ACUTE DIARRHOEA AND RACECADOTRIL · DIARRHOEA IS CAUSED BY HYPERSECRETION OF WATER • Passage of...

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ACUTE DIARRHOEA AND RACECADOTRIL

Racecadotril specifically targets the uncontrolled secretory processes that underlie acute diarrhea, reducing stool output and diarrhea duration


OVERVIEW OF DIGESTIVE SYSTEM

DIGESTIVE SYSTEM – ANATOMY

• Functions:– Movement of food

– Secretion of digestive juice followed by digestion of food

– Absorption of water and various electrolytes

1. Waugh A, et al. Ross and Wilson, Anatomy and Physiology in Health and Illness. 9th ed. Philadelphia: Churchill Livingstone. 2001:282-338.2. Hall J. Guyton and Hall Textbook of Medical Physiology.12th ed. Philadelphia: Saunders Elsevier; 2011:753-798.

Liver

GallbladderDuodenum

Transversecolon

Ascendingcolon

Caecum

Vermiformappendix

Rectum

Sigmoid flexure

Ileum

Descendingcolon

Jejunum

Pancreas

Stomach

Oesophagus

MouthPharynx

StomachSmallintestineLargeintestine

LiverGallbladder

Pancreas

Oesophagus

Alimentary canal:- mouth, pharynx,

oesophagus, stomach, small intestine, large intestine ending at anus

Accessory organs:

- tongue, teeth, salivaryglands, liver,

- biliary tract, pancreas

SECRETORY PROCESSES OCCUR AT THE VILLI

1. Waugh A, et al. Ross and Wilson, Anatomy and Physiology in Health and Illness. 9th ed. Philadelphia: Churchill Livingstone. 2001:282-338.2. Farthing MJG. Dig Dis. 2006;24:47-58.

Crypt: Secretion

Villus Tip: AbsorptionMicrovilli

Muscle layers

zoom in

Hepatic portal vein

To liver

Lumen

Capillarybed

Villi

zoom in

Intestine Villi Epithelium

Lacteal

• The intestinal lumen consists of small finger-like projections called villi. The walls of the villi are made up of enterocytes with microvilli on their edges In the intestines, water absorption

takes place at the tip of the villi whereas secretion occurs in the crypts.

DAILY FLUID EXCHANGES

1. Hall J. Guyton and Hall Textbook of Medical Physiology.12th ed. Philadelphia: Saunders Elsevier; 2011:753-798.2. Camilleri M, et al. Harrison's Principles of Internal Medicine. 18th ed. USA: McGraw-Hill; 2012. 2008:308-319.

Gastrointestinal secretions (7 L/day)

Fluid ingested1.5 L/day

Fluid excreted0.2 L/day


FLUID AND ELECTROLYTE BALANCE & DIARRHOEA

ENKEPHALINS ARE ESSENTIAL IN REGULATING WATER AND ELECTROLYTE SECRETION

1. Schwartz JC. Int J Antimicrob Agents. 2000;14(1):75-79.

Secretion Absorption

Enkephalinase

Enkephalins

DeltaReceptor

ATP

c-AMPVIP Prostaglandins

DIARRHOEA IS CAUSED BY HYPERSECRETION OF WATER

• Passage of abnormally liquid or unformed stools at an increased frequency

• Stool weight >200 g/day

• Diarrhoea is not:– Frequent passage of formed stools

– Passage of loose, "pasty“ stools by breastfed babies

1. Camilleri M, et al. Harrison's Principles of Internal Medicine. 18th ed. USA: McGraw-Hill; 2012. 2008:308-319.2. Diarrhoeal disease. WHO Web site: http://www.who.int/mediacentre/factsheets/fs330/en/index.html. 2009.3. Hodges K, et al. Gut Microbes. 2010;1(1):4-21.

PATHOPHYSIOLOGY OF ACUTE DIARRHEA

1. Farthing MJ. J Gastroenterol Hepatol. 2000;15 Suppl:G38-G45.2. WHO Web site. http://whqlibdoc.who.int/publications/2005/9241593180.pdf. Accessed 3 March 2012.

Hypersecretion

DIARRHOEA

Absorption

Enkephalinase

Enkephalins

DeltaReceptor

DIARRHOEAL RISK – SIGNS OF DEHYDRATION

1. Diarrhoeal disease. WHO Web site: http://www.who.int/mediacentre/factsheets/fs330/en/index.html. 2009.2. The World Health Organization. The Global Burden of Disease: 2004 update. 2008

• Sinking in the fontanelle in infants

• Little or no urine; urine is dark yellow

• Sudden weight loss • Loss of elasticity or stretchiness of the skin

• Fast, week pulse

• Dry mouth

• Sudden tearless eyes

AETIOLOGY OF INFECTIOUS DIARRHOEA

Developed Countries

Virus 70%(Rotavirus

40%)

Bacteria10-20%

Protozoa <10%

Developing Countries

Virus 35%(Rotavirus 15-20%)

Bacteria 50-60%

Enteropathogenic E. coli 25%

Campylobacter jejuni 10-18%

Shigella species 5%

Salmonella species 5%

1. Camilleri M, et al. Harrison's Principles of Internal Medicine. 18th ed. USA: McGraw-Hill; 2012. 2008:308-319.2. Cooke M. S Afr J Clin Nutr 2010;23(1) Supplement:S42-S46


BURDEN OF DIARRHOEA

DEFINITION: ESPHGAN 2014 GUIDELINES

Acute gastroenteritis is generally defined as a decrease in the consistency of stools (loose or liquid) and/or an increase in the frequency of evacuations (typically ≥ 3 in 24 hours), with or without fever or vomiting. However, a change in stool consistency versus previous stool consistency is more indicative of diarrhea than stool number, particularly in the first months of life. Acute diarrhea typically lasts less than 7 days and not longer than 14 days.

Guarino et al. JPGN 2014; 59:132-152

DIARRHOEA: GLOBAL PREVALENCE AND BURDEN

Segment Prevalence/Burdena

Developing world 2.5 million deaths/ year

In USA 200 to 300 million new cases in US annually with a heath expenditure of 23 million dollars/year

Infants / children (<5 years) ~1.5 billion episodes and 3 million deaths /year

In Europe (in children <3 years) 0.5 to 1.9 episodes/child/year

ElderlyAssociated with significant morbidity and quality of life9.1 % prevalence rate (according to Rome criteria)

Viral aetiology >70% of infectious diarrhoea: 600,000 to 800,000 deaths annually(Rota virus)

Bacterial aetiology 1.5%-5.6% of cases

Amoebic aetiology 50 million people resulting in 40 000 deaths per year (Entamoeba histolytica )

Traveller’s diarrhoea 30% to 40% of travellers visiting developing countries

Drug-related 7% of drugs adverse effects manifest as diarrhoea

a The true prevalence is underestimated due to misdiagnosis and lack of medical or hospital attention sought by patients.

1. Baldi F. World J Gastroenterol. 2009;15(27):3341-3348.2. The global burden of disease 2004 update. The World Health Organization. 2008.3. Gottlieb T. BMJ. 2011;02:901.4. Mackell S. CID. 2005;41(8):s547-552.5. Guarino A. J Pediatr Gastroenterol Nutr. 2008;46 (2):S81-122. 6. Steffen.CID. 2005;41:S536–40.

CAUSATIVE AGENTS IN DIARRHEA

WGO – Acute diarrhea practice guidelines 2012.


PREVENTION AND THE EVOLVING CLINICAL APPROACHES TO MANAGE DIARRHOEA

PREVENTION OF DIARRHOEA: CHILDREN & ADULTS

Preventive Measures

Exclusive Breastfeeding

Improved Feeding Practices

Use of Clean and Safe

Water

Regular Hand Wash

Food Hygiene

Lavatory Sanitation

Measles Immunisation

1. WHO. The Treatment of diarrhoea: a manual for physicians and other senior health workers: 2005.

USE OF ANTI-MICROBIAL AND ANTI-DIARRHOEAL DRUGS: WHO 2005

Anti-microbial Drugs• Should not be used routinely

– All clinical episodes might not respond to anti-microbials (ETEC)– Difficult to differentiate the clinical episodes which might respond (rotavirus)– For selection of appropriate antibiotic: Information regarding sensitivity of the causative agent is usually unknown– Incurs additional cost to the treatment– Risk of adverse reaction increases– Enhances development of resistant bacteria

• Used only for the treatment of children with – Bloody diarrhoea (probable shigellosis)– Suspected cholera with severe dehydration– Non intestinal infections and pneumonia

Anti-protozoal drugs• Are rarely indicatedAnti-diarrhoeal drugs and anti-emetics• No practical benefits in children with acute or persistent diarrhoea• Do not prevent dehydration• Do not improve nutritional status• Dangerous, sometimes fatal side effects• Not used in children below 5 years

1. WHO Web site. http://whqlibdoc.who.int/publications/2005/9241593180.pdf.Accessed 3 March 2012

CLINICAL MANIFESTATIONS AND DIAGNOSIS


GENERAL CLINICAL APPROACH IN INDIVIDUALS WITH ACUTE DIARRHOEA (WGO 2012)

1. WGO. World Gastroenterology Organisation practice guideline; Acute Diarrhea. 2012.

WGO, World Gastroenterology Organisation.

• Onset, frequency, type and volume

• Character –bile/blood/mucous

• Vomiting• Medical history• Underlying conditions• Epidemiological clues

History

• Body weight• Temperature• Pulse/Heart and

respiratory rate• Blood pressure

Physical Examination

• Appearance and alertness

• Pulse and blood pressure• Postural hypotension• Mucous membrane and

tears• Sunken eyes, skin turgor• Capillary refill, jugular

venous pressure• Sunken fontanelle

Assess Dehydration

INCUBATION PERIOD AND LIKELY CAUSES OF DIARRHEA


CLINICAL APPROACH – ADULTS WITH ACUTE DIARRHOEA (WGO 2008)

Initial Assessment- Dehydration- Duration (>1 day)- Inflammation

Symptomatic Treatment- Rehydration- Treatment of symptoms

Subsequent Management- Epidemiological clues- Clinical Clues: bloody diarrhoea,

abdominal pain, dysentery, wasting, faecal inflammation

Microbiological Analysis of Faeces

Specific Antibiotic Therapy

1. WGO. World Gastroenterology Organisation practice guideline; Acute Diarrhea. 2008 & 2012 .



THERAPEUTIC APPROACHES

TREATMENT OF ACUTE DIARRHOEA – BASED ON DEGREE OF DEHYDRATION (WGO 2008)

≥2 of the following signs:• Lethargy or unconsciousness• Sunken eyes• Unable to drink or poor drinking• Skin pinch goes back very slowly

Severe Dehydration

≥2 of the following signs:• Restless, irritable• Sunken eyes• Drinks eagerly, thirsty• Skin pinch goes back slowly

• Well alert• Normal eyes• Normal drinking• Skin pinch goes back quickly

Mild Dehydration

No Dehydration

• Pulse rate > 90 • Postural and supine hypotension • Absence of palpable pulse • Dry tongue and sunken eyeballs

Dehydration

Chi

ldre

nAd

ults

1. WGO. World Gastroenterology Organisation practice guideline; Acute Diarrhea. 2008.


CURRENT THERAPEUTIC OPTIONS FOR DIARRHOEA

1. Position statement. Paediatr Child Health. 2003;8(7):455-466.2. Imodium [summary of product characteristics]. UK, McNeil Products Limited; 2011.3 Diphenoxylate. NIH Web site. http://www.nlm.nih.gov/medlineplus/druginfo/meds/a601045.html. Accessed February 28, 2012.4. Lomotil [prescribing information]. Quebec, Pfizer Canada; 2003.5. Wittenberg DF. S Afr Med J. 2012;102(2):104-107.6. Xifaxan (rifaximin) [prescribing information]. Salix Pharmaceuticals.7. Khediri F, et al. Gastroenterol Res Pract. 2011;2011:1-8.8. World gastroenterology organisation global guidelines: probiotics and prebiotics. World Gastroenterology Organization Web site.

http://www.worldgastroenterology.org/assets/downloads/en/pdf/guidelines/19_probiotics_prebiotics.pdf. Accessed March 3, 2012.9. Seirogan. Taiko Web site. http://www.seirogan.co.jp/en/products/seirogan/index.html. Accessed March 3, 2012.10. Glycyrrhiza (licorice). Seirogan Web site. http://www.seirogan.co.jp/en/products/seirogan/ingredients/seibun03.html. Accessed March 3, 2012.11. Geranium Herb (present evidence). Seirogan Web site. http://www.seirogan.co.jp/en/products/seirogan/ingredients/seibun04.html. Accessed March 3, 2012.12. Phellodendron Bark (present evidence). Seirogan Web site. http://www.seirogan.co.jp/en/products/seirogan/ingredients/seibun02.html Accessed March 3, 2012.

Diarrhoea Therapy Options

Anti-infectives

Ciprofloxacin

Rifaximin

Nifuroxazide

Ofloxacin

Tinidazole

Adsorbents

Diosmectite

Bismuth

Probiotics

Saccharomyces boulardii

Lactobacillus acidophilus

Lactobacillus bifidus

Enterococcus faecalis

Bacillus clausii

Others

Racecadotril

Creosote

Geranium robertianum

Phellodendron

Glycyrrhiza glabra

Vaccines

RV1

RV5

Motility inhibitors

Loperamide

Atropine

ANTI-DIARRHOEALDRUGS, WGO 2008 & 2012

1. WGO. World Gastroenterology Organisation practice guideline; Acute Diarrhea.2008 AND 2012.

Anti-motility agents

Loperamide:• Agent of choice for adults

(4-6 mg/day; 2-4 mg/day for children aged >8 years)

• Inhibits intestinal peristalsis• Used for mild to moderate

traveller's diarrhoea• Avoided in febrile patients

and contraindicated in abdominal pain

• Not recommended in children aged below 2 years

Anti-secretory agents

Bismuth subsalicylate:• Alleviate stool output in

children• Alleviate symptoms of

diarrhoea, nausea• Alleviate abdominal pain in

traveler’s diarrhoeaRacecadotril:• Enkephalinase inhibitor • Has antisecretory activity• Authorised for use in

children in many countries• Used in children with

diarrhoea, not in adults with cholera

Adsorbents

Kaolin pectin, attapulgite, activated charcoal• Efficacy not proved in

acute adult diarrhoea

ACG CLINICAL GUIDELINES: DIAGNOSIS, TREATMENT, AND PREVENTION OF ACUTE DIARRHEAL INFECTIONS IN ADULTS

“Racecadotril, a specific enkephalinase inhibitor that prevents degradation of the endogenous antisecretory peptide neurotransmitter enkephalins that inhibit cyclic nucleotide secretory pathways without effect on gut motility”(103)

ANTI-MOTILITY OR ANTI-PERISTALTIC DRUGS ESPHGAN GUIDELINES (2008 and 2014)

• Loperamide

– Opioid receptor agonist– Reduces intestinal lumen motility– Used for the short-term symptomatic relief of acute diarrhoea in

adults – Should not be used for the management of AGE in infants and young

children

1. Guarino A, et al. J Pediatr Gastroenterol Nutr. 2008;46 Suppl 2:S81-S122

2014: 9.3.2 Antimotility or Antiperistaltic Drugs (Loperamide)Loperamide is not recommended in the management of AGE in children (II, B) (strong recommendation, very low quality evidence).

2. Guarino et al. JPGN 2014; 59:132-152

ANTISECRETORY DRUGS – ESPHGAN GUIDELINES 2008 & 2014

• Racecadotril (acetorphan)

– Exhibits pharmacological action by inhibiting enkephalinase– Decreases the secretion of water and electrolytes in the GIT– May be considered in the management of AGE– Used to treat children with severe watery diarrhoea as an adjunct to

ORT– Reduces stool output, intake of ORS and duration of diarrhoea

1. Guarino A, et al. J Pediatr Gastroenterol Nutr. 2008;46 Suppl 2:S81-S122.2. Guarino et al. JPGN 2014; 59:132-152

ANTIMICROBIAL THERAPY IN CHILDREN AND ADULTS

• In Children– Antibiotic agent recommended only under

specific conditions• Septicaemia• Bloody diarrhoea• Younger than 6 months with salmonella• Cholera with severe dehydration• Non-intestinal/extra-intestinal infections• Malnourished/immunocompromised• Clostridium difficile-associated

pseudomembranous enterocolitis– Children who travelled abroad: based on

specialist advice– Antiprotozoal drug for Giardia or Entamoeba

histolytica infections– Dosage of drug to depend on body weight

• In Adults – Treatment to be weighed against

• Drug cost• Risk of adverse reaction• Risk of eradication of normal intestinal flora• Induction of Shiga toxin production• Development of drug resistance

1. World gastroenterology organisation practice guideline: Acute diarrhoea. WGO Web site. http://www.worldgastroenterology.org/assets/downloads/en/pdf/guidelines/01_acute_diarrhoea.pdf. Accessed March 3, 2012.

2. Diarrhoea and vomiting caused by gastroenteritis: diagnosis assessment and management in children younger than 5 years. NICE Web site. http://www.nice.org.uk/nicemedia/pdf/CG84FullGuideline.pdf. Accessed March 20, 2012.

3. Guarino A. J Pediatr Gastroenterol Nutr. 2008;46 (2):S81-122./

“Anti-infective therapy should not be given to the vast majority of otherwise healthy children with

acute gastroenteritis (Vb, D)”

(ESPGHAN recommendation)

Guarino et al. JPGN 2014; 59:132-152

ANTI-INFECTIVE AGENTS IN ACUTE DIARRHOEA

• Antimicrobial agents are recommended only for the treatment of specific causes of diarrhoea or under special conditions

1. World gastroenterology organisation practice guideline: Acute diarrhoea. WGO Web site. http://www.worldgastroenterology.org/assets/downloads/en/pdf/guidelines/01_acute_diarrhoea.pdf., accessed March 2017.

Cholera

1st choiceDoxycyclineAdults: 300 mg once orTetracyclineAdults: 500 mg4 times a day x 3 days

AlternativesAzithromycinorCiprofloxacin

Amoebiasis

MetronidazoleChildren: 10 kg/kg 3 times a day x 5 days*Adults: 750 mg 3 times a day x 5 days*

*10 days for severe disease

Shigellosis

1st choiceCiprofloxacinChildren: 15 mg/kg 2 times a day x 3 daysAdults: 500 mg 2 times a day x 3 days

AlternativePivmecillinamChildren: 20 mg/kg 4 times a day x 5 daysAdults: 400 mg 4 times a day x 5 daysCeftriaxoneChildren: 50-100 mg/kg once a day IM x 2 to 5 day

Giardiasis

MetronidazoleChildren: 5 mg/kg 3 times a day x 5 daysAdults: 250 mg 3 times a day x 5 days

Campylobacter

Azithromycin


RACECADOTRIL – OVERVIEW EFFICACY & SAFETY

RACECADOTRIL OVERVIEW

NORMAL SECRETORY PROCESS Regulated by neurotransmitters, the enkephalins, and by an enzyme enkephalinaseBASELINE STATE• Enkephalins bring about a reduction in the level of AMPc • As a consequence, a reduction in hydroelectrolytic

secretion in the lumen of the small intestine• Enkephalinase causes an increase in the level of AMPc

and therefore of secretion: by inactivating enkaphalinsHYPERSECRETION• In diarrhoea, viral/bacterial toxins and prostaglandins

lead to breakdown of enkephalins by enkephalinase • Massive increase in the level of AMPc• Hydroelectrolytic secretion in the lumen of the small

intestineNORMALISATIONRacecadotril:• Powerful and selective inhibitor of enkephalinase, • Prolongs the antisecretory action of enkephalins • Opposes the intestinal hypersecretion of water and

electrolytes Selective inhibitor of enkephalinase that decreases intestinal hyper secretion

1. Drugs in focus. Wolters Kluwer Health. 2009.

1BASELINE STATE

2HYPERSECRETION

3NORMALISATION

enkephalin-enkephalinasebalance

enkephalinase

enkephalinase

§ receptor

Toxins,peptides

RACECADOTRIL

ENKEPHALINASEINHIBITOR

Smallintestine

Normal secretion Hypersection Normal secretion

PHARMACOLOGY

• RACECADOTRIL or racecadotril is indicated in the symptomatic treatment of acute diarrhoea in adults, children and infants older than 3 months

• It is available as:– 100 mg hard capsule– 10 mg and 30 mg granules for oral suspension

RACECADOTRIL

1. Schwartz J.C. Int J Antimicrob Agents. 2000;14:75-79.2. Racecadotril 100 mg local approved leaflet3. Racecadotril; acetorphan – Compound summary. PubChem: Accessed July 13 2012

Thiorphan

RAPID ABSORPTION OF RACECADOTRIL AND 8-HOUR ANTISECRETORY EFFECT

• Rapid onset of enkephalinase inhibition after conversion of racecadotril to thiorphan

• RACECADOTRIL can be given without regard to meals100

80

60

40

20

0

0 4 8 12 16 20 24

Racecadotril 100 mg

Inhi

bitio

n (%

)

Time (hours)

1. Racecadotril 100 mg local approved leaflet 2. Duchier J. Action of racecadotril on plasma enkephalinase in healthy volunteers – effect of a single dose (n° 88-469). Bioprojet Data on File.

RACECADOTRIL – FAVOURABLE DISTRIBUTION PROFILE

• Moderate distribution of thiorphan into bodily tissues – no accumulation

• Although RACECADOTRIL passes the blood-brain barrier:

– It is rapidly and completely converted to hydrophilic thiorphan, which cannot pass the blood-brain barrier

– Thus entry to the brain and thereby possibility of CNS adverse effects is precluded

• Thiorphan is highly protein bound (90%) – does not affect protein binding of other drugs

1. Racecadotril 100 mg local approved leaflet 2. C. Faure. International Joural of Pediatrics Volume 2013, Article ID 612403, 14 pages 3. Tormo R, et al. Acta Pediatrc. 2008; 97 (8):1008-1015

RACECADOTRIL – DRUG INTERACTION PROFILE

• Angiotensin converting enzyme inhibitors (ACE-inhibitors), such as captopril, enalapril, lisinopril, fosinopril, perindopril, ramipril are known to induce angioedema. This risk could be increased in presence of racecadotril.

• Thiorphan converted to inactive metabolites

• No accumulation after repeated administration

• Pharmacokinetics of racecadotril not altered by other medications used in treating diarrhoea (loperamide, nifuroxazide)

• In vitro data indicate that racecadotril/thiorphan and the 4 major inactive metabolites do not inhibit/induce the CYP enzymes isoforms (3A family 2A6, 2B6, 2C9/2C19, 1A family, 2E1) and UGTs conjugating enzymes to an extent that would be clinically relevant.

1. Racecadotril 100 mg local approved leafletCompany Confidential© 2015 Abbott

EXCRETION IS PRIMARILY RENAL

• Primarily eliminated renally as inactive metabolites

• In hepatic failure, Tmax and T½ remain similar and Cmax and AUC are reduced as compared to healthy subjects

• In severe renal failure, Cmax is reduced, T½ and AUC are increased as compared to healthy subjects

• Similar pharmacokinetics in adults and children

• No dosage adjustment is required in the elderly

1. Racecadotril 100 mg local approved leaflet

PHARMACODYNAMIC PROPERTIES OF RACECADOTRIL

• Thiorphan, the active metabolite of RACECADOTRIL isassociated with:

– Pure intestinal antisecretory effect

– Reduced hypersecretion but not basal secretion

– No effect on intestinal transit

– No abdominal distension

– Inhibition of enkephalinase, an enzyme responsible for breakdown of enkephalins and thus prolong their antisecretory effect

– Mechanism of action discussed in detail in up-coming slides


HYPERSECRETION RESULTS FROM REDUCED ENKEPHALIN ACTIVITY DURING INFECTIOUS DIARRHOEA

1. Farthing MJG. J Gastroenterol Hepatol. 2000;15 Suppl:G38-G45.

Hypersecretion

DIARRHOEA

Absorption

Enkephalinase

Enkephalins

DeltaReceptor

1. Schwartz JC. Int J Antimicrob Agents . 2000;14:75-79.

RACECADOTRIL NORMALISES SECRETION BY PRESERVING ENKEPHALIN ACTIVITY

Toxic peptides from viruses /

bacteria

Enkephalins

Enkephalinase

Racecadotril

c-AMP

ATP

Delta receptor

RACECADOTRIL– THERAPEUTIC INDICATIONS

• Adults

– Symptomatic treatment of acute diarrhoea. If causal treatment of acute diarrhea is possilbe, racecadotril can be co-administered.

• Children

– Complementary symptomatic treatment of acute diarrhoea in infants (older than 3 months) and children together with oral rehydration (ORS). If causal treatment of acute diarrhea is possible, racecadotril can be co-administered.


WEIGHT- BASED DOSING IN INFANTS AND CHILDREN

• Administration via the oral route, together with oral rehydration

• The recommended dose is determined according to body weight: 1.5mg/kg per dose (corresponding to 1 to 2 sachets), three times daily at regular intervals:

- in infant less than 9 kg: one 10mg sachet 3 times daily

- in infant from 9kg to 13kg: two 10mg sachets 3 times daily

- in children from 13kg to 27kg: one 30mg sachet 3 times daily

- in children of more than 27kg: two 30mg sachets 3 times daily

Due to the presence of sucrose, RACECADOTRIL is contraindicated in patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption syndrome or sucraseisomaltase insufficiency.

WEIGHT-BASED DOSING IN INFANTS AND CHILDREN

Age 3-9 months 9-30 months 30 months-9 years + 9 years

Dose (mg TID) 10 20 30 60

Sachets /Dose

1 x 10 mg sachet

‘infants’ TID

2 x 10 mg sachets ‘infants’

TID

1 x 30 mg sachet

‘children’ TID

2 x 30 mg sachets

‘children’ TID


RACECADOTRIL granules are contraindicated in patients with fructose intolerance, glucose malabsorption syndrome and saccharase-isomaltase

deficiency

WEIGHT-BASED DOSING IN INFANTS – Racecadotril 10 mg Infants


WEIGHT-BASED DOSING IN CHILDREN – Racecadotril 30 mg Children


DOSING IN ADULTS – Racecadotril 100 mg Adults

• Administration via the oral route

• One capsule initially regardless of the time of day. Then, one capsule three times daily preferably before the main meals.

• Treatment should be continued until two normal stools are recorded.

• Treatment should not exceed 7 days

• Long-term treatment with racecadotril is not recommended.


CONTRAINDICATIONS

• Hypersensitivity to the active substance or to any of the excipients.

• Patients who have reported angioedema with angiotensin converting enzyme inhibitors (such as captopril, enalapril, lisinopril, perindopril, ramipril) should not take racecadotril.


SPECIAL WARNINGS AND PRECAUTIONS FOR USE

• The administration does not modify the usual rehydration regimens.

• Presence of bloody or purulent stools and fever may indicate presence of invasive bacteria as a reason for diarrhoea or the presence of other severe disease, warranting causal (e.g. antibiotic) treatment or further investigation. Racacadotril may be given concomitantly with antibiotics in case of acute diarrhoea with a bacterial cause as a complementary treatment.

• Use of racecadotril in antibiotic-associated diarrhoea and chronic diarrhoea is not recommended due to insufficient data.

• Product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

• Occurrence of skin reactions has been reported with the use of the product.


UNDESIRABLE EFFECTS – 100mg capsule

• Nervous system disorders: Common: headache. (common: ≥1/100 to < 1/10).

• Skin and subcutaneous tissue disorders: Uncommon: rash, erythema. (uncommon: ≥ 1/1000 to < 1/100), Unkown: erythema multiforme, tongue oedema, face oedema, lip oedema, eyelid oedema, angioedema, urticaria, erythema nodosum, rash papular, prurigo, pruritus, toxic skin eruption.


PHARMACODYNAMIC PROPERTIES – 100mg capsule

• Racecadotril does not produce abdominal distension. During its clinical development, racecadotril produced secondary constipation at a rate comparable to placebo.

• When administered via the oral route, its activity is exclusively peripheral, with no effects on the central nervous system.



UNMET NEEDS

• Inhibits fluid secretion by intestinal mucosa• Prevents dehydration and malnutrition• Reduces the duration and severity of diarrhoea• Has a rapid onset of action• Limited constipating effects • High therapeutic index• Minimal central nervous system effects• Low abuse potential

THE IDEAL TREATMENT FOR ACUTE DIARRHOEA

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. Int J Antimicrob Agents. 2000;14:81-87.3. The treatment of diarrhea: A manual for physicians and other senior health workers. WHO Web site.

http://whqlibdoc.who.int/hq/2003/WHO_FCH_CAH_03.7.pdf. Accessed March 3, 2012.4. Rahim N, et al. Jpn J Infect Dis. 2010;63(4):271-274.5. Cezard JP, et al. Arch Pediatr. 2007;14 (Suppl3):S169-S175

Racecadotril was developed specifically with these characteristics in mind

UNMET NEEDS IN THE MANAGEMENT OF ACUTE DIARRHOEA

• Rational mode of action (resolve the underlying cause of acute diarrhoea)

• High efficacy rates (stool output)

• Fast onset of action

• Good tolerability and safety profile in children and infants

• Good synergy with oral rehydration therapy (ORT)

• License for use in children and small infants

1. Cezard JP, et al. Arch Pediatr. 2007;14 Suppl 3:S169-S175.2. Steffen R. Adv Std Med. 2003;3(10A):S951-S958.3. Hostos ELD, et al. Future Med Chem. 2011;3(10):1317-1325.4. Farthing MJG. J Gastroenterol Hepatol 2000; 15(Suppl.): C40-C47.5. World gastroenterology organisation practice guideline: acute diarrhoea. WGO Web site.

http://www.worldgastroenterology.org/assets/downloads/en/pdf/guidelines/01_acute_diarrhoea.pdf. Accessed March 3, 2012.6. Li ST, et al. Loperamide therapy for acute diarrhoea in children: systematic review and meta-analysis. PLoS Med. 2007;4(3):e98.7. Lomotil [Prescribing Information]. Pfizer: Canada; 2003.8. Wittenberg DF. S Afr Med J. 2012;102(2):104-107.9. World gastroenterology organisation global guidelines: probiotics and prebiotics. WGO Web site.

http://www.worldgastroenterology.org/assets/downloads/en/pdf/guidelines/19_probiotics_prebiotics.pdf. Accessed March 3, 2012.

CLINICAL ADVANTAGES OF RACECADOTRIL

5. Prado D. Scand J Gastroenterol. 2002;37(6):656-661.6. Lecomte JM. Int J Antimicrob Agents. 2000;14(1):81-87.7. Schwartz JC. Int J Antimicrob Agents. 2000;14(1):75-79.8. Duval-Iflah Y, et al. Aliment Pharmacol Ther. 1999;13(suppl 6):9-14.

1. Hostos ELD, et al. Future Med Chem. 2011;3(10):1317-1325.2. Salazar-Lindo E, et al. N Engl J Med. 2000;343(7):463-467.3. Cezard JP, et al. Gastroenterology. 2001;120(4):799-805.4. Turk, D. Aliment Pharmacol Ther. 1999;13(suppl 6): 27-32.

Reduced need for concomitant

therapy

Does not promote

bacterial growth

No dependence or abuse

No central nervous system

toxicity

High efficacy rates Reduces stool output

and decreases the duration of diarrhoea

Superior tolerability

compared to loperamide

Tolerability

Efficacy independent of rotavirus status

Multitude of clinical benefits

High therapeutic

index

No affect on gastrointestinal

motility

Racecadotril

RACECADOTRIL: PRODUCT HIGHLIGHTS

• Novel mode of action

• Rapid onset of action

• High efficacy rates

• Tolerability and safety profile similar to placebo

• Positive endorsement in paediatric guidelines (ESPHGAN & Canadian guidelines (level I))

ESPGHAN- ESPID, European Society for Paediatric Gastroenterology, Hepatology, and Nutrition/European Society for Paediatric Infectious Diseases

1. Farthing MJG. J Gastroenterol Hepatol 2000; 15(Suppl.): C40-C47.2. Schwartz J-C. Int J Antimicrobial Agents 2000; 14: 75-79.3. Lecomte JM. Int J Antimicrob Agents. 2000;14(1):81-87.5.4. Cezard JP, et al. Gastroenterology. 2001;120(4):799-805.5. Guarino A, et al. J Pediatr Gastroenterol Nutr. 2008;46 Suppl 2:S81-122.6. Position statement. Paediatr Child Health. 2003;8(7):455-466.


KEY CLINICAL TRIALS – META-ANALYSIS PEDIATRIC FORMULATION

RACECADOTRIL FOR CHILDHOOD GASTROENTERITIS: AN INDIVIDUAL PATIENT DATA META-ANALYSIS: Lehert P et al., 2011

Meta-analysis of 9 RCTs (1384 randomised patients)• Individual Patient raw Data of RCTs were used for analysis• At least racecadotril and placebo were randomised in RCTs• Male and female, infants and children from 1month to 15 years old• Outcomes

– Duration of diarrhoea– Number of diarrhoeic stools – Inpatients - stool output during the first 48 hrs.– Outpatients - Total number of diarrhoeic stools until recovery

OBJECTIVETo study the efficacy of racecadotril in infants and children with acute gastroenteritis compared to placebo from Individual Patient Raw Data (IPD)

`. Lehert P. et al., Dig Liver Dis. 2011; S43(9):707-713.

Experimental ControlWeight Risk Ratio IV, Fixed, 95% CI Risk Ratio IV, Fixed, 95% CIStudy or

Subgroup Events Total Events Total

Cezard-01 61 89 31 83 20.8% 1.84 [1.34, 2.51]

SalazarLindo-00 47 68 28 67 19.3% 1.65 [1.20, 2.29]

Savitha-05 21 30 9 30 5.7% 2.33 [1.29, 4.23]

Gutierez1-10 60 135 18 135 9.2% 3.33 [2.08, 5.33]

Cojocaru-02 27 81 11 83 5.1% 2.52 [1.34, 4.73]

Santos-09 35 88 23 91 10.6% 1.57 [1.02, 2.44]

Alvarez-09 19 84 12 86 4.7% 1.62 [0.84, 3.13]

Melendez-07 19 25 13 25 10.6% 1.46 [0.94, 2.26]

Gutierez2-10 63 92 23 92 14.0% 2.74 [1.87, 4.01]

Total (95% CI) 692 692 100% 1.98 [1.71, 2.28]

Total events 352 168

Heterogeneity: 2 = 13.06, df = 8(P=0.11); I2 = 39%

Test for overall effect: Z=9.39 (P<0.00001)

0.2 0.5 1 2 5Favours Control Favours Racecadotril

RESULTS OF INDIVIDUAL STUDIES AND META-ANALYSIS ON RESPONDER PROPORTION: Lehert P et al., 2011

1. Lehert P. et al., Dig Liver Dis. 2011; S43(9):707-713.

* Response defined as diarrhoea duration < 2 days

META-ANALYSIS RESULTS: Lehert P et al., 2011

• Highly significant predictors were dehydration level and rotavirus infection

Results Placebo Racecadotril

Diarrhoea duration after inclusion (Median days) P<0.001 2.81 1.75

Responders (patients with duration of diarrhoea <2 days) RR=1.98

25.8% 50.3%

Need for i.v. rehydration (3 studies on out-patients) P<0.05 12/37 4/35

1. Lehert P. et al., Dig Liver Dis. 2011; S43(9):707-713.


KEY CLINICAL TRIALS IN ADULTS

SUMMARY OF LIST OF STUDIES IN ADULTS

Author Study Type Inclusion N (RAC/Cont) Primary Efficacy Treatment

Baumer et al., 1992

Multicentre, double-blind, randomised, placebo-controlled, parallel-group study in France

Acute diarrhoea of presumed infectious originPatients aged >18 years

96/98 Duration of diarrhoea RAC 200 mg, then 100 mg after each unformed stool x 10 days or resolutionPlacebo for 10 days or until resolution

Hamza et al., 1999

Multicentre, double-blind, randomised, placebo-controlled study in Tunisia


32/38 (ITT) Stool weight on day 1 RAC 100 mg TID x 6 days, or until recoveryPlacebo

Rogé et al., 1993 Single-centre, double-blind, randomised, parallel-group study in France

Acute diarrhoea of presumed infectious originPatients aged > 18 years

37/32 Duration of diarrhoea RAC 200 mg, then 200 mg in 12 h. Then 100 mg TID x 7 days or resolutionLOP 2.66 mg, then 2.66 mg in 12 h. Thereafter 1.33 mg TID x 7 days or until resolution

Vetel et al., 1999 Multicentre, randomised, double-blind, double-placebo, active controlled study in France

Outpatients with acute diarrhoeaPatients aged >18 years

77/70 (ITT) Number of diarrhoeic stools passed until recovery

RAC 100 mg PO TID x 7 days, or until recoveryLOP 2 mg PO after each diarrheic stool

Prado et al., 2002 Multicentre, multinational, single-blind, randomised trial

Acute watery diarrhoea of presumed infectious originPatients aged >18 years

473/471 (ITT) Duration of diarrhoea RAC 100 mg PO TID until recoveryLOP 2 mg PO TID until recovery

Wang et al., 2005 Multicentre, randomised, single-blind controlled study in Taiwan


31/31 (ITT) Duration of diarrhoea from first treatment to recovery

RAC 100 mg PO TID until recoveryLOP 2 mg PO TID until recovery

Gallelli et al., 2010

Multicentre, randomised, double-blind, loperamide-controlled study in Italy

Elderly patients with acute diarrhoeaPatients aged 73-96 years

30/31 (ITT) Duration of diarrhoea RAC 100 mg TIDLOP 4 mg followed by 2 mg after each unformed stool

Vetel et al., 2014 Meta-analysis: racecadotril efficacy in the symtpomatic treatment of adult acute diarrhoea: a systematic review and meta-analysis

Twelve randomised trials (2619 patients) Age: > 18 years, acute diarrhoea any cause.

1422/1295 (ITT), 1378/1241 (PP)

Diarrhoea duration (DD) defined as time to recovery compared between groups

Adult formulaton, without dose restriction.

Coffin et al., 2014 Meta-analysis: racecadotril in the treatment of acute diarrhoea in adults. An individual patient data based meta-analysis

669 patients. Age: > 18 years, acute diarrhoea any cause.

387/282 Diarrhoea duration. Secondary: no. of diarrhoeicstools (NDS), proportion of responders to treatment with RAC, change in perceived symptoms.

Adult formulation, without dose restriction.

RAC=Racecadotril; ITT=Intent To Treat; TID= Thrice a day; PO=Per Oral; LOP=Loperamide;

1. Baumer P, et al., Gut. 1992;33:753-758. 2. Hamza H, et al., Aliment Pharmacol Ther. 1999;13(Suppl.6):15-19.3. Roge J, et al.,Scand J Gastroenterol 1993; 28: 352-354 4. Vetel JM, et al., Aliment Pharmacol Ther. 1999;13(6):21-26.5. Prado D. Scand J of Gastroenterol. 2002;6:656-661. 6. Wang HH, et al., World J Gastroenterol. 2005;11(10):1540-1543.7. Gallelli L, et al.. Eur J Clin Pharmacol. 2009;1-8. 8. Vetel et al. IJCM 2014;5:361-375 9. Coffin et al. IJCM 2014;5(7): 345-360

EFFECTS OF ACETORPHAN, AN ENKEPHALINASE INHIBITOR, ON EXPERIMENTAL AND ACUTE DIARRHEA: Baumer et al., 1992

1. Baumer P et al, Gut.1992;33:753-758

STUDY DESIGN

Double-blind, randomised, placebo-controlled, parallel group study

Racecadotril (Acetorphan)

Patients

96

98Placebo (Lactose)

INCLUSION CRITERIA• More than 3 stools in the last 24 hours• Onset of diarrhoea-less than 5 days

STUDY OBJECTIVETo compare the efficacy , safety and tolerability of racecadotril and placebo in adult patients with acute watery diarrhoea

Total: 194

EFFICACY AND TOLERABILITY RESULTS: Baumer et al., 1992

EventRacecadotril (Acetorphan)

(96)

Placebo(98)

Nausea 8 7

Thirstiness 6 7

Vertigo 6 7

Constipation 4 2

Headache 2 2

1. Baumer P et al, Gut.1992;33:753-758

Frequency of Adverse Events(Number of Patients)

RAC: Racecadotril

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10Duration of diarrhoea after

admission (days)

Prob

abili

ty o

f unr

esol

ved

diar

rhoe

a (%

)

Placebo(n = 98)

Racecadotril(n = 95)

P= 0.001

TOLERANCEFrequency and nature of adverse events were similar in both groups

1. Baumer P et al, Gut.1992;33:753-758

0

20

30

40

Analburning

Abdominalpain

Nausea Anorexia

* *

*

*

Pain onabdominalpalpation

Abdominaldistension

* * *

10

% O

f Sym

ptom

s Pr

esen

t D

urin

g Se

cond

Vis

it

Placebo

* P < 0.05 ; * * P < 0.001

Racecadotril

TOLERABILITY RESULTS: Baumer et al., 1992

RACECADOTRIL VS PLACEBO IN THE TREATMENT OF ACUTE DIARRHOEA IN ADULTS: Hamza et al., 1999

1. Hamza H. et al Aliment Pharmacol Ther. 1999;13(Suppl.6):15-19.

STUDY DESIGN

Two-centre, double-blind, parallel group randomised study

Racecadotril

Patients

32

38Placebo

INCLUSION CRITERIA• Age: >18 years• Suffering from acute diarrhoea• >3 loose stools in the last 24 hours • Onset of diarrhoea: less than 5 days

STUDY OBJECTIVETo compare the efficacy and tolerability of racecadotril and placebo in adult patients with acute diarrhoea

Total: 70

EFFICACY RESULTS: Hamza et al., 1999

Mean stool weight duringthe first 24 hours under treatment Stool weight

Racecadotril: 355±35g

Placebo: 499±46g

P = 0.025


450

355 ±35400

350

500

499 ± 46

n = 38 n = 32

Stoo

l wei

ght (

g)

PlaceboRacecadotril

P = 0.025

TOLERABILITY AND SAFETY RESULTS: Hamza et al., 1999

TOLERABILITY AND SAFETY

• Percentage of patients suffering from adverse events on day 4

• Racecadotril: 3.1%

• Placebo: 5.3%

• Percentage of patients suffering from abdominal distension on day 4

• Racecadotril: 5.6%

• Placebo: 18.2%

CONCLUSION• Good tolerability of racecadotril vs. placebo• Rapid efficacy in acute diarrhoea in adults

ADVERSE EVENTSRacecadotril Group:Dizziness and malaise: 1 patient

Placebo group:Moderate backache: 1 patient

Placebo group:Abdominal distension: 1 patient


THE ENKEPHALINASE INHIBITOR, ACETORPHAN, IN ACUTE DIARRHOEA: A DOUBLE-BLIND, CONTROLLED CLINICAL TRIAL VERSUS LOPERAMIDE: Roge et al., 1993

1. Roge J et al. Scand J Gastroenterol 1993; 28: 352-354

STUDY DESIGN

Single centre, double-blind, randomised, active-controlled, parallel-group study

Study period: Up to7 days or until resolution

Racecadotril

Patients

37

32Loperamide

INCLUSION CRITERIA• Age: >18 years• Acute diarrhoea of presumed infectious origin• >2 liquid stools in 24 hours• Onset of diarrhoea: less than 5 days

STUDY OBJECTIVETo compare the clinical efficacy and tolerability of racecadotril and loperamide in adult patients with acute diarrhoea

Total: 69

EFFICACY AND TOLERABILITY RESULTS: Roge et al., 1993

Criteria Racecadotril Loperamide

•Delay of diarrhoea resolution •Cumulative recovery on day 2

2.2± 0.2 days59.3%

2.3± 0.2 days (NS)50.0%(NS)

•Duration of abdominal distension•Abdominal distension for > 1 day

1.1± 0.2 days27%

1.8± 0.3 days (P<0.05)50%(P<0.05)

•Abdominal pain for > 1 day •Constipation after diarrhoea resolution

40.5%8.1%

59.4%(NS)31.3%(P<0.02)

•Duration of treatment 3.0± 0.2 days 4.4± 0.3 days

(P<0.0001)

1. Roge J et al. Scand J Gastroenterol 1993; 28: 352-354

NS: Not Significant

COMPARISON OF RACECADOTRIL AND LOPERAMIDE IN ADULTS WITH ACUTE DIARRHOEA: Vetel et al., 1999

1. Vetel JM et al, Aliment Pharmacol Ther.1999;13(6):21-26

STUDY DESIGN

Double-blind, randomised, double-placebo controlled, parallel group study

Racecadotril

Patients

82

75Loperamide

INCLUSION CRITERIA• Age: >18 years• Suffering from acute diarrhoea• >3 loose stools for a minimum of 24 hours and a maximum of 5

days• Onset of diarrhoea-less than 5 days

STUDY OBJECTIVETo compare the efficacy , safety and tolerability of racecadotril and loperamide in adult patients with acute diarrhoea

Total: 157

EFFICACY RESULTS: Vetel et al., 1999


Duration of diarrhoea 14.9 ±2.0h 13.7±2.2h

Number of stools 3.5±0.5 2.9±0.4

Efficacy on visual analogue scale

83.7±2.1 82.2±2.3


0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 60 70 80 90 100

Prob

abili

ty o

f Unr

esol

ved

Dia

rrho

ea (%

)

Duration of Diarrhoea (hours)

Racecadotril

Loperamide

Efficacy: similar

Both the groups had similar efficacy

TOLERABILITY RESULTS: Vetel et al., 1999

Tolerance: better

• As effective as loperamide in treating acute diarrhoea• Less likely to be associated with adverse events like constipation


Incidence of adverse events 7.4% 12%

Rebound constipation

9.8% 18.7%

Mean duration of constipation

1.3±0.1 1.6±0.1


RacecadotrilLoperamide

0

5

10

15

20

% o

f Pat

ient

s

Patients constipatedfor 2 days

A MULTINATIONAL COMPARISON OF RACECADOTRIL AND LOPERAMIDE IN THE TREATMENT OF ACUTE WATERY DIARRHOEA IN ADULTS: Prado et al., 2002

1. Prado D. Scand J of Gastroenterol. 2002;6:656-661.

STUDY DESIGN

Multicentre, multi-national, single- blind, randomised, parallel-group comparitive study

Racecadotril

Patients

473

472Placebo

INCLUSION CRITERIA• Age: ≥18 years• 3 or more watery stools, with no visible blood, in the last

24 hours • Onset of diarrhoea of presumed infectious origin, of at least

24 hours and less than 5 days

STUDY OBJECTIVETo compare the clinical efficacy and tolerability of racecadotril and loperamide in adult patients with acute diarrhoea

Total: 945

EFFICACY RESULTS: Prado et al., 2002

Rapid onset of action upon diarrhoea(International study)


Overall Clinical Response(%)

92 93

Duration of Diarrhoea (hours)

55 55


100

90

80

70

60

50

40

30

20

10

00 20 40 60 80 100 120 140 160

Prob

abili

ty o

f unr

esol

ved

diar

rhoe

a (%

)

Time to resolution

Racecadotril

Loperamide

TOLERABILITY RESULTS AND CONCLUSION: Prado et al., 2002

• RAC: 14.2%• LOP: 23.9%• P=0.001

Total Adverse Events

Racecadotril • Safe, efficacious and tolerable in

the treatment of acute diarrhoea in adults

• Achieved a higher clinical success rate than loperamide

• Adverse events: less constipation and a rapid resolution of abdominal distension and pain


Treatment related adverse events with an incidence of more than 1%

Adverse event (by preferred term)

Racecadotril (n=473)

Loperamide (n=472)

Constipation 16 (3.4%) 59 (12.5%)

Abdomen enlarged

8 (1.7%) 29 (6.1%)

Anorexia 4 (0.8%) 11 (2.3%)

Headache 10 (2.1%) 2 (0.4%)

Abdominal pain 1 (0.2%) 9 (1.9%)RAC: RacecadotrilLOP: Loperamide

RACECADOTRIL COMPARED WITH LOPERAMIDE IN ELDERLY PEOPLE WITH GASTROENTERITIS LIVING IN NURSING HOMES: Gallelli et al., 2010

1. Gallelli L, et al. Eur J Clin Pharmacol. 2009; 137-144.

STUDY DESIGN

Randomised, prospective, double-blind, parallel group study

100 mg RacecadotrilPatients

30

312.0 mg Loperamide

INCLUSION CRITERIA• Adults with acute diarrhoea, without signs of severe dehydration and

bacterial infection • ≥ 3 watery stools in 24 hours

STUDY OBJECTIVETo study the efficacy, tolerability, and safety of racecadotril and loperamide in elderly patients with acute diarrhoea

Total: 61

Criteria Racecadotril Loperamide Mean total stool output before recovery (hours)

120+27 g/kg 150+39 g/kg


0

10

20

30

40

50

60

70

80

90

100

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Episodes of Diarrhoea

Age

of P

atie

nts

with

Dia

rrho

ea

Racecadotril

Loperamide

EFFICACY RESULTS: RACECADOTRIL VS LOPERAMIDE: Galleli et al., 2010

TOLERABILITY AND SAFETY RESULTS: RACECADOTRIL VS LOPERAMIDE - Gallelli et al., 2010

Criteria Racecadotril (% number of patients)

Loperamide (% number of patients)

Occurrence of adverse events 12% 60%

Nausea 10% 20%

Constipation 15% 60%


Racecadotril is more effective and tolerable than loperamide


Vetel et al., International Journal of Clinical Medicine, 2014;5:361-375.

RACECADOTRIL EFFICACY IN THE SYMPTOMATIC TREATMENT OF ADULT ACUTE DIARRHOEA: A SYSTEMATIC REVIEW AND META-ANALYSIS

Systematic review of randomised controlled trials (RCTs) performed in adults suffering from acute diarrhoea using RC as one treatment arm• Twelve randomised trials (2619 patients) met the inclusion criteria• Main efficacy endpoint was diarrhoea duration (DD) defined as time to

recovery compared between groups• Constipation proportion was the main safety endpoint, evaluated

between treatments by the Relative Risks (RR)

OBJECTIVETo examine whether Racecadotril (RC) reduces diarrhoea duration, assessing the efficacy of RC for the symptomatic treatment of acute diarrhoea in adults

1. Vetel JM et al. International Journal of Clinical Medicine, 2014;5:361-375.

RACECADOTRIL EFFICACY IN THE SYMPTOMATIC TREATMENT OF ADULT ACUTE DIARRHOEA: A SYSTEMATIC REVIEW AND META-ANALYSIS: Vetel et al. 2014



STUDY DESIGNSystematic Review

All RCTs, double-blind or single blind studies exclusively using a random-effect meta-analytic model

INCLUSION CRITERIA• Age: >18 years• Male and female• Suffering from acute

diarrhoea, any cause except cholera, healthy volunteers, paediatric patients, patients with chronic HIV-related diarrhoea, or due to anti-cancerous chemotherapy

INTERVENTION

• RC

• Adult formulation, without dosage restriction

OUTCOMES

• DD from treatment onset to the last unformed stools

• Safety, in particular treatment related constipation adverse effect


Author Control group Design ITT sample sizeRC Control Total

PP sample sizeRC Control Total

Baumer P Placebo DB 96 102 198 96 102 198

Hamza H Placebo DB 32 39 71 32 38 71

Vetel JM (multidose)*

Placebo DB 173 54 112 173 54 112

Moraes E Sb = Saccharomyces

boulardii

SB 207 197 404 175 161 404

Coffin B & RampalP*

Placebo DB 86 87 173 83 87 173

Rogé J Loperamide DB 40 36 76 37 32 76

Vetel JM Loperamide DB 82 75 157 77 70 157

Prado D Loperamide SB 473 472 945 473 471 945

Coulden S* Loperamide SB 60 60 120 60 60 120

Lin Sanren SB006* Loperamide SB 112 111 223 111 104 223

Wang HH Loperamide SB 31 31 62 31 31 62

Gallelli L Loperamide DB 30 31 61 30 31 61

All studies (n = 12) 1422 1295 2717 1378 1241 2619

ITT = intention to treat, PP = per protocol, DB = double-blind; SB = single-blind

Details of the 12 RCTs used for the meta-analysis



Results: Diarrhoea duration forest plot – comparison of RC versus placebo

• 65% more patients were observed to recover in the RC group compared with placebo (HR = 1.65 [1.38 - 1.97], p < 0.00001)



Results: Constipation occurrences forest plot – comparison of RC versus placebo

• Constipation was similar between RC and placebo arms (RR = 0.95 [0.24 -3.68], p = 0.97)


Study limitations:• RC dose differed between studies and sometime from the SmPC• The definition of constipation was not homogeneous among studies as

there is no universal definition of constipation



Conclusions:• Compared to placebo, RC is characterised by a clinically relevant earlier

remission of diarrhoea in adults experiencing acute diarrhoea• When RC was compared to loperamide, diarrhoea duration was similar,

but significantly fewer secondary constipation adverse effects were observed




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