- Email: [email protected]
GI events leading to death in association with celecoxib and rofecoxib∗
AJG – December, 2001
2. Goyal RK, Bauer JL, Spiro HM. The nature and location of lower esophageal ring. N Engl J Med 1971;284:1175– 80. 3. Schatzki R, Gray JE. Dysphagia due to a diaphragm-like localized narrowing in the lower esophagus (lower esophageal ring). Am J Roentgenol 1953;70:911–22. 4. Eckardt VF, Kanzler G, Willems D. Single dilation of symptomatic Schatzki rings. Dig Dis Sci 1992;37:577– 82. 5. Johnston JH, Griffin JC. Anatomic location of the lower esophageal ring. Surgery 1967;61:528 –34. 6. Eastridge CE, Pate JW, Mann JA. Lower esophageal ring: Experiences in treatment of 88 patients. Ann Thorac Surg 1984;37:103–7. 7. Norton RA, King GD. Steakhouse syndrome; the symptomatic lower esophageal ring. Lahey Clin Bull 1963;13:55–9. 8. Haubrich WS. The first-bite syndrome. Henry Ford Hosp Med J 1986;34:275– 8. 9. Postlethwait RW, Sealy WC. Experiences with treatment of 59 patients with lower esophageal web. Ann Surg 1967;165:786 –95. 10. Wilkins EW, Bartlett MK. Surgical treatment of the lower esophageal ring. N Engl J Med 1963;268:461– 4. 11. Raskin JB, Manten H, Harary A, et al. Transendoscopic electrosurgical incision of lower esophageal (Schatzki) rings: A new treatment modality. Gastrointest Endosc 1985;31:391–3. 12. Gerami S, Cole FH. Dysphagia resulting from esophageal ring. Ann Thorac Surg 1970;10:223– 6. 13. Scharschmidt BF, Watts HD. The lower esophageal ring and esophageal reflux. Am J Gastroenterol 1978;69:544 –9. 14. Mossberg SM. Lower esophageal ring treated by pneumatic dilatation. Gastroenterology 1965;48:118 –21. Reprint requests and correspondence: N. S. Mann, M.D., VA Medical Center (111G), 150 Muir Road, Martinez, CA 945534695. Received June 14, 2001; accepted July 6, 2001.
GI Events Leading to Death in Association With Celecoxib and Rofecoxib* TO THE EDITOR: We read with interest Caroli and Monica’s case report (1) of serious GI complications associated with rofecoxib in an elderly but otherwise healthy woman. As the repository for such unexpected adverse event reports for the United States, our office collected and reviewed similar reports for both rofecoxib and celecoxib in support of the public advisory committee meeting (February, 2001) on the possible regulatory implications of the CLASS (2) and VIGOR (3) outcomes trials. Our postmarketing surveillance reviews and other Food and Drug Administration (FDA) analyses, less any proprietary information, are available on the Internet (4). Here we add to the information presented by the Caroli and Monica case. As of October, 2000, the United States FDA’s Adverse Event Reporting System database contained in excess of 1,300 United States reports of GI bleeding, obstruction, perforation, or stenosis associated with rofecoxib or cele*The views expressed are those of the authors and do not necessarily represent those of, nor imply endorsement from, the Food and Drug administration or the United States Government.
Letters to the Editor
3449
coxib, including 73 fatalities. We compiled these 73 case reports, involving 36 cases for celecoxib and 37 cases for rofecoxib, into a case series in an attempt to isolate risk factors for a fatal GI event associated with selective cyclooxygenase-2 (COX-2) therapy. Forty-six of the 73 case reports (63%) involved females. The median age was 79 yr (range ⫽ 28 –99). The median time to onset was 15 days. Dosing was within the recommended, labeled range in all but three case reports. Fifteen patients (20%) had histories of peptic ulcer disease, and seven patients (10%) had histories of GI bleeding. Although Caroli and Monica describe their patient as a possible anomaly because she was at low risk for a GI event (except for age), 17 of our case reports (23%) included no information to suggest that the patient was at increased risk for a GI complication (except for age). Seven cases involved concomitant use of a proton pump inhibitor or misoprostol. In five cases, GI bleeding apparently precipitated other events that directly caused death. The site of bleeding was reported in 31 cases, and included 16 gastric events, 10 duodenal events, two events each in the large intestine and rectum, and one event in the small intestine. Perforation was reported in nine cases. One case report described obstruction as the principal, clinical event. As noted by Caroli and Monica for their one patient, it is not possible to infer risk or causality from case reports. We do not know if these case reports represent a causal association with the selective COX-2 agents or the background incidence of serious GI events in this population. It is unknown if clinicians are preferentially using these agents in high risk patients in whom they might otherwise elect to employ nonpharmacological modalities or possibly acetaminophen. Furthermore, it is also not known if the modest clinical improvements in GI adverse events reported in the CLASS and VIGOR trials, which excluded individuals with poor overall health, apply to patients at high risk for GI events. Based on our case series of 73 fatalities, advanced age alone may be a profound risk factor for a serious GI complication with selective COX-2 therapy. This case series has been based on contributions from the medical community, including gastroenterologists, rheumatologists, and internists. Voluntary reporting by clinicians of unexpected events in association with drug products aids both clinicians and patients in thoughtful drug therapy. We encourage the medical community to participate in this process through such programs as FDA’s MedWatch (1800-FDA-1088). Joyce Weaver, Pharm.D. Renan A. Bonnel, Pharm.D., M.P.H. Claudia B. Karwoski, Pharm.D. Allen D. Brinker, M.D. Julie Beitz, M.D. Office of Postmarketing Drug Risk Assessment Center for Drug Evaluation and Research United States Food and Drug Administration Rockville, Maryland
3450
Letters to the Editor
REFERENCES 1. Caroli A, Monica F. Severe upper gastrointestinal bleeding during treatment with rofecoxib for osteoarthritis. Am J Gastroenterol 2001;96:1663– 4. 2. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: The CLASS study: A randomized controlled trial. Celecoxib Long-Term Arthritis Safety Study. JAMA 2000;284:1247–55. 3. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000;343:1520 – 8. 4. Arthritis Advisory Committee. CDER 2001 meeting documents (see 2/7 and 2/8). Available at: http://www.fda.gov/ohrms/ dockets/ac/cder01.htm#Arthritis. Accessed September 24, 2001.
Reprint requests and correspondence: Renan A. Bonnel, Pharm.D., M.P.H. Food and Drug Administration, Department of Health and Human Services, Public Health Service, Rockville, MD 20857. Received June 15, 2001; accepted July 6, 2001.
Acute Pancreatitis Associated With Salmonella enteritidis TO THE EDITOR: Salmonella infections usually present with gastroenteritis, but they are also known to be associated with diffuse organ involvement, most commonly including such organs as bones and joints, meninges, heart, liver, and gallbladder (1). Development of pancreatitis associated with a Salmonella infection is rare, initially reported in the 1970s (2), but most of the well-documented cases were described in the late 1980s and early 1990s (3, 4). The majority of such pancreatitis cases have been usually observed in patients infected with S. typhi (2, 3). We describe a patient with documented S. enteritidis infection and acute pancreatitis with typical clinical, laboratory, and radiographic findings. A 45-yr-old Greek man was admitted with acute diarrhea, fever, and vomiting. He denied any travel abroad within the last 6 months, alcohol consumption, drug abuse, recent exposure to animals or pets, homosexual contact, prior episodes of diarrhea, or any significant medical illness. He had no previous surgery and he was not taking any medication. Abdominal examination revealed a diffuse tenderness without guarding or rebound and relatively increased bowel sounds. Abnormal initial laboratory values were white blood cell count, 5.9 ⫻ 109/L (polymorphonuclear, 85%); erythrocyte sedimentation rate, 40 mm/h; urea, 110 mg/ dl; and creatinine, 2.6 mg/dl. A chest radiograph, electrocardiogram, and abdominal radiograph and ultrasound were normal. Sigmoidoscopy showed an edematous and
AJG – Vol. 96, No. 12, 2001
reddish mucosa of the rectosigmoid with scarce tiny ulcerations. The patient was rehydrated, several stool and blood samples were taken for culturing, and i.v. ciprofloxacin infusion (200 mg b.i.d.) was started. Stool cultures were positive for S. enteritidis. All blood cultures and Widal and Wright tests were negative. The patient gradually improved, and 4 days after admission he was completely asymptomatic with normal laboratory tests. On the seventh hospital day, however, he complained of intense epigastric pain with radiation in the back and nausea, and started vomiting. Physical examination was unremarkable. Laboratory examination revealed leukocytosis (white blood count, 12.5 ⫻ 109/L, [polymorphonuclear, 72%]) and increased amylase levels in both serum (430 U/L, upper limit of normal ⫽ 210) and urine (6620 U/L, upper limit of normal ⫽ 250). Both a repeat ultrasound and a CT showed moderate enlargement, edema, and heterogeneity of the pancreas without other abnormalities. The patient’s pain gradually subsided, disappearing completely 3 days later without any treatment change, whereas amylase levels returned to normal within the next week. New ultrasound showed resolution of the pancreatic changes. Because a possible association between salmonellosis-associated pancreatitis and pancreas divisum has been questioned (4), 1 month after discharge the patient had an ERCP, which showed no abnormality of the pancreatic or bile ducts. To our knowledge, this is the fourth case in the literature of acute pancreatitis caused by an S. enteritidis infection (4 – 6). Two additional cases of pseudopancreatitis and S. enteritidis infection characterized by increased amylase and lipase levels but without clinical or radiographic sign of pancreatitis have also been described (7). Acute pancreatitis in our patient presented 1 wk after the onset of GI symptoms and despite early treatment with ciprofloxacin. Such a relatively delayed onset has also been observed in the previously reported cases of acute pancreatitis associated with S. typhi or S. enteritidis infection (3– 6). The pathogenetic mechanism of Salmonella-associated pancreatitis has been suggested to be the direct invasion of the pancreas by the organism (3). However, neither the delayed onset nor the development of pancreatitis despite early antibiotic therapy can be easily explained. Therefore, other mechanisms, such as immunological ones, might also be involved in the development of this complication. In summary, we described a case of typical acute pancreatitis associated with S. enteritidis, which currently represents the most common serotype of Salmonella infections in many developed countries (1). Therefore, physicians must be aware of such an association, which may often explain the relatively delayed abdominal complaints of patients with acute S. enteritidis infection. Because the course of the Salmonella-associated pancreatitis has always been described to be relatively mild and self-limited, reassurance
2. Goyal RK, Bauer JL, Spiro HM. The nature and location of lower esophageal ring. N Engl J Med 1971;284:1175– 80. 3. Schatzki R, Gray JE. Dysphagia due to a diaphragm-like localized narrowing in the lower esophagus (lower esophageal ring). Am J Roentgenol 1953;70:911–22. 4. Eckardt VF, Kanzler G, Willems D. Single dilation of symptomatic Schatzki rings. Dig Dis Sci 1992;37:577– 82. 5. Johnston JH, Griffin JC. Anatomic location of the lower esophageal ring. Surgery 1967;61:528 –34. 6. Eastridge CE, Pate JW, Mann JA. Lower esophageal ring: Experiences in treatment of 88 patients. Ann Thorac Surg 1984;37:103–7. 7. Norton RA, King GD. Steakhouse syndrome; the symptomatic lower esophageal ring. Lahey Clin Bull 1963;13:55–9. 8. Haubrich WS. The first-bite syndrome. Henry Ford Hosp Med J 1986;34:275– 8. 9. Postlethwait RW, Sealy WC. Experiences with treatment of 59 patients with lower esophageal web. Ann Surg 1967;165:786 –95. 10. Wilkins EW, Bartlett MK. Surgical treatment of the lower esophageal ring. N Engl J Med 1963;268:461– 4. 11. Raskin JB, Manten H, Harary A, et al. Transendoscopic electrosurgical incision of lower esophageal (Schatzki) rings: A new treatment modality. Gastrointest Endosc 1985;31:391–3. 12. Gerami S, Cole FH. Dysphagia resulting from esophageal ring. Ann Thorac Surg 1970;10:223– 6. 13. Scharschmidt BF, Watts HD. The lower esophageal ring and esophageal reflux. Am J Gastroenterol 1978;69:544 –9. 14. Mossberg SM. Lower esophageal ring treated by pneumatic dilatation. Gastroenterology 1965;48:118 –21. Reprint requests and correspondence: N. S. Mann, M.D., VA Medical Center (111G), 150 Muir Road, Martinez, CA 945534695. Received June 14, 2001; accepted July 6, 2001.
GI Events Leading to Death in Association With Celecoxib and Rofecoxib* TO THE EDITOR: We read with interest Caroli and Monica’s case report (1) of serious GI complications associated with rofecoxib in an elderly but otherwise healthy woman. As the repository for such unexpected adverse event reports for the United States, our office collected and reviewed similar reports for both rofecoxib and celecoxib in support of the public advisory committee meeting (February, 2001) on the possible regulatory implications of the CLASS (2) and VIGOR (3) outcomes trials. Our postmarketing surveillance reviews and other Food and Drug Administration (FDA) analyses, less any proprietary information, are available on the Internet (4). Here we add to the information presented by the Caroli and Monica case. As of October, 2000, the United States FDA’s Adverse Event Reporting System database contained in excess of 1,300 United States reports of GI bleeding, obstruction, perforation, or stenosis associated with rofecoxib or cele*The views expressed are those of the authors and do not necessarily represent those of, nor imply endorsement from, the Food and Drug administration or the United States Government.
Letters to the Editor
3449
coxib, including 73 fatalities. We compiled these 73 case reports, involving 36 cases for celecoxib and 37 cases for rofecoxib, into a case series in an attempt to isolate risk factors for a fatal GI event associated with selective cyclooxygenase-2 (COX-2) therapy. Forty-six of the 73 case reports (63%) involved females. The median age was 79 yr (range ⫽ 28 –99). The median time to onset was 15 days. Dosing was within the recommended, labeled range in all but three case reports. Fifteen patients (20%) had histories of peptic ulcer disease, and seven patients (10%) had histories of GI bleeding. Although Caroli and Monica describe their patient as a possible anomaly because she was at low risk for a GI event (except for age), 17 of our case reports (23%) included no information to suggest that the patient was at increased risk for a GI complication (except for age). Seven cases involved concomitant use of a proton pump inhibitor or misoprostol. In five cases, GI bleeding apparently precipitated other events that directly caused death. The site of bleeding was reported in 31 cases, and included 16 gastric events, 10 duodenal events, two events each in the large intestine and rectum, and one event in the small intestine. Perforation was reported in nine cases. One case report described obstruction as the principal, clinical event. As noted by Caroli and Monica for their one patient, it is not possible to infer risk or causality from case reports. We do not know if these case reports represent a causal association with the selective COX-2 agents or the background incidence of serious GI events in this population. It is unknown if clinicians are preferentially using these agents in high risk patients in whom they might otherwise elect to employ nonpharmacological modalities or possibly acetaminophen. Furthermore, it is also not known if the modest clinical improvements in GI adverse events reported in the CLASS and VIGOR trials, which excluded individuals with poor overall health, apply to patients at high risk for GI events. Based on our case series of 73 fatalities, advanced age alone may be a profound risk factor for a serious GI complication with selective COX-2 therapy. This case series has been based on contributions from the medical community, including gastroenterologists, rheumatologists, and internists. Voluntary reporting by clinicians of unexpected events in association with drug products aids both clinicians and patients in thoughtful drug therapy. We encourage the medical community to participate in this process through such programs as FDA’s MedWatch (1800-FDA-1088). Joyce Weaver, Pharm.D. Renan A. Bonnel, Pharm.D., M.P.H. Claudia B. Karwoski, Pharm.D. Allen D. Brinker, M.D. Julie Beitz, M.D. Office of Postmarketing Drug Risk Assessment Center for Drug Evaluation and Research United States Food and Drug Administration Rockville, Maryland
3450
Letters to the Editor
REFERENCES 1. Caroli A, Monica F. Severe upper gastrointestinal bleeding during treatment with rofecoxib for osteoarthritis. Am J Gastroenterol 2001;96:1663– 4. 2. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: The CLASS study: A randomized controlled trial. Celecoxib Long-Term Arthritis Safety Study. JAMA 2000;284:1247–55. 3. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000;343:1520 – 8. 4. Arthritis Advisory Committee. CDER 2001 meeting documents (see 2/7 and 2/8). Available at: http://www.fda.gov/ohrms/ dockets/ac/cder01.htm#Arthritis. Accessed September 24, 2001.
Reprint requests and correspondence: Renan A. Bonnel, Pharm.D., M.P.H. Food and Drug Administration, Department of Health and Human Services, Public Health Service, Rockville, MD 20857. Received June 15, 2001; accepted July 6, 2001.
Acute Pancreatitis Associated With Salmonella enteritidis TO THE EDITOR: Salmonella infections usually present with gastroenteritis, but they are also known to be associated with diffuse organ involvement, most commonly including such organs as bones and joints, meninges, heart, liver, and gallbladder (1). Development of pancreatitis associated with a Salmonella infection is rare, initially reported in the 1970s (2), but most of the well-documented cases were described in the late 1980s and early 1990s (3, 4). The majority of such pancreatitis cases have been usually observed in patients infected with S. typhi (2, 3). We describe a patient with documented S. enteritidis infection and acute pancreatitis with typical clinical, laboratory, and radiographic findings. A 45-yr-old Greek man was admitted with acute diarrhea, fever, and vomiting. He denied any travel abroad within the last 6 months, alcohol consumption, drug abuse, recent exposure to animals or pets, homosexual contact, prior episodes of diarrhea, or any significant medical illness. He had no previous surgery and he was not taking any medication. Abdominal examination revealed a diffuse tenderness without guarding or rebound and relatively increased bowel sounds. Abnormal initial laboratory values were white blood cell count, 5.9 ⫻ 109/L (polymorphonuclear, 85%); erythrocyte sedimentation rate, 40 mm/h; urea, 110 mg/ dl; and creatinine, 2.6 mg/dl. A chest radiograph, electrocardiogram, and abdominal radiograph and ultrasound were normal. Sigmoidoscopy showed an edematous and
AJG – Vol. 96, No. 12, 2001
reddish mucosa of the rectosigmoid with scarce tiny ulcerations. The patient was rehydrated, several stool and blood samples were taken for culturing, and i.v. ciprofloxacin infusion (200 mg b.i.d.) was started. Stool cultures were positive for S. enteritidis. All blood cultures and Widal and Wright tests were negative. The patient gradually improved, and 4 days after admission he was completely asymptomatic with normal laboratory tests. On the seventh hospital day, however, he complained of intense epigastric pain with radiation in the back and nausea, and started vomiting. Physical examination was unremarkable. Laboratory examination revealed leukocytosis (white blood count, 12.5 ⫻ 109/L, [polymorphonuclear, 72%]) and increased amylase levels in both serum (430 U/L, upper limit of normal ⫽ 210) and urine (6620 U/L, upper limit of normal ⫽ 250). Both a repeat ultrasound and a CT showed moderate enlargement, edema, and heterogeneity of the pancreas without other abnormalities. The patient’s pain gradually subsided, disappearing completely 3 days later without any treatment change, whereas amylase levels returned to normal within the next week. New ultrasound showed resolution of the pancreatic changes. Because a possible association between salmonellosis-associated pancreatitis and pancreas divisum has been questioned (4), 1 month after discharge the patient had an ERCP, which showed no abnormality of the pancreatic or bile ducts. To our knowledge, this is the fourth case in the literature of acute pancreatitis caused by an S. enteritidis infection (4 – 6). Two additional cases of pseudopancreatitis and S. enteritidis infection characterized by increased amylase and lipase levels but without clinical or radiographic sign of pancreatitis have also been described (7). Acute pancreatitis in our patient presented 1 wk after the onset of GI symptoms and despite early treatment with ciprofloxacin. Such a relatively delayed onset has also been observed in the previously reported cases of acute pancreatitis associated with S. typhi or S. enteritidis infection (3– 6). The pathogenetic mechanism of Salmonella-associated pancreatitis has been suggested to be the direct invasion of the pancreas by the organism (3). However, neither the delayed onset nor the development of pancreatitis despite early antibiotic therapy can be easily explained. Therefore, other mechanisms, such as immunological ones, might also be involved in the development of this complication. In summary, we described a case of typical acute pancreatitis associated with S. enteritidis, which currently represents the most common serotype of Salmonella infections in many developed countries (1). Therefore, physicians must be aware of such an association, which may often explain the relatively delayed abdominal complaints of patients with acute S. enteritidis infection. Because the course of the Salmonella-associated pancreatitis has always been described to be relatively mild and self-limited, reassurance