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Tiorfan / Hidrasec®
RacecadotrilINN
O
CONH - CH2 - C
CH2
CH
O
O CH2
CH2 - S - C
CH3
N-(R,S)-[(acetylthio) methyl-1-oxo-3-phenylpropyl]-glycin benzyl ester
Formula : C21H23NO4S
Molecular weight : 385
. Enkephalinase inhibitor (EC 3.4.24.11)
. Antidiarrheal agent
. Intestinal antisecretory activity
Racecadotril: in vivo metabolism
Racecadotril
:proof of concept / animal
studies
HYDROELECTROLYTIC HYPERSECRETION INDUCED
BY CHOLERA TOXIN
. Dog jejunum
. Rat jejunum
200
+1
OH2
+50
+0,5
0
-0.5
-1
+100
Na+
+2
0
*
-50
+4
K+
0
*
-100
-2
*
-4
AFTER CHOLERA TOXIN
NaCl
Racecadotril
Cholera toxin
Primi et al.
Aliment Pharmacol Ther 1999;13(suppl.6):3-7
Net water flux (µl/30 cm/h)
Net fluxes (ml or mEq/min)
BEFORE CHOLERA TOXIN
*
0
*
*
*
*
*
-200
*
*
-400
-600
0 ID 1
2
3
4
Chol. Tox. + DMSO
Chol. Tox. + Racecadotril 2 mg /kg
Chol. Tox. + Racecadotril 10 mg/kg
Gleizes-Escala et al.
Gastroenterol Biol Clin 1994;18:A63
5
*
6
hours
Racecadotril
INTESTINAL ANTISECRETORY ACTIVITY BOTH IN RAT AND MAN
. Rat jejunum
. Jejunal perfusion in human volunteer
150
*
0
*
*
*
*
Net water flux (ml/30 cm/h)
Net water flux (µl/cm/h)
200
*
-200
*
*
*
-400
-600
0 ID 1
hours
2
3
4
5
Cholera toxin + DMSO
Cholera toxin + Racecadotril 2 mg /kg
Cholera toxin + Racecadotril 10 mg/kg
0
-150
*
-300
6
*p<0.05
hours
TC
Control 1
2
3
4
*p<0.05
Cholera toxin + Racecadotril 5 mg/kg [n = 6]
Cholera toxin [n = 4]
Gleizes-Escala C, Fioramonti J, Bérard H, Bueno L
Gastroenterol Biol Clin 1994;18:A63
Hinterleitner T, Petritsch W, Dimsity G, Bérard H, Lecomte JM
and Krejs GJ. Eur J Gastroenterol Hepatol 1997; 9:887-91
Racecadotril
CASTOR-OIL INDUCED EXPERIMENTAL DIARRHOEA
• rats
• healthy volunteers
5
3
2
Racecadotril
Loperamide
200
0
0
120
180 Time (min)
Marçais-Collado et al.
Eur J Pharmacol 1987; 144: 125-132
**
Racecadotril
*
100
60
**
300
1
0
Placebo
400
Stool weight (g)
Racecadotril
+ Naloxone
4
Stool weight (g)
500
Vehicle
**
Time (hr)
2
4
Baumer et al.,
Gut 1992; 33: 753-58
6
8
10
Racecadotril: no motility inhibition
PURE ANTISECRETORY INTESTINAL AGENT
WITHOUT INHIBITORY EFFECT ON TRANSIT
MICE
HEALTHY VOLUNTEERS
(charcoal meal test)
(salazopyrine) (radio-opaque marker)
N.S.
300
Placebo
Racecadotril
25
Loperamide
200
20
100
0
Marçais-Collado H, Uchida G, Schwartz JC,
Lecomte JM. Eur J Pharmacol 1987;144: 125-32
0
Time (hr)
*
N.S.
30
* p<0.01
Time (min)
Distance (%)
50
N.S.
10
0
Bergmann JF, Chaussade S, Couturier D, Baumer Ph,
Schwartz JC, Lecomte JM
Aliment Pharmacol Ther 1992;6: 305-313
Racecadotril: rapid onset of action
Enkephalinase inhibition kinetics
in healthy volunteers
after a single oral dose (100 mg)
Stool weight at D1 in patients
Enkephalinase activity (pmol/ml/min)
Placebo
Stool weight (g)
Racecadotril
500
550
400
500
300
450
* p = 0.02
200
100
400
**
** p < 0.01
**
**
*
350
**
Time (min)
0
0 30 60 120
240
Duchier J., NDA report, 1989
480
300
24 hrs
Hamza H, Ben Khelifa, Bérard H, Baumer Ph,
Lecomte JM. Aliment Pharmacol Ther
1999;13(Suppl 6):15-19
Racecadotril
:
lack of motility effect
. Absence of
secondary constipation
Absence of
bacterial proliferation
Newborn germ-free piglets
Patients (%)
40
N.S.
17
30
N.S.
18
10
Control
20
Stomach
Loperamide
120*
Racecadotril
10
*
Jejunum
4,3
0
1,2
*p<0.02
Secondary constipation
Rogé J, Baumer Ph, Bérard H, Schwartz JC, Lecomte
JM . Scand J Gastroenterol 1993;28:352-4
*p<0.01
E. coli quantity (106/g content)
Duval Y et al.
Aliment Pharmacol Ther 1999;13(suppl.6):9-14.
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
CLINICAL STUDIES IN ADULTS
1,883 subjects evaluated in clinical trials
1,439 subjects treated with racecadotril :
. at least 15 days
. at least 1 month
. at least 2 months
. at least 3 months
:
:
:
:
840
760
194
100
Racecadotril
Clinical studies in infants and children with acute diarrhea
 Cézard’s study (Gastroenterology 2001) : A MULTICENTER, DOUBLEBLIND, 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 OCCURING
IN 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
Racecadotril
Cézard’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
Cézard’s study : A MULTICENTER, DOUBLE-BLIND, PLACEBO
CONTROLLED STUDY IN ACUTE DIARRHEA OCCURING IN 172
HOSPITALIZED CHILDREN
Characteristics of population at inclusion
Criteria
.
.
.
.
.
.
Age [months]
Sex : [M / F]
Height [m]
Weight [kg]
Stool number [n]
Duration of diarrhea
[days]
. Population with
Rotavirus [%]
. Population with
Adenovirus [%]
Racecadotril
Placebo
[n = 89]
[n = 83]
P
12.0 ± 0.9
51 / 38
0.73 ± 0.01
13.6 ± 1.0
50 / 33
NS
NS
0.75 ± 0.01
NS
8.54 ± 0.25
6.0 ± 0.3
9.27 ± 0.29
6.5 ± 0.4
NS
NS
2.0 ± 0.2
1.9 ± 0.1
NS
44
48
NS
7
11
NS
mean ± SEM
Cézard JP et al. Gastroenterology 2001 ;120:799-805.
Racecadotril
Cézard’s study : A MULTICENTER, DOUBLE-BLIND, PLACEBO
CONTROLLED STUDY IN ACUTE DIARRHEA OCCURING IN 172
HOSPITALIZED CHILDREN
Stool weight (g/hour) up to 48
hours (or recovery) for full data
set and per-protocol population
(mean ± SEM).
Cézard JP et al
Gastroenterology 2001;120:799-805.
Racecadotril
Cézard’s study : A MULTICENTER, DOUBLE-BLIND, PLACEBO
CONTROLLED STUDY IN ACUTE DIARRHEA OCCURING IN 172
HOSPITALIZED CHILDREN
Efficacy criteria
Placebo
Stool output (g/h)
during the first 48 h
or up to recovery
15.1 ± 14.7
9.3 ± 11.6
[n=82]
[n=84]
18.2 ± 17.8
11.5 ± 15.8
[n=63]
[n=58]
Stool output (g/h)
during the first 24 h
or up to recovery
Frequency of dehydration
during the first 24 h (%)
53.3
Racecadotril
24.1
P
< 0.001
< 0.05
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]
Cézard JP et al. Gastroenterology 2001;120:799-805.
Racecadotril
Cézard’s study : A MULTICENTER, DOUBLE-BLIND, PLACEBO
CONTROLLED STUDY IN ACUTE DIARRHEA OCCURING IN 172
HOSPITALIZED CHILDREN
Stool weight (g/hour) up to 48
hours (or recovery)
for rotavirus-positive and
rotavirus-negative patients
(mean ± SEM).
Cézard JP et al. Gastroenterology 2001;120:799-805.
Racecadotril
Cézard’s study : A MULTICENTER, DOUBLE-BLIND, PLACEBO
CONTROLLED STUDY IN ACUTE DIARRHEA OCCURING IN 172
HOSPITALIZED CHILDREN
POPULATION WITH ROTAVIRUS AT INCLUSION
Placebo
Racecadotril
Stool output (g/h)
during the first 48 h
or up to recovery
19.6 ± 15.3
8.7 ± 6.9
[n=31]
[n=24]
Stool output (g/h)
during the first 24 h
or up to recovery
20.1 ± 17.6
Efficacy criteria
Recovery rate
[median]
12.4 ± 16.5
[n=31]
[n=27]
36 h
7h
Cézard JP et al. Gastroenterology 2001;120:799-805.
P
0.001
< 0.01
0.02
(Log Rank test)
Racecadotril
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)
Duration of diarrhea
[median, hours]
Racecadotril
Placebo
[n = 32]
[n = 35]
P
6.9
36
0.02
Cézard JP et al.
Gastroenterology 2001;120:799-805.
RacecadotrilINN
Cézard’s study : A MULTICENTER, DOUBLE-BLIND, PLACEBO
CONTROLLED STUDY IN ACUTE DIARRHEA OCCURING IN 172
HOSPITALIZED CHILDREN
48 HOUR STOOL OUTPUT / BODYWEIGHT (g/kg)
Population
All patients
Racecadotril
92.2 (97.2)
[n=68]
Rotavirus positive
104.6 (96.9)
[n=34]
Placebo
169.6 (124.5)
Reduction by
racecadotril
45.6 %
[n=67]
194.7 (125.3)
46.3 %
[n=39]
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%
Cézard JP et al. Gastroenterology 2001;120:799-805.
Racecadotril
Cézard’s study : A MULTICENTER, DOUBLE-BLIND, PLACEBO
CONTROLLED STUDY IN ACUTE DIARRHEA OCCURING IN 172
HOSPITALIZED CHILDREN
TOTAL STOOL OUTPUT / BODYWEIGHT (g/kg)
Population
All patients
Racecadotril
Placebo
165.5 (220.2)
331.0 (320.9)
[n=68]
Rotavirus positive
174.4 (21.8)
[n=34]
Reduction by
racecadotril
53.0 %
[n=67]
369.7 (353.0)
56.0 %
[n=37]
mean ± SD
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%
Cézard JP et al. Gastroenterology 2001;120:799-805.
Racecadotril
Turck’s study : MULTICENTER, DOUBLE BLIND VERSUS
LOPERAMIDE STUDY IN ACUTE DIARRHEA OCCURING
IN 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’s study : MULTICENTER, DOUBLE BLIND VERSUS
LOPERAMIDE STUDY IN ACUTE DIARRHEA OCCURING
IN 102 AMBULATORY CHILDREN
Characteristics of population at inclusion
Racecadotril
Loperamide
P
. Stool number in the last 24 h
5.0 + 0.3
4.9 + 0.3
NS
. Duration of diarrhea [days]
1.6 + 0.8
1.4 + 0.8
NS
. Age [years]
4.8 + 0.3
4.7 + 0.3
NS
m ± SEM
Turck D, Bérard H, Frétault N, Lecomte JM. Aliment Pharmacol Ther 1999;13(Suppl 6) :27-32
Racecadotril
Turck’s study : MULTICENTER, DOUBLE BLIND VERSUS
LOPERAMIDE STUDY IN ACUTE DIARRHEA OCCURING
IN 102 AMBULATORY CHILDREN
hours
15
Racecadotril
Loperamide
10
5
0
Number of stools
4
3
2
1
0
Duration of diarrhea
Stool number
Racecadotril is as efficient as loperamide
Turck D, Bérard H, Frétault N, Lecomte JM. Aliment Pharmacol Ther 1999;13(Suppl 6):27-32
Racecadotril
Turck’s study : MULTICENTER, DOUBLE BLIND VERSUS
LOPERAMIDE STUDY IN ACUTE DIARRHEA OCCURING
IN 102 AMBULATORY CHILDREN
*
60
*
50
*
P = 0.03
Racecadotril
40
Loperamide
30
20
% of patients
% of patients
50
P = 0.04
40
*
30
20
10
10
0
0
Patients with a
modification of concomitant
medications
Racecadotril is better tolerated than loperamide
Constipated patients
Turck D, Bérard H, Frétault N, Lecomte JM. Aliment Pharmacol Ther 1999;13(Suppl 6):27-32
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
EFFICACY
Major 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
Salazar-Lindo’s study : EFFICACY AND SAFETY OF
RACECADOTRIL IN THE TREATMENT OF 135 PERUVIAN
HOSPITALIZED MALE CHILDREN WITH ACUTE DIARRHOEA
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
Salazar-Lindo’s study : EFFICACY AND SAFETY OF
RACECADOTRIL IN THE TREATMENT OF 135 PERUVIAN
HOSPITALIZED MALE CHILDREN WITH ACUTE DIARRHOEA
Characteristics of population at inclusion
Racecadotril
Placebo
[n = 68]
[n = 67]
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)
Criteria
. Age [months]
. Duration of diarrhea before inclusion [hrs] 47.4 (30.0)
. Stool number in the last 24 hours
8.6 (4.9)
Means (standard deviation)
Salazar-Lindo E, Santisteban-Ponce J, Chea-Wood E and Guterriez M.
N Engl J Med 2000;343:463-467
51.5 (31.4)
9.7 (4.6)
Racecadotril
Salazar-Lindo’s study : EFFICACY AND SAFETY OF
RACECADOTRIL IN THE TREATMENT OF 135 PERUVIAN
HOSPITALIZED MALE CHILDREN WITH ACUTE DIARRHOEA
48 hour stool output /
bodyweight (g / kg)
Salazar-Lindo E, SantistebanPonce J, Chea-Wood E and
Guterriez M.
N Engl J Med 2000;343:463 -7
Racecadotril
Salazar-Lindo’s study : EFFICACY AND SAFETY OF
RACECADOTRIL IN THE TREATMENT OF 135 PERUVIAN
HOSPITALIZED MALE CHILDREN WITH ACUTE DIARRHOEA
48 hour stool output / Bodyweight (g/kg)
Population
All patients
Racecadotril
92.2 (97.2)
[n=68]
Rotavirus positive
104.6 (96.9)
[n=34]
Placebo
169.6 (124.5)
Reduction by
racecadotril
45.6 %
[n=67]
194.7 (125.3)
46.3 %
[n=39]
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 %
Salazar-Lindo E, Santisteban-Ponce J, Chea-Wood E and Guterriez M.
N Engl J Med 2000;343:463-467
Racecadotril
Salazar-Lindo’s study : EFFICACY AND SAFETY OF
RACECADOTRIL IN THE TREATMENT OF 135 PERUVIAN
HOSPITALIZED MALE CHILDREN WITH ACUTE DIARRHOEA
Total stool output /
bodyweight (g / kg)
Salazar-Lindo E, SantistebanPonce J, Chea-Wood E and
Guterriez M.
N Engl J Med 2000;343:463 -7
Racecadotril
Salazar-Lindo’s study : EFFICACY AND SAFETY OF
RACECADOTRIL IN THE TREATMENT OF 135 PERUVIAN
HOSPITALIZED MALE CHILDREN WITH ACUTE DIARRHOEA
Total stool output / Bodyweight (g/kg)
Population
All patients
Racecadotril
Placebo
Reduction by
racecadotril
156.5 (220.2)
331.0 (320.9)
53 %
[n=67]
[n=68]
Rotavirus positive
174.4 (21.8)
396.7 (353.0)
[n=34]
56 %
[n=37]
mean ± SD
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 %
Salazar-Lindo E, Santisteban-Ponce J, Chea-Wood E and Guterriez M.
N Engl J Med 2000;343:463-467
Racecadotril
Salazar-Lindo’s study : EFFICACY AND SAFETY OF
RACECADOTRIL IN THE TREATMENT OF 135 PERUVIAN
HOSPITALIZED MALE CHILDREN WITH ACUTE DIARRHOEA
Duration of diarrhea (actuarial curves)
Salazar-Lindo E, Santisteban-Ponce J, Chea-Wood E and Guterriez M.
N Engl J Med 2000;343:463-467
Racecadotril
Salazar-Lindo’s study : EFFICACY AND SAFETY OF RACECADOTRIL IN THE TREATMENT OF
135 PERUVIAN HOSPITALIZED MALE CHILDREN WITH ACUTE DIARRHOEA
295 ml / Kg
658+/- 59 ml
600
500 439+/- 49 ml
ORS: ml
Racecadotril
400
Placebo
300
200
ORS: ml / Kg
250
200
152 ml / Kg
150
100
P = 0.0001
50
100
0
0
ORS intake / Day 1
Total ORS intake (ml / Kg) *
Racecadotril vs placebo: Need for Rehydration
Salazar-Lindo E, Santisteban-Ponce J, Chea-Wood E and Guterriez M.
N Engl J Med 2000; 343:463-467 , and * Expert Report
Racecadotril
Salazar-Lindo’s study : EFFICACY AND SAFETY OF
RACECADOTRIL IN THE TREATMENT OF 135 PERUVIAN
HOSPITALIZED MALE CHILDREN WITH ACUTE DIARRHOEA
Tolerance
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).
Salazar-Lindo E, Santisteban-Ponce J, Chea-Wood E and Guterriez M. N Engl J Med 2000;343:463-467
Racecadotril
Cojocaru’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.
Racecadotril
Cojocaru’s study : the effect of racecadotril on the need
for care in the treatment of acute diarrhoea in children.
Clinical characteristics at admission
Population
Group
Group rehydration
racecadotril +
alone
rehydration
Total number (M / F)
81 (51 / 33)
83 (43 / 40)
12 ± 6.1
12.1 ± 7.2
41.5 ± 26.3
39.9 ± 28.3
8.5
8.1
5.0 ± 3.9
5.0 ± 3.5
Age (months)*
Start of diarrhoea (h)*
Average number of stools in the previous 24 h
Weight loss in %
* = mean ± SD
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.
Racecadotril
Cojocaru’s study : the effect of racecadotril on the need
for care in the treatment of acute diarrhoea in children.
Efficacy results
Criteria *
Number of stools in the
first 48 hours
Total duration of diarrhea
(hours)
Group
racecadotril +
rehydration
Group
rehydration
alone
P
6.8 ± 3.8
9.5 ± 4.5
< 0.001
97.2 ± 35.6
137.7 ± 42.4
< 10 -9
* = mean ± SD
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.
Racecadotril
Cojocaru’s study : The effect of racecadotril on the need
for care in the treatment of acute diarrhoea in children.
Further visits after Day 2
racecadotril +
rehydration
(n = 81)
rehydration
alone
(n = 83)
P
14 / 76 (18.4%)
27 / 78 (34.6%)
< 0.05
- PO
10 / 41
15 / 41
NS
- IV
4 / 35
12 / 37
< 0.05
8 / 76
21 / 78
< 0.05
6
2
2
8
13
8
6
6
37
(37)
45
(43)
Total
Initial hydration
Reason for consultation
- Same episode of diarrhoea
Concern
Worsening
Secondary hospitalisation
- Other reason
Days of hospitalisation for infusion
(number of children)
Racecadotril
TOLERANCE : Number of children with adverse events
Placebo
Racecadotril
9 / 83 (11%)
9 / 89 (10%)
-
6 / 52 (12%)
5 / 67 (7%)
7 / 68 (10%)
Study
Cézard
Turck
Salazar-Lindo
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 % )
Racecadotril
TOLERANCE
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%)
Racecadotril
PHARMACOVIGILANCE up to 31st December 2005
Number of patients treated in France by Tiorfan® sachets
Overall
10mg sachets
30mg sachets
Overall
Number of
adverse events
(AE) *
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).
Racecadotril
CONCLUSION 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.
Racecadotril
CONCLUSION from RECOMMANDATIONS in
“Drug therapy of infant and child infectious acute diarrhea” * :
“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.
Racecadotril
Events following RECOMMANDATIONS in
“Drug therapy of infant and child infectious acute diarrhea” * :
 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).