CS-1 Zelnorm® (tegaserod maleate)
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CS-1 Zelnorm® (tegaserod maleate) Presentation Transcript

  • 1. Zelnorm ® (tegaserod maleate) Safety Overview Bo Joelsson, MD, PhD Vice President Head GI Clinical Research and Development Novartis Pharmaceuticals Corporation C
  • 2. Safety Overview
    • Safety data CC sNDA versus IBS-C NDA
    • Topics for discussion
      • Serious consequences of diarrhea
      • Rectal bleeding
      • Ischemic colitis and other forms of intestinal ischemia
      • Biliary tract disorders
      • Ovarian cysts
    • Overall safety conclusions
    C
  • 3. Adverse Events Summary of Clinical Safety PTT 2.2-1, PTT 4.9-1, Zelnorm package insert. C ‡ 6 mg BID. 9 4 Diarrhea 7 5 AEs leading to discontinuation IBS-C NDA July 2002 11 12 Placebo n = 1305 12 Abdominal pain Patients, % 15 Headache Zelnorm ®‡ n = 1327
  • 4. Adverse Events Summary of Clinical Safety PTT 2.2-1, PTT 4.9-1, Zelnorm package insert. C ‡ 6 mg BID. 7 3 9 4 Diarrhea 5 4 7 5 AEs leading to discontinuation 5 13 Placebo n = 861 CC sNDA Oct 2003 IBS-C NDA July 2002 11 12 Placebo n = 1305 5 12 Abdominal pain Patients, % 11 15 Headache Zelnorm ‡ n = 881 Zelnorm ®‡ n = 1327
  • 5. Serious Adverse Events Clinical Overview T5-3, CSR T 10-5 C ‡ 6 mg BID. IBS-C NDA July 2002 Patients, % 0.7 0.6 SAEs leading to discontinuations 1.6 1.1 SAEs Zelnorm ®‡ n = 2446 Placebo n = 1589
  • 6. Serious Adverse Events Clinical Overview T5-3, CSR T 10-5 C ‡ 6 mg BID. CC sNDA Oct 2003 IBS-C NDA July 2002 0.3 1.6 Placebo n = 861 Patients, % 0.3 0.7 0.6 SAEs leading to discontinuations 1.4 1.6 1.1 SAEs Zelnorm ‡ n = 881 Zelnorm ®‡ n = 2446 Placebo n = 1589
  • 7. Extensive Experience With Zelnorm ®
    • Clinical trials
      • 15,393 patients (pooled indications population)
        • 11,640 patients on Zelnorm (3456 patient-yr)
      • 10,779 patients in controlled trials
        • 6864 patients on Zelnorm
    • Postmarketing
      • Registered in 56 countries
      • Available Jan 2001 worldwide, July 2002 in the US
      • Approximately 3 million patients treated worldwide
        • 2 million in the US
      • 367,944 patient-yr worldwide (May 31, 2004)
      • 233,751 patient-yr US (May 31, 2004)
    C
  • 8. Topics for Discussion
    • Serious consequences of diarrhea
    • Rectal bleeding
    • Ischemic colitis and other forms of intestinal ischemia
    • Biliary tract disorders
    • Ovarian cysts
    C
  • 9. Diarrhea
    • Diarrhea is an expected adverse event based on mechanism of action
    • Diarrhea is generally mild, transient, and self limiting
    • Rarely leads to serious consequences
    C
  • 10. Definition Serious Consequences of Diarrhea
    • Any serious adverse event as defined by regulatory requirements (eg, hospitalization, life threatening, death)
    • Hypokalemia (< 3.3 mmol/L)
    • Hypovolemia
    • Intravenous fluids administered
    • Medically significant events, such as hypotension, syncope, or cardiac effects
    C SCS diarrhea evaluation
  • 11. Serious Consequences of Diarrhea Are Rare in Clinical Studies
    • 6 cases in clinical studies on Zelnorm ® with > 11,600 patients (4 cases in completed studies, 2 in ongoing)
      • 4 hospitalizations
      • 2 received intravenous fluids
      • 2 possible alternative causes (gastroenteritis, antibiotics)
      • All recovered without complication
      • 4 negative re-challenge
      • 2 stopped treatment
    C
  • 12. Serious Consequences of Diarrhea in Postmarketing Experience
    • 30 reported cases (approximately 3 million patients treated)
      • 16 hospitalizations
      • 11 received intravenous fluids
      • 8 hypotension
      • 4 syncope
      • 4 life threatening
      • 1 hypokalemia
      • 1 unrelated death (aspiration pneumonia, pancreatitis, cirrhosis)
    C
  • 13. Serious Consequences of Diarrhea in Postmarketing Experience (n = 30) #3 unknown, ‡8 unknown, §15 unknown. C n = 9 > 65 1 - 5 § Range Treatment duration before event, days 1 Median 4 - 12 ‡ Range Highest daily dose, mg 12 Median Male Female Median Range 2 28 Gender, n 49 18 - 82 # Age, yr
  • 14.
    • Serious consequences of diarrhea
    • Rectal bleeding
    • Ischemic colitis and other forms of intestinal ischemia
    • Biliary tract disorders
    • Ovarian cysts
    Topics for Discussion C
  • 15. Frequency of Rectal Bleeding is Similar in Placebo- and Zelnorm ® -Treated Patients C n = 4078 n = 7037 C
  • 16. Reported Cases of Rectal Bleeding Postmarketing Experience
    • Postmarketing experience: 82 reports (May 14, 2004)
      • 21 suspected ischemic colitis
      • 1 intestinal ischemia
      • 3 other colitis
      • 23 hemorrhoids
      • 3 diverticular disorders
      • 2 anorectal disorders
      • 2 angiodysplasia
      • 2 gastroenteritis
      • 1 trauma (enema)
      • 7 prior history of rectal bleeding
      • 2 normal colonoscopy
      • 15 not investigated
    C
  • 17. Zelnorm ® Is Not Related to Rectal Bleeding
    • Our clinical trial data indicating a similar reporting rate in Zelnorm- and placebo-treated patients, and the rare reports of rectal bleeding from postmarketing experience demonstrate that Zelnorm therapy is not causally related to rectal bleeding
  • 18. Topics for Discussion
    • Serious consequences of diarrhea
    • Rectal bleeding
    • Ischemic colitis and other forms of intestinal ischemia
    • Biliary tract disorders
    • Ovarian cysts
    C
  • 19. Ischemic Colitis
    • Ischemic colitis is a rare condition
    • Potentially serious, but generally mild and transient
    • Characterized by mucosal erosions in colon seen at colonoscopy
    • Rectal bleeding and abdominal pain most common clinical presentation
    • Usually no specific treatment needed
    C AGA Medical Position Statement: Intestinal Ischemia Gastroenterology 2000;118:951-968.
  • 20. Ischemic Colitis Is More Common in IBS C #Per 100,000 patient-yr. ‡ Per 100,000 colonoscopies. Singh et al. Gastroenterology 2004;126:A349;A41 Cole et al. American Journal of Gastro. 2004;486-491 21 7 47 Non-IBS 93 CORI, ASGE ‡ (2000 - 2003) 43 United Health Care # (1995 - 1999) 179 Medi-Cal # (1995 - 2002) IBS
  • 21. Misdiagnosis of Ischemic Colitis as IBS Brinker et al. Clin Pharmacol Ther. 2003;73:33 Abstract C Time of diagnosis after first IBS claim 53 51 42 560 Rate per 100,000 patient-yr > 12 months > 6 months and ≤ 12 months > 3 wk and ≤ 6 months ≤ 3 wk
  • 22. Ischemic Colitis In IBS
    • Ischemic colitis may be misdiagnosed as IBS in the first 3 wk of IBS diagnosis
    • Patients with a stable diagnosis of IBS > 1 yr have an ischemic colitis incidence of 53/100,000 patient-yr (recorded rate in control population is 7)
    • Why is ischemic colitis more common in IBS?
      • Ascertainment bias
      • Common pathophysiologic mechanism?
    C
  • 23. No Cases of Ischemic Colitis in Clinical Trials With Zelnorm ®
    • Extensive search using FDA-agreed preferred terms to identify all patients with rectal bleeding and/or colitis
    • No cases of ischemic colitis on Zelnorm ® in clinical trials with > 11,600 patients on Zelnorm
    • 1 patient with ischemic colitis on placebo in clinical trials with > 3700 patients on placebo
    C
  • 24. Very Rare Reported Cases of Ischemic Colitis in Postmarketing Experience
    • 26 reported cases of suspected ischemic colitis as of June 1, 2004
    • Reporting rate 7/100,000 patient-yr (12/100,000 patient-yr in US) is consistent with background incidence in IBS patients (43 - 179/100,000 patient-yr)
    • No pattern with regard to duration of treatment, dose, age of patient, comorbid conditions, or subgroups of patients
    C
  • 25. Tegaserod Has No Effect on Mesenteric/Colonic Vessels
    • No 5-HT 4 receptors in human vascular system 1,2
    • In vivo animal studies demonstrated no effect on colonic vascular conductance 3
    • Tegaserod has affinity for human 5-HT 1B receptors but does not cause vasoconstriction
    • Tegaserod has negligible affinity for the 5-HT 3 receptor
    C 1. Ullmer et al. FEBS Letters 1995;370:215-221. 2. Cortijo et al. BR. J. Pharmacol . 1997;122:1455-1463 3. Holzer P et al. Gastroenterology 2003;124(4):A148-149.
  • 26. Tegaserod Has No Effect on Isolated Coronary Arteries of Nonhuman Primates 10 –10 10 –9 10 –8 10 –7 10 –6 10 –5 0 10 20 30 Contractile responses, % of 100 mM KCl Agonist concentration, M Tegaserod Ergotamine Sumatriptan Placebo C
  • 27. No Evidence for Causal Association Between Zelnorm ® and IC C Consistent with ischemic colitis rate in IBS patients Marketed use ~3 million patients No ischemic colitis among > 11,600 patients treated with Zelnorm Clinical trial database Tegaserod has no vasoconstrictive potential Preclinical studies
  • 28. Fatalities in Patients With Reports of Intestinal Ischemia
    • 4 fatalities
      • Untreated central line sepsis
      • Untreated chronic abdominal angina
      • Untreated hypothyroidism with fecal impaction
      • Multiorgan failure
    C
  • 29. Case Review Michael Shetzline, MD, PhD Senior Medical Director US Clinical Development and Medical Affairs
  • 30. 76-yr-old Woman Untreated Sepsis (1 of 2)
    • Past medical history:
      • 16 years of constipation
      • IBS with constipation diagnosis 2000, started Zelnorm ® Nov 2002
      • Alzheimer’s dementia
      • History of breast cancer
      • History of neuropathy related to spinal stenosis
    • Present illness:
      • After 282 days on Zelnorm she was found “down” at home, admitted with abdominal pain, vomiting, hypotension and hypothermia, and altered mental status
      • Urine grew E. coli. Abdominal CT noted dilated loops of small bowel consistent with partial small bowel obstruction and focal ischemic changes of the left colon. She was treated with antibiotics and hydration
  • 31. 76-yr-old Woman Untreated Sepsis (2 of 2)
    • Present illness (continued):
      • 9 days after admission, colonoscopy (guaiac +) sigmoid, splenic flexure ulcers with areas of regeneration and healing consistent with IC. Zelnorm discontinued. Biopsies consistent with IC, placed on bowel rest, TPN
      • Transferred to extended care facility, colonoscopy (x 2), noted improved colonic mucosa, resolving IC. She remained on TPN
      • Hypotensive, febrile E. coli UTI, re-admitted for failure to thrive, febrile, more acutely ill. At request of family and patient, only supportive care.
      • Diagnosed with central line sepsis, given her medical co-morbidities she was made a DNR. Antibiotics were discontinued and she expired.
    • Summary:
      • Ischemic colitis resulted from hypotension/urosepsis
  • 32. 66-yr-old Woman Untreated Chronic Abdominal Angina (1 of 2)
    • Past medical history:
      • HTN, COPD, tobacco use
      • Prior CVA “small vessel disease”
      • Chronic colitis (non-specific)
      • 2 - 3 yr history of symptoms consisted with abdominal angina (chronic abdominal pain with food intake, lost 36 lbs)
      • IBS diagnosed in Jan, 2000
    • Present illness:
      • October, 2003 with continued post-prandial abdominal pain and constipation, she was given samples of Zelnorm ® 6 mg BID by her PCP. Caregiver does not recall patient taking Zelnorm, but increasing use of Vicodin due to abdominal pain
      • 5 days later admitted to hospital with severe abdominal pain and bloody diarrhea. Zelnorm not listed as an active medication
    Core safety cases V2.ppt
  • 33. 66-yr-old Woman Untreated Chronic Abdominal Angina (2 of 2)
    • Present illness (continued):
      • Developed acute abdomen, had exploratory laparotomy for “probable chronic intestinal ischemia, acutely worse,” infarcted bowel from the ligament of Treitz to the terminal ileum, cecum, and proximal ascending colon - consistent with occlusion of the SMA
      • Comfort measures only provided and she expired
      • Cause of death: bowel infarction due to peripheral vascular disease
    • Summary:
      • This is the natural history of end stage chronic abdominal/mesenteric angina and it is likely Zelnorm was not taken by patient
    Core safety cases V2.ppt
  • 34. 41-yr-old Woman Untreated Hypothyroidism (1 of 2)
    • Past medical history:
      • COPD, tobacco abuse, asthma, alcohol/drug abuse, OCD
      • Peripheral vascular disease with claudication
      • Constipation, recurrent UTIs, hypothyroidism
      • Appendectomy with rupture, abscess and partial colectomy
      • Medical and medication non-compliance (PCP visit Nov, 2003)
    • Present illness:
      • Severe abdominal pain at home; next day collapsed with a cardiorespiratory arrest. No admission notes document she was taking Zelnorm ® or her thyroid supplement.
      • Abdominal x-ray with free air in abdomen
      • Exploratory laparotomy: rectum and distal sigmoid densely packed with rock-hard stool with ischemic colitis involving colon and terminal ileum and early gangrene of distal colon and marked dilatation (toxic megacolon)
    Core safety cases V2.ppt
  • 35. 41-yr-old Woman Untreated Hypothyroidism (2 of 2)
    • Present illness (continued):
      • Sub-total colectomy with ileostomy, treated with vent support, antibiotics and vasopressors
      • Neurology evaluation revealed anoxic brain injury, suspicion of herniation
      • She developed multi-organ failure and expired
    • Summary:
      • Bowel obstruction from untreated hypothyroidism with secondary perforation and it is likely Zelnorm was not taken by this patient
    Core safety cases V2.ppt
  • 36. 67-yr-old Woman Multi-Organ Failure (1 of 2)
    • Past medical history:
      • CAD, CABG, angioplasty with stent, CHF, HTN
      • Atrial fibrillation, diabetes mellitus
      • Chronic and acute renal failure
      • Obesity
      • Zelnorm ® 6 mg BID (indication UNK)
    • Present illness:
      • After 52 days of Zelnorm therapy, admitted with progressive shoulder and chest pain with SOB and was hospitalized for &quot;rule out myocardial infarction&quot;. Abdomen was soft, non-tender. She had no diarrhea, melena or blood per rectum
      • On hospital day 3 abdominal pain and nausea, surgery consult indicated soft abdomen, not distended, with left lower quadrant tenderness. Abdominal x-ray showed large amount of fecal material in the colon. No gaseous distention or free air
      • Laboratory results: amylase 7,570 U/L and lipase 424 U/dL, and a pulmonary consult (for dyspnea) indicated respiratory failure and required mechanical ventilation.
  • 37. 67-yr-old Woman Multi-Organ Failure (2 of 2)
    • Present illness (continued):
      • Clinical evaluation &quot;In view of her acute deterioration and chronic medical problems, her prognosis is extremely poor. Consequently, continuation of heroic intervention may be inappropriate.&quot;
      • A cardiologist summary indicates hypotension and it was felt the patient had a catastrophic abdominal event.
      • The patient was made &quot;no code&quot; and expired
      • Death certificate listed cardiorespiratory failure as primary immediate cause of death.
    • Summary:
      • Likely cardiovascular collapse with history of CAD, CHF and other medical co-morbidities, unrelated to Zelnorm
  • 38. Fatalities in Patients With Reports of Intestinal Ischemia
    • 4 fatalities
      • Untreated central line sepsis
      • Untreated chronic abdominal angina
      • Untreated hypothyroidism with fecal impaction
      • Multiorgan failure
    C
  • 39. Topics for Discussion
    • Serious consequences of diarrhea
    • Rectal bleeding
    • Ischemic colitis and other forms of intestinal ischemia
    • Biliary tract disorders
    • Ovarian cysts
    C
  • 40. Cholecystectomies Pooled Indications Population C #Schoenfeld P. Aliment Pharmacol Ther. 2004;19:263-269. Patients, n (%) 6 (0.13) 8 (0.12) 4 (0.06) 1 (0.03) 1 (0.03) Cholecystectomies After adjudication # Zelnorm n = 4614 Zelnorm ® n = 6864 Placebo n = 3915 Uncontrolled trials Placebo-controlled trials
  • 41. Reports of Biliary Tract Events in Postmarketing Experience
    • 30 biliary tract events
      • 18 cholecystectomies
      • 2 cholelithiasis
      • 10 other
    • No serious sequelae
    C
  • 42. Zelnorm ® Does Not Affect Gallbladder Motility
    • No impact on ejection fraction, ejection rate and period, maximal emptying
    • No impact on fasting and residual volume
    • No stimulus effect on gallbladder contraction during fasting
    A2201 Synopsis 39 Fisher R, et al. Am J Gastroenterol . 2004. In press.
  • 43. Topics for Discussion
    • Serious consequences of diarrhea
    • Rectal bleeding
    • Ischemic colitis and other forms of intestinal ischemia
    • Biliary tract disorders
    • Ovarian cysts
    C
  • 44. Reports of Ovarian Cysts C Patients, n (%) 6 Postmarketing experience 6 (0.13) Uncontrolled clinical trials 4 (0.06) 3 (0.08) Controlled clinical trials Zelnorm ® Placebo
  • 45. The Safety Profile of Zelnorm ® Supports the Use in Patients With Chronic Constipation
    • Overall safety of Zelnorm is well established in clinical trials and postmarketing experience
    • Except for diarrhea, adverse events are similar to placebo
    • Serious consequences of diarrhea are very rare
    • The evidence does not suggest that Zelnorm increases the risk of
      • Rectal bleeding
      • Ischemic colitis
      • Other forms of intestinal ischemia
      • Cholecystectomies
      • Ovarian cysts
    C
  • 46.
    • Zelnorm ® is a safe and well-tolerated drug and has a safety profile that supports its use in chronic constipation patients.
    C CS-