis and for the management of pain.
Etodolac was approved January 31, 1991. The labeling for etodolac
includes information about gastrointestinal bleeding in the *Warnings*
and *Adverse Reactions* sections. The possibility of fatal outcomes is
discussed. The *Warnings* section presents risk factors for developing
gastrointestinal bleeding, including a prior history of serious GI
events and risk factors known to be associated with peptic ulcer
disease; for example, alcoholism and smoking.

Celecoxib is a nonsteroidal anti-inflammatory drug indicated for relief
of the signs and symptoms of osteoarthritis and rheumatoid arthritis,
and to reduce the number of adenomatous colorectal polyps in familial
adenomatous polyposis (FAP), as an adjunct to usual care. Celecoxib was
approved December 31, 1998. The labeling for celecoxib includes
information about gastrointestinal bleeding in the *Warnings* and
*Adverse Reactions* sections. The possibility of fatal outcomes is
discussed. The *Warnings* section presents additional risk factors not
addressed in the labeling for etodolac; for example, treatment with oral
corticosteroids or anticoagulants. Intestinal obstruction is included in
the *Adverse Reactions* section of the labeling. The *Drug Interactions*
section states that celecoxib can be used with low dose aspirin;
however, concomitant administration of aspirin with celecoxib may result
in an increased rate of GI ulcerations. Additionally, the *Drug
Interactions* section states there is an increased risk of bleeding
complications with concomitant use of warfarin, particularly in elderly
patients.

Rofecoxib is a nonsteroidal anti-inflammatory drug indicated for relief
of the signs and symptoms of osteoarthritis, for the management of acute
pain, and for the treatment of primary dysmenorrhea. Rofecoxib was
approved May 20, 1999. The labeling for rofecoxib includes information
about gastrointestinal bleeding and obstruction in the *Warnings* and
*Adverse Reactions* sections. The possibility of fatal outcomes is
discussed. The *Warnings* section presents information about risk
factors in a manner similar to the labeling for celecoxib. The *Drug
Interactions* section states that concomitant administration of aspirin
or warfarin with rofecoxib may result in an increased rate of GI
complications.

MEDICAL LITERATURE SUMMARY

MEDLINE was searched for additional case reports of gastrointestinal
bleeding or obstruction. A MEDLINE search performed December 7, 2000
using the MESH terms *Etodolac, Celecoxib, Rofecoxib*, *Intestinal
Obstruction*, and *Gastrointestinal Hemorrhage* did not locate any
additional case reports with fatal outcomes in the medical literature.

## **SELECTION OF CASE SERIES**

On October 25, 2000 we searched the AERS database for cases of
gastrointestinal bleeding, perforation, obstruction, or stenosis related
to etodolac, celecoxib, and rofecoxib. The cases were identified using
the higher level group terms (HLGTs) *Gastrointestinal Haemorrhages NOS,
Gastrointestinal Stenosis and Obstruction,* and *Gastrointestinal
Ulceration and Perforation.* AERS contained 214 reports (190 domestic)
linked to etodolac, 744 (705 domestic) linked to celecoxib, and 829 (613
domestic) linked to rofecoxib. We limited our summary to domestic cases
of gastrointestinal bleeding, perforation, obstruction, or stenosis
resulting in death linked to these 3 drugs. AERS contained 82 unique
domestic deaths, 9 linked to etodolac, 36 linked to celecoxib, and 37
linked to rofecoxib.

#### [SUMMARY OF CASES]{.underline}

#### 

See Attachment 1 for a summary of the data for all 3 drugs.

#### Etodolac 

#### 

Demographic data and a summary of the 9 cases are provided below.

  ----------------- -----------------------------------------------------
  Age in years      Mean 79, median 78, range 69 to 94

  Gender            Male (5), Female (3), Unknown (1)

  Year              1991 (2), 1992 (4), 1993 (1), 1994 (1), 1996 (1)

  Indication        Osteoarthritis (2), Gouty arthritis (1), Unknown (6)

  Time to onset     Mean 35.7, median 30 (range, 17 to 60) days

  Dose              At or below labeled range (3), Unknown (6)

  GI event          Hemorrhage (6), Perforation (2), Melena (1),
                    Hematemesis (1), Stenosis/Obstruction (1)

  Location          Esophageal (1), Gastric (2), Duodenal (1), Large
                    intestine (1), Unknown (4)

  Pertinent PMH     Diabetic gastroparesis (1), Bowel obstruction (1),
                    CAD (3)

  Major event       CABG (1)
  preceding bleed   

  Significant       Warfarin (1)
  concomitant       
  medications       
  ----------------- -----------------------------------------------------

#### 

#### Eight patients taking etodolac died after experiencing gastrointestinal bleeding, and one patient died after experiencing esophageal stenosis. In the latter patient, death occurred after an etodolac capsule or tablet lodged in the patient's esophagus. One death was not directly due to bleeding, but was instead the result of a cerebrovascular accident resulting from discontinuation of warfarin after serious gastrointestinal bleeding occurred. The site of bleeding was not reported in 4 cases. Gastric bleeding occurred in 2 cases. In one case each bleeding occurred in the duodenum and the large intestine.

#### 

#### The mean age of the patients was 79 years. In most cases the indication for which etodolac was prescribed was not stated. The mean onset of gastrointestinal bleeding was 35.7 days after instituting therapy with etodolac. In one case bleeding occurred on the day of hospital discharge after coronary artery bypass surgery. In 5 of the 9 cases the patients were at increased risk of bleeding or having a poor outcome with a bleed because of past medical history, a recent major systemic medical event, or concomitant therapy with warfarin. 

Two cases are presented below.

AERS 4932128, MFR 892324001B, US (FL), 1992

An 82-year-old man with a prior medical history of cataracts,
unspecified prostate surgery, and diabetes was prescibed etodolac 300 mg
as needed for unspecified pain. After taking etodolac for 2 to 3 months,
the patient experienced coffee-ground emesis, and he was hospitalized.
Nasogastric aspiration resulted in retrieval of 900 milliliters of
coffee-ground material. Surgery was performed to repair a perforated
gastric ulcer. The patient died 3 days after admission to the hospital.

AERS 4919199, Direct, US (IA), 1992

A 79-year-old woman taking etodolac for an unknown period for
unspecified arthritis was hospitalized after a 2-to-3-month history of
dark stools and a 2-week history of vomiting. Hemoglobin and hematocrit
on admission were 5.8 g/dL and 16.6%, respectively. A bleeding duodenal
ulcer was diagnosed. The patient was treated with surgery, an
H~2~-receptor antagonist, and blood transfusions. She died after 26 days
of hospitalization.

#### 

#### Celecoxib

Demographic data and a summary of the 36 cases are provided below.

+----------------+-----------------------------------------------------+
| Age in years   | Mean 77, median 78.5, range 46 to 99                |
+----------------+-----------------------------------------------------+
| Gender         | Male (12), Female (22), Unknown (2)                 |
+----------------+-----------------------------------------------------+
| Year           | 1999 (30), 2000 (6)                                 |
+----------------+-----------------------------------------------------+
| Indication     | Osteoarthritis (12), Rheumatoid arthritis (4),      |
|                | Acute pain (3), Unspecified arthritis (3), Other    |
|                | (5), Unknown (9)                                    |
+----------------+-----------------------------------------------------+
| Time to onset  | Mean 25.7, median 14 (range, 1 to 115) days         |
+----------------+-----------------------------------------------------+
| Dose           | At or below labeled range (18), Higher than labeled |
|                | range (2), Unknown (16)                             |
+----------------+-----------------------------------------------------+
| GI event       | Hemorrhage (22), Perforation (2), Melena (7),       |
|                | Hematemesis (10)                                    |
+----------------+-----------------------------------------------------+
| Location       | Gastric (3), Duodenal (5), Rectal (2), Small        |
|                | intestine (1),                                      |
|                |                                                     |
|                | Unknown (25)                                        |
+----------------+-----------------------------------------------------+
| Pertinent PMH  | Alcoholism (3), Anemia (5), CAD (7), Cirrhosis (1), |
|                | CVA (1), Diabetes (6), Diverticulitis (1),          |
|                | Esophageal varices (1), Factor V def (1), Gastritis |
|                | (2), GI AVM (2), Gastrectomy (1), previous GI bleed |
|                | (6), Malignancy (4), PUD (11), Thrombocytopenia (1) |
+----------------+-----------------------------------------------------+
| Major event    | Exacerbation of asthma, inc in steroid dose (1),    |
| preceding      | Hospitalization for CP & anemia (1), Liver failure  |
| bleed          | (2), Metastatic ca (2), Multiple myeloma (1),       |
|                | Pancreatitis (1), Pneumonia (1), Surgery (2), TEN   |
|                | (1)                                                 |
+----------------+-----------------------------------------------------+
| Significant    | Alendronate (1), ASA (8), Corticosteroid (5), NSAID |
| concomitant    | (4), Warfarin (5), H~2~-blocker or PPI (8)          |
| medications    |                                                     |
+----------------+-----------------------------------------------------+

#### Thirty-six patients taking celecoxib died after experiencing gastrointestinal bleeding or perforation. In 4 cases, gastrointestinal bleeding apparently precipitated other events that directly caused death. The immediate causes of death were probable septic shock, aspiration pneumonia, multiple organ failure, and unspecified cardiac complications. 

#### 

#### The mean age of the patients was 77 years. The case series had a 1.8:1 predominance of females. Celecoxib was prescribed most often for osteoarthritis. The mean time to onset of gastrointestinal bleeding was 25.7 days after instituting therapy with celecoxib. The site of bleeding was not reported in most cases. Gastric bleeding occurred in 4 cases and duodenal bleeding occurred in 5 cases. In one case each bleeding occurred in the rectum and the small intestine. 

#### 

#### In 30 of the 36 cases the patients were at increased risk of bleeding or having a poor outcome with a bleed because of past medical history, a recent major systemic medical event, and/or concomitant medication. Many patients had more than one risk factor for bleeding. Five patients were taking warfarin concomitantly with celecoxib, 8 patients were taking aspirin concomitantly, 5 patients were taking corticosteroids concomitantly, and 4 patients were taking another nonsteroidal anti-inflammatory drug concomitantly with celecoxib. 

About one-half of the patients had clinically significant prior medical
histories. Eleven patients had a prior medical history of peptic ulcer
disease and 6 patients had experienced gastrointestinal bleeding before
celecoxib was prescribed. One of the patients with a history of
gastrointestinal bleeding had required banding of esophageal varices.
Five patients had a history of anemia, 4 patients had a history of
malignancy, 7 patients had arteriosclerotic heart disease, and 3
patients were alcoholic.

Additionally, the gastrointestinal bleeding in 12 patients may have been
precipitated by a major systemic event. The major events included
exacerbation of asthma accompanied by an increase in corticosteroid
dose, hospitalization for chest pain and anemia, liver failure,
metastatic solid organ cancer, multiple myeloma, pancreatitis,
pneumonia, surgery, and toxic epidermal necrolysis.

Eight patients bled despite taking an H~2~-receptor antagonist or proton
pump inhibitor concomitantly with celecoxib.

Two cases are presented below.

AERS 3305112, MFR 990709-SK489, US (MD), 1999

An 87-year-old woman with past medical history of peptic ulcer disease,
arteriosclerotic heart disease, aortic valve disorder, and diabetes was
prescribed an unknown dose of celecoxib to treat osteoarthritis. Her
concomitant medications included warfarin. After 37 days of therapy with
celecoxib, the patient presented to the emergency room with
gastrointestinal bleeding. She died in the emergency room.

AERS 3472602, US (NC), 2000

A 92-year-old female nursing home resident with past medical history of
hypertension, chronic obstructive pulmonary disease, glaucoma,
parkinsonism, and arteriosclerotic heart disease, but with no history of
peptic ulcer disease, was prescribed celecoxib 100 mg twice a day for an
unknown reason. After receiving celecoxib for an unknown period of time,
she was transferred to the hospital with lethargy, nausea, diarrhea, and
abdominal pain. Her hemoglobin and hematocrit dropped from 12 g/dL and
36%, respectively, on admission to 10.7 g/dL and 31.7%, respectively,
after one day of hospitalization. Esophagogastroduodenoscopy (EGD)
revealed a one-centimeter bleeding ulcer. Epinephrine was injected in an
attempt to stop the bleeding. The patient's condition deteriorated, a
do-not-resuscitate (DNR) order followed, and the patient died.

**Rofecoxib**

Demographic data and a summary of the 37 cases are provided below.

+----------------+-----------------------------------------------------+
| Age in years   | Mean 76, median 80, range 28 to 93                  |
+----------------+-----------------------------------------------------+
| Gender         | Male (14), Female (22), Unknown (1)                 |
+----------------+-----------------------------------------------------+
| Year           | 1999 (3), 2000 (34)                                 |
+----------------+-----------------------------------------------------+
| Indication     | Osteoarthritis (14), Acute pain (6), Unspecified    |
|                | arthritis (6), Other (6), Unknown (5)               |
+----------------+-----------------------------------------------------+
| Time to onset  | Mean 43, median 21 (range, 0 to 131) days           |
+----------------+-----------------------------------------------------+
| Dose           | At or below labeled range (24), Higher than labeled |
|                | range (1), Unknown (12)                             |
+----------------+-----------------------------------------------------+
| GI event       | Hemorrhage (23), Perforation (7), Melena (4),       |
|                | Hematemesis (6), Erosions (1), Stenosis/Obstruction |
|                | (1), Other (10)                                     |
+----------------+-----------------------------------------------------+
| Location       | Gastric (13), Duodenal (5), Large intestine (2),    |
|                | Other (2), Unknown (15)                             |
+----------------+-----------------------------------------------------+
| Pertinent PMH  | Anemia (1), ASA allergy (1), sulfa allergy (1),     |
|                | Crohn\'s disease (1), CVA (1), Diabetes (1),        |
|                | Diverticulitis (1), Functional intestinal disorder  |
|                | (1), Gastrostomy (1), Previous GI bleed (1),        |
|                | Irritable bowel syndrome (1), Hepatic dysfunction   |
|                | (1), PUD (4)                                        |
+----------------+-----------------------------------------------------+
| Major event    | Metastatic gastric cancer (1), Pancreatitis,        |
| preceding      | hepatitis (1), Shock (1)                            |
| bleed          |                                                     |
|                | Surgery (3)                                         |
+----------------+-----------------------------------------------------+
| Significant    | ASA (8), Clopidogril (2), Corticosteroid (2),       |
| concomitant    | Warfarin (6)                                        |
| medications    |                                                     |
|                | Antacid, H2 blocker, or PPI (4)                     |
+----------------+-----------------------------------------------------+

#### 

#### Thirty-seven patients taking rofecoxib died after experiencing gastrointestinal bleeding, perforation, stenosis, or obstruction. One death might have been the result of a cerebrovascular accident resulting from discontinuation of warfarin because of serious gastrointestinal bleeding. In another case, a patient died after gastrointestinal bleeding precipitated an exacerbation of congestive heart failure. Four deaths occurred as a result of postoperative complications following surgery to repair ulcers or perforations. 

#### 

#### The mean age of the patients was 76 years. The case series had a 1.6:1 predominance of females. Rofecoxib was prescribed most often for osteoarthritis. The mean time to onset of gastrointestinal bleeding was 43 days after instituting therapy with rofecoxib. Gastric bleeding was most commonly reported, occurring in 13 cases. Duodenal bleeding occurred in 5 cases, and bleeding in the large intestine occurred in 2 cases. 

#### 

#### In 26 of the 37 cases the patients were at increased risk of bleeding or having a poor outcome with a bleed because of past medical history, a recent major systemic medical event, and/or concomitant medication. Six patients were taking warfarin concomitantly with rofecoxib, 8 patients were taking aspirin concomitantly, 2 patients were taking corticosteroids concomitantly, and 2 patients were taking clopidogril concomitantly with rofecoxib. 

About one-third of the patients had clinically significant prior medical
histories. These included anemia, cerebrovascular accident, Crohn\'s
disease, diabetes, diverticulitis, functional intestinal disorder,
gastrostomy, irritable bowel syndrome, and hepatic function impairment.
Four patients had a prior medical history of peptic ulcer disease, and
previous gastrointestinal bleeding was reported for one patient.

Gastrointestinal bleeding in 6 patients may have been precipitated by a
major systemic event. The major events included previously undiagnosed
metastatic gastric cancer, pancreatitis, hepatitis, and surgery.

#### Four patients bled despite taking a gastrointestinal-protectant drug concomitantly with rofecoxib.

Two cases are presented below.

AERS 3397744, WAES 99111907, US (FL), 1999

An 87-year-old female independent retirement village resident with a
past medical history of irritable bowel syndrome, paroxysmal atrial
tachycardia, hypertension, and spastic colon, but no history of peptic
ulcer disease, was prescribed rofecoxib 25 mg a day for sciatic
neuralgia. Five days later she presented to the emergency room via
ambulance with diaphoresis, weakness, and hypotension. The diagnosis on
admission was septic or cardiogenic shock. An exploratory laparotomy
revealed a perforated duodenal ulcer. Two liters of dark grayish fluid
were removed from the peritoneal cavity, and the perforated ulcer was
repaired. The patient was transferred to the post-anesthesia care unit
on vasopressor support with a blood pressure of 80/30 mm Hg, a heart
rate of 60 beats per minute, and respiratory rate of 13 per minute. She
went into cardiac arrest and died despite attempts to resuscitate her.

AERS 3424661, WAES 00010945, US (SC), 2000

An 85-year-old man with a history of atrial fibrillation, and an
unspecified vascular disorder was prescribed rofecoxib to treat back
pain. Concomitant medications included clopidogril and warfarin. Six
days later the patient was hospitalized with unspecified
gastrointestinal bleeding confirmed by endoscopy. On admission, the
patient's hemoglobin was 5-7 g/dL. Rofecoxib and warfarin were
discontinued. Vitamin K and 4 units of packed red blood cells were
administered, and the patient stabilized. However, 3 days later the
patient developed an arrhythmia and died suddenly. The attending
physician believed the patient might have had a cerebrovascular accident
caused by discontinuation of warfarin.

CONCLUSION

We evaluated 82 deaths from gastrointestinal bleeding, obstruction,
perforation, or stenosis in the AERS database temporally related to
therapy with etodolac, celecoxib, or rofecoxib. The patients in the case
series were mostly high-risk elderly patients. In 56% (5/9) of the
etodolac cases, 83% (30/36) of the celecoxib cases, and 70% (26/37) of
the rofecoxib cases the patients were at increased risk of bleeding or
having a poor outcome with a bleed because of past medical history, a
recent major systemic medical event, or concomitant medication. Many
patients had more than one risk factor. Eleven of the patients taking
celecoxib had a past medical history of peptic ulcer disease, and 6 of
these patients had experienced gastrointestinal bleeding in the past.
Four patients taking rofecoxib had a past medical history of peptic
ulcer disease, and one of these patients had experienced
gastrointestinal bleeding in the past. Thirteen (36%) of the patients
taking celecoxib and 13 (35%) of the patients taking rofecoxib were
taking aspirin or warfarin concomitantly. Twelve patients, 16% of the
cases in the celecoxib and rofecoxib series, bled and died despite
taking a gastrointestinal-protectant drug concomitantly.

We conclude that the labeling for celecoxib and rofecoxib reflect the
risk of fatal gastrointestinal bleeding, obstruction, perforation, and
stenosis observed in the postmarketing experience.

### Signed 12-29-00 by

+-----------------------------------------------------------------------+
| Joyce Weaver, Pharm.D., Safety Evaluator                              |
|                                                                       |
| Concur:                                                               |
|                                                                       |
| ##### Signed 12-29-00 by                                              |
+-----------------------------------------------------------------------+
| Claudia B. Karwoski, Pharm.D., Team Leader                            |
+-----------------------------------------------------------------------+

Attachment 1. Summary Data---Domestic Cases of Fatal Gastrointestinal
Bleeding, Perforation, Obstruction, or Stenosis

+-----------------------------------+----------------------------------+
| Drug                              | Lodine (Etodolac)                |
+===================================+==================================+
| Total cases                       | 9                                |
+-----------------------------------+----------------------------------+
| Mean age                          | 79                               |
|                                   |                                  |
| Median age                        | 78                               |
|                                   |                                  |
| range                             | 69 -- 94                         |
+-----------------------------------+----------------------------------+
| Gender                            | M---5                            |
|                                   |                                  |
|                                   | F---3                            |
|                                   |                                  |
|                                   | Unk---1                          |
+-----------------------------------+----------------------------------+
| Event date                        | 1991---2                         |
|                                   |                                  |
|                                   | 1992---4                         |
|                                   |                                  |
|                                   | 1993---1                         |
|                                   |                                  |
|                                   | 1994---1                         |
|                                   |                                  |
|                                   | 1996---1                         |
+-----------------------------------+----------------------------------+
| Indication                        | Osteoarthritis---2               |
|                                   |                                  |
|                                   | Gouty arthritis---1              |
|                                   |                                  |
|                                   | Unknown---6                      |
+-----------------------------------+----------------------------------+
| Mean onset                        | 35.7 days                        |
|                                   |                                  |
| Median onset                      | 30 days                          |
|                                   |                                  |
| range                             | 17 -- 60 days                    |
|                                   |                                  |
|                                   | (Onset data available for 3      |
|                                   | cases)                           |
+-----------------------------------+----------------------------------+
| Dose at or below labeled range    | Yes---3                          |
|                                   |                                  |
|                                   | Unk---6                          |
+-----------------------------------+----------------------------------+
| GI event^†^                       | Hemorrhage---6                   |
|                                   |                                  |
|                                   | Perforation---2                  |
|                                   |                                  |
|                                   | Melena---1                       |
|                                   |                                  |
|                                   | Hematemesis---1                  |
|                                   |                                  |
|                                   | Stenosis/obstr---1               |
+-----------------------------------+----------------------------------+
| Location of GI event              | Esophageal---1                   |
|                                   |                                  |
|                                   | Gastric---2                      |
|                                   |                                  |
|                                   | Duodenal---1                     |
|                                   |                                  |
|                                   | Large intestine---1              |
|                                   |                                  |
|                                   | Unknown---4                      |
+-----------------------------------+----------------------------------+
| Mean nadir Hgb and Hct            | Hgb 5.8 Hct 16.6                 |
|                                   |                                  |
|                                   | (Info from 1 case)               |
+-----------------------------------+----------------------------------+
| Concomitant NSAID                 |                                  |
+-----------------------------------+----------------------------------+
| Concomitant warfarin              | 1                                |
+-----------------------------------+----------------------------------+
| Concomitant corticosteroid        |                                  |
+-----------------------------------+----------------------------------+
| Concomitant antiplatelet          |                                  |
+-----------------------------------+----------------------------------+
| Concomitant ASA                   |                                  |
+-----------------------------------+----------------------------------+
| Concomitant alendronate           |                                  |
+-----------------------------------+----------------------------------+
| ETOH use                          |                                  |
+-----------------------------------+----------------------------------+
| Smoker                            |                                  |
+-----------------------------------+----------------------------------+
| Pertinent PMH^†^                  | Diabetic gastroparesis (1)       |
|                                   |                                  |
|                                   | Bowel obstruction (1)            |
|                                   |                                  |
|                                   | CAD (3)                          |
+-----------------------------------+----------------------------------+
| Major systemic illness preceding  | CABG (1)                         |
| bleed^†^                          |                                  |
+-----------------------------------+----------------------------------+
| Concomitant H2 blocker, antacid,  |                                  |
| or PPI                            |                                  |
+-----------------------------------+----------------------------------+
| Bleeding other than GI            |                                  |
+-----------------------------------+----------------------------------+
| Diagnosis confirmed by diagnostic | 4                                |
| procedure                         |                                  |
|                                   | Surgery (2)                      |
|                                   |                                  |
|                                   | CT scan (1)                      |
|                                   |                                  |
|                                   | EGD (1)                          |
+-----------------------------------+----------------------------------+
| Pos Dechallenge                   |                                  |
+-----------------------------------+----------------------------------+
| Pos Rechallenge                   |                                  |
+-----------------------------------+----------------------------------+
| Reviewer impression of quality of | Good---0                         |
| report                            |                                  |
|                                   | Adequate---2                     |
|                                   |                                  |
|                                   | Poor---7                         |
+-----------------------------------+----------------------------------+

† more than one possible per case

+-----------------------------------+----------------------------------+
| Drug                              | Celebrex (Celecoxib)             |
+===================================+==================================+
| Total cases                       | 36                               |
+-----------------------------------+----------------------------------+
| Mean age                          | 77                               |
|                                   |                                  |
| Median age                        | 78.5                             |
|                                   |                                  |
| range                             | 46 -- 99                         |
+-----------------------------------+----------------------------------+
| Gender                            | M---12                           |
|                                   |                                  |
|                                   | F--- 22                          |
|                                   |                                  |
|                                   | Unk---2                          |
+-----------------------------------+----------------------------------+
| Event date                        | 1999---30                        |
|                                   |                                  |
|                                   | 2000---6                         |
+-----------------------------------+----------------------------------+
| Indication                        | RA---4                           |
|                                   |                                  |
|                                   | Osteoarthritis---12              |
|                                   |                                  |
|                                   | Acute pain--- 3                  |
|                                   |                                  |
|                                   | Unspecified arthritis---3        |
|                                   |                                  |
|                                   | Other---5                        |
|                                   |                                  |
|                                   | Unknown---9                      |
+-----------------------------------+----------------------------------+
| Mean onset                        | 25.7 days                        |
|                                   |                                  |
| Median onset                      | 14 days                          |
|                                   |                                  |
| range                             | 1 -- 115 days                    |
+-----------------------------------+----------------------------------+
| Dose at or below labeled range    | Yes---18                         |
|                                   |                                  |
|                                   | No---2                           |
|                                   |                                  |
|                                   | Unk---16                         |
+-----------------------------------+----------------------------------+
| GI event^†^                       | Hemorrhage---22                  |
|                                   |                                  |
|                                   | Perforation---2                  |
|                                   |                                  |
|                                   | Melena---8                       |
|                                   |                                  |
|                                   | Hematemesis---10                 |
+-----------------------------------+----------------------------------+
| Location of GI event              | Gastric---3                      |
|                                   |                                  |
|                                   | Duodenal---5                     |
|                                   |                                  |
|                                   | Rectal---2                       |
|                                   |                                  |
|                                   | Small intestine---1              |
|                                   |                                  |
|                                   | Unknown---25                     |
+-----------------------------------+----------------------------------+
| Mean nadir Hgb and Hct            | Hgb 8                            |
|                                   |                                  |
|                                   | (range, 6 -- 10.8)               |
|                                   |                                  |
|                                   | Hct 26.1                         |
|                                   |                                  |
|                                   | (range, 20.1 -- 31.8)            |
+-----------------------------------+----------------------------------+
| Concomitant NSAID                 | 4                                |
|                                   |                                  |
|                                   | Ibuprofen (1)                    |
|                                   |                                  |
|                                   | Nabumetone (2)                   |
|                                   |                                  |
|                                   | Naproxen (1)                     |
+-----------------------------------+----------------------------------+
| Concomitant warfarin              | 5                                |
+-----------------------------------+----------------------------------+
| Concomitant corticosteroid        | 5                                |
+-----------------------------------+----------------------------------+
| Concomitant antiplatelet          |                                  |
+-----------------------------------+----------------------------------+
| Concomitant ASA                   | 8                                |
|                                   |                                  |
|                                   | 80 mg---1                        |
|                                   |                                  |
|                                   | 325 mg---1                       |
|                                   |                                  |
|                                   | Yes, dose unk---6                |
+-----------------------------------+----------------------------------+
| Concomitant alendronate           | 1                                |
+-----------------------------------+----------------------------------+
| ETOH use                          | Never---2                        |
|                                   |                                  |
|                                   | Past or current---6              |
+-----------------------------------+----------------------------------+
| Smoker                            | Never---2                        |
|                                   |                                  |
|                                   | Past---1                         |
|                                   |                                  |
|                                   | Current---2                      |
+-----------------------------------+----------------------------------+
| Pertinent PMH^†^                  | Alcoholism (3)                   |
|                                   |                                  |
|                                   | Anemia (5)                       |
|                                   |                                  |
|                                   | CAD (7)                          |
|                                   |                                  |
|                                   | Cirrhosis (1)                    |
|                                   |                                  |
|                                   | CVA (1)                          |
|                                   |                                  |
|                                   | Diabetes (6)                     |
|                                   |                                  |
|                                   | Diverticulitis (1)               |
|                                   |                                  |
|                                   | Esophageal varices (1)           |
|                                   |                                  |
|                                   | Factor V def (1)                 |
|                                   |                                  |
|                                   | Gastrectomy (1)                  |
|                                   |                                  |
|                                   | Gastritis (2)                    |
|                                   |                                  |
|                                   | GI AVM (2)                       |
|                                   |                                  |
|                                   | Hx PUD (11)                      |
|                                   |                                  |
|                                   | Hx GI bleed (6)                  |
|                                   |                                  |
|                                   | Malignancy (4)                   |
|                                   |                                  |
|                                   | Thrombocytopenia (1)             |
+-----------------------------------+----------------------------------+
| Major systemic illness preceding  | 12                               |
| bleed^†^                          |                                  |
|                                   | Liver failure (2)                |
|                                   |                                  |
|                                   | Metastatic ca (2)                |
|                                   |                                  |
|                                   | Multiple myeloma (1)             |
|                                   |                                  |
|                                   | Recent surgery (2)               |
|                                   |                                  |
|                                   | Recent admission for CP & anemia |
|                                   | (1)                              |
|                                   |                                  |
|                                   | Exacerbation of asthma, inc in   |
|                                   | steroid dose (1)                 |
|                                   |                                  |
|                                   | Pneumonia (1)                    |
|                                   |                                  |
|                                   | TEN (1)                          |
|                                   |                                  |
|                                   | Pancreatitis (1)                 |
+-----------------------------------+----------------------------------+
| Concomitant H2 blocker, antacid,  | 8                                |
| or PPI                            |                                  |
+-----------------------------------+----------------------------------+
| Bleeding other than GI            | 1                                |
+-----------------------------------+----------------------------------+
| Diagnosis confirmed by diagnostic | 11                               |
| procedure                         |                                  |
|                                   | CT scan (1)                      |
|                                   |                                  |
|                                   | EGD (6)                          |
|                                   |                                  |
|                                   | Flex sig (1)                     |
|                                   |                                  |
|                                   | Surgery (2)                      |
|                                   |                                  |
|                                   | Autopsy (1)                      |
+-----------------------------------+----------------------------------+
| Pos Dechallenge                   | 1                                |
+-----------------------------------+----------------------------------+
| Pos Rechallenge                   | 1                                |
+-----------------------------------+----------------------------------+
| Reviewer impression of quality of | Good---3                         |
| report                            |                                  |
|                                   | Adequate---24                    |
|                                   |                                  |
|                                   | Poor---9                         |
+-----------------------------------+----------------------------------+

† more than one possible per case

+---------------------------------+------------------------------------+
| Drug                            | Vioxx (Rofecoxib)                  |
+=================================+====================================+
| Total cases                     | 37                                 |
+---------------------------------+------------------------------------+
| Mean age                        | 76                                 |
|                                 |                                    |
| Median age                      | 80                                 |
|                                 |                                    |
| range                           | 28 -- 93                           |
+---------------------------------+------------------------------------+
| Gender                          | M---14                             |
|                                 |                                    |
|                                 | F---22                             |
|                                 |                                    |
|                                 | Unk---1                            |
+---------------------------------+------------------------------------+
| Event date                      | 1999---3                           |
|                                 |                                    |
|                                 | 2000---34                          |
+---------------------------------+------------------------------------+
| Indication                      | Osteoarthritis---14                |
|                                 |                                    |
|                                 | Acute pain---6                     |
|                                 |                                    |
|                                 | Unspecified arthritis---6          |
|                                 |                                    |
|                                 | Other---6                          |
|                                 |                                    |
|                                 | Unknown---5                        |
+---------------------------------+------------------------------------+
| Mean onset                      | 43 days                            |
|                                 |                                    |
| Median onset                    | 21 days                            |
|                                 |                                    |
| range                           | 0 -- 131 days                      |
+---------------------------------+------------------------------------+
| Dose at or below labeled range  | Yes---24                           |
|                                 |                                    |
|                                 | No---1                             |
|                                 |                                    |
|                                 | Unk---12                           |
+---------------------------------+------------------------------------+
| GI event^†^                     | Hemorrhage---23                    |
|                                 |                                    |
|                                 | Perforation---7                    |
|                                 |                                    |
|                                 | Melena---4                         |
|                                 |                                    |
|                                 | Hematemesis---6                    |
|                                 |                                    |
|                                 | Erosions---1                       |
|                                 |                                    |
|                                 | Stenosis/obstr---1                 |
|                                 |                                    |
|                                 | Other---10                         |
+---------------------------------+------------------------------------+
| Location of GI event            | Gastric---13                       |
|                                 |                                    |
|                                 | Duodenal---5                       |
|                                 |                                    |
|                                 | Large intestine---2                |
|                                 |                                    |
|                                 | Other---2                          |
|                                 |                                    |
|                                 | Unknown---15                       |
+---------------------------------+------------------------------------+
| Mean nadir Hgb and Hct          | Hgb 8.7                            |
|                                 |                                    |
|                                 | (range, 6 -- 13.8)                 |
|                                 |                                    |
|                                 | Hct 18 & 29.6 (Hct values reported |
|                                 | in 2 cases)                        |
+---------------------------------+------------------------------------+
| Concomitant NSAID               |                                    |
+---------------------------------+------------------------------------+
| Concomitant warfarin            | 6                                  |
+---------------------------------+------------------------------------+
| Concomitant corticosteroid      | 2                                  |
+---------------------------------+------------------------------------+
| Concomitant antiplatelet        | 2 (clopidogril)                    |
+---------------------------------+------------------------------------+
| Concomitant ASA                 | 8                                  |
|                                 |                                    |
|                                 | 80 mg---2                          |
|                                 |                                    |
|                                 | 325 mg---1                         |
|                                 |                                    |
|                                 | Yes, dose unk---5                  |
+---------------------------------+------------------------------------+
| Concomitant alendronate         |                                    |
+---------------------------------+------------------------------------+
| ETOH use                        | Never---3                          |
|                                 |                                    |
|                                 | Past or current---2                |
+---------------------------------+------------------------------------+
| Smoker                          | Never---2                          |
|                                 |                                    |
|                                 | Past---2                           |
+---------------------------------+------------------------------------+
| Pertinent PMH^†^                | Anemia (1)                         |
|                                 |                                    |
|                                 | ASA, sulfa allergy (2)             |
|                                 |                                    |
|                                 | Crohn\'s disease (1)               |
|                                 |                                    |
|                                 | CVA (1)                            |
|                                 |                                    |
|                                 | Diabetes (1)                       |
|                                 |                                    |
|                                 | Diverticulitis (1)                 |
|                                 |                                    |
|                                 | Functional intestinal disorder (1) |
|                                 |                                    |
|                                 | Gastrostomy (1)                    |
|                                 |                                    |
|                                 | Irritable bowel syndrome (1)       |
|                                 |                                    |
|                                 | Hepatic dysfunction (1)            |
|                                 |                                    |
|                                 | Hx PUD (4)                         |
|                                 |                                    |
|                                 | Hx GI bleed (1)                    |
+---------------------------------+------------------------------------+
| Major systemic illness          | 6                                  |
| preceding bleed^†^              |                                    |
|                                 | Metastatic gastric cancer (1)      |
|                                 |                                    |
|                                 | Pancreatitis, hepatitis (1)        |
|                                 |                                    |
|                                 | Shock (1)                          |
|                                 |                                    |
|                                 | Recent surgery (3)                 |
+---------------------------------+------------------------------------+
| Concomitant H2 blocker,         | 4                                  |
| antacid, or PPI                 |                                    |
+---------------------------------+------------------------------------+
| Bleeding other than GI          | 2                                  |
+---------------------------------+------------------------------------+
| Diagnosis confirmed by          | 18                                 |
| diagnostic procedure            |                                    |
|                                 | EGD (5)                            |
|                                 |                                    |
|                                 | Surgery (4)                        |
|                                 |                                    |
|                                 | Autopsy (4)                        |
|                                 |                                    |
|                                 | GI series X-ray (2)                |
|                                 |                                    |
|                                 | Not specified (3)                  |
+---------------------------------+------------------------------------+
| Pos Dechallenge                 | 2                                  |
+---------------------------------+------------------------------------+
| Pos Rechallenge                 |                                    |
+---------------------------------+------------------------------------+
| Reviewer impression of quality  | Good---6                           |
| of report                       |                                    |
|                                 | Adequate---13                      |
|                                 |                                    |
|                                 | Poor---18                          |
+---------------------------------+------------------------------------+

† more than one possible per case