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Tiorfan / Hidrasec ®

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 : 385. . Enkephalinase inhibitor (EC 3.4.24.11) . Antidiarrheal agent . Intestinal antisecretory activity.

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Tiorfan / Hidrasec ®

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  1. Tiorfan / Hidrasec®

  2. RacecadotrilINN N-(R,S)-[(acetylthio) methyl-1-oxo-3-phenylpropyl]-glycin benzyl ester Formula : C21H23NO4SMolecular weight : 385 . Enkephalinase inhibitor (EC 3.4.24.11). Antidiarrheal agent. Intestinal antisecretory activity

  3. Racecadotril: in vivo metabolism

  4. Racecadotril :proof of concept / animal studies HYDROELECTROLYTIC HYPERSECRETION INDUCED BY CHOLERA TOXIN . Dog jejunum . Rat jejunum 200 BEFORE CHOLERA TOXIN * * Na+ OH2 K+ +1 +100 +4 * * * 0 * +50 +2 +0,5 -200 Net fluxes (ml or mEq/min) * Net water flux (µl/30 cm/h) 0 0 0 * * * -400 * * -0.5 -50 -2 -600 hours -4 -1 -100 0 3 5 6 1 2 4 ID AFTER CHOLERA TOXIN Chol. Tox. + DMSO Chol. Tox. + Racecadotril 2 mg /kg Cholera toxin NaCl Chol. Tox. + Racecadotril 10 mg/kg Racecadotril Primi et al.Aliment Pharmacol Ther 1999;13(suppl.6):3-7 Gleizes-Escala et al.Gastroenterol Biol Clin 1994;18:A63

  5. 150 0 Net water flux (ml/30 cm/h) -150 * -300 hours TC *p<0.05 1 2 3 4 Control Cholera toxin + Racecadotril5 mg/kg [n = 6] Cholera toxin [n = 4] Racecadotril INTESTINAL ANTISECRETORY ACTIVITY BOTH IN RAT AND MAN . Rat jejunum . Jejunal perfusion in human volunteer 200 * * * * * 0 * -200 Net water flux (µl/cm/h) * * * -400 -600 hours 0 ID 1 4 5 2 3 6 *p<0.05 Cholera toxin + DMSO Cholera toxin + Racecadotril 2 mg /kg • Cholera toxin + Racecadotril 10 mg/kg Hinterleitner T, Petritsch W, Dimsity G, Bérard H, Lecomte JM and Krejs GJ. Eur J Gastroenterol Hepatol 1997; 9:887-91 Gleizes-Escala C, Fioramonti J, Bérard H, Bueno LGastroenterol Biol Clin 1994;18:A63

  6. Racecadotril CASTOR-OIL INDUCED EXPERIMENTAL DIARRHOEA • rats • healthy volunteers 500 Placebo 5 Vehicle Racecadotril + Naloxone 4 400 ** ** 300 3 Racecadotril Stool weight (g) * Stool weight (g) 2 200 ** Racecadotril Loperamide 100 1 Time (hr) 0 0 Time (min) 4 10 2 6 180 8 60 120 0 Baumer et al., Gut 1992; 33: 753-58 Marçais-Collado et al. Eur J Pharmacol 1987; 144: 125-132

  7. MICE HEALTHY VOLUNTEERS (charcoal meal test) (salazopyrine) (radio-opaque marker) N.S. N.S. N.S. 300 50 30 * p<0.01 Placebo * 200 Time (min) Time (hr) Distance (%) 20 25 Loperamide 100 10 0 0 0 Bergmann JF, Chaussade S, Couturier D, Baumer Ph, Schwartz JC, Lecomte JM Aliment Pharmacol Ther 1992;6: 305-313 Marçais-Collado H, Uchida G, Schwartz JC, Lecomte JM. Eur J Pharmacol 1987;144: 125-32 Racecadotril: no motility inhibition PURE ANTISECRETORY INTESTINAL AGENTWITHOUT INHIBITORY EFFECT ON TRANSIT Racecadotril

  8. 550 500 450 * p = 0.02 400 * 350 300 Racecadotril: rapid onset of action Enkephalinase inhibition kineticsin healthy volunteers after a single oral dose (100 mg) Stool weight at D1 in patients Placebo Stool weight (g) Racecadotril 500 400 300 Enkephalinase activity (pmol/ml/min) 200 ** ** p < 0.01 ** ** 100 ** Time (min) 0 24 hrs 480 0 60 120 240 30 Duchier J., NDA report, 1989 Hamza H, Ben Khelifa, Bérard H, Baumer Ph, Lecomte JM. Aliment Pharmacol Ther 1999;13(Suppl 6):15-19

  9. Patients (%) 40 30 Control 20 Loperamide Racecadotril * 10 *p<0.02 0 Secondary constipation Racecadotril: lack of motility effect . Absence of Absence of secondary constipation bacterial proliferation Newborn germ-free piglets N.S. N.S. 18 17 10 Stomach 120* Jejunum 4,3 1,2 *p<0.01 E. coli quantity (106/g content) 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.

  10. 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)

  11. Racecadotril CLINICAL STUDIES IN ADULTS 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

  12. Racecadotril • Clinical 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

  13. 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.

  14. Characteristics of population at inclusion Racecadotril [n = 89] Placebo [n = 83] P Criteria . Age [months] . Sex : [M / F] . Height [m] . Weight [kg] . Stool number [n] . Duration of diarrhea [days] . Population with Rotavirus [%] . Population with Adenovirus [%] mean ± SEM NS 12.0 ± 0.9 13.6 ± 1.0 NS 50 / 33 51 / 38 NS 0.73 ± 0.01 0.75 ± 0.01 NS 8.54 ± 0.25 9.27 ± 0.29 NS 6.0 ± 0.3 6.5 ± 0.4 2.0 ± 0.2 NS 1.9 ± 0.1 44 48 NS NS 11 7 Racecadotril Cézard’s study : A MULTICENTER, DOUBLE-BLIND, PLACEBO CONTROLLED STUDY IN ACUTE DIARRHEA OCCURING IN 172 HOSPITALIZED CHILDREN Cézard JP et al. Gastroenterology 2001 ;120:799-805.

  15. 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.

  16. Racecadotril Cézard’s study : A MULTICENTER, DOUBLE-BLIND, PLACEBO CONTROLLED STUDY IN ACUTE DIARRHEA OCCURING IN 172 HOSPITALIZED CHILDREN Efficacy criteria Racecadotril Placebo P Stool output (g/h) during the first 48 h or up to recovery 9.3 ± 11.6 15.1 ± 14.7 < 0.001 [n=84] [n=82] Stool output (g/h) during the first 24 h or up to recovery 11.5 ± 15.8 18.2 ± 17.8 < 0.05 [n=63] [n=58] Frequency of dehydration during the first 24 h (%) 53.3 24.1 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.

  17. 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.

  18. POPULATION WITH ROTAVIRUS AT INCLUSION Placebo Racecadotril Efficacy criteria Stool output (g/h) during the first 48 h or up to recovery 19.6 ± 15.3 8.7 ± 6.9 0.001 [n=24] [n=31] Stool output (g/h) during the first 24 h or up to recovery 20.1 ± 17.6 12.4 ± 16.5 < 0.01 [n=31] [n=27] Recovery rate [median] 7 h 0.02 (Log Rank test) 36 h Racecadotril Cézard’s study : A MULTICENTER, DOUBLE-BLIND, PLACEBO CONTROLLED STUDY IN ACUTE DIARRHEA OCCURING IN 172 HOSPITALIZED CHILDREN P Cézard JP et al. Gastroenterology 2001;120:799-805.

  19. 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 [n = 32] Placebo [n = 35] P 6.9 36 0.02 Cézard JP et al. Gastroenterology 2001;120:799-805.

  20. 48 HOUR STOOL OUTPUT / BODYWEIGHT (g/kg) Reduction by racecadotril Racecadotril Placebo Population 169.6 (124.5) 45.6 % 92.2 (97.2) All patients [n=67] [n=68] 194.7 (125.3) 46.3 % 104.6 (96.9) Rotavirus positive [n=39] [n=34] 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% RacecadotrilINN Cézard’s study : A MULTICENTER, DOUBLE-BLIND, PLACEBO CONTROLLED STUDY IN ACUTE DIARRHEA OCCURING IN 172 HOSPITALIZED CHILDREN Cézard JP et al. Gastroenterology 2001;120:799-805.

  21. Reduction by racecadotril Racecadotril Placebo Population 331.0 (320.9) 53.0 % 165.5 (220.2) All patients [n=67] [n=68] 369.7 (353.0) 56.0 % 174.4 (21.8) Rotavirus positive [n=37] [n=34] 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% 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) Cézard JP et al. Gastroenterology 2001;120:799-805.

  22. Racecadotril Turck’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

  23. Racecadotril Turck’s study : MULTICENTER, DOUBLE BLIND VERSUS LOPERAMIDE STUDY IN ACUTE DIARRHEA OCCURINGIN 102 AMBULATORY CHILDREN Characteristics of population at inclusion Racecadotril Loperamide P 4.9 + 0.3 5.0 + 0.3 . Stool number in the last 24 h NS . Duration of diarrhea [days] 1.6 + 0.8 1.4 + 0.8 NS NS 4.8 + 0.3 4.7 + 0.3 . Age [years] m ± SEM Turck D, Bérard H, Frétault N, Lecomte JM. Aliment Pharmacol Ther 1999;13(Suppl 6) :27-32

  24. 4 15 Racecadotril 3 Loperamide 10 Number of stools hours 2 5 1 0 0 Duration of diarrhea Stool number Racecadotril is as efficient as loperamide Racecadotril Turck’s study : MULTICENTER, DOUBLE BLIND VERSUS LOPERAMIDE STUDY IN ACUTE DIARRHEA OCCURINGIN 102 AMBULATORY CHILDREN Turck D, Bérard H, Frétault N, Lecomte JM. Aliment Pharmacol Ther 1999;13(Suppl 6):27-32

  25. Racecadotril Turck’s study : MULTICENTER, DOUBLE BLIND VERSUS LOPERAMIDE STUDY IN ACUTE DIARRHEA OCCURINGIN 102 AMBULATORY CHILDREN * 60 50 * * P = 0.03 P = 0.04 50 * 40 Racecadotril 40 30 % of patients % of patients Loperamide 30 20 20 10 10 0 0 Patients with a modification of concomitant medications Constipated patients Racecadotril is better tolerated than loperamide Turck D, Bérard H, Frétault N, Lecomte JM. Aliment Pharmacol Ther 1999;13(Suppl 6):27-32

  26. 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

  27. 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

  28. 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 [n = 68] Placebo [n = 67] Criteria . 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) Salazar-Lindo E, Santisteban-Ponce J, Chea-Wood E and Guterriez M. N Engl J Med 2000;343:463-467

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

  30. 48 hour stool output / Bodyweight (g/kg) Reduction by racecadotril Racecadotril Placebo Population 169.6 (124.5) 45.6 % 92.2 (97.2) All patients [n=67] [n=68] 194.7 (125.3) 46.3 % 104.6 (96.9) Rotavirus positive [n=39] [n=34] 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 % Racecadotril Salazar-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;343:463-467

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

  32. Total stool output / Bodyweight (g/kg) Reduction by racecadotril Racecadotril Placebo Population 331.0 (320.9) 53 % 156.5 (220.2) All patients [n=67] [n=68] 396.7 (353.0) 56 % 174.4 (21.8) Rotavirus positive [n=37] [n=34] mean ± SD Racecadotril Salazar-Lindo’s study : EFFICACY AND SAFETY OF RACECADOTRIL IN THE TREATMENT OF 135 PERUVIAN HOSPITALIZED MALE CHILDREN WITH ACUTE DIARRHOEA 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

  33. 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

  34. 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 600 250 500 439+/- 49 ml 200 Racecadotril 152 ml / Kg 400 150 ORS: ml / Kg Placebo 300 ORS: ml 100 200 P = 0.0001 50 100 0 0 Total ORS intake (ml / Kg) * ORS intake / Day 1 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

  35. 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

  36. 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.

  37. 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 * = 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.

  38. Racecadotril Cojocaru’s study : the effect of racecadotril on the need for care in the treatment of acute diarrhoea in children. Efficacy results * = 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.

  39. 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

  40. Racecadotril TOLERANCE : Number of children with adverse events

  41. Racecadotril TOLERANCE Severity of adverse events in paediatric Bioprojet studies

  42. Racecadotril PHARMACOVIGILANCE up to 31st December 2005 Number of patients treated in France by Tiorfan® sachets * : 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).

  43. 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.

  44. 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.

  45. 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).

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