cs-1 zelnorm® (tegaserod maleate)
TRANSCRIPT
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Zelnorm®
(tegaserod maleate)Safety Overview
Bo Joelsson, MD, PhD
Vice President
Head GI Clinical Research and Development
Novartis Pharmaceuticals Corporation
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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
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Adverse Events
Summary of Clinical Safety PTT 2.2-1, PTT 4.9-1, Zelnorm package insert.C
94Diarrhea
75AEs leading todiscontinuation
IBS-C NDAJuly 2002
11
12
Placebon = 1305
12Abdominal pain
Patients, %
15Headache
Zelnorm®‡
n = 1327
‡6 mg BID.
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Adverse Events
Summary of Clinical Safety PTT 2.2-1, PTT 4.9-1, Zelnorm package insert.C
‡6 mg BID.
7394Diarrhea
5475AEs leading todiscontinuation
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Placebon = 861
CC sNDAOct 2003
IBS-C NDAJuly 2002
11
12
Placebon = 1305
512Abdominal pain
Patients, %
1115Headache
Zelnorm‡
n = 881Zelnorm®‡
n = 1327
CS-5Clinical Overview T5-3, CSR T 10-5C
Serious Adverse Events
IBS-C NDAJuly 2002
Patients, %
0.70.6 SAEs leading todiscontinuations
1.61.1SAEs
Zelnorm®‡
n = 2446Placebon = 1589
‡6 mg BID.
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CC sNDAOct 2003
IBS-C NDAJuly 2002
0.3
1.6
Placebon = 861
Patients, %
0.30.70.6 SAEs leading todiscontinuations
1.41.61.1SAEs
Zelnorm‡
n = 881Zelnorm®‡
n = 2446Placebon = 1589
Clinical Overview T5-3, CSR T 10-5 C
Serious Adverse Events
‡6 mg BID.
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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)
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Topics for Discussion
Serious consequences of diarrhea Rectal bleeding Ischemic colitis and other forms of
intestinal ischemia Biliary tract disorders Ovarian cysts
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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
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DefinitionSerious 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
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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
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Serious Consequences of Diarrhea in Postmarketing Experience
30 reported cases (approximately 3 millionpatients treated)– 16 hospitalizations– 11 received intravenous fluids– 8 hypotension
– 4 syncope
– 4 life threatening– 1 hypokalemia– 1 unrelated death
(aspiration pneumonia, pancreatitis, cirrhosis)
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Serious Consequences of Diarrhea in Postmarketing Experience (n = 30)
n = 9> 65
1 - 5§RangeTreatment durationbefore event, days 1Median
4 - 12‡RangeHighest daily dose, mg12Median
MaleFemale
MedianRange
228Gender, n
4918 - 82#Age, yr
#3 unknown, ‡8 unknown, §15 unknown.
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Serious consequences of diarrhea Rectal bleeding Ischemic colitis and other forms of
intestinal ischemia Biliary tract disorders Ovarian cysts
Topics for Discussion
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Frequency of Rectal Bleeding is Similarin Placebo- and Zelnorm®-Treated Patients
1.31.2
0.0
0.5
1.0
1.5
Placebo Zelnorm
Pa
tie
nts
, %
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n = 4078 n = 7037
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Reported Cases of Rectal BleedingPostmarketing 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
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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
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Topics for Discussion
Serious consequences of diarrhea Rectal bleeding Ischemic colitis and other forms of
intestinal ischemia Biliary tract disorders Ovarian cysts
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Ischemic Colitis
Ischemic colitis is a rare condition
Potentially serious, but generally mildand transient
Characterized by mucosal erosions in colon seen at colonoscopy
Rectal bleeding and abdominal pain most common clinical presentation
Usually no specific treatment needed
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AGA Medical Position Statement: Intestinal Ischemia Gastroenterology 2000;118:951-968.
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Ischemic Colitis Is More Common in IBS
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Non-IBS
93CORI, ASGE‡ (2000 - 2003)
43United Health Care# (1995 - 1999)
179Medi-Cal# (1995 - 2002)
IBS
#Per 100,000 patient-yr.‡Per 100,000 colonoscopies.Singh et al. Gastroenterology 2004;126:A349;A41Cole et al. American Journal of Gastro. 2004;486-491
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Misdiagnosis of Ischemic Colitis as IBS
Time of diagnosis after first IBS claim
535142560Rate per100,000patient-yr
> 12 months
> 6 months and≤ 12 months
> 3 wk and≤ 6 months≤ 3 wk
Brinker et al. Clin Pharmacol Ther. 2003;73:33 Abstract
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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 of53/100,000 patient-yr (recorded rate in control population is 7)
Why is ischemic colitis more common in IBS?
– Ascertainment bias
– Common pathophysiologic mechanism?
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No Cases of Ischemic Colitisin 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
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Very Rare Reported Cases ofIschemic 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
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Tegaserod Has No Effect on Mesenteric/Colonic Vessels
No 5-HT4 receptors in human vascular system1,2
In vivo animal studies demonstrated no effect on colonic vascular conductance3
Tegaserod has affinity for human 5-HT1B
receptors but does not cause vasoconstriction
Tegaserod has negligible affinity for the5-HT3 receptor
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1. Ullmer et al. FEBS Letters 1995;370:215-221.2. Cortijo et al. BR. J. Pharmacol. 1997;122:1455-14633. Holzer P et al. Gastroenterology 2003;124(4):A148-149.
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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
Co
ntr
acti
le r
esp
on
ses,
% o
f 10
0 m
M K
Cl
Agonist concentration, M
Tegaserod
Ergotamine Sumatriptan
Placebo
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No Evidence for Causal Association Between Zelnorm® and IC
Consistent with ischemic colitis rate in IBS patients
Marketed use~3 million patients
No ischemic colitis among > 11,600 patients treatedwith Zelnorm
Clinical trial database
Tegaserod has novasoconstrictive potential
Preclinical studies
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Fatalities in Patients WithReports of Intestinal Ischemia
4 fatalities
– Untreated central line sepsis
– Untreated chronic abdominal angina
– Untreated hypothyroidism withfecal impaction
– Multiorgan failure
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Case Review
Michael Shetzline, MD, PhD
Senior Medical DirectorUS Clinical Development and Medical Affairs
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76-yr-old WomanUntreated 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
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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
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66-yr-old WomanUntreated 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
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66-yr-old WomanUntreated 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 peripheralvascular 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
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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
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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
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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 "rule out myocardial infarction". 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.
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67-yr-old Woman Multi-Organ Failure (2 of 2)
Present illness (continued):– Clinical evaluation "In view of her acute deterioration and
chronic medical problems, her prognosis is extremely poor. Consequently, continuation of heroic intervention may be inappropriate."
– A cardiologist summary indicates hypotension and it was felt the patient had a catastrophic abdominal event.
– The patient was made "no code" 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
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Fatalities in Patients WithReports of Intestinal Ischemia
4 fatalities– Untreated central line sepsis– Untreated chronic abdominal angina
– Untreated hypothyroidism withfecal impaction
– Multiorgan failure
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Topics for Discussion
Serious consequences of diarrhea Rectal bleeding Ischemic colitis and other forms of
intestinal ischemia Biliary tract disorders Ovarian cysts
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Cholecystectomies Pooled Indications Population
Patients, n (%)
6 (0.13)8 (0.12)
4 (0.06)
1 (0.03)
1 (0.03)
Cholecystectomies
After adjudication#
Zelnormn = 4614
Zelnorm®
n = 6864Placebon = 3915
Uncontrolled trialsPlacebo-controlled trials
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#Schoenfeld P. Aliment Pharmacol Ther. 2004;19:263-269.
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Reports of Biliary Tract Eventsin Postmarketing Experience
30 biliary tract events
– 18 cholecystectomies
– 2 cholelithiasis
– 10 other
No serious sequelae
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Zelnorm® Does Not AffectGallbladder 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
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Fisher R, et al. Am J Gastroenterol. 2004. In press.
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Topics for Discussion
Serious consequences of diarrhea Rectal bleeding Ischemic colitis and other forms of
intestinal ischemia Biliary tract disorders Ovarian cysts
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Reports of Ovarian Cysts
Patients, n (%)
6Postmarketing experience
6 (0.13)Uncontrolled clinical trials
4 (0.06)3 (0.08)Controlled clinical trials
Zelnorm®Placebo
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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 similarto 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
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Zelnorm® is a safe andwell-tolerated drug and has a safety
profile that supports its use inchronic constipation patients.
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