Hidrasec Adults 9-11-07

A Novel Approach in the Treatment of Acute Diarrhea Maria Teresita Andal-Gamutan, MD,FPCP,FPSG,FPSDE

INTRODUCTION

PRESENTATION OUTLINE Fluid and electrolyte balance and diarrhea Burden of diarrhea and its management Racecadotril – an intestinal antisecretory agent Clinical trials Safety and tolerability profile Conclusions

FLUID AND ELECTROLYTE BALANCE IN THE INTESTINES

How much fluid passes through the intestine each day? A. 2 Liters B. 5 Liters C. 7 Liters D. 9 Liters

Li te rs

0%

9

Li te rs

0%

7

Li te rs

0%

5

2

Li te rs

0%

FLUID AND ELECTROLYTE BALANCE IN THE INTESTINES

DAILY WATER EXCHANGES Water absorption Exogenous sources: (2 liters)

Endogenous sources: (7 liters) Saliva Gastric juices Intestinal secretions Pancreatic juices Biliary secretions

Food Fluid intake

Sellin JH. Intestinal electrolyte absorption and secretion. In: Feldman M, et al, eds. Sleisenger & Fordtrans Gastrointestinal and Liver Disease. 8th ed. 2006

Water secretion (<5ml/kg – children) (< 200 ml – adults)

FLUID AND ELECTROLYTE BALANCE IN THE INTESTINES

DAILY WATER EXCHANGES Duodenum / Jejunum 5.5 liters

Ileum 2 liters

Colon/ Rectum 1.3 liters

Food and fluid intake (drinks, meals…) 2 liters

Stool (<5ml/kg – children) (< 200 ml – adults)

7 liters Endogenous secretions: intestinal, pancreatic, salivary, biliary and gastric juices

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

WATER FOLLOWS THE MOVEMENT OF ELECTROLYTES AND GLUCOSE Glucose, Na+, K+, Cl-, Water Gut lumen

Enterocyte

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.

FLUID AND ELECTROLYTE BALANCE IN THE INTESTINES

NORMAL STATE Villus Tip: Absorption

Crypt: Secretion

Farthing M. Digestive Diseases (Review Article) 2006;24:47-58

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.

Farthing M. Digestive Diseases (Review Article) 2006;24:47-58

FLUID AND ELECTROLYTE BALANCE IN THE INTESTINES

MECHANISMS OF INTESTINAL SECRETION 5-HT – potent intestinal secretagogue; has a key role in Endogenous secretagogues 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

Functions independently of the CNS through a variety of neurotransmitters: VIP and enkephalins

Farthing M. Digestive Diseases (Review Article) 2006;24:47-58

FLUID AND ELECTROLYTE BALANCE IN THE INTESTINES

REGULATION OF INTESTINAL SECRETION Enkephalin

- opioid neurotransmitter that binds to delta receptors to reduce the levels of cAMP

Enkephalinase - enzyme that degrades enkephalins VIP (Vasoactive Intestinal Peptide) Prostaglandin E2 Cyclic AMP

- increase cAMP levels

- induces secretion of water and electrolytes

Schwartz. International Journal of Antimicrobial Agents 14(2000) 75-79

FLUID AND ELECTROLYTE BALANCE IN THE INTESTINES

OPIOIDS AND THEIR RECEPTORS Opioids

Opioid receptors

µ (mu)

δ (delta)

has inhibitory effects on intestinal smooth muscles

decreases cAMP formation

+++ +++

+ +

+

+++

Exogenous - Morphine - Loperamide Endogenous - Enkephalins

Farthing M. Digestive Diseases (Review Article) 2006;24:47-58

FLUID AND ELECTROLYTE BALANCE IN THE INTESTINES

REGULATION OF WATER AND ELECTROLTYE SECRETION – NORMAL STATE

Delta receptor

c-AMP ATP Enkephalins

Enkephalinase

Schwartz. International Journal of Antimicrobial Agents 14(2000) 75-79

VIP Prostaglandins

DIARRHEA

What is Diarrhea? A. Passage of

0% ot h

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0%

20 0 > gh t

lw ei St oo

Pa

ss

ag e

of a

bn

or m al ly ...

0%

B

abnormally liquid stools at increased frequency B. Stool weight > 200 grams/day C. Both

DIARRHEA

DIARRHEA Passage of abnormally liquid or unformed stools at an increased frequency Stool weight > 200 grams / day

Harrison’s Principles of Internal Medicine 16th Edition. Volume 1. 2005

DIARRHEA

DIARRHEA Over-secretion of water leads to diarrhea.

Secretion

Absorption

Hypersecretion Absorption

Normal State DIARRHEA

(> 200 grams /day)

It’s considered acute diarrhea if the duration is? A. < 2 weeks B. 2 – 4 weeks C. > 4 weeks

ks

w ee

ee – 2

4 >

4

w

w ee 2 <

0% ks

0%

ks

0%

DIARRHEA

ACUTE, PERSISTENT, AND CHRONIC DIARRHEA 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 Harrison’s Principles of Internal Medicine 16th Edition. Volume 1. 2005

DIARRHEA

ACUTE WATERY DIARRHEA (Infectious) Bacteria: - ETEC - V. cholerae, V. parahaemolyticus - Aeromonas, Plesiomonas, Shigella, Salmonella, EHEC Viruses:

- Rotavirus - Enteric adenovirus (types 40 & 41) - SRSVs Protozoa: - C. parvum, G. intestinalis Duration: < 14 days; lasts several hours or days

1. Farthing M. Digestive Diseases (Review Article) 2006;24:47-58 2. 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

1,2

DIARRHEA

ACUTE WATERY DIARRHEA (Infectious)

NORMAL VILLI

BLUNTED VILLI

DIARRHEA

ACUTE WATERY DIARRHEA (Infectious) 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

BURDEN OF DIARRHEA

How many cases of Diarrhea do you see in your clinic? A. 1 patient a week B. 3 – 4 patients a week C. > 7 patients a week 0%

0%

3

k ee w nt s

7 >

–

4

1

pa

pa tie

tie

pa t ie

nt

nt s

a

a

a

w

w ee

ee

k

k

0%

BURDEN OF DIARRHEA

BURDEN OF DIARRHEA 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.

Harrison’s Principles of Internal Medicine 16th Edition. Volume 1. 2005

BURDEN OF DIARRHEA

BURDEN OF DIARRHEA 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)

Harrison’s Principles of Internal Medicine 16th Edition. Volume 1. 2005

BURDEN OF DIARRHEA

DIARRHEA IN THE PHILIPPINES 2nd leading cause of morbidity (general population) 1000

R a tes*

800

7 7 0 .9

7 4 8 .2

M a le

6 9 5 .0

6 5 5 .0

F e m a le 6 3 9 .6

6 7 7 .0

600 4 5 5 .4

5 0 3 .1 4 2 0 .7 3 2 5 .4

400

200

0 A cu te L o w e r R T I a n d P n e u m o n ia

D ia rrh e a s

B r o n c h it is/ B ro n ch io lit is

In f lu e n z a

*rate/100,000 of sex-specific population

2003 Annual Report Field Health Service Information System, 2000 Philippine Health Statistics, Department of Health, Philippines

H y p e r t e n si o n

MANAGEMENT OF DIARRHEA

ORS Antibiotics Loperamide Racecadotril Others

th e

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0%

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ac R

pe Lo

0% tri l

0%

ra m id e

s

0%

nt ib io t ic A

RS

0%

O

A. B. C. D. E.

What Drugs/Management do you utilized in your practice?

MANAGEMENT OF DIARRHEA

APPROACH TO THE PATIENT WITH ACUTE DIARRHEA The decision to evaluate acute diarrhea depends on its severity and duration, and on various host factors. Indications for evaluation: profuse diarrhea with dehydration grossly bloody stools fever ≥ 38.5oC duration > 48 hours without improvement new community outbreaks severe abdominal pain in patients > 50 years, and elderly or immunocompromised patients

Harrison’s Principles of Internal Medicine 16th Edition. Volume 1. 2005

MANAGEMENT OF DIARRHEA

THE TREATMENT OF ACUTE DIARRHEA Fluid and electrolyte replacement are of central importance to all forms 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

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

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

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 with Fluid replacement alone

anti-secretory agent

UNMET MEDICAL NEEDS IN THE TREATMENT OF ACUTE DIARRHEA

THE IDEAL TREATMENT FOR ACUTE DIARRHEA 1

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

Are you aware that Racecadotril was already in the market in late 90’s?

A. Yes B. No

o

0% N

Ye

s

0%

RACECADOTRIL: AN INTESTINAL ANTISECRETORY AGENT

RACECADOTRIL: AN INTESTINAL ANTISECRETORY AGENT

REGULATION OF INTESTINAL SECRETION Enkephalin

- opioid neurotransmitter that binds to delta receptors to reduce the levels of cAMP

Enkephalinase - enzyme that degrades enkephalins VIP (Vasoactive Intestinal Peptide) Prostaglandin E2 Cyclic AMP

- increase cAMP levels

- induces secretion of water and electrolytes

Schwartz. International Journal of Antimicrobial Agents 14(2000) 75-79

RACECADOTRIL: AN INTESTINAL ANTISECRETORY AGENT

REGULATION OF WATER AND ELECTROLTYE SECRETION – NORMAL STATE

Delta receptor

c-AMP ATP Enkephalins

Enkephalinase

Schwartz. International Journal of Antimicrobial Agents 14(2000) 75-79

VIP Prostaglandins

RACECADOTRIL: AN INTESTINAL ANTISECRETORY AGENT

REGULATION OF INTESTINAL SECRETION - HYPERSECRETORY STATE

Delta receptor

c-AMP

ATP Enkephalins

Enkephalinase

Schwartz. International Journal of Antimicrobial Agents 14(2000) 75-79

Toxic peptides from viruses / bacteria

RACECADOTRIL: AN INTESTINAL ANTISECRETORY AGENT

MODE OF ACTION OF RACECADOTRIL NORMALIZATION OF SECRETION

Delta receptor

c-AMP

ATP Enkephalins Racecadotril

Enkephalinase

Schwartz. International Journal of Antimicrobial Agents 14(2000) 75-79

Toxic peptides from viruses / bacteria

RACECADOTRIL: AN INTESTINAL ANTISECRETORY AGENT

METABOLISM OF RACECADOTRIL H 2O H 2O

H 2O H 2O R A C E C A D O T R IL R A C E C A D O T R IL

A c - S - C H RACECADOTRIL (B z ) - C O - N H - C H 2- C O 2- B z A c - S - C H (B z ) - C O - N H - C H 2- C O 2- B z ( N o n - s p e c i f i cesterase) e st e r a se ) (Non-specific (N o n - sp e c if i c e st e r a se )

Hydrolysis

H S - C H ( B z ) - C O -(potent-enkephalinase N H -C H 2-C O 2-H THIORPHAN H S-C H (B z )-C O -N H -C H -C O -H

T h i o r p h a n ( p o t e ninhibitor) t - e n k e p h a l i n a s2e i n h i b2 i t o r ) T h i o r p h a n (p o t e n t - e n k e p h a li n a se in h ib it o r )

Schwartz. International Journal of Antimicrobial Agents 14(2000) 75-79

RACECADOTRIL: AN INTESTINAL ANTISECRETORY AGENT

METABOLISM OF RACECADOTRIL

O

O O

N H

H

h y d r o ly sis

O

S

OH

N H

H

O

HS O

H 3C

RACECADOTRIL (pro-drug)

Schwartz. International Journal of Antimicrobial Agents 14(2000) 75-79

THIORPHAN (active metabolite)

RACECADOTRIL: AN INTESTINAL ANTISECRETORY AGENT

ONSET OF ACTION OF RACECADOTRIL Enkephalinase inhibition kinetics in healthy volunteers after a single oral dose (100 mg)

E n k e p h a lin a se a ct iv it y ( p m o l /m l / m i n u t e )

500

400

300 ** 200

* * p <0 .0 1

**

** 100

R A CE CA D O T R IL

** 0

0

30 60

P la ce b o

120

240

480 T im e (m in )

Lecomte JM. International Journal of Antimicrobial Agents 14 (2000) 81-87

24 h rs

CLINICAL TRIALS

INFANTS AND CHILDREN

RACECADOTRIL IN THE TREATMENT OF ACUTE WATERY DIARRHEA IN CHILDREN (Salazar-Lindo et al.) 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 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

RACECADOTRIL IN THE TREATMENT OF ACUTE WATERY DIARRHEA IN CHILDREN (Salazar-Lindo et al.) Total stool output / body weight (g/kg)

P < 0 .0 0 1 P <0 .0 0 1

T o t a l S t o o l O u t p u t ( g /k g )

400 350 300 250

56%

53%

200 150 100 50 0 R A CE CA D O T R IL + O R S (n =6 8 )

P la ce b o + O R S (n =6 7 )

In t e n t io n t o t re a t g ro u p

R A CE CA D O T R IL + O R S (n =3 4 )

P la ce b o + O R S (n =3 9 )

R o t a v i r u s -P o s i t i v e S u b g r o u p

Salazar-Lindo E, Santisteban-Ponce J, Chea-Wood E and Guterriez M. N Engl J Med 2000;343:463-467

INFANTS AND CHILDREN

RACECADOTRIL IN THE TREATMENT OF ACUTE WATERY DIARRHEA IN CHILDREN (Salazar-Lindo et al.) P ro b a b ilit y o f U n re so lv e d D ia r r h e a (% )

Time to recovery 100

R o t a v ir u s- p o sit iv e b o y s

80

R A CE C A D O T R IL + O R S P la ce b o + O R S

A ll b o y s

60

40

R o t a v i r u s - p o si t i v e b o y s A ll b o y s

20

0

10

20

30

40

50

60

70

80

90

100

D u ra t io n o f D ia rr h e a (h r)

Salazar-Lindo E, Santisteban-Ponce J, Chea-Wood E and Guterriez M. N Engl J Med 2000;343:463-467

110

120

INFANTS AND CHILDREN

RACECADOTRIL IN THE TREATMENT OF ACUTE WATERY DIARRHEA IN CHILDREN (Salazar-Lindo et al.)

Total intake of oral rehydration solution

O R S co n su m p t io n (m l)

700 600

p < 0 .0 0 1

500 400 300 R A CE CA D O T R IL + O R S (n =6 8 )

200

P la ce b o + O R S (n = 6 7 )

100 0 Day 1

Day 2

Salazar-Lindo E, Santisteban-Ponce J, Chea-Wood E and Guterriez M. N Engl J Med 2000;343:463-467

INFANTS AND CHILDREN

RACECADOTRIL IN THE TREATMENT OF ACUTE WATERY DIARRHEA IN CHILDREN (Salazar-Lindo et al.) 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

INFANTS AND CHILDREN

RACECADOTRIL IN THE TREATMENT OF ACUTE WATERY DIARRHEA IN CHILDREN (Salazar-Lindo et al.) 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.

Salazar-Lindo E, Santisteban-Ponce J, Chea-Wood E and Guterriez M. N Engl J Med 2000;343:463-467

INFANTS AND CHILDREN

EFFICACY AND TOLERABILITY OF RACECADOTRIL IN ACUTE DIARRHEA IN CHILDREN (Cézard et al.) 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.

INFANTS AND CHILDREN

EFFICACY AND TOLERABILITY OF RACECADOTRIL IN ACUTE DIARRHEA IN CHILDREN (Cézard et al.) TREATMENT – Oral rehydration + racecadotril 1.5 mg/kg t.i.d. – Oral rehydration + placebo t.i.d. 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

Cézard JP et al. Gastroenterology 2001;120:799-805.

INFANTS AND CHILDREN

EFFICACY AND TOLERABILITY OF RACECADOTRIL IN ACUTE DIARRHEA IN CHILDREN (Cézard et al.) Stool weight (g/hour) up to 48 hours

S t o o l o u t p u t ( g /h o u r )

20

15

40%

50%

**

10

*** * * p = 0 .0 0 9 * * * p = 0 .0 0 1

5

0 R a ce c a d o tr il + ORS (n =8 4 )

P la ce b o + O RS (n =8 2 )

Fu ll d a ta se t

Cézard JP et al. Gastroenterology 2001;120:799-805.

R a ce ca d o tr il + ORS (n =5 3 )

P la ce b o + O RS (n =6 3 )

P e r -p r o t o c o l p o p u la t i o n

INFANTS AND CHILDREN

EFFICACY AND TOLERABILITY OF RACECADOTRIL IN ACUTE DIARRHEA IN CHILDREN (Cézard et al.) Time to recovery in rotavirus-positive patients

P ro b a b ilit y o f u n re s o lv e d d ia r rh e a (% )

Duration of diarrhea [median, hours] 100

Racecadotril [n = 32]

Placebo [n = 35]

P

6.9

36

0.02

80

P la ce b o + O R S R A C E C A D O TR IL + O R S

60

40

20

0

0

10

20

30

40

50

D u r a t io n o f d ia rr h e a (h o u r s )

Cézard JP et al. Gastroenterology 2001;120:799-805.

60

70

80

90

INFANTS AND CHILDREN

EFFICACY AND TOLERABILITY OF RACECADOTRIL IN ACUTE DIARRHEA IN CHILDREN (Cézard et al.) TOLERABILITY Number of Adverse Events (AE)

Racecadotril + ORS Placebo + ORS

10 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.

INFANTS AND CHILDREN

EFFICACY AND TOLERABILITY OF RACECADOTRIL IN ACUTE DIARRHEA IN CHILDREN (Cézard et al.) CONCLUSION

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.

Cézard JP et al. Gastroenterology 2001;120:799-805.

ADULTS

A MULTINATIONAL COMPARISON OF RACECADOTRIL AND LOPERAMIDE IN THE TREATMENT OF ACUTE DIARRHEA IN ADULTS David Prado for the Global Adult Racecadotril Study Group Scandinavian Journal of Gastroenterology 2002

AIM: to comp ar e the effi cac y, safe ty an d tol erab ility of Rac eca dot ril with those of Lo per amide in pat ient s wi th acu te diarrh ea .

ADULTS

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 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

Prado D. Scand J Gastroenterol 2002;37:656-61

ADULTS

A MULTINATIONAL COMPARISON OF RACECADOTRIL AND LOPERAMIDE IN THE TREATMENT OF ACUTE DIARRHEA IN ADULTS (Prado D.) TREATMENT – Racecadotril: 100 mg, 3 times daily / Loperamide: 2 mg, 3 times daily

ANALYZED POPULATION – Racecadotril: 461 patients / Loperamide: 454 patients

Prado D. Scand J Gastroenterol 2002;37:656-61

ADULTS

A MULTINATIONAL COMPARISON OF RACECADOTRIL AND LOPERAMIDE IN THE TREATMENT OF ACUTE DIARRHEA IN ADULTS (Prado D.) Duration of Diarrhea P ro b a b ility o f u n re so lv e d d ia rrh e a (% )

100 90 80

R A C E C A D O T R I L (N = 4 7 3 ) L o p e r a m i d e (N = 4 7 1 )

70 60

P =N S

50 40 30 20 10 0

0

20

40

60

80

100

120

T im e t o re s o lu t io n (h o u r s) Prado D. Scand J Gastroenterol 2002;37:656-61

140

160

ADULTS

A MULTINATIONAL COMPARISON OF RACECADOTRIL AND LOPERAMIDE IN THE TREATMENT OF ACUTE DIARRHEA IN ADULTS (Prado D.) Treatment-related adverse events with an incidence of more than 1% 14

1 2 .5

% o f P a tie n ts

12 R A C E C A D O T R I L (n =4 7 3 ) L o p e r a m id e (n =4 7 2 )

10 8

6 .1

6 4

3.4 1.7

2

2 .3

0 .8

0 C o n st ip a t io n

Prado D. Scand J Gastroenterol 2002;37:656-61

A b d o m in a l e n la r g e m e n t

A n o re x ia

ADULTS

A MULTINATIONAL COMPARISON OF RACECADOTRIL AND LOPERAMIDE IN THE TREATMENT OF ACUTE DIARRHEA IN ADULTS (Prado D.) 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

RACECADOTRIL’S SAFETY AND TOLERABILITY PROFILE

SAFETY AND TOLERABILITY

PHARMACOVIGILANCE

Prevalence of adverse events associated with Racecadotril (France)

Adults Infants & Children

TOTAL

Period covered

# of reported adverse events

Prevalence

March 1993 to March 2007

75

0.00047 %

November 2000 to March 2007

30

0.00032 %

105

0.00042 %

Most common AE for adults and children: “Cutaneous disorders and miscellaneous allergic reactions”

13th Periodic Safety Update Report for Active Substance: Racecadotril. May 2007 Laboratoires Bioprojet Pharma.

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?

A. Re-infection with

m ot ic

ro l lp hi s

is

os

te ria ac B

0% ia rr he a

ife ra t

n. . a ith w n ct io ein fe R

0% io n

0%

D

a new bacteria/virus B. Bacterial proliferation C. This is osmotic Diarrhea

SAFETY AND TOLERABILITY

EFFECTS OF RACECADOTRIL AND LOPERAMIDE ON BACTERIAL PROLIFERATION (Duval-Iflah Y. et al.) E. Coli content of the proximal jejunum (gnotobiotic piglets) p =0 .0 4 p =0 .8 6

p =0 .0 0 5

120

1 0 6 E . C o li / g co n t e n t (m e d ia n )

120 100 80

R A CE CA D O T R IL C o n tro l L o p e ra m id e

60 40 20 0

1

4

Duval-Iflah Y. Et al.,Alimentary Pharmacology, 1999; (suppl. 6); 9-14

SAFETY AND TOLERABILITY

RACECADOTRIL DOES NOT CROSS THE BLOOD-BRAIN BARRIER Racecadotril Does not induce CNS Toxicity1,2,3 Does not impair mental performance4 Has no potential for abuse or physical dependence5

Blood-Brain Barrier

Carrier-mediated transport

Lipid soluble transport 1. Lecomte JM, Int.J. Of Antimicrobial Agents, 2000; 14:81-87 2. Scwartz J-C, Int.J. Of Antimicrobial Agents, 2000; 14:75-79 3. Duval-Iflah Y. Et al.,Alimentary Pharmacology, 1999; (suppl. 6): 9-14 4. Bergmann JF et al, Alimentary Pharmacology and Therapeutics, 1992; 6:305-313 5. Knisely JS,Drug and Alcohol Dependence,1989;23:143-151

Astrocyte processes

SAFETY AND TOLERABILITY

RACECADOTRIL HAS A HIGH THERAPEUTIC INDEX Therapeutic Index =

LD50

(median lethal dose)

ED50

(median effective dose)

The higher the Therapeutic Index, the lower the risk of overdose. Therapeutic dose

Relevance of high therapeutic index

100 mg TID (adults)

20 times this dose was given to healthy adults with no ill effects

Lecomte JM, Int.J. Of Antimicrobial Agents, 2000; 14:81-87

Case Number 2 A 20 y/o Female develops diarrhea, voluminous but not blood streaked. She is afebrile but dehydrated, your treatment of choice would be?

A. ORS/Fluid Replacement B. Racecadotril C. Loperamide D. Antibiotics

O

RS /

Fl u

id

s nt ib io t ic A

ra m id e pe

Lo

ec ac R

R

ep la

ce m

ad o

tri l

en t

0% 0% 0% 0%

Case Number 3 A 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?

A. Racecadotril B. Antibiotic C. Both

R

ot h

0% B

nt ib io t ic

0%

A

ac

ec

ad o

tri l

0%

Case Number 4 A 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?

A. Repeat Metronidazole at higher dose B. Ba Enema C. Colonoscopy D. Stool Exam

R

ep

xa m St oo

lE

op y os c

ol on

B

a

En C

ea tM et

ro ni d

az o

le

em

...

a

0% 0% 0% 0%

SUMMARY AND CONCLUSIONS

OVERALL CONCLUSIONS

RACECADOTRIL IN THE TREATMENT OF ACUTE DIARRHEA Prevention of Dehydration and Control of Diarrhea

Fluid replacement

Diarrhea

Diarrhea

Fluid replacement

Normalization

Racecadotril

OVERALL CONCLUSIONS

RACECADOTRIL VERSUS LOPERAMIDE Efficacy variable

Racecadotril

Loperamide

Motility1

-

+++

Secretion2

+++

+

Bacterial overgrowth1

-

+

Constipation2

-

++

CNS effects1

-

+

 

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

RACECADOTRIL 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. 2005 Racecadotril summary of product characteristics

OVERALL CONCLUSIONS

RACECADOTRIL Absorption

- Rapid

Maximum concentration - Maintained for at least four hours Concentration in plasma - Maintained for at least eight hours after administration

Racecadotril summary of product characteristics

OVERALL CONCLUSIONS

RACECADOTRIL 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: A Novel Approach in the Treatment of Acute Diarrhea

Thank you