Trust Guideline for Ciclosporin Treatment & Monitoring for Adult* Patients with Acute, Severe Ulcerative Colitis (*ie aged 16 years and over) abc A guideline recommended for use In: Gastroenterology/Medical Wards and Outpatients clinics, Pharmacy By: Gastroenterologists, Clinical Nurse Specialists and Pharmacists For: Adult patients (aged 16 years and over) with acute severe ulcerative colitis refractory to steroids Key Words: Ciclosporin, inflammatory bowel disease, ulcerative colitis Written by: Deborah Morris (Inflammatory Bowel Disease Specialist Nurse) Dr Martyn Carter (Consultant Gastroenterologist) Supported by: All Consultant Gastroenterologists Surinder Bhatia (Pharmacist for Gastroenterology) Approved by: Therapeutics Policy Committee Dr Adie Viljoen (Chair) November 2012 Ratified by: Clinical Guidelines Steering Group: Dr Diane Harvey (Chair) May 2013 Guideline issued: May 2013 To be reviewed before: May 2015 To be reviewed by: Guideline supersedes: Location of archived copy: IBD Nurse Specialist and Pharmacist for Gastroenterology Not applicable Clinical Governance U: Drive CGSG Guideline Registration No. 130 Version No. 01 Authors: Deborah Morris, Dr M Carter Date of issue: May 2013 Page 1 of 6
Index Section Page Number Introduction 3 Indications for Use 3 Prior to Commencing Therapy 4 Dosage 4 Clinical Monitoring 5 Non-responders 5 Responders 6 Follow-up 6 References 6 Dissemination and Access This Guideline can only be considered valid when viewed via the East & North Hertfordshire NHS Trust Knowledge Centre. If this document is printed in hard copy, or saved at another location, you must check that it matches the version on the Knowledge Centre. Equality Impact Assessment This Guideline, and its impact upon equality, has been reviewed in line with the Trust s Equality Scheme and no detriment was identified. Authors: Deborah Morris, Dr M Carter Date of issue: May 2013 Page 2 of 6
INTRODUCTION Acute severe ulcerative colitis is a potentially life threatening illness and as such is treated as a medical emergency. Patients are admitted for intensive intravenous steroid therapy for up to 5 days. If symptoms do not respond after 3 days patients are started on rescue therapy with either intravenous ciclosporin or infliximab. NICE recommends ciclosporin as first-line (and infliximab use only if ciclosporin is contraindicated). If there is no clinical response after 7 days of rescue therapy then colectomy is considered. Ciclosporin is a potent immunosuppressant and although it s use in the treatment of acute ulcerative colitis is standard good practice (as recommended by NICE and by British Gastroenterology Society in national guideline), it is not licensed for this indication. This guideline is essential to ensure that all relevant clinical tests are performed and that the patient is carefully and closely monitored throughout treatment. It is relevant for adults aged 16 years and over. INDICATIONS FOR USE Acute severe ulcerative colitis (steroid refractory disease not requiring immediate surgery). Introduce ciclosporin on day 3 if patient continues to have >8 stools daily OR has >3 stools daily AND C - reactive protein >45. Introduce ciclosporin if patient fails to maintain response when changed from Intravenous hydrocortisone to oral prednisolone after 5 days. Absolute Contraindications Known hypersensitivity to ciclosporin or any excipients in preparations (eg polyoxyl castor oil) Presence of perforation, major haemorrhage, intestinal obstruction Renal impairment egfr </= 60ml/min Current malignancy Uncontrolled hypertension (ciclosporin can worsen hypertension) Neutropaenia Relative Contraindications Past history of malignancy Evidence of infection Live vaccinations within 4 weeks (non-live vaccines are not contra-indicated eg influenza vaccine) Authors: Deborah Morris, Dr M Carter Date of issue: May 2013 Page 3 of 6
PRIOR TO COMMENCING THERAPY: ENSURE SURGICAL TEAM AWARE Stool culture (MC&S and C-diff toxin) Urine analysis (exclude UTI) Full blood count Urea and electrolytes Cholesterol Magnesium Liver function tests C-reactive protein Blood pressure Refer to Dietitians, Stoma Nurse and IBD Nurse DOSAGE Oral or IV therapy may be used, as determined by Consultant Gastroenterologists, depending on the patient. Oral Therapy 8mg/kg/day as two divided doses Capsules are available as 100mg, 50mg and 25mg adjust dose accordingly and ensure patient stays on same brand of ciclosporin for whole treatment course (between 4 6 months). Ensure co-trimoxazole 480mg daily given for prophylaxis against Pneumocystis carinii pneumonia. Intravenous therapy 2mg/kg/day by slow continuous pump-controlled IV infusion over 24 hours. IV therapy should be continued for 2 days post clinical remission. If clinical remission has not occurred by day 7 this would indicate failure to respond. Once clinical remission has been obtained switch to oral therapy. When switching to oral dosing, give in two divided doses (total 8mg/kg/day) for maximum 4 6 months with prophylactic oral co-trimoxazole 480mg once daily. To administer CICLOSPORIN infusion: Dilute ONE QUARTER OF TOTAL DAILY DOSE (0 5mg/kg) of ciclosporin concentrate for infusion to 48ml with either Glucose 5% for injection or Sodium Chloride 0 9% for injection and administer intravenously over 6 hours via syringe driver. Repeat every six hours to give a 24 hour continuous infusion. (Total dose 2mg/kg/day) NB you must use a non-pvc IVAC infusion line (PTFE/PE lined, same as GTN infusions). Observe the patient closely for the first 30 minutes of the first infusion for any signs of anaphylaxis. Authors: Deborah Morris, Dr M Carter Date of issue: May 2013 Page 4 of 6
Clinical Monitoring Every 15 minutes for first hr of infusion: Pulse Rate; Blood Pressure; Respiratory Rate; Temperature Daily: Bristol Stool Chart; Abdominal Assessments; Disease Activity Scoring. Response is usually within 2 3 days. Whilst an In-patient: Every 1 2 days: FBC; LFTs; U+Es; Magnesium; CRP; ESR; ciclosporin levels. For patients on oral therapy blood taken immediately before dose to obtain trough levels Abdominal X-ray and endoscopy as directed by clinician. Whilst an Out-patient: Patients should be seen weekly for at least the first month with weekly blood monitoring (as for in-patients), then at least 2 weekly for the second month with subsequent tailoring of follow-up according to clinical assessment and stability of ciclosporin levels. General Practitioners are not expected to continue prescriptions for ciclosporin or co-trimoxazole. Drug level monitoring Drug levels to be maintained as follows: For IV Infusion it should be 150 250ng/ml (Steady State) For oral dosing it should be 150 300ng/ml (trough level) Blood monitoring is done at Harefield Hospital and results usually available after 2 3 days. To chase up levels call 01895 828570. Levels may be affected by concomitant medication eg NSAIDS, aminoglycosides, systemic antibiotics, calcium channel blockers and anticonvulsants. (Check current edition of BNF for full list of drugs). Patients should be warned not to consume grapefruit including juice as this can increase ciclosporin levels. NON-RESPONDERS Response is usually rapid therefore if no obvious clinical response after 7 days of therapy or deterioration whilst on ciclosporin, proceed to surgery. Contact Stoma Nurses Authors: Deborah Morris, Dr M Carter Date of issue: May 2013 Page 5 of 6
RESPONDERS Continue IV steroids whilst on IV ciclosporin. Steroids can be changed when patient enters remission. Ciclosporin is used as a bridge to thiopurine therapy. Consider starting thiopurine 2 6 weeks after discharge. NB Initial thiopurine to use is azathioprine. 6-mercaptopurine is only used if patient is intolerant to azathioprine. (Intolerance usually manifests as flu-like symptoms eg myalgia, fever, headache.) Check thiopurine methyltransferase enzyme levels before commencing thiopurine therapy. These checks are done at Guys and St Thomas Hospital and take 2 weeks. Call 0207 1888008 to chase levels. If thiopurine methyltransferase levels in normal range 25 50 pmol/h/mg haemoglobin use azathioprine 2 2 5mg/kg/day If thiopurine methyltransferase partially deficient, levels 10 25 pmol/h/mg haemoglobin use azathioprine 1mg/kg/day If thiopurine methyltransferase levels < 10 pmol/h/mg haemoglobin do not commence azathioprine. Consider reducing dose of ciclosporin, 6 weeks after thiopurine started. FOLLOW-UP Review bloods at least weekly for the first month then at least 2 weekly for the following month with subsequent tailoring of follow-up according to clinical assessment and stability of ciclosporin levels. Clinical state Renal and Liver Function Full Blood Count and Inflammatory Markers Ciclosporin level (patients should be asked to delay morning dose until bloods taken) Aim for ciclosporin trough levels between 150 300ng/ml Steroid dose reduction Consider commencing thiopurine at week 6 Avoid live vaccines for up to 6 months after stopping ciclosporin References 1. British National Formulary September 2012 2. Mowat C, Cole A, Windsor A, et al. Gut (2011). doi:10.1136/gut.2010.224154 3. Dignass A, et al, Second European evidence-based Consensus on the diagnosis and 4. Management of ulcerative colitis: Current management, Journal of Crohn's and Colitis (2012)4. www.medicinescomplete.com Authors: Deborah Morris, Dr M Carter Date of issue: May 2013 Page 6 of 6