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Horizon Scanning Centre September 2014

Prucalopride (Resolor) for adult males with chronic – third line

SUMMARY NIHR HSC ID: 10238

Prucalopride (Resolor) is intended to be used as third line therapy for the treatment of chronic constipation in adult males. If licensed, it would offer an additional treatment option for this patient group who do not respond to at least two previous treatments. Prucalopride is a highly selective This briefing is serotonin 5-HT4 receptor antagonist that has demonstrated prokinetic properties on gastric, intestinal and colonic smooth muscle. Prucalopride is based on currently licensed for the treatment of chronic constipation in women in information whom fail to provide adequate relief. available at the time

of research and a It is estimated that the prevalence of chronic constipation is 16%. It is more limited literature common in women than men and prevalence increases with age. Patients search. It is not with constipation report a decreased quality of life, more job absenteeism, intended to be a and loss of work productivity. In 2012, there were 60,567 admissions for definitive statement constipation in England, resulting in 151,319 bed days and 72,567 finished on the safety, consultant episodes; in the same year there were 58 deaths registered in efficacy or England and Wales due to constipation. effectiveness of the health technology Management of chronic constipation may involve dietary and lifestyle covered and should changes in addition to medication such as bulk-forming laxatives, stimulant not be used for laxatives, osmotic laxatives or faecal softeners. When oral laxative therapy is commercial ineffective, use of suppositories, , , prucalopride (for purposes or women), rectal irrigation or manual disimpaction may be appropriate. commissioning Prucalopride is currently in one phase III clinical trial comparing its effect on without additional spontaneous bowel movements against treatment with placebo. information.

This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.

NIHR Horizon Scanning Centre, University of Birmingham Email: [email protected] Web: http://www.hsc.nihr.ac.uk NIHR Horizon Scanning Centre

TARGET GROUP

• Chronic constipation: adult males – third line.

DESCRIPTION

Prucalopride (Resolor) is a highly selective serotonin 5-HT4 receptor antagonist that has been shown to have prokinetic properties on gastric, intestinal and colonic smooth muscle. In animal models it increases the peristaltic reflexes and giant colonic migrating contractions. The mechanism of action of prucalopride is thought to be through facilitation of non- cholinergic/cholinergic and non-adrenergic neurotransmission1. In the phase III clinical trial, prucalopride is administered orally at 1 or 2mg once daily2.

Prucalopride is currently licensed for the treatment of chronic constipation in women in whom laxatives fail to provide adequate relief. Very common (>10%) adverse effects (AEs) of prucalopride when used for its licensed indication include headache, nausea, diarrhoea, and abdominal pain. Common (1% to <10%) AEs include dizziness, vomiting, dyspepsia, rectal haemorrhage, flatulence, abnormal bowel sounds, pollakiuria and fatigue.

INNOVATION and/or ADVANTAGES

If licensed, prucalopride will offer an additional treatment option for adult males with chronic constipation who do not respond to at least two previous laxative treatments.

DEVELOPER

Janssen; Shire (UK licence holder).

AVAILABILITY, LAUNCH OR MARKETING

Prucalopride is currently in phase III clinical trials.

PATIENT GROUP

BACKGROUND

The term constipation describes the subjective impression that the contents of the intestine are not evacuated at adequate frequency, and/or in adequate volumes, the consistency of the stool is too hard, and/or the stool is passed with discomfort3. Constipation can also contribute to secondary complications including abdominal distension, urinary retention, nausea, vomiting, anorexia, haemorrhoids, anal fissures, perianal abscesses, and intestinal obstruction, which may lead to life-threatening faecal impaction3. The Rome III criteria for Functional Bowel Disorders define chronic constipation as 2 or more of the following symptoms for at least 3 months with symptom onset at least 6 months prior to diagnosis4:

• Straining during at least 25% of defecations. • Lumpy or hard stools in at least 25% of defecations. • Sensation of incomplete evacuation for at least 25% of defecations. • Sensation of anorectal obstruction/blockage for at least 25% of defecations.

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• Manual manoeuvres to facilitate at least 25% of defecations (e.g. digital evacuation, support of the pelvic floor). • Fewer than 3 defecations per week. • Loose stools are rarely present without the use of laxatives. • Insufficient criteria for irritable bowel syndrome (IBS).

NHS or GOVERNMENT PRIORITY AREA

This topic is relevant to: • Improving quality of life for people with long term conditions (2013).

CLINICAL NEED and BURDEN OF DISEASE

Reported prevalence rates for constipation in the UK vary widely between studies, with figures ranging from 4% to 20%5. Research suggests that the prevalence of chronic constipation is approximately 16%6. Constipation is more common in women than men and prevalence increases with age1. Patients with constipation report a decreased quality of life, more job absenteeism, and loss of work productivity7. Additionally, research estimates that only half of patients using prescription laxatives feel that such products are effective in relieving the symptoms of constipation8. In 2012, there were 60,567 admissions for constipation (ICD-10 K59.0) in England, resulting in 151,319 bed days and 72,567 finished consultant episodes9. In the same year there were 58 deaths registered in England and Wales due to constipation10. The population likely to be eligible to receive prucalopride could not be estimated from available published sources.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal. Lubiprostone for treating chronic idiopathic constipation. (TA318). July 2014. • NICE technology appraisal. Prucalopride for the treatment of chronic constipation in women (TA211). December 2010.

Other Guidance

• World Gastroenterology Organisation. Practice Guidelines: Constipation. 200711

CURRENT TREATMENT OPTIONS

Guidelines recommend that the first step in the management of constipation should be appropriate dietary and lifestyle changes12. Patients should be advised on adequate fluid intake and consuming adequate amounts of food with a high fibre content (such as fruit, vegetables, high-fibre bread, baked beans and wholegrain breakfast cereals)13. A short course of laxatives may relieve symptoms and restore normal bowel function. There are several laxatives available for this purpose, including14,15: • Bulk-forming laxatives such as methylcellulose, ispaghula () husk, sterculia, • Stimulant laxatives such as , senna, . • Faecal softeners such as liquid paraffin and sodium.

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• Osmotic laxatives such as (polyethylene glycols), , and salts ( or magnesium sulphate).

Long-term laxative use should be avoided where possible. When oral laxative therapy is ineffective at producing a bowel movement, a suppository (such as or sodium phosphate) or may be appropriate13,14. For women in whom treatment with at least two laxatives from different classes, at the highest tolerated recommended doses (for at least 6 months) has failed to provide adequate relief, and invasive treatment for constipation is being considered, current guidance suggests prucalopride may also be used13. Lubiprostone is recommended as an option for treating adults with chronic idiopathic constipation, in whom treatment with at least 2 laxatives from different classes, at the highest tolerated recommended dose for at least 6 months, has failed to provide adequate relief and for whom invasive treatment for constipation is being considered13. Rectal irrigation and manual disimpaction are alternative treatment options for those who continue to have rectal emptying difficulties13.

EFFICACY and SAFETY

Trial NCT01147926, prucalopride vs. placebo; phase III. Sponsor Shire. Status Complete and published in abstract. Source of Abstract16, trial registry2, manufacturer. information Location EU (incl UK). Design Randomised, placebo-controlled. Participants n=374; aged ≥18 years; males; chronic constipation; ≤2 spontaneous bowel movementsa/week that result in a feeling of complete evacuation, and one or more of the following in ≥25% of stools for ≥6 months: very hard and/or hard stools; sensation of incomplete evacuation; straining at defecation; no SBMs. Schedule Randomised to: prucalopride 1mg oral daily for subjects >65 years (in case of insufficient response, 2 mg at week 2 or week 4) and 2mg oral daily for subjects >18 to <65 years; or placebo oral daily. Follow-up Active treatment for 12 weeks. Primary Percentage of subjects with an average ≥3 spontaneous bowel movements week that outcome/s result in a feeling of complete evacuation (SCBM)/week over treatment period. Secondary Safety and tolerability, quality of life (QoL) measured using the patient assessment of outcome/s constipation-quality of life questionnaire. Key results For prucalopride and placebo groups, respectively: % of subjects with an average ≥3 SCBM/week over treatment period, 37.9% vs 17.7% (p<0.0001); median time to first SCBM after first dose, 110.3 hours vs 218.9 hours (p=0.009); use of rescue medication during treatment period, 41.2% vs 56.9%. Adverse Common (≥1% to <10%) AEs for prucalopride and placebo groups, respectively: effects (AEs) abdominal pain, 4.3% vs 5.9%; diarrhoea, 6.5% vs 1.6%; nausea, 6.0% vs 2.2%, headache, 9.2% vs 3.8%.

ESTIMATED COST and IMPACT

COST

Prucalopride is already marketed in the UK for the treatment chronic constipation in women; a pack of 28 x 1mg tablets costs £38.69, and a pack of 28 x 2mg tablets costs £59.5217.

a Spontaneous bowel movement (SBM) is defined as bowel movements not proceeded within a period of 24 hours by the intake of a laxative agent or by the use of an enema.

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IMPACT - SPECULATIVE

Impact on Patients and Carers

 Reduced mortality/increased length of survival  Reduced symptoms or disability

 Other: wider societal benefits - earlier return  No impact identified to normal activities, including employment.

Impact on Health and Social Care Services

 Increased use of existing services  Decreased use of existing services

 Re-organisation of existing services  Need for new services

 Other  None identified

Impact on Costs and Other Resource Use

 Increased drug treatment costs: new  Reduced drug treatment costs treatment option.

 Other increase in costs  Other reduction in costs:

 Other:  None identified

Other Issues

 Clinical uncertainty or other research question  None identified identified:

REFERENCES

1 Rezaie A, Cheng E, Jijon H, et al. Prucalopride for the treatment of chronic constipation. Cochrane Database of Systematic Reviews 2012, Issue 2. Art. No.: CD009636 2 ClinicalTrials.gov. Evaluation of prucalopride in male subjects with chronic constipation. http://clinicaltrials.gov/ct2/show/NCT01147926?term=prucalopride&cond=chronic+constipation&le ad=shire&phase=2&rank=1 Accessed 4 September 2014. 3 Clemens K, and Klaschik E. Managing opioid-induced constipation in advanced illness: focus on bromide. Therapeutics and clinical risk management 2010;(6):77-82. 4 Wang B, Wu T, He P et al. for chronic constipation in adults. Cochrane Database of Systematic Reviews 2007, Issue 2. Art. No.: CD006502. 5 National Institute for Health and Care Excellence. Constipation (chronic idiopathic) - lubiprostone: final scope. Technology appraisal in development ID725. London: NICE; November 2013. 6 Wirta S, Hodgkins P, and Joseph A. Economic burden associated with chronic constipation in Sweden: a retrospective cohort study. ClinicoEconomics and outcomes research 2014;6:369. 7 Gonzalez-Martinez M, Ortiz-Olvera N, and Mendez-Navarro J. Novel pharmacological therapies for management of chronic constipation. Journal of clinical gastroenterology 2014;48(1):21. 8 Johanson J, and Kralstein J. Chronic constipation: a survey of the patient perspective. Alimentary pharmacology & therapeutics 2007;25(5):599-608. 9 Health & Social Care Information Centre. Hospital episode statistics for England. Inpatient statistics, 2012-13. www.hscic.gov.uk 10 Office for National Statistics. Mortality statistics: deaths registered in England and Wales, series DR, 2012. http://www.ons.gov.uk 11 World Gastroenterology Organisation. Practice Guidelines: Constipation. 2007 http://www.worldgastroenterology.org/assets/downloads/en/pdf/guidelines/05_constipation.pdf 12 National Institute for Health and Clinical Excellence. Constipation (women) – prucalopride: final scope. Technology appraisal ID211. London: NICE; December 2010.

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13 National Institute for Health and Care Excellence. Pathways. Clinical management of idiopathic constipation in children and young people. http://pathways.nice.org.uk/pathways/constipation-in- children-and-young-people/constipation-in-children-and-young-people-overview Accessed 4 September 2014. 14 The British Pain Society. Opioids for persistent pain: Good practice. London: January 2010 15 Map of Medicine. Chronic constipation management. http://app.mapofmedicine.com/mom/1/page.html?department-id=4&specialty-id=1016&pathway- id=3143&page-id=7563&pathway-prov-cert=/attachments/15324_provcert.pdf Accessed 10 June 2014. 16 Yiannakou Y, Bouchoucha M, Schiefke I, et al. Efficacy and safety of prucalopride in men with chronic constipation: a phase 3, randomized, double-blind, placebo-controlled trial. Gastroenterology 2014;146(5):S-160,Abstract 929g. 17 British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary. BNF September 2014. http://www.bnf.org/

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