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Transcript of racecadotril
A Novel Approach in the Treatmentof Acute Diarrhea
Maria Teresita Andal-Gamutan, MD,FPCP,FPSG,FPSDE
Fluid and electrolyte balance and diarrhea
Burden of diarrhea and its management
Racecadotril – an intestinal antisecretory agent
Clinical trials
Safety and tolerability profile
Conclusions
PRESENTATION OUTLINE
INTRODUCTION
FLUID ANDELECTROLYTEBALANCE IN THE INTESTINES
How much fluid passes through the intestine each day?
2 L
iters
5 L
iters
7 L
iters
9 L
iters
0% 0%0%0%
A. 2 Liters
B. 5 Liters
C. 7 Liters
D. 9 Liters
DAILY WATER EXCHANGES
Sellin JH. Intestinal electrolyte absorption and secretion. In: Feldman M, et al, eds. Sleisenger & Fordtrans Gastrointestinal and Liver Disease. 8th ed. 2006
FLUID AND ELECTROLYTE BALANCE IN THE INTESTINES
Food
Fluid intake
Water absorption
Water secretion(<5ml/kg – children)(< 200 ml – adults)
Exogenous sources:(2 liters)
Endogenous sources:(7 liters)
Saliva
Gastric juices
Intestinal secretions
Pancreatic juices
Biliary secretions
Duodenum /Jejunum5.5 liters
Endogenous secretions: intestinal, pancreatic, salivary, biliary and gastric juices
7 liters
Sellin JH. Intestinal electrolyte absorption and secretion. In: Feldman M, et al, eds. Sleisenger & Fordtrans. Gastrointestinal and Liver Disease. 8th ed. 2006
Ileum2 liters
Colon/Rectum1.3 liters
Stool(<5ml/kg – children)(< 200 ml – adults)
Food and fluid intake
(drinks, meals…)2 liters
FLUID AND ELECTROLYTE BALANCE IN THE INTESTINES
DAILY WATER EXCHANGES
Glucose, Na+, K+, Cl-, Water
WATER FOLLOWS THE MOVEMENT OF ELECTROLYTES AND GLUCOSE
Gut lumen
Enterocyte
FLUID AND ELECTROLYTE BALANCE IN THE INTESTINES
Fluid is required to solubilize complex foods in preparation for digestion and to produce an istonoic absorbate consisting of small molecules by which nutrient absorption can take place.
Crypt: Secretion
Villus Tip: Absorption
Farthing M. Digestive Diseases (Review Article) 2006;24:47-58
NORMAL STATE
FLUID AND ELECTROLYTE BALANCE IN THE INTESTINES
MECHANISMS OF INTESTINAL SECRETION
Enterocyte Intestinal fluid secretion results from the active secretion of chloride and bicarbonate ions.
Active chloride ion secretion has several components that maintain its secretion from the apical membrane of the enterocyte.
The final common secretory pathway occurs through the chloride channel.
FLUID AND ELECTROLYTE BALANCE IN THE INTESTINES
Farthing M. Digestive Diseases (Review Article) 2006;24:47-58
MECHANISMS OF INTESTINAL SECRETION
Endogenoussecretagogues
5-HT – potent intestinal secretagogue; has a key role in cholera toxin (CT) induced intestinal secretion
PGE2 – potent intestinal secretagogue; CT-induced
secretion is inhibited by a COX-2 inhibitor but not by a COX-1 inhibitor
Enteric Nervous System
FLUID AND ELECTROLYTE BALANCE IN THE INTESTINES
Farthing M. Digestive Diseases (Review Article) 2006;24:47-58
Functions independently of the CNS through a variety of neurotransmitters: VIP and enkephalins
REGULATION OF INTESTINAL SECRETION
Enkephalin - opioid neurotransmitter that binds to delta receptors to reduce the levels of cAMP
Schwartz. International Journal of Antimicrobial Agents 14(2000) 75-79
VIP (Vasoactive Intestinal Peptide)Prostaglandin E2
- increase cAMP levels
Cyclic AMP - induces secretion of water and electrolytes
Enkephalinase - enzyme that degrades enkephalins
FLUID AND ELECTROLYTE BALANCE IN THE INTESTINES
OPIOIDS AND THEIR RECEPTORS
Exogenous
- Morphine- Loperamide
µ (mu)has inhibitory effects on
intestinal smooth muscles
(delta)decreases cAMP formation
++++++
++
Endogenous
- Enkephalins + +++
Farthing M. Digestive Diseases (Review Article) 2006;24:47-58
Opioids Opioid receptors
FLUID AND ELECTROLYTE BALANCE IN THE INTESTINES
c-AMP
ATP
VIPProstaglandins
Schwartz. International Journal of Antimicrobial Agents 14(2000) 75-79
Enkephalins
REGULATION OF WATER AND ELECTROLTYE SECRETION– NORMAL STATE
Enkephalinase
Delta receptor
FLUID AND ELECTROLYTE BALANCE IN THE INTESTINES
DIARRHEA
What is Diarrhea?
Pas
sage
of a
bnorm
ally
...
Sto
ol wei
ght >
200
g...
Both
0% 0%0%
A. Passage of abnormally liquid stools at increased frequency
B. Stool weight > 200 grams/day
C. Both
Passage of abnormally liquid or unformed stools at an increased frequency
Stool weight > 200 grams / day
DIARRHEA
Harrison’s Principles of Internal Medicine 16th Edition. Volume 1. 2005
DIARRHEA
Over-secretion of water leads to diarrhea.
Hypersecretion
DIARRHEA (> 200 grams /day)
SecretionSecretion AbsorptionAbsorption AbsorptionAbsorption
Normal State
DIARRHEA
DIARRHEA
It’s considered acute diarrhea if the duration is?
< 2
wee
ks
2 –
4 w
eeks
> 4
wee
ks
0% 0%0%
A. < 2 weeks
B. 2 – 4 weeks
C. > 4 weeks
Acute diarrhea
- < 2 weeks duration
- more than 90% are caused by infectious agents
- often accompanied by vomiting, fever, and abdominal pain
Persistent diarrhea
- 2 to 4 weeks duration
Chronic diarrhea
- > 4 weeks duration
- needs further evaluation to exclude serious underlying pathology
- usually non-infectious in origin
ACUTE, PERSISTENT, AND CHRONIC DIARRHEA
DIARRHEA
Harrison’s Principles of Internal Medicine 16th Edition. Volume 1. 2005
ACUTE WATERY DIARRHEA (Infectious)1,2
1. Farthing M. Digestive Diseases (Review Article) 2006;24:47-582. The Treatment of Diarrhea: A manual for physicians and other senior health workers, Department of Child and Adolescent
Health and Development, World Health Organization 2005
Bacteria: - ETEC- V. cholerae, V. parahaemolyticus- Aeromonas, Plesiomonas, Shigella, Salmonella, EHEC
Viruses: - Rotavirus- Enteric adenovirus (types 40 & 41)- SRSVs
Protozoa: - C. parvum, G. intestinalisDuration: < 14 days; lasts several hours or days
DIARRHEA
NORMAL VILLI BLUNTED VILLI
ACUTE WATERY DIARRHEA (Infectious)
DIARRHEA
Destruction of enterocytes: EIEC, rotavirus, shigella
Defective absorption
Hypersecretion:Vibrio cholerae, rotavirus,
ETEC, shigella
IMBALANCE BETWEEN ABSORPTION AND SECRETION
The Treatment of Diarrhea: A manual for physicians and other senior health workers, Department of Child and Adolescent Health and Development, World Health Organization 2005
ACUTE WATERY DIARRHEA (Infectious)
DIARRHEA
BURDEN OF DIARRHEA
How many cases of Diarrhea do you see in your clinic?
1 p
atie
nt a w
eek
3 –
4 p
atie
nts
a w
eek
> 7
pat
ients
a w
eek
0% 0%0%
A. 1 patient a week
B. 3 – 4 patients a week
C. > 7 patients a week
More than 1 billion people suffer one or more episodes of acute diarrhea each year.
Because of poor sanitation and more limited access to health care, acute infectious diarrhea remains one of the most common causes of mortality in developing countries.
BURDEN OF DIARRHEA
BURDEN OF DIARRHEA
Harrison’s Principles of Internal Medicine 16th Edition. Volume 1. 2005
100 million people affected annually in the US
- nearly 50% must restrict activities
- 10% consult physicians
- 250,000 require hospitalization
- roughly 3,000 die (primarily the elderly)
BURDEN OF DIARRHEA
BURDEN OF DIARRHEA
Harrison’s Principles of Internal Medicine 16th Edition. Volume 1. 2005
DIARRHEA IN THE PHILIPPINES
*rate/100,000 of sex-specific population
2003 Annual Report Field Health Service Information System, 2000 Philippine Health Statistics, Department of Health, Philippines
2nd leading cause of morbidity (general population)
1000
800
600
400
200
0Acute Lower RTIand Pneumonia
Ra
tes*
770.9695.0
639.6
455.4
325.4
748.2
655.0 677.0
503.1
420.7
Diarrheas Bronchitis/Bronchiolitis
Influenza Hypertension
M ale
Female
BURDEN OF DIARRHEA
MANAGEMENTOF DIARRHEA
What Drugs/Management do you utilized in your practice?
ORS
Antib
iotic
s
Loper
amid
e
Rac
ecad
otril
Oth
ers
0% 0% 0%0%0%
A. ORS
B. Antibiotics
C. Loperamide
D. Racecadotril
E. Others
APPROACH TO THE PATIENT WITH ACUTE DIARRHEA
Indications for evaluation:profuse diarrhea with dehydrationgrossly bloody stoolsfever ≥ 38.5oCduration > 48 hours without improvementnew community outbreakssevere abdominal pain in patients > 50 years, and elderly or immunocompromised patients
MANAGEMENT OF DIARRHEA
The decision to evaluate acute diarrhea depends on its severity and duration, and on various host factors.
Harrison’s Principles of Internal Medicine 16th Edition. Volume 1. 2005
Fluid and electrolyte replacement are of central importance to all forms of acute diarrhea.
MANAGEMENT OF DIARRHEA
THE TREATMENT OF ACUTE DIARRHEA
In moderately severe, non-febrile and non-bloody diarrhea, antimotility antisecretory agents can be useful adjuncts to control symptoms.
Judicious use of antibiotics is appropriate in selected instances of acute diarrhea.
Harrison’s Principles of Internal Medicine 16th Edition. Volume 1. 2005
UNMET MEDICAL NEEDS IN THE TREATMENT OF ACUTE DIARRHEA
LIMITATIONS OF CURRENT THERAPY
Fluid replacement
- No significant reduction of diarrhea- Diarrhea may continue
“Antidiarrheals” - Limited efficacy- CNS effects- Bloating- Rebound constipation
Antibiotics - Resistance- Unwanted adverse effects
Farthing M. Digestive Diseases (Review Article) 2006;24:47-58
UNMET MEDICAL NEEDS IN THE TREATMENT OF ACUTE DIARRHEA
inhibits fluid secretion by intestinal mucosa
has a rapid onset of action
has limited constipating effects
has a high therapeutic index
has minimal central nervous system effects
has low abuse potential
Edelman R. Prevention and treatment of infectious diarrhea. Speculations on the next 10 years. Am J Med 1985;78:99-106.
UNMET MEDICAL NEEDS IN THE TREATMENT OF ACUTE DIARRHEA
THE IDEAL TREATMENT FOR ACUTE DIARRHEA
Prevention of Dehydration and Control of Diarrhea
Fluid replacement alone
Fluid replacement with
anti-secretory agent
UNMET MEDICAL NEEDS IN THE TREATMENT OF ACUTE DIARRHEA
THE IDEAL TREATMENT FOR ACUTE DIARRHEA
inhibits fluid secretion by intestinal mucosa
has a rapid onset of action
has limited constipating effects
has a high therapeutic index
has minimal central nervous system effects
has low abuse potential
Racecadotril was developed specifically with these characteristics in mind.2
1. Edelman R. Prevention and treatment of infectious diarrhea. Speculations on the next 10 years. Am J Med 1985;78:99-106.
2. Lecomte JM. International Journal of Antimicrobial Agents 14 (2000) 81-87
THE IDEAL TREATMENT FOR ACUTE DIARRHEA1
UNMET MEDICAL NEEDS IN THE TREATMENT OF ACUTE DIARRHEA
Are you aware that Racecadotril was already in the market in late 90’s?
Yes N
o
0%0%
A. Yes
B. No
RACECADOTRIL:AN INTESTINALANTISECRETORY AGENT
c-AMP
ATP
VIPProstaglandins
Schwartz. International Journal of Antimicrobial Agents 14(2000) 75-79
Enkephalins
REGULATION OF WATER AND ELECTROLTYE SECRETION– NORMAL STATE
Enkephalinase
Delta receptor
RACECADOTRIL: AN INTESTINAL ANTISECRETORY AGENT
c-AMP
ATP
Schwartz. International Journal of Antimicrobial Agents 14(2000) 75-79
Enkephalins
Enkephalinase
Delta receptor
Toxic peptides from viruses /
bacteria
REGULATION OF INTESTINAL SECRETION - HYPERSECRETORY STATE
RACECADOTRIL: AN INTESTINAL ANTISECRETORY AGENT
c-AMP
ATP
Schwartz. International Journal of Antimicrobial Agents 14(2000) 75-79
Enkephalins
Enkephalinase
Delta receptor
Toxic peptides from viruses /
bacteria
Racecadotril
MODE OF ACTION OF RACECADOTRIL -NORMALIZATION OF SECRETION
RACECADOTRIL: AN INTESTINAL ANTISECRETORY AGENT
METABOLISM OF RACECADOTRIL
Schwartz. International Journal of Antimicrobial Agents 14(2000) 75-79
Ac-S-CH(Bz)-CO-NH-CH -CO -Bz22
Th io rphan (potent-enkephalinase inhibitor)
(Non-specific esterase)
RACECADOTRIL
HS-CH(Bz)-CO-NH-CH -CO -H2 2
H O2 H O2
RACECADOTRIL
THIORPHAN (potent-enkephalinase inhibitor)
Ac-S-CH(Bz)-CO-NH-CH -CO -Bz22
Th io rphan (potent-enkephalinase inhibitor)
(Non-specific esterase)
RACECADOTRIL
HS-CH(Bz)-CO-NH-CH -CO -H2 2
H O2 H O2
(Non-specific esterase) Hydrolysis
RACECADOTRIL: AN INTESTINAL ANTISECRETORY AGENT
O O
H HH H
N N
O
O O
O OH
H C3
hydrolysis
S HS
RACECADOTRIL(pro-drug)
THIORPHAN(active metabolite)
Schwartz. International Journal of Antimicrobial Agents 14(2000) 75-79
RACECADOTRIL: AN INTESTINAL ANTISECRETORY AGENT
METABOLISM OF RACECADOTRIL
Enkephalinase inhibition kinetics in healthy volunteers after a single oral dose (100 mg)
Lecomte JM. International Journal of Antimicrobial Agents 14 (2000) 81-87
ONSET OF ACTION OF RACECADOTRIL
500
400
300
200
100
00 30 60 120 240 480 24 hrs
** p<0.01
En
ke
ph
ali
na
se a
ctiv
ity
(pm
ol/
ml/
min
ute
)
Tim e (m in)
**
**
**
**
RA CECA DOT RIL
Placebo
RACECADOTRIL: AN INTESTINAL ANTISECRETORY AGENT
CLINICAL TRIALS
STUDY DESIGN – Randomized, double-blind, placebo-controlled study with
2 parallel groups
OBJECTIVE – To assess the efficacy and safety of racecadotril as an
adjunct to oral rehydration therapy for children with acute watery diarrhea
RACECADOTRIL IN THE TREATMENT OF ACUTE WATERY DIARRHEA IN CHILDREN (Salazar-Lindo et al.)
TREATMENT – Oral rehydration + racecadotril 1.5 mg/kg t.i.d. – Oral rehydration + placebo t.i.d.
Salazar-Lindo E, Santisteban-Ponce J, Chea-Wood E and Guterriez M. N Engl J Med 2000;343:463-467
INFANTS AND CHILDREN
Total stool output / body weight (g/kg)
400
350
300
250
200
150
100
50
0RA CECA DOT R IL
+ ORS (n=68)
Intent io n to t reat g ro up Ro tavirus-Posit ive Subg roup
RA CECA DOT R IL(n=34)+ ORS
Placebo+ ORS (n=67)
P<0.001
P<0.001
Placebo+ ORS (n=39)
Tota
l S
too
l O
utp
ut
(g/k
g)
53% 56%
Salazar-Lindo E, Santisteban-Ponce J, Chea-Wood E and Guterriez M. N Engl J Med 2000;343:463-467
RACECADOTRIL IN THE TREATMENT OF ACUTE WATERY DIARRHEA IN CHILDREN (Salazar-Lindo et al.)
INFANTS AND CHILDREN
Time to recovery
0 10 20 30 40 50 60 70 80 90 100 110 120
20
40
60
80
100
Durat ion o f Diarrhea (hr)
Rotavirus-positive boys
All boys
All boys
Rotavirus-positive boys
RA CECA DOT RIL + ORSPlacebo + ORS
Pro
ba
bil
ity
of
Un
reso
lve
d D
iarr
he
a (
%)
Salazar-Lindo E, Santisteban-Ponce J, Chea-Wood E and Guterriez M. N Engl J Med 2000;343:463-467
RACECADOTRIL IN THE TREATMENT OF ACUTE WATERY DIARRHEA IN CHILDREN (Salazar-Lindo et al.)
INFANTS AND CHILDREN
Salazar-Lindo E, Santisteban-Ponce J, Chea-Wood E and Guterriez M. N Engl J Med 2000;343:463-467
700
600
500
400
300
200
100
0
OR
S c
on
sum
pti
on
(m
l) p<0.001
Day 1 Day 2
RA CECA DOT RIL+ ORS (n=68)
Placebo + ORS (n=67)
Total intake of oral rehydration solution
RACECADOTRIL IN THE TREATMENT OF ACUTE WATERY DIARRHEA IN CHILDREN (Salazar-Lindo et al.)
INFANTS AND CHILDREN
TOLERABILITY
Adverse Events (%)
Racecadotril + ORS 10
Placebo + ORS 7
The incidence of vomiting did not differ between the racecadotril and placebo groups.
Salazar-Lindo E, Santisteban-Ponce J, Chea-Wood E and Guterriez M. N Engl J Med 2000;343:463-467
RACECADOTRIL IN THE TREATMENT OF ACUTE WATERY DIARRHEA IN CHILDREN (Salazar-Lindo et al.)
INFANTS AND CHILDREN
Salazar-Lindo E, Santisteban-Ponce J, Chea-Wood E and Guterriez M. N Engl J Med 2000;343:463-467
CONCLUSION
The results of this study provide evidence that racecadotril, as an adjunct to oral rehydration solution, is effective and well tolerated in reducing the duration and severity of acute watery diarrhea in hospitalized infants and children.
The antidiarrheal effect is obtained more rapidly than with oral rehydration alone, particularly in infants with rotavirus infection.
RACECADOTRIL IN THE TREATMENT OF ACUTE WATERY DIARRHEA IN CHILDREN (Salazar-Lindo et al.)
INFANTS AND CHILDREN
EFFICACY AND TOLERABILITY OF RACECADOTRIL IN ACUTE DIARRHEA IN CHILDREN (Cézard et al.)
INFANTS AND CHILDREN
STUDY DESIGN – Randomized, double-blind, placebo-controlled, multicenter study
INCLUSION CRITERIA – Severe acute diarrhea– Aged 3 months to 4 years – 3 or more watery stools per day– Onset of diarrhea - less than 3 days
POPULATION – Racecadotril + ORS: 84 patients – Placebo + ORS: 82 patients
Cézard JP et al. Gastroenterology 2001;120:799-805.
EVALUATION CRITERIA – Stool output during the first 48 hrs (primary end point) – Stool output during the first 24 hrs – Dehydration status at 24 hrs (Urine Na+ / K+ ratio) – Duration of diarrhea– Number and characteristics of stools
TREATMENT – Oral rehydration + racecadotril 1.5 mg/kg t.i.d. – Oral rehydration + placebo t.i.d.
Cézard JP et al. Gastroenterology 2001;120:799-805.
EFFICACY AND TOLERABILITY OF RACECADOTRIL IN ACUTE DIARRHEA IN CHILDREN (Cézard et al.)
INFANTS AND CHILDREN
Stool weight (g/hour) up to 48 hours
20
15
10
5
0Racecadotr i l
+ ORS(n=84)
Fu l l data set Per-p ro toco l po pu lat ion
Racecadotr i l
(n=53)+ ORS
Placebo+ ORS(n=82)
Placebo+ ORS(n=63)
**
***
Sto
ol
ou
tpu
t (g
/ho
ur)
** p = 0.009*** p = 0.001
40%
50%
Cézard JP et al. Gastroenterology 2001;120:799-805.
EFFICACY AND TOLERABILITY OF RACECADOTRIL IN ACUTE DIARRHEA IN CHILDREN (Cézard et al.)
INFANTS AND CHILDREN
Time to recovery in rotavirus-positive patients
Cézard JP et al. Gastroenterology 2001;120:799-805.
100
80
60
40
20
00 10 20 30 40 60 70 80 9050
Pro
ba
bil
ity
of
un
reso
lve
d d
iarr
he
a (
%)
Placebo + ORS
RA CECA DOTRIL + ORS
Durat io n o f d iarrhea (hours)
EFFICACY AND TOLERABILITY OF RACECADOTRIL IN ACUTE DIARRHEA IN CHILDREN (Cézard et al.)
INFANTS AND CHILDREN
Duration of diarrhea [median, hours]
Racecadotril[n = 32]
Placebo[n = 35]
P
6.9 36 0.02
TOLERABILITY
Number of Adverse Events (AE)
Racecadotril + ORS 10
Placebo + ORS 11
The incidence of adverse events was similar in both groups of patients.
Most common AE: Vomiting
Cézard JP et al. Gastroenterology 2001;120:799-805.
EFFICACY AND TOLERABILITY OF RACECADOTRIL IN ACUTE DIARRHEA IN CHILDREN (Cézard et al.)
INFANTS AND CHILDREN
Cézard JP et al. Gastroenterology 2001;120:799-805.
CONCLUSION
EFFICACY AND TOLERABILITY OF RACECADOTRIL IN ACUTE DIARRHEA IN CHILDREN (Cézard et al.)
INFANTS AND CHILDREN
This study demonstrates the efficacy (up to 50% reduction in stool output) and tolerability of racecadotril as an adjunct therapy to oral rehydration solution in the treatment of severe diarrhea in infants and children.
ADULTS
A MULTINATIONAL COMPARISON OF RACECADOTRIL AND LOPERAMIDE IN THE
TREATMENT OF ACUTE DIARRHEA IN ADULTSDavid Prado for the Global Adult Racecadotril Study Group
Scandinavian Journal of Gastroenterology 2002
AIM: to compare the efficacy, safety and tolerability of
Racecadotril with those of Loperamide in patients with acute
diarrhea.
A MULTINATIONAL COMPARISON OF RACECADOTRIL AND LOPERAMIDE IN THE TREATMENT OF ACUTE DIARRHEA IN ADULTS (Prado D.)
STUDY DESIGN single, blind, randomized– Multicenter (21 centers in 14 countries) – Parallel groups – Ambulatory patients
Prado D. Scand J Gastroenterol 2002;37:656-61
INCLUSION CRITERIA – 3 or more watery stools, with no visible blood, in the last 24 hours – onset of diarrhea of presumed infectious origin, of at least 24
hours and less than 5 days
ADULTS
TREATMENT – Racecadotril: 100 mg, 3 times daily / Loperamide: 2 mg, 3
times daily
ADULTS
ANALYZED POPULATION – Racecadotril: 461 patients / Loperamide: 454 patients
Prado D. Scand J Gastroenterol 2002;37:656-61
A MULTINATIONAL COMPARISON OF RACECADOTRIL AND LOPERAMIDE IN THE TREATMENT OF ACUTE DIARRHEA IN ADULTS (Prado D.)
Duration of Diarrhea
ADULTS
A MULTINATIONAL COMPARISON OF RACECADOTRIL AND LOPERAMIDE IN THE TREATMENT OF ACUTE DIARRHEA IN ADULTS (Prado D.)
100
90
80
70
60
50
40
30
20
10
0
Pro
ba
bil
ity
of
un
reso
lve
dd
iarr
he
a (
%)
Tim e to reso lut ion (hours)
0 20 40 60 80 100
P=NS
120 140 160
RA CECA DOT R IL (N=473)
Loperamide (N=471)
Prado D. Scand J Gastroenterol 2002;37:656-61
Treatment-related adverse events with an incidence of more than 1%
Prado D. Scand J Gastroenterol 2002;37:656-61
ADULTS
1 4
1 2
1 0
8
6
4
2
0Constipation Abdominal enlargement Anorexia
% o
f P
ati
en
ts
RA CECA DOT RIL (n=473)Loperamide (n=472)
3.4
1.70 .8
12.5
6.1
2.3
A MULTINATIONAL COMPARISON OF RACECADOTRIL AND LOPERAMIDE IN THE TREATMENT OF ACUTE DIARRHEA IN ADULTS (Prado D.)
ADULTS
CONCLUSION
Racecadotril resolved the symptoms of acute diarrhea rapidly and effectively, and produced more rapid resolution of abdominal symptoms and less constipation than loperamide.
Prado D. Scand J Gastroenterol 2002;37:656-61
A MULTINATIONAL COMPARISON OF RACECADOTRIL AND LOPERAMIDE IN THE TREATMENT OF ACUTE DIARRHEA IN ADULTS (Prado D.)
RACECADOTRIL’S SAFETY AND TOLERABILITY PROFILE
PHARMACOVIGILANCE
13th Periodic Safety Update Report for Active Substance: Racecadotril. May 2007 Laboratoires Bioprojet Pharma.
Adults
Infants & Children
TOTAL
Period covered # of reportedadverse events
Prevalence
March 1993 to March 2007
November 2000 to March 2007
75
30
105
0.00047 %
0.00032 %
0.00042 %
Prevalence of adverse events associated with Racecadotril (France)
Most common AE for adults and children: “Cutaneous disorders and miscellaneous allergic reactions”
SAFETY AND TOLERABILITY
Case Number 1:A 35 year old male developed diarrhea and was given Loperamide, his symptom improved but
after 2 days he consults you because of recurrence of Diarrhea. What is the likely
explanation?
Re-
infe
ctio
n with
a n
..
Bac
teria
l pro
lifer
atio
n
This
is o
smotic
Dia
rrhe
a
0% 0%0%
A. Re-infection with a new bacteria/virus
B. Bacterial proliferation
C. This is osmotic Diarrhea
E. Coli content of the proximal jejunum (gnotobiotic piglets)
Duval-Iflah Y. Et al.,Alimentary Pharmacology, 1999; (suppl. 6); 9-14
EFFECTS OF RACECADOTRIL AND LOPERAMIDE ON BACTERIAL PROLIFERATION (Duval-Iflah Y. et al.)
120
100
80
60
40
20
0
10
/
g c
on
ten
t(m
ed
ian
)
6E
. C
oli
RA CECA DOT RILControlLoperamide
p=0.04
p=0.86 p=0.005
1 4
120
SAFETY AND TOLERABILITY
1. Lecomte JM, Int.J. Of Antimicrobial Agents, 2000; 14:81-872. Scwartz J-C, Int.J. Of Antimicrobial Agents, 2000; 14:75-793. Duval-Iflah Y. Et al.,Alimentary Pharmacology, 1999; (suppl. 6): 9-144. Bergmann JF et al, Alimentary Pharmacology and Therapeutics, 1992; 6:305-3135. Knisely JS,Drug and Alcohol Dependence,1989;23:143-151
Blood-Brain Barrier
Astrocyteprocesses
Lipid solubletransport
Carrier-mediatedtransport
Does not induce CNS Toxicity1,2,3
Racecadotril
RACECADOTRIL DOES NOT CROSS THE BLOOD-BRAIN BARRIER
Does not impair mental performance4
Has no potential for abuse or physical dependence5
SAFETY AND TOLERABILITY
Therapeutic Index = LD50
ED50
Lecomte JM, Int.J. Of Antimicrobial Agents, 2000; 14:81-87
100 mg TID (adults) 20 times this dose was given to healthy adults with no ill effects
Therapeutic dose Relevance of high therapeutic index
The higher the Therapeutic Index, the lower the risk of overdose.
RACECADOTRIL HAS A HIGH THERAPEUTIC INDEX
(median lethal dose)
(median effective dose)
SAFETY AND TOLERABILITY
Case Number 2A 20 y/o Female develops diarrhea, voluminous
but not blood streaked. She is afebrile but dehydrated, your treatment of choice would be?
ORS/F
luid
Rep
lace
men
t
Rac
ecad
otril
Loper
amid
e
Antib
iotic
s
0% 0%0%0%
A. ORS/Fluid Replacement
B. Racecadotril
C. Loperamide
D. Antibiotics
Case Number 3A 30 y/o male has been having Diarrhea for 5 days,
with 38 degree celcius temperature. He ingested raw egg 2 days prior to developing diarrhea, your
treatment will be?
Rac
ecad
otril
Antib
iotic
Both
0% 0%0%
A. Racecadotril
B. Antibiotic
C. Both
Case Number 4A 50 y/o male consults you due to diarrhea of > 4 weeks. It is in small amounts and did not
respond to Antibiotics/Metronidazole. What will be your next step?
Rep
eat M
etro
nidaz
ole...
Ba
Enema
Colo
nosco
py
Sto
ol Exa
m
0% 0%0%0%
A. Repeat Metronidazole at higher dose
B. Ba Enema
C. Colonoscopy
D. Stool Exam
SUMMARY AND CONCLUSIONS
Prevention of Dehydration and Control of Diarrhea
NormalizationDiarrhea
OVERALL CONCLUSIONS
RACECADOTRIL IN THE TREATMENT OF ACUTE DIARRHEA
Diarrhea
Fluid replacement
Racecadotril
Fluid replacement
LoperamideRacecadotrilEfficacy variable
Motility1
Secretion2
Bacterial overgrowth1
CNS effects1
Constipation2
-
+++
-
-
-
+++
+
+
+
++
RACECADOTRIL VERSUS LOPERAMIDE
1. Duval-Iflah Y. Et al.,Alimentary Pharmacology, 1999; (suppl. 6); 9-14 2. D. Turck et al. Aliment Pharmacol Ther 1999; 13 (Suppl. 6), 27-32.
OVERALL CONCLUSIONS
Active metabolite - Thiorphan
Indication - treatment of acute diarrhea
Recommended dose - 100 mg capsule every 8 hours
Total daily dose: - should not exceed 300 mg
Duration of treatment: - should not exceed 7 days
Certificate of Product Registration of Racecadotril, Bureau of Food and Drugs, Department of Health. 2005Racecadotril summary of product characteristics
RACECADOTRIL
OVERALL CONCLUSIONS
Absorption - Rapid
Maximum concentration - Maintained for at least four hours
Concentration in plasma - Maintained for at least eight hours after administration
RACECADOTRIL
OVERALL CONCLUSIONS
Racecadotril summary of product characteristics
Efficacy - together with ORS, significantly reduces stool output and duration of diarrhea in infants and children
Safety and tolerability
- similar to placebo- fewer adverse events compared with loperamide- does not induce CNS toxicity- high therapeutic index
RACECADOTRIL
OVERALL CONCLUSIONS
Racecadotril: A Novel Approachin the Treatment of Acute Diarrhea
Thank you