Aminosalicylates in Inflammatory Bowel Disease in Adults (Review date: July 2020) Page 1

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1 Full Title of Guideline: Author (include and role): Aminosalicylates in Inflammatory Bowel Disease in Adults Natalie Tse- Senior Clinical Pharmacist Dr. Nina Lewis- Consultant Gastroenterologist Division & Speciality: Scope (Target audience, state if Trust wide): Review date (when this version goes out of date): Explicit definition of patient group to which it applies (e.g. inclusion and exclusion criteria, diagnosis): Diagnostics and Clinical Support Nursing, Pharmacy and Medical staff July 2020 This guideline is intended to be used in adults receiving aminosalicylate treatment for inflammatory bowel disease within gastroenterology. Changes from previous version (not applicable if this is a new guideline, enter below if extensive): Summary of evidence base this guideline has been created from: N/A European Crohn s & Colitis Organisation Consensus Update 2017 National Institute for Health and Care Excellence (NICE) CG166 (2013), CG152 (2012) British Society of Gastroenterology Guidelines for the management of inflammatory bowel disease in adults for the 2011 Consultation Process Ratification BNF 74 Consultant Gastroenterologists Senior Specialist Pharmacists IBD Specialist Nurses Consultant Nephrologists Ratified by: Dr. Gordon Moran (Consultant Gastroenterologist) Date: 2/11/2017 This guideline has been registered with the trust. However, clinical guidelines are guidelines only. The interpretation and application of clinical guidelines will remain the responsibility of the individual clinician. If in doubt contact a senior colleague or expert. Caution is advised when using guidelines after the review date or outside of the Trust. Page 1

2 Aminosalicylates in Inflammatory Bowel Disease in Adults Objectives: This guideline is intended to provide guidance to healthcare professionals to manage adults (over 18 years old) with inflammatory bowel disease (IBD) who are newly started on or those who are already on 5-aminosalicylate (5-ASA) treatment. Background: 5-Aminosalicylates are recommended for the treatment of mild to moderate ulcerative colitis and the maintenance of remission in ulcerative colitis (UC) 2,4,9. Certain brands of 5-ASA are also licensed for the maintenance of remission in Crohn s ileo-colitis 1,3. The drugs that contain 5-ASA include sulfasalazine, mesalazine, olsalazine and balsalazide. They have different mode of actions (See Table 1 for individual mode of action). The newer 5-ASA s i.e. mesalazine, osalazine and balsalazide are better tolerated than sulfasalazine 2. At Nottingham University Hospitals mesalazine is recommended as the first choice of 5-ASA therapy for patients with IBD 16. Indications 1 : Treatment of mild to moderate ulcerative colitis, acute attack Maintenance of remission of ulcerative colitis Maintenance of remission in Crohn s Disease (CD) and active disease. (Only certain brands are licensed ) Route of administration 1 : Depending on the location of inflammation in the bowel, the 5-ASA can be given: Orally - tablets, granules and suspensions Rectally suppositories, foam and enemas Page 2

3 Formulations 1 : The four currently available 5-ASA drugs are used in several formulations, targeted at specific areas of the bowel. Table 1 Drug Mesalazine Release mechanism 4 Brand Formulation Site of Action 4,7 Timecontrolled Pentasa Tablets Duodenum Granules to rectum release Enema ph dependent release/resin coated Suppositories Octasa Tablets Terminal ileum & colon Salofalk Asacol Asacol MR *Restricted to existing patients only Tablets Granules M/R Enema Foam Enema Tablets Suppositories Terminal ileum & colon Terminal ileum & large bowel (colon & rectum) Balsalazide Olsalazine (Nonformulary) Sulfasalazine (Nonformulary) Mezavant and Ipocol brands are Non-formulary drugs. Delivery by Colazide Capsules Colon carrier molecules, Dipentum Capsules/Tablets Colon with release Generic of 5-ASA after brand splitting by bacterial Salazopyrin Tablets Colon enzymes in Generic Suspension the large brand Suppositories intestine There are differences in licensed indications, dose frequency, interactions, pharmaceutical, pharmacological and pharmacokinetic properties between different formulations. Therefore it is recommended to prescribe the drug by brand name 1. Page 3

4 Octasa and Pentasa brand are generally preferred for new patients as they are more cost effective. There is very little difference in terms of efficacy between mesalazine preparations so the choice of formulation should depend on factors that may aid adherence to therapy, and the proximal extent of the inflammation 1,7. Page 4

5 Contraindications 1,8 : Hypersensitivity to salicylate Hypersensitivity to sulphonamide/co-trimoxazole Side Effects 1,8 : The most common and dose related side effects are headaches, rash, nausea, epigastric pain and diarrhoea. Side effects that occur rarely include: - Skin disorders (Steven Johnson Syndrome, lupus erythematosis like syndrome); - Blood disorders (agranulocytosis, aplastic anaemia, leucopenia, methaemoglobinaemia, neutropenia, and thrombocytopenia); - Lung disorders (fibrosing alveolitis, eosinophilia); - Renal impairment (interstitial & nephritic syndrome) Others include acute pancreatitis, hepatitis, myocarditis, pericarditis, alopecia, and peripheral neuropathy. Sulphasalazine is associated with a reversible reduction in male fertility, yellow-orange discoloration of skin, urine, and other body fluids. Cautions 1,8 : Renal impairment (See Table 2 -Monitoring) Avoid in patients with severe renal failure. Discuss with renal team if appropriate. Blood disorder Patients should be advised to report any unexplained bleeding, bruising, purpura, sore throat, fever or malaise that occurs during treatment. Hepatic impairment Elderly History of allergy or asthma (Sulphasalazine, Basalazide) Glucose 6 phosphate dehydrogenase deficiency (Sulphasalazine may cause haemolysis) Page 5

6 Interactions 1,8 : Concurrent use of other known nephrotoxic agents, such as NSAIDs and azathioprine, may increase the risk of renal toxicity. Sulfasalazine may reduce absorption of digoxin and folate. Concomitant treatment in patients receiving azathioprine can increase the risk of blood dyscrasias. Asacol MR, Ipocol, Salofolk should not be given with lactulose or similar preparations which lower the stool ph and may prevent the release of mesalazine. For further information about cautions, side effects and interactions for individual drug, please see individual summary product characteristic accessible via medicines.org.uk or contact pharmacy medicines information on ext Pregnancy/ Breastfeeding: Careful assessment of risk versus benefit should be carried out before use during pregnancy and breastfeeding. Consult specialists for further advice. Consider folate acid supplementation during pregnancy in high-risk individuals such as for those taking sulphasalazine 1. Duration of treatment: Lifelong maintenance therapy is recommended for all patients with Ulcerative Colitis especially those with left sided disease or extensive disease who relapse more than once a year. Those with distal disease who have been in remission for 2 years should have a discontinuation assessment performed. However, it is suggested that maintenance therapy reduces the risk of colorectal cancer 4,9. There is limited evidence to support the use of 5ASA s in Crohn's disease however current BSG guidelines (2004) recommend there use in mild ileocolonic disease. The 5-ASA drugs are of little benefit for either inducing remission, or maintaining medically-induced remission. They may be of use for maintenance of surgically-induced remission 3, 13. Page 6

7 Recommended monitoring schedule 1,10,11 : Table 2 Pre-treatment assessment Monitoring Following dose change FBC, U&E, LFT FBC & LFT at 1 month FBC, U&E, Creatinine, LFT at 3 months of then every six months Repeat FBC, LFT, U&E 1 month after increase. If results stable repeat FBC, U&E s and LFT s once yearly Actions to be taken 10 : Table 3 Nausea, dizziness, headache, worsening diarrhoea WBC < 4.0 x 10 9 /l Neutrophils < 2.0 x 10 9 /l Platelets < 150 x 10 9 /l Severe abdominal pain > 2 fold rise above upper limit of normal reference range for ALT(0-45 U/L), AST (0-35 U/L) Rise of creatinine level above the If troublesome, reduce or stop treatment and consider alternative Refer to hospital specialist team. Monitor carefully if WBC continues to fall, withhold until discussed with Gastroenterologist Monitor carefully if neutrophil count continues to fall, withhold until discussed with Gastroenterologist Monitor carefully if platelet count continues to fall, withhold until discussed with Gastroenterologist Check amylase level; Withhold and consider ultrasound or CT scanning Withhold until discussed with specialist team; Ultrasound liver. Withhold until discussed with Page 7

8 normal range (or rise of > 20% compared to baseline) Abnormal bruising or severe sore throat Unexplained acute widespread rash specialist team; Urinalysis for proteinuria etc.; renal ultrasound; nephrology opinion. Check FBC immediately and withhold until result available. Discuss with Gastroenterologist Withhold; seek urgent specialist (preferably Dermatological) advice Dosage & individual treatment 1 NOTE: If no symptomatic improvement is evident after 2 weeks on the maximum dose of either oral or PR medication treatment escalation is necessary 2 Table 4 : Oral formulation Name Maintenance dose for UC Treatment dose for active UC Pentasa (tablets/granules) 2g daily 4g daily (in 2-4 divided doses) Use in CD Octasa g once daily (or in divided doses) g once daily (or in divided doses) Maintenance of remission: g once daily, alternatively daily in divided doses Salofalk (tablets/granules) 500mg TDS 1.5-3g daily, preferably in the morning (or 0.5-1g TDS) Asacol MR *Restricted to existing patients only g daily (in divided doses) Max 4.8g daily (in divided doses) Maintenance of remission: Up to 2.4 g daily in divided doses Page 8

9 Balsalazide Olsalazine (Non-formulary) 1.5g BD (max. per dose 3g) Max. 6g per day 500mg BD after food 2.25g TDS Maximum dose for 12/52. 1 g daily in divided doses taken after meals. Dose may be titrated upwards over a period of one week to a maximum of 3 g daily. A single dose should not exceed 1 g. Sulphasalazine (Nonformulary) 500mg QDS Max 8g daily (1-2g QDS) Active CD: 1 2 g QDS Table 5: Rectal Medication Name Pentasa Suppository Maintenance dose for UC 1g daily Treatment dose for active UC Max 1g at night for up to 2-4 weeks. Use in CD unlicensed Continue for 2/52 after symptomatic relief occurs then taper to stop Pentasa liquid enema (retention) 1g at night 1g at night unlicensed Salofalk Enema 2g at night 2g at night unlicensed Salofalk Rectal Foam unlicensed 2g at night (or in 2 divided doses) unlicensed Page 9

10 Salofalk Suppositories unlicensed Max g, 2-3 times a day, adjusted according to response. unlicensed Asacol Suppository g daily in divided doses. Last dose to be administered at bedtime g daily in divided doses. Last dose to be administered at bedtime unlicensed Asacol Foam Enema unlicensed 1-2g daily for 4-6 weeks unlicensed Sulphasalazine suppositories 0.5-1g BD Administered alone or in conjunction with oral therapy, morning and night after a bowel movement 0.5-1g BD Active Crohn s disease 0.5 1g BD References 1. Joint Formulary Committee. British National Formulary. 74th ed. London: BMJ Publishing Group and Royal Pharmaceutical Society. Nov Accessed 01/11/2017. Available online at 2. National Institute for Health and Care Excellence (NICE) Clinical Guideline 166. Ulcerative colitis; Management in adults, children and young people. June Accessed 09/01/2017. Available online at 3. National Institute for Health and Care Excellence (NICE) Clinical Guideline 152. Crohn s disease; Management in adults, children and young people. October Accessed 09/01/2017. Available online at 4. Mowat C, Cole A, Windsor A, et al. Guidelines for the management of inflammatory bowel disease in adults for the BSG. Gut 2011; 60 (5): Accessed 09/01/2017. Available online at Page 10

11 011.pdf 5. The second European evidence based consensus on the diagnosis & management of Crohn s disease: current management National Institute for Health and Care Excellence (NICE) Clinical Knowledge Summaries. Ulcerative colitis. Accessed 09/01/2017. Available online via 7. Smith K. UKMi Q&A What are the differences between different brands of mesalazine tablets? 1 May Accessed 09/01/2017. Available online at European evidence based consensus on the management of Ulcerative colitis Disease Modifying Drugs in Inflammatory Bowel Disease. Written by Dr A.F. Muller On behalf on the Inflammatory Bowel Disease Committee of the British Society of Gastroenterology. Accessed 09/01/17. Available online Crohn s and Colitis UK. 12. Summary of Product Characteristics Asacol 800mg MR tablets. Warner Chilcott UK Limited. Last updated 14-Apr Accessed via on 09/01/ National Institute for Health and Care Excellence (NICE) Clinical Knowledge Summaries. Crohn s Disease. Accessed 09/01/2017. Available online via Suggestions for Drug Monitoring in Adults in Primary Care. February A collaboration between London and South East Medicine Information Service, South West Medicine Information Service and Croydon Clinical Commissioning Group. Accessed 09/01/17. Available online ug%20monitoring%20document%20feb% pdf 15. K. Chakravarty et.al. BSR/BHPR guideline for disease-modifying antirheumatic drug (DMARD) therapy in consultation with the British Association of Dermatologists. British Healthcare Professionals of Rheumatology. Page 11

12 16. Nottinghamshire Joint Formulary. Accessed on 09/01/17. Available on European Crohn s & Colitis Organisation E-Guide. Accessed on 09/01/17. Available on Page 12