Download Primary care slides

Improving Standards of Care
in Irritable Bowel Syndrome
Definition of Irritable Bowel
Syndrome (IBS)
• IBS is a chronic, episodic medical condition
characterized by abdominal pain or discomfort
associated with altered bowel function
• IBS with constipation is abdominal pain/discomfort
associated with at least 2 of the 3:
- < 3 bowel movements per week
- Hard or lumpy stools
- Straining with a bowel movement
Drossman et al, Gastroenterology 1997; 112: 2120
Overall prevalence of IBS
greater in females
Prevalence (%)
14
13.5
Female
13.0
Male
9.4
0
15–34
35–44
>45
Ages (years)
Drossman et al, Dig Dis Sci 1993; 38: 1569
Prevalence by IBS subgroups
Survey respondents (%)
Overall
Females
Males
8
6.7
5.5 5.3 5.6
5.2
3.5
5.2
5.6
4.7
3022 residents
surveyed in
Minnesota
536 respondents
0
IBSIBSIBSconstipation
diarrhea
alternating
Adapted from Talley et al, Am J Epidemiol 1995; 142: 76
IBS patients suffer
 In a recent survey (n = 350) conducted by
the International Foundation for Functional
Gastrointestinal Disorders, it was found that:
•
•
•
42% of respondents reported having symptoms
for 10 years or more
43% reported symptoms as 'severe', 40% described them
as 'moderate'
two-thirds of IBS sufferers describe their symptoms as
extremely or very bothersome
www.iffgd.org; in press
IBS patients with constipation (abc-ibs)
suffer from abdominal pain/discomfort,
bloating, and constipation
Gas / gas pain
Constipation
Straining with BM
Abdominal pain / discomfort
Hard / lumpy stool
Incomplete evacuation after BM
Bloating / distension
Inability to have BM
Heartburn / acid reflux
IBS with constipation
Sudden urges to have BM
General US population
Rectal pain
0
10
20
30
40
50
60
70
% IBS patients that suffer once a week or more
Lieberman Research Inc. 2000, GI Sufferer Study
Who treats IBS?
IBS is a common diagnosis in
primary care and gastroenterology
IBSpractices
IBS
12%
28%
All other
diagnoses
88%
Primary care
All other
diagnoses
72%
Gastroenterology
Mitchell et al, Gastroenterology, 1987; 92: 1282
Drossman, Gastroenterology 1997; 112: 2120
Impact of IBS on work or school
IBS patients
13.4 ***
Non-IBS
patients
4.9
0
5
10
15
Days missed from work or school in past year
***p<0.0001
Adapted from Drossman et al, Dig Dis Sci 1993; 38: 1569
Mechanisms in IBS
Enhanced
perception
Vagal
nuclei
5-HT
Altered
motility
Sympathetic
Visceral
hypersensitivity
Adapted from Camilleri and Choi, Aliment Pharmacol Ther 1997; 11:3
Physiologic distribution of 5-HT
CNS: 5%
GI tract: 95%
Kim and Camilleri, Am J Gastroenterol 2000; 95: 2698
Summary of Hypotheses on the
Pathophysiology of IBS
• IBS is characterized by changes in motility in
response to environmental or enteric stimuli1
• Visceral hypersensitivity is well documented
in IBS patients2
• Serotonin, which has both motility and
sensory modulating properties, could
represent a common factor linking the
symptoms of IBS3
1AGA
Patient Care Committee Gastroenterology 1997;112:2120-2137
from Camilleri and Choi et al., Aliment Pharmacol Ther 1997; 11: 3
3Kim and Camilleri et al., Am J Gastroenterol 2000; 95(10): 2698
2 Adapted
Identify Red Flags
 History
- Unintentional Weight loss
- Onset in older patient
(>50 years)
- Family history of cancer or IBD
 Physical
- Abnormal exams
- Rectal bleeding/obstruction
- Positive FOBT/flex.
sigmoidoscopy or colonoscopy
(>50 years)
 Initial Labs
-
 HGB
 WBC
 ESR
Abnormal chemistry
 TSH
Red Flags
Adapted from A technical review, Gastroenterology 1997; 112: 2120
Paterson et al., Can Med Assoc J 1999; 161: 154
Camilleri et al., Aliment Pharmacol Ther 1997; 11: 3
IBS: An enduring diagnosis
No change in
diagnosis: 97%
112 consecutive Olmstead
County residents first
diagnosed with IBS during
1961–63. Median follow-up:
29 years (range 1–32 years)
Most have no change in diagnosis
after initial evaluation
Owens et al, Ann Intern Med 1995; 122: 107
Goals of Pharmacotherapy in
IBS with Constipation
• Overall Relief (including impact on patients’ overall well-being)4
• Multi-symptom relief4



4Drossman
Abdominal pain
Bloating
Constipation
DA, Corazziari E, Talley NJ, Thompson WG, Whitehead,WE eds. Rome II
The Functional Gastrointestinal Disorders 2nd ed. McLean, Va 2000:355,360,594-596
Dietary advice
 Patients often relate their functional symptoms
to certain foods
 Dietary restrictions are common, but may be
inappropriate
•
dairy products, sorbitol, caffeine, alcohol, citrus fruit,
gas-forming vegetables, grains
Jones et al, Gut 2000; 47(suppl. II): 1
Traditional therapies focused on individual
symptoms of IBS with constipation
Abdominal pain / discomfort
 Antispasmodics
 Tricyclics
 Analgesics
Bloating and distention
Abdominal
pain /
discomfort
Bloating /
distention





Dietary modifications
Antispasmodics
Antiflatulants
Digestive enzymes
Antibiotics
Constipation
 Fiber
 Laxatives
Constipation
 None of these medications effectively treat the multiple symptoms of IBS.
May exacerbate individual symptoms e.g., fiber and bloating; antispasmodics and constipation
Tegaserod: Indication and Dosage
• Zelnorm (tegaserod maleate) is indicated for the
short-term treatment of women with irritable bowel
syndrome (IBS) whose primary bowel symptom is
constipation
• The safety and effectiveness in men have not
been established
• Recommended dosage: tegaserod (Zelnorm)
6 mg twice daily orally before meals for 4–6 weeks
• For patients who respond to therapy at 4–6 weeks,
an additional 4–6 weeks can be considered
• Efficacy of tegaserod beyond 12 weeks has not been
established
Novartis, data on file
Tegaserod: A New Class of Compound
OH
NH
O
NH
N
NH2
NH
NH
NH
Tegaserod
Serotonin (5-HT)
• Tegaserod is a 5-HT4 receptor agonist
• new class of compound: aminoguanidine indoles
• Structure similar to serotonin
Camilleri, Aliment Pharmacol Ther 2001; 15: 277
Tegaserod: Pharmacological Effects
• Stimulates 5-HT4 receptors and improves GI
function
• Stimulates the peristaltic reflex
• Alters the chloride secretion in the intestine
• Reduces visceral sensitivity*
* animal data
Camilleri M. Review article: Tegaserod. Aliment Pharmacol Ther. 2001; 15: 277-89.
Subject’s Global Assessment of relief
% Responders
B301
70
*
60
*
*
*
*
*
*
*
*
*
50
40
Tegaserod 6 mg bid (n = 294)
Placebo (n = 288)
30
0
*
0
1
2
3
4
5
6 7 8
Weeks
9
10 11 12
*p<0.05
Responders are defined as at least “somewhat relieved”
ITT population
Müller-Lissner et al, Aliment Pharmacol Ther 2001; 15: 1655
Mean relief in abdominal
pain / discomfort score
Change from baseline (pain score)
Baseline
Week
0
1
2
3
4
5
6
7
8
9
10
11
12
0
B301
-0.2
-0.4
-0.6
-0.8
-1.0
*
*
*
*
*
*
Placebo (n = 288)
*
*
*
Tegaserod 6 mg bid (n = 294)
*
*
* p<0.05 (6 mg bid vs placebo)
ITT analysis. 100mm Visual Analogue Scale with 6 descriptors: none to very severe
Baseline pain score: placebo = 2.77; tegaserod = 2.78
Müller-Lissner et al, Aliment Pharmacol Ther 2001; 15: 1655
Change in number of bowel movements
Change from baseline (number of weekly bowel movements)
*
3
Placebo (n = 288)
2
*
Tegaserod 6 mg bid (n = 294)
B301
*
*
*
4
5
*
*
*
*
7
8
9
*
*
1
0
0
1
Baseline
2
*p<0.05 (6 mg bid vs placebo)
ITT analysis
3
6
Week
10
11
12
 Improvement seen on Day 1
Müller-Lissner et al, Aliment Pharmacol Ther 2001; 15: 1655
Mean change in bloating score
Change from baseline (bloating score)
Week
Baseline
0
1
2
3
4
5
6
7
8
9
10
11
12
0
B301
-0.2
-0.4
*
*
-0.6
*
*
*
*
*
-0.8
Placebo
*
*
Tegaserod 6 mg bid
-1.0
*p<0.05 (6 mg bid vs placebo)
ITT analysis
6-point scale: 0 = none to 6 = very severe
Baseline bloating score: placebo = 2.67; tegaserod = 2.72
Müller-Lissner et al, Aliment Pharmacol Ther 2001; 15: 1655
Summary of Tegaserod Efficacy
• Significant improvement in Subject's Global
Assessment of relief
• Relief of individual IBS symptoms:
- Abdominal pain / discomfort
- Bloating
- Constipation
Müller-Lissner et al., Aliment Pharmacol Ther 2001; 15: 1655
Zelnorm: Safety Data
Adverse events occurring >1%
System / adverse experience
Zelnorm 6 mg bid
(n = 1327)
%
Placebo
(n = 1305)
%
Gastrointestinal system disorders
Abdominal pain
Diarrhea
Nausea
Flatulence
12
9
8
6
11
4
7
5
Central and peripheral nervous system
Headache
Dizziness
Migraine
15
4
2
12
3
1
Body as a whole – general disorders
Accidental trauma
Leg pain
3
1
2
<1
Musculoskeletal disorders
Back pain
Arthropathy
5
2
4
1
Novartis, data on file
Overall Safety and
Tolerability of Tegaserod
• Tegaserod was generally well tolerated.
Side effects reported significantly more often
with tegaserod than with placebo were
headache (15% vs 12%) and diarrhea (9% vs
4%)
Novartis, data on file
Overall Safety and
Tolerability of Tegaserod
• Diarrhea:
• tegaserod 9% vs placebo 4%
• In most cases, diarrhea occurred within the first
week of treatment
• Typically, diarrhea resolved with continued
therapy
• Overall, the discontinuation rate from the
studies due to diarrhea was 1.6% among the
tegaserod-treated patients
Novartis, data on file
Summary of Drug–Drug Interactions
• In vitro: no inhibition of CYP2C8, CYP2C9, CYP2C19, CYP2E1
and CYP3A4
• No clinically relevant drug–drug interactions were observed
in healthy volunteers with:
•
•
•
•
•
theophylline
dextromethorphan
Digoxin3
Warfarin4
oral contraceptives5
 Dose adjustment is not required for any of the above drugs
co-administered with tegaserod
1Zhou,
et al., Am J Gastroenterol 1999; 94: 2623: 184
et al., Gastroenterology 2000; 118 (suppl. 2): A1179: 5422
3Zhou, et al., J Pharm Sci 1999; 1: A2077
4Ledford, et al., Gastroenterology 2000; 118 (suppl. 2): A1184: 5445
5Zhou, et al., Gastroenterology 2000; 118 (suppl. 2): A1207: 5539
2Kalbag,
Conclusions
• Tegaserod is the first treatment proven to
provide multi-symptom IBS relief of:
- Abdominal pain/discomfort
- Bloating
- Constipation
• Favorable tolerability demonstrated in
well-controlled clinical trials with more
than 2,600 IBS patients
Digestive Diseases
Week Key Findings
Orlando, FL
May 17-22, 2003
Tegaserod Improves Gastric
Emptying in Patients with
Gastroparesis and
Dyspeptic Symptoms
Tougas G et al. Oral Presentation, DDW 2003
Objective
 To evaluate whether 8 weeks of
tegaserod can improve abnormally
delayed gastric emptying in patients with
dyspeptic symptoms and delayed gastric
emptying
Tougas G et al. Oral Presentation, DDW 2003
Gastric retention (%) of meal
at 2 hours post meal
Baseline (%)
8 weeks (%)
Retention (%) at 2 hours
post meal
60
50
*
*‘normal’ gastric
retention rate at
2 hours is 40%
**
40
30
↓ 24%
↓ 35%
↓ 15%
↓ 6%
24
18
Tegaserod dose
12
Placebo
20
10
0
*p=0.077 vs placebo; **p=0.003 vs placebo
Tougas G et al. Oral Presentation, DDW 2003
Results and Conclusions
•
•
•
•
Gastric retention was reduced consistently
with tegaserod, especially at 2 and 4 hours
after meal
Tegaserod 18mg/day and 24mg/day
decreased food retention in late phase
emptying by 2x over placebo
80% of patients given 18mg/day developed
normal gastric emptying vs. 50% of placebo
patients
Tegaserod improves gastric emptying in
patients with gastroparesis and dyspeptic
Tougas G et al. Oralsymptoms
Presentation, DDW 2003
Efficacy and Safety of Tegaserod in
Patients with Chronic Constipation
Conclusions
 Significant improvement as compared to placebo:

• Number of complete, spontaneous bowel movements
• Time to first complete, spontaneous bowel movement
• Straining
• Distention and bloating
• Abdominal discomfort/pain
• Satisfaction with bowel habits
• Bothersome constipation
Additional evidence for safety
• Most frequent adverse effects leading to discontinuation included
nausea, diarrhea, abdominal pain, headache
• No serious adverse events were noted with the use of tegaserod for
up to 12 weeks in pts with CC.
Johanson J, et al. Oral presentation. DDW 2003.
Tegaserod provides rapid,
effective relief of abdominal
pain/discomfort, bloating and
constipation in Chinese
patients with irritable bowel
syndrome with constipation
(IBS-C)
Lin S, et al. Poster S1017.DDW 2003.
Results and Conclusions
• Adverse events were reported in 10% of
patients on tegaserod and 6% on placebo.
• The most common adverse events seen in
tegaserod group were diarrhea, abdominal
pain and dizziness (frequency <3%). They
did not result in discontinuation.
• Tegaserod provided rapid relief of IBS-C
symptoms including abdominal pain,
bloating and constipation and was well
tolerated in Chinese patients with IBS-C.

Lin S, et al. Poster S1017. DDW 2003.
Tegaserod is an effective and
safe therapy for irritable
bowel syndrome in a Nordic
population
Nyhlin H, et al. Poster M1645. DDW 2003. In press, Gastroenterology.
Results and Conclusions
• The overall frequency of adverse events
(AE) was comparable between treatments.
 The most frequently reported AE was diarrhea : 9.2%
tegaserod vs. 1.3% placebo.
 Discontinuations due to diarrhea were 2.8% for
tegaserod vs. 0% for placebo .
•

Tegaserod 6mg bid is an effective, safe
and well tolerated therapy in a Nordic
population of IBS patients with non-D IBS.
Nyhlin H, et al. Poster M1645. DDW 2003. In press, Gastroenterology.
Results
•
•

Tegaserod treated patients with less than
10 yrs duration of IBS symptoms had a
gain in weekly therapeutic effect (range
10% to 26%) each week (p<0.05) over
weeks 1-12.
Tegaserod significantly affected number
of days with no bowel movements and
days with >3 bowel movements for weeks
1-4 (p<0.0001).
Nyhlin H, et al. Poster M1645. DDW 2003. In press, Gastroenterology.
Relapse of Symptoms Following Withdrawal of
Tegaserod Treatment in Irritable Bowel Syndrome
with Constipation (IBS-C)
Munoz V, et al, Poster T1804. DDW 2003.
Conclusions
•
•
•
•
•
IBS-C patients respond favorably to initial
treatment with tegaserod for 1 month (82%)
IBS-C patients respond favorably to
maintenance therapy with tegaserod for
another 2 months (90%)
Upon discontinuation of tegaserod, 2/3 of
patients will relapse within 3 weeks
10% of maintenance treatment patients
relapsed (p<0.0001)
Patients who continue treatment 18x less likely
to relapse
Munoz V, et al, Poster T1804. DDW 2003.
Tegaserod Treatment for
IBS: A Model of Indirect
Costs
Smith D, et al. Poster T1303. DDW 2003.
Conclusions
• IBS has substantial impact on worker
productivity
• Net annual savings of $1,497 for employer
per employee treated for IBS
– Model can be tailored to match individual employers’
needs
• Treatment of IBS with tegaserod may be
cost-effective in reducing indirect costs
under a variety of scenarios, using a
series of assumptions on wages,
epidemiology, therapy, and costs
– Further validation of this model is warranted
 Smith D, et al. Poster T1303. DDW 2003.
Impact of IBS on Worker Productivity
in an Employed U.S. Population
Dean B, et al. Poster T 1302, DDW 2003.
Results and Conclusions
 1,776 of 11,806 employees participated in

both surveys
41% met Rome II criteria for IBS

•
•
•
Participants with IBS more likely to be female and Caucasian
or Hispanic, otherwise similar to those without IBS
Participants with IBS had work productivity losses
of 19.8% due to GI symptoms compared with 5.6%
among those without IBS
This reduction is equivalent to working 4 days out
of a 5-day work-week
Reduced productivity of this magnitude may have
substantial impact on employers.
Dean B, et al. Poster T 1302, DDW 2003.
Conclusions
 Employees with IBS




~20% reduced work productivity due to GI Sx
~14% reduced work productivity compared to
non-IBS co-workers
Work less than 4 days out of total 5 day work
week
May have substantial financial impact on
employers
Bonnie Dean, Daniel Aguilar, et al. Poster Presentation DDW 2003.
Tegaserod is Effective in the Retreatment of
Irritable Bowel Syndrome with Constipation (IBSC)
Mueller-Lissner S., et al. Poster T1821. DDW 2003.
Conclusions
•
•
•
High rate of recurrence of IBS symptoms
was seen with discontinuation of tegaserod
(84% of patients)
Response rate achieved during re-treatment
was similar to response rate achieved
during initial treatment (85-88%)
Therapy with tegaserod is highly effective
and well-tolerated for initial treatment, as
well as re-treatment in patients with IBS-C
Mueller-Lissner S., et al. Poster T1821. DDW 2003.
Primary Efficacy Variable

Increase ≥ 1 CSBM/Week
50%
41.4%
43.2%
% Responders
40%
30%
25.1%
20%
10%
0%
Johanson J, Tougas G, Chey W, et al. Oral presentation. DDW 2003.
2mg BID
6mg BID
PBO
An Open Label Study to
Determine the Efficacy and
Tolerability of Tegaserod in
the Treatment of Constipation
Dominant Irritable Bowel
Syndrome (IBS-C)
Shah, S et al. Poster T1435. DDW 2003.
Conclusions
•
•
•

Tegaserod 6mg BID is equally effective in
male and females in relieving the
symptoms of abdominal pain, bloating
and straining at defecation.
It increases the number of bowel
movements per week in both sexes. This
effect was more statistically more
significant in males.
This is the first study of tegaserod
demonstrating significant efficacy in
males.
Shah, S et al. Poster T1435. DDW 2003.