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Medicines Q&As Q&A 332.2 What are the differences between non-oral mesalazine preparations? Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp Date prepared: 28th August 2014 Background Mesalazine is an aminosalicylate that is used routinely to induce and maintain remission in chronic inflammatory bowel disease – ulcerative colitis (UC) and Crohn’s disease. Acute mild to moderate disease affecting the rectum (proctitis) or the recto-sigmoid is treated initially with local application of an aminosalicylate. Diffuse inflammatory bowel disease or disease that does not respond to local therapy requires oral treatment. A combination of a local and an oral aminosalicylate can be used in proctitis or distal colitis. (1) The locally acting preparations that are currently available are liquid and foam enemas and suppositories which are inserted in to the rectum. Available formulations have differences in licensed indications, strengths, and dose frequency. (2-9) Answer There are various differences between the 4 enema products (2, 4, 6, 8) and the 3 brands of suppositories. (3, 5, 7, 9) These are set out in table 1 and 2 below. Licensed indication All the rectal products are licensed for treatment of UC distal disease, however there are slight differences between them. (2-9) Distal disease refers to disease up to the sigmoid descending junction, including that limited to the rectum (proctitis). (10) Salofalk foam and liquid enemas are for treatment of active, mild UC of the sigmoid colon and rectum. (6, 8) The 2g enema can also be used for colitis in the descending colon and prophylaxis of colitis attacks. (8) Salofalk suppositories are indicated for treatment of acute mild and moderate UC in the rectum. (7, 9) The 500mg suppositories can also be used where there is colitis in the sigmoid colon and descending colon. (9) Asacol foam enema and suppositories are licensed for treatment of mild to moderate acute exacerbations. (2, 3) The suppositories are also licensed for maintenance of remission. (3) The licensed indication for the Pentasa liquid enema is treatment of UC affecting the distal colon and rectum. (4) The licence for the suppositories is for treatment of ulcerative proctitis, which is disease limited to the rectum. (5) Strength & formulation There are 2 strengths of enema products - 1g and 2g. These are presented in 2 different formulations, a pressurised canister which administers a dose in a stiff foam or a liquid enema (either 1g in 100ml or 2g in 59ml). (2, 4, 6, 8) There is only one strength of the Pentasa suppositories - 1g, whereas there are two strengths of Asacol suppositories - 250mg and 500mg and Salofalk suppositories - 500mg and 1g. (3, 5, 7, 9) A MeReC bulletin in 2011 suggested that the proximal extent of the inflammation and patient preference, including ease of insertion or retention of enemas, should determine the topical formulation chosen. Suppositories are indicated for disease to the rectosigmoid junction because they deliver the drug more effectively to the rectum than enemas, whereas foam enemas usually treat up to the proximal sigmoid colon and liquid enemas can deliver medication as proximal as the splenic flexure in most patients. Foam and liquid enemas appear to be equally effective in treating patients with proximal ulcerative colitis, but generally foam enemas are preferred because they are easier to administer and retention is more comfortable. Suppositories are usually better tolerated than enemas. (10) Dose frequency The products which have a strength of 1g and 2g are given once daily, preferably at bedtime. (2, 4-8) The 500mg and 250mg suppositories are inserted at regular intervals, (up to 3-6 times) throughout the day with the last dose at bedtime. (3, 9) Available through NICE Evidence Search at www.evidence.nhs.uk 1 Medicines Q&As Pharmacokinetics Absorption from mesalazine rectal dosage forms varies widely and is affected by factors such as the dose and the formulation; mean absorption of around 10 to 30% of a rectal dose has been reported. (11) Table 1 – Comparison of Asacol, Pentasa and Salofalk rectal enemas Brand Formulation Strength Licensed indications Adult dose frequency Asacol (2) Foam enema in a pressurised canister containing 14 doses. 1g per metered dose Mild to moderate acute exacerbations of UC affecting the distal colon. Pentasa (4) Liquid enema in single use bottles. Salofalk (8) Liquid enema in single use bottles. 1g in 100ml Salofolk (6) Foam enema in a pressurised canister containing 14 doses. 1g per actuation Treatment of UC affecting the distal colon and rectum. Active, mild UC of the sigmoid colon and rectum. 1g (one enema) once daily at bedtime. Two metered applications (2g) once daily at bedtime for 4-6 weeks. Can also administer in divided doses – 1 at bedtime and 1 during the night or in the morning if the patient has difficulty in holding in 2 doses at once. Little experience, only limited documentation for an effect in children. Treatment and prophylaxis of acute attacks of mild UC in the rectum, sigmoid colon & descending colon. 2g (one enema) once daily at bedtime. Disease affecting the rectosigmoid region: 1g (1 dose) once daily for 4-6 weeks. Disease affecting the descending colon: 2g (2 doses) once daily for 4-6 weeks. Use in children Adverse effects related to administration No dosage recommendation, contraindicated in children under 2 years old. BNF-C: Not licensed for use in children under 18 years. For child aged 12-18 years dose as for adults (unlicensed use). (12) Local irritation No dosage recommendation. BNF-C: Not licensed for use in children under 18 years. For child aged 12-18 years dose as for adults (unlicensed use). (12) Pruritus, rectal discomfort and urge to defeacate. BNF-C: Not licensed for use in children under 18 years. For child aged 12-18 years dose as for adults (unlicensed use). (12) Abdominal distension, anal discomfort, application site irritation, painful rectal tenesmus. 2g in 59ml Little experience, only limited documentation for an effect in children. BNF-C: Not licensed for use in children under 18 years. For child aged 12-18 years dose as for adults (unlicensed use). (12) None listed in summary of product characteristics. BNF-C: BNF for Children Available through NICE Evidence Search at www.evidence.nhs.uk 2 Medicines Q&As Table 2 - Comparison of Asacol, Pentasa and Salofalk rectal suppositories Brand Formulation Strength Licensed indications Adult dose frequency Use in children Asacol (3) Suppositories 250mg and 500mg Mild to moderate acute exacerbations of UC, particularly those affecting the distal colon. Maintenance of remission in UC. 250mg: 3 – 6 suppositories per day in divided doses, with the last dose at bedtime. 500mg: maximum of 3 suppositories per day in divided doses, with the last dose at bedtime. No dosage recommendation, use contraindicated in children under 2 years old. BNF-C: Not licensed for use in children under 18 years. Child 12-18 years: 250mg- 500mg 3 times daily with last dose at bedtime (unlicensed use). (12) Adverse effects related to administration Local irritation Pentasa (5) Suppositories 1g Treatment of ulcerative proctitis. Salofalk (7, 9) Suppositories 500mg & 1g Active, mild to moderate UC of the rectum. 500mg: can also use if UC in the sigmoid colon and descending colon. Acute treatment: 1 suppository daily for 2-4 weeks. Maintenance treatment: 1 suppository daily 500mg: 1-2 suppositories, 2-3 times daily. 1g: 1 suppository daily, preferably at bedtime. Duration of use to be determined by the physician. Use not recommended. Use contraindicated in children under 15 years. Little experience, only limited documentation for an effect in children. Not licensed for use in children under 18 years. BNF-C: Not licensed for use in children under 15 years. Child 12-18 years: dose as for adults. Dose unlicensed in children 1214 years. (12) Pruritus, rectal discomfort and urge to defeacate BNF-C: Not licensed for use in children under 15 years. Child 12-18 years: 500mg suppositories only, 0.5-1g 2-3 times daily, adjusted according to response (unlicensed use). (12) None listed in summary of product characteristics BNF-C: BNF for Children Guidance for use A review of the delivery and efficacy of topical mesalazine therapy in the treatment of UC published in 2011 concluded that there is strong evidence from randomised controlled trials to support use of topical mesalazine as a first line treatment for patients with mildly to moderately active distal UC. There is supportive data to suggest that topical therapy, particularly suspensions should be used as an adjunct to the treatment of extensive disease in the first 4 weeks of therapy. The choice of dosage form should reflect both the proximal disease extent and patient preference. (13) The 2011 British Society of Gastroenterology guidelines for the management of inflammatory bowel disease in adults do not make any specific recommendations for use of rectal aminosalicylates for treatment of UC. (14) A MeReC Bulletin addressed common questions around medicines used for inflammatory bowel disease (IBD) in 2011. (10) The bulletin states that aminosalicylates are considered first-line drugs for patients with mild to moderate ulcerative colitis. They are effective for inducing and maintaining remission in ulcerative colitis. The choice of drug and preparation in IBD depends on its safety, effectiveness, cost and patient factors. Patient factors include the current disease activity, area of the GI tract affected (e.g. proctitis, recto-sigmoid, or extensive), patient preference and adherence, which Available through NICE Evidence Search at www.evidence.nhs.uk 3 Medicines Q&As may also influence the dosing frequency chosen. Rectal aminosalicylates are also added to oral treatment in mild to moderate extensive ulcerative colitis. The European Crohn's and Colitis Organisation evidence-based consensus on the diagnosis and management of ulcerative colitis states that a mesalazine 1 g suppository once daily is the preferred initial treatment for mild or moderately active proctitis. Mesalazine foam enemas are an alternative. Suppositories may deliver drug more effectively to the rectum and are better tolerated than enemas. (15) The NICE clinical guideline on management of ulcerative colitis in adults, children and young people published in June 2013 highlights that topical aminosalicylates can be used to induce remission as first step therapy for mild to moderate ulcerative colitis. There is no recommendation to use a particular preparation. (16) The Crohns and Colitis UK booklet about drugs used in IBD says that foam enemas are often easier to retain than liquid enemas so can be particularly useful at the beginning of a flare-up, when the gut is most sensitive. Liquid enemas can usually travel further along the colon, so will reach more of the inflammation, especially if inserted just before lying down. (17) Summary There are 9 non-oral mesalazine preparations – 4 enemas and 5 suppositories which have slightly different licences for treatment of ulcerative colitis (UC) distal disease. Distal disease refers to disease up to the sigmoid descending junction, including that limited to the rectum (proctitis). The enema products are 1g or 2g in strength, but are presented in 2 different formulations, a pressurised canister which administers a dose in a stiff foam or a liquid enema (1g/100ml or 2g/59ml). There are 3 strengths of suppositories - 1g, 500mg and 250mg. All the 1g and 2g products are given once daily, preferably at bedtime. The 500mg and 250mg suppositories are inserted up to 3 to 6 times throughout the day with the last dose at bedtime. Absorption from mesalazine rectal dosage forms varies widely and is affected by factors such as the dose and the formulation; mean absorption of around 10 to 30% of a rectal dose has been reported. There is strong evidence from randomised controlled trials to support use of topical mesalazine as a first line treatment for patients with mildly to moderately active distal UC. Guidelines and reviews of inflammatory bowel disease do not differentiate between topical mesalazine therapies or specify which one to use. The choice of dosage form should reflect the current disease activity, area of the GI tract affected (e.g. proctitis, recto-sigmoid, or extensive), patient preference and adherence, which may also influence the dosing frequency chosen and cost. Limitations This information is only applicable to the mesalazine products which are for rectal use. Information on mesalazine tablets is available in medicines Q&A 67.5. References 1. Martin J, editor. British National Formulary No 67. London: British Medical Association and The Royal Pharmaceutical Society of Great Britain; March-September 2014. Accessed 28/08/14 via http://www.bnf.org/bnf/ 2. Summary of Product Characteristics. Asacol Foam Enema, Warner Chilcott UK Limited. Date last updated 01/12/10. Accessed 28/08/14 via http://www.emc.medicines.org.uk. 3. Summary of Product Characteristics. Asacol Suppositories 250mg & 500mg, Warner Chilcott UK Limited. Date last updated 06/10/10. Accessed 28/08/14 via http://www.emc.medicines.org.uk. 4. Summary of Product Characteristics. Pentasa Mesalazine Enema, Ferring Pharmaceuticals Ltd. Date last updated 25/07/12. Accessed 28/08/14 via http://www.emc.medicines.org.uk. 5. Summary of Product Characteristics. Pentasa Suppositories 1g, Ferring Pharmaceuticals Ltd. Date last updated 25/07/12. Accessed 28/08/14 via http://www.emc.medicines.org.uk. 6. Summary of Product Characteristics. Salofalk 1g/actuation Rectal Foam. Dr Falk Pharma UK Ltd Date last updated 06/03/14. Accessed 28/08/14 via http://www.emc.medicines.org.uk. Available through NICE Evidence Search at www.evidence.nhs.uk 4 Medicines Q&As 7. Summary of Product Characteristics. Salofalk 1g Suppositories. Dr Falk Pharma UK Ltd. Date last updated 20/05/14. Accessed 28/08/14 via http://www.emc.medicines.org.uk. 8. Summary of Product Characteristics. Salofalk Enema 2g. Dr Falk Pharma UK Ltd. Date last updated 08/10/13. Accessed 28/08/14 via http://www.emc.medicines.org.uk. 9. Summary of Product Characteristics. Salofalk Suppositories 500mg. Dr Falk Pharma UK Ltd. Date last updated 08/03/12. Accessed 28/08/14 via http://www.emc.medicines.org.uk. 10. Common questions around medicines used for inflammatory bowel disease. MeReC Bulletin 2011; 21 (4). http://www.npc.nhs.uk/merec/other_non_clinical/resources/merec_bulletin_vol21_no4.pdf 11. Martindale Sweetman S, editor. Martindale: The Complete Drug Reference 37th ed. Mesalazine. Date of revision of the text 13/12/13. Accessed 28/08/14 via www.medicinescomplete.com. 12. BNF –C Martin J, editor. BNF for Children 2014-15. London: British Medical Association, the Royal Pharmaceutical Society of Great Britain, the Royal College of Paediatrics and Child Health, and the Neonatal and Paediatric Pharmacists Group. Accessed 28/08/14 via http://bnfc.org/bnfc/ 13. Harris MS, Lichtenstein GR. Review article: delivery and efficacy of topical 5-aminosalicylic acid (mesalazine) therapy in the treatment of ulcerative colitis. Alimentary Pharmacology and Therapeutics 2011; 33: 996-1009. 14. Mowat C; Cole A; Windsor A; Ahmad T; et al. Guidelines for the management of inflammatory bowel disease in adults. Gut 2011; 60 (5): 571-607. http://www.bsg.org.uk/images/stories/docs/clinical/guidelines/ibd/ibd_2011.pdf 15. Dignass A, Lindsay JO et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis Part 2: Current management. Journal of Crohn's and Colitis (2012) 6, 991–1030. https://www.ecco-ibd.eu/images/6_Publication/6_3_ECCO%20Guidelines/2012_UC_Cosensus_Update_2_Current_Management.pdf 16. National Institute for Health & Care Excellence. Clinical guideline 166. Ulcerative colitis: Management in adults, children and young people. June 2013. http://www.nice.org.uk/guidance/CG166/ 17. Crohns and Colitis UK. Drugs used in IBD. Edition 5, March 2014. http://www.crohnsandcolitis.org.uk/Resources/CrohnsAndColitisUK/Documents/Publications/Bookl ets/Drugs-Used-in-IBD.pdf Quality Assurance Prepared by Katie Smith, East Anglia Medicines Information Service Date Prepared 28th August 2014 Checked by Sarah Cavanagh, East Anglia Medicines Information Service Date of check 10th September 2014 Search strategy In-house enquiry database, British National Formulary, Martindale, The Complete Drug Reference, Electronic Medicines Compendium, NICE Evidence: search term: mesalazine IDISweb, search terms: "MESALAMINE 56400007" and Disease(s): "PROCTOCOLITIS, IDIOPATHIC 556." and Descriptor(s): "ADM RECTAL 101" Years: 2012-2014 Medline, 1946 to date, search terms: [exp MESALAMINE/ AND exp ADMINISTRATION, RECTAL/] AND exp COLITIS, ULCERATIVE/dt [dt=Drug Therapy] [Limit to: English Language and Humans and Publication Year 2012-2014] Embase, 1980 to date, search terms: exp MESALAZINE/rc [rc=Rectal Drug Administration] AND exp ULCERATIVE COLITIS/dt [dt=Drug Therapy][Limit to: Human and English Language and Publication Year 2012-2014] Available through NICE Evidence Search at www.evidence.nhs.uk 5