Tegaserod and Ischemic Colitis
http://www.100md.com
《新英格兰医药杂志》
To the Editor: Tegaserod (Zelnorm, Novartis Pharmaceuticals) is a partial serotonin 5-hydroxytryptamine4 (5-HT4)–receptor agonist approved by the Food and Drug Administration (FDA) for the short-term treatment of constipation-predominant irritable bowel syndrome in women. From the initiation of marketing, in August 2002, through March 2004, the FDA MedWatch system received 20 spontaneous reports of cases of ischemic colitis associated with the use of tegaserod. These reports were first identified by two of us and classified as ischemic colitis on the basis of clinical symptoms, features on lower gastrointestinal endoscopy, histopathologic examination of the colon, and intestinal surgery, in accordance with the guidelines of the American Gastroenterological Association and our own judgment, based on FDA experience with drug-associated ischemic colitis.
After a review of all available information, we summarized these reports (Table 1). A mechanism of action for tegaserod-associated ischemic colitis is not known at this time. The development of three cases after 7 to 13 months of tegaserod therapy indicates that the risk of colitis may persist for an extended period after the initiation of therapy. It is unknown whether these cases are directly attributable to tegaserod or are due to an interaction with another medical condition or an added medication.1 As a result of these reports, the precautions section of the approved labeling of Zelnorm was recently updated to alert the medical community to tegaserod-associated ischemic colitis. As stated in the description of this new information in the "Dear Health Care Professional" letter from Novartis (April 26, 2004) and an "FDA Talk Paper" (April 28, 2004), no cases of ischemic colitis were reported among 7000 patients randomly assigned to receive tegaserod in placebo-controlled trials of at least three months' duration. On the basis of a Poisson distribution analysis, ischemic colitis occurs no more frequently in the population studied than approximately 1 case in 2000.
Table 1. Characteristics of 20 Case Reports of Ischemic Colitis in Association with Tegaserod Therapy.
Ischemic colitis typically includes bloody diarrhea and is generally considered a disease of the elderly.2 Although most cases are self-limited and require only medical management, in rare cases, severe ischemic colitis is complicated by transmural infarction and acute abdomen.2,3 Ischemic colitis has been described in younger patients with selected conditions and selected exposures, including exposure to the antimigraine drug sumatriptan, a serotonin 5-HT1–receptor agonist.4,5 An interaction through serotonin has been suggested to explain an apparent overrepresentation of new selective serotonin-reuptake-inhibitor antidepressants among reported cases.1,4,5
Clinicians should review the diagnostic criteria for the irritable bowel syndrome in order to avoid misdiagnosis of an underlying gastrointestinal disease or ischemic colitis as the irritable bowel syndrome (or another condition) and should be on the alert for the development of signs and symptoms of ischemic colitis, such as new or worsening abdominal pain and bloody diarrhea or stools in patients receiving tegaserod.
Allen D. Brinker, M.D.
Ann Corken Mackey, R.P.H., M.P.H.
Robert Prizont, M.D.
Food and Drug Administration
Rockville, MD 20857
brinkera@cder.fda.gov
References
Schwartz CE. A surfeit of serotonin: sumatriptan and serotonergic antidepressants. Arch Intern Med 1999;159:1141-1142.
Gandhi SK, Hanson MM, Vernava AM, Kaminski DL, Longo WE. Ischemic colitis. Dis Colon Rectum 1996;39:88-100.
Arnott ID, Ghosh S, Ferguson A. The spectrum of ischaemic colitis. Eur J Gastroenterol Hepatol 1999;11:295-303.
Knudsen JF, Friedman B, Chen M, Goldwasser JE. Ischemic colitis and sumatriptan use. Arch Intern Med 1998;158:1946-1948.
Naik M, Potluri R, Almasri E, Arnold GL. Sumatriptan-associated ischemic colitis. Dig Dis Sci 2002;47:2015-2016.
The above letter was referred to Novartis Pharmaceuticals, the manufacturer of tegaserod, which offers the following reply:
To the Editor: In the post-marketing use of tegaserod for the treatment of abdominal pain, bloating, and constipation in the irritable bowel syndrome, we have noted rare reports of cases of ischemic colitis. The implication by Brinker et al. that these cases may be associated with tegaserod therapy contradicts the preclinical mechanistic data and the extensive clinical trial experience. We would like to provide physicians with the data we have accumulated in more than three years of tegaserod use, including data on approximately 3 million patients treated, as well as information on the rate of ischemic colitis in the general population and its increased rate in the population with the irritable bowel syndrome.
First, the most rigorous data related to medication safety come from randomized, controlled trials in which drug administration and outcomes were carefully monitored. In clinical trials involving over 11,600 patients using tegaserod, with a total of 3456 patient-years of exposure, no case of ischemic colitis was reported. One case of "segmental erosive colitis" was reported in a patient in the placebo group in a trial involving 780 patient-years of exposure to placebo (Table 1).
Table 1. Incidence of Ischemic Colitis.
Second, patients with the irritable bowel syndrome are approximately three to four times as likely to receive a diagnosis of ischemic colitis as are patients without the irritable bowel syndrome.1,2 In addition, according to an abstract by the FDA, among patients in whom the irritable bowel syndrome had been diagnosed more than one year earlier, ischemic colitis was diagnosed at a rate of 53 cases per 100,000 person-years.3
Third, during post-marketing surveillance (as of March 2004), 21 cases of ischemic colitis were reported worldwide. On the basis of worldwide use of tegaserod, a post-marketing incidence of seven cases of ischemic colitis per 100,000 patient-years can be calculated. This approximates the incidence of ischemic colitis in the general population (7 to 47 cases per 100,000 patient-years) and is significantly lower than that in the population of patients with the irritable bowel syndrome (43 to 179 cases per 100,000 patient-years). Even if only 10 percent of cases were reported, the incidence of ischemic colitis would be 70 per 100,000 patient-years, which is consistent with the rate in the population of patients with the irritable bowel syndrome.
Finally, the pharmacologic data do not suggest a visceral vasoconstrictor action of tegaserod. Even high in vitro concentrations (e.g., such as those used in the study of isolated coronary arteries) and high in vivo exposures (e.g., in anesthetized rats) do not trigger vasomotor or vasoconstrictor effects.4 These observations suggest that there is no apparent vascular mechanism that would lead to mesenteric or colonic ischemia with tegaserod. On the basis of the data available, we conclude that there has been no increase in the incidence of ischemic colitis among patients receiving tegaserod.
Bo E. Joelsson, M.D., Ph.D.
Michael A. Shetzline, M.D., Ph.D.
Stephen Cunningham, M.D.
Novartis Pharmaceuticals
East Hanover, NJ 07936
References
Cole JA, Cook SF, Sands BE, Ajene AN, Miller DP, Walker AM. Occurrence of colon ischemia in relation to irritable bowel syndrome. Am J Gastroenterol 2004;99:486-491.
Singh G, Mithal A, Triadafilopoulos G. Patients with irritable bowel syndrome have a high risk of developing ischemic colitis. Gastroenterology 2004;126:A349-A349. abstract.
Brinker A, Senior J, Beitz J. Misdiagnosis of ischemic colitis as irritable bowel syndrome. Clin Pharmacol Ther 2003;73:PII-16. abstract.
Holzer P, Painsipp E, Eckhard W, Pfannkuche HJ. 5HT-3 receptor antagonists, alosetron and cilansetron, impair mesenteric blood flow in rats. Gastroenterology 2003;124:Suppl 4:A148-A149. abstract.
After a review of all available information, we summarized these reports (Table 1). A mechanism of action for tegaserod-associated ischemic colitis is not known at this time. The development of three cases after 7 to 13 months of tegaserod therapy indicates that the risk of colitis may persist for an extended period after the initiation of therapy. It is unknown whether these cases are directly attributable to tegaserod or are due to an interaction with another medical condition or an added medication.1 As a result of these reports, the precautions section of the approved labeling of Zelnorm was recently updated to alert the medical community to tegaserod-associated ischemic colitis. As stated in the description of this new information in the "Dear Health Care Professional" letter from Novartis (April 26, 2004) and an "FDA Talk Paper" (April 28, 2004), no cases of ischemic colitis were reported among 7000 patients randomly assigned to receive tegaserod in placebo-controlled trials of at least three months' duration. On the basis of a Poisson distribution analysis, ischemic colitis occurs no more frequently in the population studied than approximately 1 case in 2000.
Table 1. Characteristics of 20 Case Reports of Ischemic Colitis in Association with Tegaserod Therapy.
Ischemic colitis typically includes bloody diarrhea and is generally considered a disease of the elderly.2 Although most cases are self-limited and require only medical management, in rare cases, severe ischemic colitis is complicated by transmural infarction and acute abdomen.2,3 Ischemic colitis has been described in younger patients with selected conditions and selected exposures, including exposure to the antimigraine drug sumatriptan, a serotonin 5-HT1–receptor agonist.4,5 An interaction through serotonin has been suggested to explain an apparent overrepresentation of new selective serotonin-reuptake-inhibitor antidepressants among reported cases.1,4,5
Clinicians should review the diagnostic criteria for the irritable bowel syndrome in order to avoid misdiagnosis of an underlying gastrointestinal disease or ischemic colitis as the irritable bowel syndrome (or another condition) and should be on the alert for the development of signs and symptoms of ischemic colitis, such as new or worsening abdominal pain and bloody diarrhea or stools in patients receiving tegaserod.
Allen D. Brinker, M.D.
Ann Corken Mackey, R.P.H., M.P.H.
Robert Prizont, M.D.
Food and Drug Administration
Rockville, MD 20857
brinkera@cder.fda.gov
References
Schwartz CE. A surfeit of serotonin: sumatriptan and serotonergic antidepressants. Arch Intern Med 1999;159:1141-1142.
Gandhi SK, Hanson MM, Vernava AM, Kaminski DL, Longo WE. Ischemic colitis. Dis Colon Rectum 1996;39:88-100.
Arnott ID, Ghosh S, Ferguson A. The spectrum of ischaemic colitis. Eur J Gastroenterol Hepatol 1999;11:295-303.
Knudsen JF, Friedman B, Chen M, Goldwasser JE. Ischemic colitis and sumatriptan use. Arch Intern Med 1998;158:1946-1948.
Naik M, Potluri R, Almasri E, Arnold GL. Sumatriptan-associated ischemic colitis. Dig Dis Sci 2002;47:2015-2016.
The above letter was referred to Novartis Pharmaceuticals, the manufacturer of tegaserod, which offers the following reply:
To the Editor: In the post-marketing use of tegaserod for the treatment of abdominal pain, bloating, and constipation in the irritable bowel syndrome, we have noted rare reports of cases of ischemic colitis. The implication by Brinker et al. that these cases may be associated with tegaserod therapy contradicts the preclinical mechanistic data and the extensive clinical trial experience. We would like to provide physicians with the data we have accumulated in more than three years of tegaserod use, including data on approximately 3 million patients treated, as well as information on the rate of ischemic colitis in the general population and its increased rate in the population with the irritable bowel syndrome.
First, the most rigorous data related to medication safety come from randomized, controlled trials in which drug administration and outcomes were carefully monitored. In clinical trials involving over 11,600 patients using tegaserod, with a total of 3456 patient-years of exposure, no case of ischemic colitis was reported. One case of "segmental erosive colitis" was reported in a patient in the placebo group in a trial involving 780 patient-years of exposure to placebo (Table 1).
Table 1. Incidence of Ischemic Colitis.
Second, patients with the irritable bowel syndrome are approximately three to four times as likely to receive a diagnosis of ischemic colitis as are patients without the irritable bowel syndrome.1,2 In addition, according to an abstract by the FDA, among patients in whom the irritable bowel syndrome had been diagnosed more than one year earlier, ischemic colitis was diagnosed at a rate of 53 cases per 100,000 person-years.3
Third, during post-marketing surveillance (as of March 2004), 21 cases of ischemic colitis were reported worldwide. On the basis of worldwide use of tegaserod, a post-marketing incidence of seven cases of ischemic colitis per 100,000 patient-years can be calculated. This approximates the incidence of ischemic colitis in the general population (7 to 47 cases per 100,000 patient-years) and is significantly lower than that in the population of patients with the irritable bowel syndrome (43 to 179 cases per 100,000 patient-years). Even if only 10 percent of cases were reported, the incidence of ischemic colitis would be 70 per 100,000 patient-years, which is consistent with the rate in the population of patients with the irritable bowel syndrome.
Finally, the pharmacologic data do not suggest a visceral vasoconstrictor action of tegaserod. Even high in vitro concentrations (e.g., such as those used in the study of isolated coronary arteries) and high in vivo exposures (e.g., in anesthetized rats) do not trigger vasomotor or vasoconstrictor effects.4 These observations suggest that there is no apparent vascular mechanism that would lead to mesenteric or colonic ischemia with tegaserod. On the basis of the data available, we conclude that there has been no increase in the incidence of ischemic colitis among patients receiving tegaserod.
Bo E. Joelsson, M.D., Ph.D.
Michael A. Shetzline, M.D., Ph.D.
Stephen Cunningham, M.D.
Novartis Pharmaceuticals
East Hanover, NJ 07936
References
Cole JA, Cook SF, Sands BE, Ajene AN, Miller DP, Walker AM. Occurrence of colon ischemia in relation to irritable bowel syndrome. Am J Gastroenterol 2004;99:486-491.
Singh G, Mithal A, Triadafilopoulos G. Patients with irritable bowel syndrome have a high risk of developing ischemic colitis. Gastroenterology 2004;126:A349-A349. abstract.
Brinker A, Senior J, Beitz J. Misdiagnosis of ischemic colitis as irritable bowel syndrome. Clin Pharmacol Ther 2003;73:PII-16. abstract.
Holzer P, Painsipp E, Eckhard W, Pfannkuche HJ. 5HT-3 receptor antagonists, alosetron and cilansetron, impair mesenteric blood flow in rats. Gastroenterology 2003;124:Suppl 4:A148-A149. abstract.