Tiorfan / Hidrasec ®. Racecadotril INN N-(R,S)-[(acetylthio) methyl-1-oxo-3-phenylpropyl]-glycin benzyl ester Formula : C 21 H 23 NO 4 S Molecular weight.

Tiorfan / Hidrasec®

RacecadotrilINN

CH2 CH

CH2 - S - CO

CONH - CH2 - CO

CH3

O CH2

N-(R,S)-[(acetylthio) methyl-1-oxo-3-phenylpropyl]-glycin benzyl esterFormula : C21H23NO4SMolecular weight : 385

. Enkephalinase inhibitor (EC 3.4.24.11)

. Antidiarrheal agent

. Intestinal antisecretory activity

Racecadotril: in vivo metabolism

RacecadotrilRacecadotril :proof of concept / animal studies

BY CHOLERA TOXIN

. Dog jejunum . Rat jejunum

0 1 2 3 4 5 6hours-600

-400

-200

0

200

**

*

*

*

*

*

**

IDChol. Tox. + DMSOChol. Tox. + Racecadotril 2 mg /kgChol. Tox. + Racecadotril 10 mg/kg

Gleizes-Escala et al.Gastroenterol Biol Clin 1994;18:A63

BEFORE CHOLERA TOXIN

+1

+0,5

0

-0.5

-1

+100

0

-100

+50

-50

+4

0

-4

+2

-2

OH2 Na+ K+

* *

AFTER CHOLERA TOXIN

NaClRacecadotril

*

Primi et al.Aliment Pharmacol Ther 1999;13(suppl.6):3-7

HYDROELECTROLYTIC HYPERSECRETION INDUCED

Ne

t fl

ux

es

(m

l o

r m

Eq

/min

)

Ne

t w

ate

r fl

ux

(µ

l/3

0 c

m/h

)

Cholera toxin

Hinterleitner T, Petritsch W, Dimsity G, Bérard H, Lecomte JM and Krejs GJ. Eur J Gastroenterol Hepatol 1997; 9:887-91

RacecadotrilRacecadotrilINTESTINAL ANTISECRETORY ACTIVITY BOTH IN RAT AND MAN

*

0 1 2 3 4 5 6hours-600

-400

-200

0

200

*

*

*

*

*

*

**

ID

Cholera toxin + DMSOCholera toxin + Racecadotril 2 mg /kgCholera toxin + Racecadotril 10 mg/kg

*p<0.05

. Rat jejunum

Gleizes-Escala C, Fioramonti J, Bérard H, Bueno LGastroenterol Biol Clin 1994;18:A63

. Jejunal perfusion in human volunteer

Ne

t w

ate

r fl

ux

(µ

l/c

m/h

)

hours-300

-150

0

150

Control 1 2 3 4

Cholera toxin + Racecadotril 5 mg/kg [n = 6]

Cholera toxin [n = 4]

**

*p<0.05TC

Ne

t w

ate

r fl

ux

(m

l/3

0 c

m/h

)

CASTOR-OIL INDUCED EXPERIMENTAL DIARRHOEA

• rats • healthy volunteers

00 60 120 180

1

2

3

4

5

Time (min)

Vehicle

Racecadotril+ Naloxone

RacecadotrilLoperamide

500

400

300

200

100

0Time (hr)

2 4 6 8 10

Placebo

Racecadotril

Marçais-Collado et al.Eur J Pharmacol 1987; 144: 125-132

Baumer et al.,Gut 1992; 33: 753-58

**

*

**

**

RacecadotrilRacecadotrilS

too

l w

eig

ht

(g)

Sto

ol

wei

gh

t (g

)

PURE ANTISECRETORY INTESTINAL AGENTWITHOUT INHIBITORY EFFECT ON TRANSIT

Racecadotril

Placebo

Loperamide

MICE(charcoal meal test)

50

25

0

N.S.

** p<0.01

Marçais-Collado H, Uchida G, Schwartz JC,Lecomte JM. Eur J Pharmacol 1987;144: 125-32

Dis

tanc

e (%

)

300

200

100

0

HEALTHY VOLUNTEERS(salazopyrine) (radio-opaque marker)

N.S.N.S.

30

20

10

0

Bergmann JF, Chaussade S, Couturier D, Baumer Ph, Schwartz JC, Lecomte JMAliment Pharmacol Ther 1992;6: 305-313

Tim

e (h

r)

Tim

e (m

in)

Racecadotril: no motility inhibitionRacecadotril: no motility inhibition

Racecadotril: rapid onset of action

Enkephalinase inhibition kineticsin healthy volunteers

after a single oral dose (100 mg)

Stool weight at D1 in patients

En

ke

ph

ali

na

se

ac

tiv

ity

(p

mo

l/m

l/m

in)

400

300

200

100

0

500

0 30 60 120

**

**

****

240 480 24 hrs

Time (min)

** p < 0.01

550

*

450

300

400

350

500

* p = 0.02

Placebo

RacecadotrilStool weight (g)

Duchier J., NDA report, 1989 Hamza H, Ben Khelifa, Bérard H, Baumer Ph, Lecomte JM. Aliment Pharmacol Ther 1999;13(Suppl 6):15-19

RacecadotrilRacecadotril:: lack of motility effect lack of motility effect

. Absence of Absence of secondary constipation bacterial proliferation

Patients (%)

0

10

20

30

40

Secondary constipation

*p<0.02

*

Control

Loperamide

Racecadotril

Stomach10

17 18

4,3 1,2

120*

Jejunum

E. coli quantity (106/g content)*p<0.01

N.S. N.S.

Rogé J, Baumer Ph, Bérard H, Schwartz JC, Lecomte JM . Scand J Gastroenterol 1993;28:352-4

Duval Y et al.Aliment Pharmacol Ther 1999;13(suppl.6):9-14.

Newborn germ-free piglets

Racecadotril: high therapeutic index

• Therapeutic dose : 1.5 mg/kg t.i.d.

• 100 fold less than the dose with no toxic

effect in the 12 month toxicological study in

monkey

• 20 fold less than the highest dose given in

man (written in French SPC)

Racecadotril

1,883 subjects evaluated in clinical trials

1,439 subjects treated with racecadotril :

. at least 15 days : 840 . at least 1 month : 760 . at least 2 months : 194 . at least 3 months : 100

CLINICAL STUDIES IN ADULTS

RacecadotrilClinical studies in infants and children with acute diarrhea

Cézard’s study (Gastroenterology 2001) : A MULTICENTER, DOUBLE-BLIND, PLACEBO CONTROLLED STUDY IN ACUTE DIARRHEA OCCURING IN 172 HOSPITALIZED CHILDREN ; Turck’s study (Aliment Pharmacol Ther 1999) : MULTICENTER, DOUBLE BLIND VERSUS LOPERAMIDE STUDY IN ACUTE DIARRHEA OCCURINGIN 102 AMBULATORY CHILDREN ;

Salazar-Lindo’s study (N Engl J Med 2000) : EFFICACY AND SAFETY OF RACECADOTRIL IN THE TREATMENT OF 135 PERUVIAN HOSPITALIZED MALE CHILDREN WITH ACUTE DIARRHOEA ;

Cojocaru’s study (Arch Pediatr 2002) : The effect of racecadotril on the need for care in the treatment of acute diarrhea in 164 children ;

Debbabi and Ben Becher’s studies : 2 pharmacokinetics studies in Tunisia in young children hospitalized for acute diarrhea.

overall, 595 children were treated for acute diarrhea, 312 with racecadotril

RacecadotrilCézard’s study : A MULTICENTER, DOUBLE-BLIND, PLACEBO

CONTROLLED STUDY IN ACUTE DIARRHEA OCCURING IN 172 HOSPITALIZED CHILDREN

STUDY DESIGN. Parallel groups

INCLUSION CRITERIA. Hospitalized children from 3 months to 4 years. More than 3 loose stools per day. Onset of diarrhea of less than 3 days

TREATMENT. 1.5 mg/kg t.i.d.

POPULATION. Racecadotril : 86 patients. Placebo : 82 patients

EVALUATION CRITERIA. Stool output during the first 48 h or up to recovery (main criterion) . Stool output during the first 24 h. Duration of diarrhea. Dehydration status at 24 h (Urine Na / K ratio < 1)

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

Racecadotril

. Age [months]

. Sex : [M / F]

. Height [m]

. Weight [kg]

. Stool number [n]

. Duration of diarrhea

[days]

. Population with Rotavirus [%]

. Population with Adenovirus [%]

mean ± SEM

Characteristics of population at inclusion

Criteria Racecadotril[n = 89]

Placebo[n = 83]

P

12.0 ± 0.9 13.6 ± 1.0

0.73 ± 0.01 0.75 ± 0.01

NS

8.54 ± 0.25 9.27 ± 0.296.0 ± 0.3 6.5 ± 0.4

2.0 ± 0.2 1.9 ± 0.1

44 48

117

51 / 38 50 / 33 NS

NS

NS

NS

NS

NS

NS

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

Cézard’s study : A MULTICENTER, DOUBLE-BLIND, PLACEBO CONTROLLED STUDY IN ACUTE DIARRHEA OCCURING IN 172

HOSPITALIZED CHILDREN

Racecadotril

Cézard JP et alGastroenterology 2001;120:799-805.



Stool weight (g/hour) up to 48 hours (or recovery) for full data set and per-protocol population

(mean ± SEM).

Racecadotril

Placebo Racecadotril P

Stool output (g/h)during the first 48 h or up to recovery

Stool output (g/h) during the first 24 hor up to recovery

Frequency of dehydrationduring the first 24 h (%)

15.1 ± 14.7 < 0.001

< 0.05

24.153.3 0.001

At a dose of 1.5 mg/kg, t.i.d., racecadotril reduces significantly stool weight and resolves acute diarrhea very quickly [median = 8 h vs 26 h]

[n=82] [n=84]

[n=63] [n=58]

9.3 ± 11.6

18.2 ± 17.8 11.5 ± 15.8

Efficacy criteria




Racecadotril




Stool weight (g/hour) up to 48 hours (or recovery)

for rotavirus-positive and rotavirus-negative patients

(mean ± SEM).

Racecadotril

P

POPULATION WITH ROTAVIRUS AT INCLUSION

Placebo Racecadotril

Stool output (g/h)during the first 48 hor up to recovery

Stool output (g/h) during the first 24 hor up to recovery

19.6 ± 15.3 8.7 ± 6.90.001

20.1 ± 17.6 12.4 ± 16.5 < 0.01

7 h 0.02(Log Rank test)

Recovery rate [median]

36 h

[n=31] [n=24]

[n=31] [n=27]

Efficacy criteria




Racecadotril

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

Duration of diarrhea[median, hours]

Racecadotril[n = 32]

Placebo[n = 35] P

6.9 36 0.02

Cézard’s study : A MULTICENTER, DOUBLE-BLIND, PLACEBO CONTROLLED STUDY IN ACUTE DIARRHEA OCCURING

IN 172 HOSPITALIZED CHILDREN

Time to recovery in rotavirus-positive patients receiving racecadotril (n=32) or placebo (n=35)

RacecadotrilINN

48 HOUR STOOL OUTPUT / BODYWEIGHT (g/kg)

Racecadotril Placebo

All patients 92.2 (97.2) 169.6 (124.5) 45.6 %[n=68] [n=67]

Population

mean ± SD

Reduction by racecadotril

Rotavirus positive 104.6 (96.9) 194.7 (125.3) 46.3 %[n=34] [n=39]

With adjusted means (taking into account age and rotavirus) the estimated reduction was31 % (95% C.I. 16%-46%) (P = 0.0001). The per protocol analysis (n = 117) results = 33% reduction, 95% C.I. 17 % - 49%




Racecadotril

TOTAL STOOL OUTPUT / BODYWEIGHT (g/kg)


All patients 165.5 (220.2) 331.0 (320.9) 53.0 %[n=68] [n=67]

Population

mean ± SD



With adjusted means (taking into account age and rotavirus) the estimated reduction was38 % (95% C.I. 20%-56%) (P=0.0001).The per protocol analysis (n=117) results = 42 % reduction, 95% C.I. 21%-62%




RacecadotrilTurck’s study : MULTICENTER, DOUBLE BLIND VERSUS

LOPERAMIDE STUDY IN ACUTE DIARRHEA OCCURINGIN 102 AMBULATORY CHILDREN

STUDY DESIGN. Double placebo. Parallel groups

INCLUSION CRITERIA. Ambulatory children from 2 to 10 years. More than 3 loose stools in the last 24 h. Onset of diarrhea of less than 5 days

ANALYSED POPULATION. Racecadotril : 52 children. Loperamide : 50 children

EVALUATION CRITERIA. Number of diarrheic stools assessed from diary card (main criterion). Duration of diarrhea. Evolution of abdominal circumference

Turck D, Bérard H, Frétault N, Lecomte JM. Aliment Pharmacol Ther 1999 ;13(Suppl 6) :27-32

Racecadotril

Turck D, Bérard H, Frétault N, Lecomte JM. Aliment Pharmacol Ther 1999;13(Suppl 6) :27-32

Racecadotril Loperamide

. Stool number in the last 24 h

. Duration of diarrhea [days]

4.9 + 0.35.0 + 0.3

1.6 + 0.8 1.4 + 0.8

. Age [years]

4.8 + 0.3 4.7 + 0.3


P

NS

NS

NS

Turck’s study : MULTICENTER, DOUBLE BLIND VERSUS LOPERAMIDE STUDY IN ACUTE DIARRHEA OCCURING

IN 102 AMBULATORY CHILDREN

m ± SEM

Duration of diarrhea

Racecadotril

Loperamide

Racecadotril is as efficient as loperamide

0

5

10

15

Stool number

0

1

2

3

4

hour

s

Num

ber

of s

tool

s

Racecadotril

Turck D, Bérard H, Frétault N, Lecomte JM. Aliment Pharmacol Ther 1999;13(Suppl 6):27-32



Racecadotril

Loperamide

Racecadotril

Turck D, Bérard H, Frétault N, Lecomte JM. Aliment Pharmacol Ther 1999;13(Suppl 6):27-32

Racecadotril is better tolerated than loperamide

0

10

20

30

40

50

60

0

10

20

30

40

50

Constipated patients

*

*

Patients with a modification of concomitant

medications

P = 0.03

% o

f p

atie

nts

% o

f p

atie

nts

*



* P = 0.04

RacecadotrilINN

Salazar-Lindo’s study : EFFICACY AND SAFETY OF RACECADOTRIL IN THE TREATMENT OF 135 PERUVIAN

HOSPITALIZED MALE CHILDREN WITH ACUTE DIARRHOEA

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

TEST PRODUCTS . Racecadotril : 1.5 mg/kg, 3 times a day, every 8 hours (granulated powder) until

diarrhea stops or for a maximum of 5 days

EFFICACYMajor end point: 48-stool output (per kg of patient weight at inclusion)Other end points:. Total stool output i.e. sum of stool weights until diarrhea stops or during 5 days

(for patients not cured during 5 days). Duration of diarrhea. Number of cured patients. Total ORS intake

(A subgroup of patients with rotavirus was analysed separately according to the same criteria)

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

Racecadotril

SAFETY. Frequency of adverse events reported as per CRF

CRITERIA FOR INCLUSION. Acute diarrhea requiring hospitalization (because of some level of dehydration to be

corrected during the initial 4-6 hours)

. Diarrhea defined as 3 or more liquid stools during the last 24 hours and at least one during the observation period

. Excluding patients with diarrhea lasting for more than 5 days, blood in stools, severe

dehydration (requiring IV therapy) and other illness

Number of planned patients: 2 x 68

Number of analyzed cases :. Intention to treat analysis: 135 (all the patients that were randomized and treated). Per protocol analysis: 117 cases

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



Racecadotril

. Age [months] 13 (6.8) 12.5 (7.1)

. Height [cm] 74.9 (7.3) 73.9 (7.9)

. Weight [kg] 9.0 (1.7) 8.7 (2.1)

. Duration of diarrhea before inclusion [hrs] 47.4 (30.0) 51.5 (31.4)

. Stool number in the last 24 hours 8.6 (4.9) 9.7 (4.6)

Means (standard deviation)


CriteriaRacecadotril

[n = 68]Placebo[n = 67]




RacecadotrilSalazar-Lindo’s study : EFFICACY AND SAFETY OF

RACECADOTRIL IN THE TREATMENT OF 135 PERUVIAN HOSPITALIZED MALE CHILDREN WITH ACUTE DIARRHOEA

Salazar-Lindo E, Santisteban-Ponce J, Chea-Wood E and Guterriez M. N Engl J Med 2000;343:463 -7

48 hour stool output / bodyweight (g / kg)

Racecadotril


All patients 92.2 (97.2) 169.6 (124.5) 45.6 %[n=68] [n=67]

Population

Mean (SD)



With adjusted means (taking into account age and rotavirus),the estimated reduction was 31 % (95% C.I. 16 % - 46 %) (P = 0.0001).The per protocol analysis (n=117) results = 33 % reduction, 95% C.I. 17 % - 49 %

48 hour stool output / Bodyweight (g/kg)




RacecadotrilSalazar-Lindo’s study : EFFICACY AND SAFETY OF

RACECADOTRIL IN THE TREATMENT OF 135 PERUVIAN HOSPITALIZED MALE CHILDREN WITH ACUTE DIARRHOEA

Salazar-Lindo E, Santisteban-Ponce J, Chea-Wood E and Guterriez M. N Engl J Med 2000;343:463 -7

Total stool output / bodyweight (g / kg)

Racecadotril

With adjusted means (taking into account age and rotavirus),the estimated reduction was 38 % (95% C.I. 20 % - 56 %) (P=0.0001).The per protocol analysis (n=117) results = 42 % reduction, 95% C.I. 21 % - 62 %


All patients 156.5 (220.2) 331.0 (320.9) 53 %[n=68] [n=67]

Population

mean ± SD


Rotavirus positive 174.4 (21.8) 396.7 (353.0) 56 %[n=34] [n=37]

Total stool output / Bodyweight (g/kg)




Racecadotril

Duration of diarrhea (actuarial curves)




Racecadotril

Placebo

Racecadotril

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

Racecadotril vs placebo: Need for Rehydration

0

100

200

300

400

500

600

0

50

100

150

200

250

ORS intake / Day 1

658+/- 59 ml

295 ml / Kg

Total ORS intake (ml / Kg) *

439+/- 49 ml

OR

S:

ml

OR

S:

ml

/ K

g

Salazar-Lindo’s study : EFFICACY AND SAFETY OF RACECADOTRIL IN THE TREATMENT OF 135 PERUVIAN HOSPITALIZED MALE CHILDREN WITH ACUTE DIARRHOEA

152 ml / Kg

P = 0.0001

Racecadotril

There was no significant difference between groups in the

incidence of vomiting or in the total vomitis output.

Twelve patients, seven on racecadotril and five on placebo,

experienced unexpected events while on study medication. Only

four patients (all on racecadotril) had events possibly related to

treatment: mild hypokalaemia (2), ileus (1) and mild fever (1).




Tolerance

RacecadotrilCojocaru’s study : the effect of racecadotril on the need for care in the treatment of acute diarrhoea in children.

Racecadotril and rehydration was compared with rehydration alone

. Children aged 3 months to 3 years who had acute diarrhoea

. Evaluated in an emergency department (Hôpital Necker Enfants Malades, Paris, France).

Primary end point :

. Number of medical visits during the week after starting treatment.

Secondary end points :

. Number of stools during the first 48 hours

. Duration of the diarrhoea and the weight on day 7

Cojocaru B, Bocquet N, Timsit S, Wille C, Boursiquot C, Marcombes F, Garel D, Sannier N, Chéron G. Effet du racécadotril sur le recours aux soins dans le traitement des diarrhées aiguës du nourrisson et de l’enfant. Arch Pediatr (Paris) 2002 ; 8:774-9.


Clinical characteristics at admission

Cojocaru B, Bocquet N, Timsit S, Wille C, Boursiquot C, Marcombes F, Garel D, Sannier N, Chéron G. Arch Pediatr (Paris) 2002 ; 8:774-9.

Population Group racecadotril + rehydration

Group rehydration alone

Total number (M / F) 81 (51 / 33) 83 (43 / 40)

Age (months)* 12 ± 6.1 12.1 ± 7.2

Start of diarrhoea (h)* 41.5 ± 26.3 39.9 ± 28.3

Average number of stools in the previous 24 h 8.5 8.1

Weight loss in % 5.0 ± 3.9 5.0 ± 3.5

* = mean ± SD


Efficacy results

Cojocaru B, Bocquet N, Timsit S, Wille C, Boursiquot C, Marcombes F, Garel D, Sannier N, Chéron G. Arch Pediatr (Paris) 2002 ; 8:774-9.

Criteria * Group racecadotril + rehydration

Group rehydration

aloneP

Number of stools in the first 48 hours

6.8 ± 3.8 9.5 ± 4.5 < 0.001

Total duration of diarrhea (hours)

97.2 ± 35.6 137.7 ± 42.4 < 10 -9

* = mean ± SD

RacecadotrilCojocaru’s study : The effect of racecadotril on the need for care in the treatment of acute diarrhoea in children.

Further visits after Day 2racecadotril + rehydration

(n = 81)

rehydration alone

(n = 83)

P

Total 14 / 76 (18.4%) 27 / 78 (34.6%) < 0.05

Initial hydration

- PO 10 / 41 15 / 41 NS

- IV 4 / 35 12 / 37 < 0.05

Reason for consultation

- Same episode of diarrhoea 8 / 76 21 / 78 < 0.05

ConcernWorseningSecondary hospitalisation

622

8138

- Other reason 6 6

Days of hospitalisation for infusion(number of children)

37(37)

45(43)

RacecadotrilTOLERANCE : Number of children with adverse events

StudyPlacebo Racecadotril

Cézard 9 / 83 (11%) 9 / 89 (10%)

Turck - 6 / 52 (12%)

Salazar-Lindo 5 / 67 (7%) 7 / 68 (10%)

Debbabi 0 / 10 (0%)

Ben Becher 2 / 12 (17%)

Chéron 0 / 83 (0%) 6 / 81 (7%)

Total 14 / 233(6.0 % )

30 / 312(9.6 % )

RacecadotrilTOLERANCE

Severity of adverse events in paediatric Bioprojet studies

Severity (%)Placebo

( n = 150 )Racecadotril( n = 231 )

Mild 8 (5.3%) 10 (4.3%)

Moderate 7 (4.7%) 13 (5.6%)

Severe 1 (0.7%) 4 (1.7%)

Total 16 (10.7%) 27 (11.7%)

RacecadotrilPHARMACOVIGILANCE up to 31st December 2005

Number of patients treated in France by Tiorfan® sachets

10mg sachets 30mg sachets Overall Number of adverse events

(AE) *

Overall 5 029 608 3 500 488 8 530 096 20

* : number of AE with full declaration.The overall number of AE, with or without full declarations, was 24.

Safety management reports 24 adverse events, that is a prevalence less than 1 for 304 000 patients (0.000328%).The imputability was known for 13 case reports (among 18 full declarations) : 2 times "I4" (very likely), 2 times "I3" (likely), 3 times "I2" (plausible) and 7 times "I1" (dubious).

RacecadotrilCONCLUSION from RECOMMANDATIONS in

“Drug therapy of infant and child infectious acute diarrhea” * :

Gastro-paediatricians from: Algeria, Belgium, Canada, Congo, Croatia, France, Gabon, Italy, Lebanon, Morocco, Romania, Spain, Switzerland, Syria, Tunisia, Turkey & Vietnam

Rehydration is the main objective of AD management

Early food intake (4 hours) should be initiated with previous milk, except specific situations (breast-feeding, etc..)

Among antidiarrheic drugs currently marketed, only very few ones have been properly assessed (DB vsPc, Stool output)

* Cézard JP, Chouraqui JP, Girardet JP, Gottrand F et le Groupe francophone d’hépatologie, gastroentérologie et nutrition pédiatriques. Traitement médicamenteux des diarrhées aiguës

infectieuses du nourrisson et de l’enfant. Arch Pédiatr 2002 ; 9 : 620 – 8.

RacecadotrilCONCLUSION from RECOMMANDATIONS in


“Le racécadotril est le seul médicament à avoir démontré une diminution significative du débit des selles” =

“ Racecadotril is the only drug that induces a demonstrated and significant decrease in stool output”.

Fast onset of action (24th Hour) and very significant (-60%, p< 0.001) on stool output, including Rotavirus diarrhea,

Other drugs have only a symptomatic effect (if any), and should not be prescribed without family warnings about dehydration.

* Cézard JP, Chouraqui JP, Girardet JP, Gottrand F et le Groupe francophone d’hépatologie, gastroentérologie et nutrition pédiatriques. Traitement médicamenteux des diarrhées aiguës

infectieuses du nourrisson et de l’enfant. Arch Pédiatr 2002 ; 9 : 620 – 8.

RacecadotrilEvents following RECOMMANDATIONS in


French Health Authorities decided the delisting of many antidiarrheic drugs, including all yeasts (Saccharomyces boulardii, Lactobacillus acidophilus, etc.), clays (Bedelix), coals & coal-derived products (Off. Journal of French Rep., 29 Jan 2006)

The Canadian Paediatric Society included in it’s official guidelines: Racecadotril, an antisecretoty drug, is safe and effective and can be used routinely in children for treatment of watery diarrhea (evidence: level I, B), (Paed Child Health, 7 Sep

2003).

The Racecadotril file has been reassessed by the French Transparency Commission, which upheld the reimbursement status of Tiorfan, (HAS, 7 Sep 2005).

Tiorfan / Hidrasec ®. Racecadotril INN N-(R,S)-[(acetylthio) methyl-1-oxo-3-phenylpropyl]-glycin benzyl ester Formula : C 21 H 23 NO 4 S Molecular weight.

Documents

racecadotril racecadotril

metabolism slide

racecadotril inn nr

tiorfan hidrasec slide

rat jejunum

brard h

net fluxes

dog jejunum