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Home , Diphenoxylate, Oral rehydration therapy, Racecadotril

Racecadotril (Hidrasec) for acute diarrhoea

June 2012

This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes.

The National Horizon Scanning Centre Research Programme is part of the National Institute for Health Research

June 2012

Racecadotril (Hidrasec) for acute diarrhoea

Target group • Acute diarrhoea: (older than 3 months), children and adults – add on to oral rehydration .

Technology description Racecadotril (Acetorphan; Hidrasec) is an antisecretory inhibitor. It is the racemic mixture of the enantiomers dexecadotril (retorphan) and (sinorphan). Racecadotril inhibits the degradation of endogenous , which reduces the hypersecretion of and into the intestinal lumen1. Racecadotril exerts its action without modifying the duration of intestinal transit. Racecadotril is administered at 1.5mg/kg three times daily for infants and children, and 60mg three times daily for adults, for a maximum of 7 days.

Innovation and/or advantages If licensed, racecadotril would represent the first in a new class of treatments for this patient group.

Developer Abbott Healthcare Products Ltd (Licensee); Bioprojet Europe Ltd.

NHS or Government priority area This topic is relevant to The National Service Framework for Child Health and Maternity (2004).

Relevant guidance • NICE clinical guideline. Diarrhoea and in children: Diarrhoea and vomiting caused by : diagnosis, assessment and management in children younger than 5 years. 20092.

Clinical need and burden of disease Severe diarrhoea can quickly cause and become a life-threatening condition2. The majority of cases are attributed to either bacterial or viral , although many other chronic medical conditions can also cause diarrhoea, including Crohn’s disease, ulcerative and irritable bowel syndrome2.

In adults, the incidence of acute diarrhoea is estimated to be one episode per adult per year3. Severe acute diarrhoea is more prevalent in travellers, older people, adults in contact with children, homosexual men and immunocompromised patients4. Infectious diarrhoea occurs much more commonly in developing countries; in these settings, children typically experience 6 to 12 episodes per year, compared to 2 episodes per year in industrialised countries5. In a systematic analysis of population health data available for 2001, diarrhoeal diseases accounted for 1.78 million deaths (3.7% of total deaths) in low and middle income countries6. Most of these deaths occurred in children under 5 years of age. In a UK study, diarrhoeal illness accounted for 16% of medical presentations to a major paediatric emergency department7. In industrialised countries, deaths from infectious diarrhoea occur mainly in the elderly.

Existing comparators and treatments The symptoms of acute diarrhoea usually resolve within a few days and are normally managed at home with an increase fluid intake. In patients who are more vulnerable to 2 June 2012

dehydration associated with diarrhoea, such as the very young or old, oral rehydration solution (ORS) can be used to help replace lost fluids and electrolytes. Anti-motility agents such as , and co-phenotrope ( hydrochloride 2.5mg, sulphate 25µg) may also be used to reduce the number of diarrhoeal episodes, however these are not recommended for acute diarrhoea in children8.

Efficacy and safety

Trial Use of racecadotril as outpatient treatment Racecadotril in the treatment of acute for acute gastroenteritis: a prospective, watery diarrhoea in children. randomised, parallel study. Sponsor Ferrer. Bioprojet Pharma. Status Published. Published. Source of Publication9. Publication10. information Location EU. Peru. Design Randomised, controlled. Randomised, placebo-controlled. Participants n=189; children aged 3 to 36 months; n=135; boys aged 3 to 35 months; and schedule acute gastroenteritis (3 loose stools within hospitalisation due to dehydration; watery the previous 24hrs). diarrhoea for 5 days or less with 3 or Randomised to racecadotril 10mg, 20mg more diarrhoeic stools in the past 24hrs. or 30mg three times daily in combination Randomised to racecadotril 1.5mg/kg with oral rehydration solution (ORS) or three times daily or placebo, both in ORS only. combination with ORS. Follow-up Active treatment until resolution of Active treatment until resolution of diarrhoea (occurrence of 2 stools of diarrhoea (occurrence of 2 stools of normal consistency or 12hrs without any normal consistency or 12hrs without any bowel movement) or until 7 days of bowel movement) or until 5 days of treatment; follow-up at 48hrs and 7 days treatment. after treatment initiation. Primary Number of diarrhoeic stools within 48hrs 48hr stool output. outcome of initiation of therapy. Secondary Duration of diarrhoea; number of visits to Total stool output; duration of diarrhoea; outcome the emergency room or primary care ORS intake. doctor; safety. Key results For racecadotril plus ORS vs ORS alone For racecadotril plus ORS vs placebo plus respectively (+SD): ORS respectively (+SE): Number of diarrhoeic stools after 24hrs, Mean 48hr stool output, 92g/kg (+12g/kg) 4.6 (+2.7) vs 4.6 (+2.5) (p>0.05); number vs 170g/kg (+15g/kg) (p<0.001); total of diarrhoeic stools after 48hrs, 3.8 (+2.4) stool output, 157g/kg (+27g/kg) vs vs 4.1 (+2.7) (p>0.05); average duration 331g/kg (+39g/kg) (p<0.001); median of diarrhoea, 4 days (+ 2.1) vs 4.7 days duration of diarrhoea, 28hrs (regardless of (+2.2) (p>0.05); number of emergency status) vs 72 and 52hrs room visits within 48hrs, 5 vs 8 (p>0.05); (rotavirus positive and negative patients number of paediatrician visits within respectively) (p<0.001); mean ORS intake 48hrs, 6 vs 6 (p>0.05); number of on day 1, 439ml (+49ml) vs 658ml emergency room visits within 7 days, 5 vs (+59ml), mean ORS intake on day 2, 2 (p>0.05); number of paediatrician visits 414ml (+68ml) vs 640ml (+68ml) within 7 days, 1 vs 3 (p>0.05). (p<0.001). Adverse For racecadotril plus ORS vs ORS alone For racecadotril plus ORS vs placebo plus effects (AEs) respectively: ORS respectively: AEs occurred in 18 (19.1%) vs 19 AEs occurred in 7 (10%) vs 5 (7%). Most (20.2%) patients. Most frequent AEs frequent AEs included hypokalaemia, included respiratory illness (rhinitis, , mild fever and vomiting. bronchitis, coughing, pneumonia and upper respiratory ). 3 June 2012

Trial Efficacy and tolerability of racecadotril in Benefit of racecadotril for acute diarrhoea acute diarrhoea in children. treatment and visit. Sponsor Bioprojet Pharma. Investigator led. Status Published. Published. Source of Publication11. Publication12. information Location EU. EU. Design Randomised, placebo-controlled. Randomised, controlled. Participants n=172; children aged 3 months to 4 years; n=164; children aged 3 to 36 months; acute and schedule acute diarrhoea (3 or more watery stools diarrhoea (3 watery stools within the last within the last 24hrs). 12hrs). Randomised to racecadotril 1.5mg/kg Randomised to racecadotril 10mg or 20mg three times daily or placebo. ORS three times daily in combination with ORS administered as required during the first or ORS only. 24hrs of the study. Follow-up Active treatment until resolution of Active treatment until resolution of diarrhoea (occurrence of 2 stools of diarrhoea (occurrence of 2 stools of normal normal consistency or 12hrs without any consistency or 12hrs without any bowel bowel movement) or until 5 days of movement) or until 7 days of treatment. treatment. Primary 48hr stool output. Number of medical examinations during outcome week after treatment initiation. Secondary 24hr stool output; recovery rate; food and Duration of diarrhoea; weight at day 7; outcome ORS intake. number of stools after 48hrs. Key results For racecadotril vs placebo respectively For racecadotril plus rehydration vs (121 patients fully evaluable): rehydration alone (+SD): Mean 48 hr stool, 9g/hr vs 15g/hr Number of medical examinations during (p=0.009) [per-protocol analysis, 7g/hr vs week after treatment initiation, 14 (18%) vs 16g/hr (p=0.001)]; mean 24 hr stool 27 (35%) (p<0.05); duration of diarrhoea, output, 10.5g/hr vs 16g/hr (p=0.025) [per- 97.2hrs (+35.6hrs) vs 137.7hrs (+42.4hrs) protocol analysis, 11g/hr vs 18g/hr (p<0.001); weight change at day 7, +4.4% (p=0.015)]; patients recovery within 5 vs +3.5% (p>0.05); number of stools in the days, males, 88% vs 79%, females, 90% first 48hrs, 6.8 (+3.8) vs 9.5 (+4.5) vs 82%. (p<0.001). Both groups had similar intake of food and ORS. However ORS intake decreased more rapidly in racecadotril group; patients requiring ORS on the second day, 19% and 35% in racecadotril and placebo group respectively. Adverse 9 patients reported a total of 21 AEs (10 Only AEs reported involved difficulties in effects (AEs) racecadotril and 11 placebo). Most AEs taking racecadotril due to taste. were classified as mild to moderate, and only 2 were thought to be due to related treatment – 1 case of moderate vomiting (racecadotril group) and 1 case of moderate facial eczema (placebo). The most common AE was vomiting seen in 7 patients receiving racecadotril and 3 receiving placebo.

Trial Racecadotril – a novel for treatment The effectiveness of racecadotril in the of acute watery diarrhoea in Indian treatment of acute gastroenteritis. children. Sponsor Investigator led. Ferrer. 4 June 2012

Status Published. Published. Source of Abstract13. Publication14. information Location India. EU. Design Randomised, placebo-controlled. Non-randomised, controlled. Participants n=60; children aged 3 months to 5 years; n=148; children aged 3 to 36 months; and schedule acute diarrhoea (3 watery stools within acute diarrhoea (3 watery stools within the last 12hrs) of 5 days duration or less. the last 12hrs) of 7 days duration or less. Randomised to racecadotril 1.5mg/kg Patients were given racecadotril in three times daily or placebo, both in combination with ORS vs ORS alone. combination with ORS. Follow-up Active treatment until resolution of Active treatment until resolution of diarrhoea (occurrence of 2 stools of diarrhoea (occurrence of 2 stools of normal consistency or 12hrs without any normal consistency or 12hrs without any bowel movement) or until 5 days of bowel movement) or until 7 days of treatment. treatment; follow-up at 24hrs, 48hrs and 7-10 days after first visit. Primary Duration of diarrhoea. Number of daily stools within 48hrs of outcome initiation of therapy.

Secondary ORS intake. Duration of diarrhoea and treatment outcome period; hospital admission within 24 and 48hrs; visits to emergency services. Key results For racecadotril plus ORS vs placebo plus For racecadotril plus ORS vs ORS alone ORS respectively: respectively (+SD): Duration of diarrhoea, 40.0hrs vs 61.6hrs Daily stools at 24hrs in bottle-fed (p<0.01); total ORS intake, 841.7ml vs children, 4.1 (+4.4) vs 7.2 (+3.5) 1385.0ml (p<0.001). (p=0.003); daily stools at 48hrs in bottle- fed children, 2.9 (+2.4) vs 5.9 (+3.6) (p<0.001); daily stools at 24hrs in children who attend nursery/school, 4.0 (+2.9) vs 7.1 (+3.4) (p<0.001); daily stools at 48hrs in children who attend nursery/school, 3.1 (+2.8) vs 5.0 (+2.9) (p<0.001); daily stools at 24hrs in rotavirus positive patients, 5.0 (+4.1) vs 7.5 (+3.6) (p<0.001); daily stools at 48hrs in rotavirus positive patients, 3.6 (+3.4) vs 5.7 (+3.5) (p<0.001); duration of treatment in days, 3.5 (+ 1.9) vs 5.6 (+2.8) (p<0.001); duration of diarrhoea in days, 5.9 (+2.6) vs 7.6 (+3.1) (p<0.001); patients admitted to hospital at 24hrs, 8.6% vs 26.9% (p<0.001); patients admitted to hospital at 48hrs, 6.1% vs 35.9% (p<0.001); number of visits to emergency services, 1.3 (+1.4) vs 2.4 (+1.7) (p<0.001). Adverse No AEs were reported. AEs included rash, nervousness, effects (AEs) sleepiness, stomach ache and haematuria. No patient experienced more than one AE.

Trial Racecadotril vs placebo in the treatment of acute gastroenteritis in children. Sponsor Investigator led. Status Published. 5 June 2012

Source of Company supplied information. information Location Mexico. Design Randomised, placebo-controlled. Participants n=454 (n=270 inpatient setting, n=184 outpatient setting); children aged 1 month to 2 and schedule years; acute diarrhoea (3 watery stools within the last 12hrs) of 1 to 5 days duration. Randomised to racecadotril 1.5mg/kg three times daily or placebo, both in combination with ORS. Follow-up Active treatment until resolution of diarrhoea (occurrence of 2 stools of normal consistency or 12hrs without any bowel movement) or until 5 days of treatment. Primary Inpatient group outcomes Stool output duration during rehydration; 48hr stool output; total stool output; duration of diarrhoea; requirement for a second rehydration schedule; need for IV treatment; AEs. Outpatient group Number of stools after 48hrs; number of stools after 7 days; number of diarrhoeic stools after 48hrs; number of diarrhoeic stools after 7 days; duration of diarrhoea; AEs. Key results For racecadotril plus ORS vs placebo plus ORS respectively (+SD): Inpatient group Stool output during rehydration, 63g (+11g) vs 114g (+14.2g) (p<0.01); 48hr stool output, 102g (+18g) vs 189g (+34g) (p<0.01); total stool output, 176g (+24g) vs 398g (+27g) (p<0.001); duration of diarrhoea, 33.8hrs (+8hrs) vs 97hrs (+11hrs) (p<0.05); requirement for a second rehydration schedule, 26% vs 54% (p<0.001); need for IV treatment, 6% vs 17% (p<0.05). Outpatient group Number of stools after 48hrs, 9.8 (+2.8) vs 14.6 (+3.1) (p<0.01); number of stools after 7 days, 2.2 (+1.2) vs 3.0 (+1.4) (p<0.05); number of diarrhoeic stools after 48hrs, 5.6 (+1.7) vs 11.3 (+2.7) (p<0.01); number of diarrhoeic stools after 7 days, 0.0 (+1.4) vs 0.73 (+0.89) (p<0.001); duration of diarrhoea, 75.5hrs (+11.6hrs) vs 142.5hrs (+15.45hrs) (p<0.01). Adverse For racecadotril plus ORS vs placebo plus ORS respectively: effects (AEs) Abdominal distension 22% vs 24% of patients in the hospitalised group; abdominal distension and abdominal pain, 4.35% vs 3.26% of patients in the outpatient group.

In addition to the studies listed above, a systematic review and meta-analysis conducted by Lehert et al., 201115 also identified an additional study conducted in Guatemala by Melendez Garcia and Rodriguez, 200716. This study recruited 50 children aged 3 months to 6 years with a primary outcome of the total number of diarrhoeic stools following racecadotril treatment.

Estimated cost and cost impact

Drug Dose Cost8 Loperamide 4mg initially followed by 2mg after 6 x loperamide 2mg, simeticone 125 mg (tablets) each bowel movement for up to 5 = £2.27. days. Codeine (tablets) 30mg, 4 times daily. 28 x 30mg = £1.18 Co-phenotrope Initially 4 tablets, followed by 2 100 x 2.5mg/0.025µg = £8.95 tablets every 6hrs until diarrhoea is controlled.

6 June 2012

Claimed or potential impact – speculative

Patients Reduced mortality or increased  Reduction in associated morbidity Quicker, earlier or more accurate length of survival or improved quality of life for diagnosis or identification of patients and/or carers disease Other: None identified

Services Increased use Service organisation Staff requirements

Decreased use Other:  None identified

Costs Increased unit cost compared to Increased costs: more patients Increased costs: capital alternative coming for treatment investment needed  New costs: new additional Savings: Other: treatment option.

Other issues  Clinical uncertainty or other research question identified: Expert opinion None identified suggests there are already well established effective treatment options available for diarrhoea and clinicians are generally reluctant to use anti- diarrhoeal medications in this patient groupa.

References

1 Matheson AJ, Noble S. Racecadotril. 2000;59(4):829-835. 2 National Institute for Health and Clinical Excellence. Diarrhoea and vomiting in children: Diarrhoea and vomiting caused by gastroenteritis: diagnosis, assessment and management in children younger than 5 years. Clinical guideline CG84. London: NICE; April 2009. 3 Feldman RA, Banatvala N. The frequency of culturing stools from adults with diarrhoea in Great Britain. Epidemiology and Infection 1994;113(1):41-44. 4 Gore JI, Surawicz C. Severe acute diarrhoea. Gastroenterology Clinics on North America 2003;32(4):1249- 1267. 5 Guerrant RL, Hughes JM, Lima NL et al. Diarrhoea in developed and developing countries: magnitude, special settings and etiologies. Reviews of Infectious Disease 1990;12:41-50. 6 Lopez AD, Mathers CD, Ezzati M et al. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 2006;367(9524):1747-1757. 7 Armon K, Stephenson Y, Gabriel V et al. Determining the common medical presenting problems to an accident emergency department. Archives of Disease in Childhood 2001;84:390-392. 8 British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary BNF 63. London: BMJ Group and RPS Publishing, March 2012. 9 Santos M, Maranon R, Miguez C et al. Use of racecadotril as outpatient treatment for acute gastroenteritis: a prospective, randomised, parallel study. The Journal of 2009;155:62-67. 10 Salazar-Lindo E, Santisteban-Ponce J, Chea-Woo E et al. Racecadotril in the treatment of acute watery diarrhoea in children. New England Journal of Medicine 2000;343:463-467. 11 Cezard JP, Duhamel JF, Meyer M et al. Efficacy and tolerability of racecadotril in acute diarrhoea in children. Gastroenterology 2001;120:799-805. 12 Cojocaru B, Bocquet N, Timsit S et al. Benefit of racecadotril for acute diarrhoea treatment and emergency department visit. Archives de Pédiatrie 2002;8:774-779. English translation available from: http://static.vademecum.es/documentos/evidencia/tiorfan/DOC050Cojocaru.PDF

a Expert personal communication. 7 June 2012

13 Savita MR. Racecadotril – a novel drug for treatment of acute watery diarrhoea in Indian children. Karnataka Pedicon 2005 – Conference Abstracts. Pediatric Oncall [serial online]; 2006 [cited 1 January 2006]; 3, Available from: http://www.pediatriconcall.com/fordoctor/Conference_abstracts/racecadotrial.asp 14 Alvarez Calatayud G, Simon G, Taboada Castro L et al. The effectiveness of racecadotril in the treatment of acute gastroenteritis. Acta Pediátrica Española 2009;67(3):117-122. 15 Lehert P, Cheron G, Alvarez Calatayud G et al. Racecadotril for childhood gastroenteritis: an individual patients data meta-analysis. Digestive and Disease 2011;43:707-713. 16 Melendez Garcia JM and Rodriguez JT. Racecadotril en el tratamiento de la diarrea aguda en ninos. Revista de la Facultad de Medicina (Guatemala) 2007;4:25-28.

The National Institute for Health Research National Horizon Scanning Centre Research Programme is funded by the Department of Health. The views expressed in this publication are not necessarily those of the NHS, the NIHR or the Department of Health

The National Horizon Scanning Centre, Department of Public Health and Epidemiology University of Birmingham, 90 Vincent Drive, Edgbaston, Birmingham, B15 2SP, England Tel: +44 (0)121 414 7831 Fax +44 (0)121 414 2269 www.haps.bham.ac.uk/publichealth/horizon

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