cs-1 zelnorm® (tegaserod maleate)

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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

5

13

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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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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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


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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)


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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


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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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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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CS-42A2201 Synopsis

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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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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cs-1 zelnorm® (tegaserod maleate)

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