Scottish Paediatric Cystic Fibrosis MCN Protocols / Guidelines Ivacaftor: A guideline for use in paediatric CF patients in Scotland Authors: Dr Carol Dryden Dr Jane Wilkinson Miss Julie Crocker, Registered Dietitian Miss Katharine Fok, Senior Paediatric Clinical Pharmacist Dr Richard Brooker Review group: Scottish Paediatric Cystic Fibrosis MCN Steering Group Date: September 2016 Review date: September 2018 1
Contents Page 1. Background 3 2. Scottish data 4 3. Dose 5 4. Interactions & dose adjustments 5 5. Preparing to commence treatment 6 6. Monitoring 6 7. Summary (table) 8 8. Future audit 8 9. References 9 2
1. Background Ivacaftor potentiates cystic fibrosis conductance regulator (CFTR) by increasing the time that chloride channels remain open at the cell surface in cells with susceptible CF mutations. It was approved for use by the European Medicines Agency in July 2012 for use in people with cystic fibrosis (CF) 6 years who have at least one copy of the G551D mutation in the CFTR gene. In July 2014 the indication was extended to patients who have one of 8 non- G551D gating mutation in the CFTR gene. The additional mutations are G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P and G1349D. In November 2015 the European commission approved expanded use in children with CF aged 2-5 years with one of the 9 gating mutations and use in people with CF aged 18 years and older with an R117H mutation. The evidence for use of ivacaftor in children 6 years of age comes mainly from two manufacturer-sponsored, randomised, placebo-controlled, double blind, multicentred trials 1,2 which reported significant increases in FEV 1 and weight gain in addition to a significant reduction in sweat chloride. The mean rise in FEV 1 in children 6-12 years of age was 10.7% at 48 weeks (p<0.001) which compares favourably with other relatively new treatment options such as DNAse (5-8%) and long term azithromycin (5.5%). The mean absolute change in body mass index (BMI) was 1.09 and the mean reduction in sweat chloride was 53.5mmol/L. Other investigators 3,4 have reported similar but less impressive results for FEV 1. Data on ivacaftor s safety, pharmacokinetics and pharmacodynamics in children 2 5 years of age were recently published 5 and cautioned that liver function tests should be monitored more frequently in this group. 3
2. Scottish data In 2015 the SPCFMCN carried out a national review of the impact of 12 months treatment with ivacaftor on paediatric patients 6 years of age 6. The findings are presented in the table below. Table 1: Scottish data (n=26) Baseline 1 year Mean FEV1 (% predicted) Mean Weight Mean (kg) 85.1 28.4 107.5 32.2 17.8 65.0 92.2 45.1 108.2 39.0 19.7 86.1 change P value +7.1 < 0.001 +6.8 < 0.001 Z score BMI Mean (kg/m 2 ) 0.03-1.9 2.0 17.2 13.5 23.8 0.48-1.8 2.2 18.7 13.5-26.5 +0.45 +1.5 < 0.001 < 0.001 Z score (mean) Sweat chloride (mmol/l) Mean 0.15-1.5 2.2 112.1 90.5 148.0 0.57-1.7 2.3 47.6 13.0 73.0 +0.42 <0.001-64.5 < 0.001 Three children who were of healthy weight at baseline became overweight. Information from the All Wales Adult CF Centre 7 suggests that the increase in weight is mainly fat free mass (which is associated with better lung function 8 ), but there are no comparative data for children. Other clinically significant findings were: of the 5 children receiving regular IV antibiotics at baseline, 1 child was able to stop and 2 had the frequency reduced; 7 (27%) required fewer courses of oral antibiotics for mild respiratory exacerbations; and 7 (27%) were able to reduce their dose of pancreatic enzyme replacement therapy (PERT). This is an area that requires further exploration. No significant adverse effects (including clinically significant derangements in liver function tests) were observed. 4
3. Dose Children aged 2 years and older: o < 14kg: 50mg twice daily (granules) o 14kg 75mg twice daily (granules) o 25kg 150mg tablet twice daily Both tablets and granules should be taken with or shortly after a high fat snack as absorption is poor otherwise. 4. Interactions & dose adjustments: Ivacaftor is a substrate of CYP3A4 and CYP3A5 and a weak inhibitor of CYP3A and therefore there are significant drug interactions which may require dosage adjustment. Please see manufacturer s summary of product characterisitics 9 and/or BNFC 10 for full details. Potential interactions encountered commonly include the following but this list is not exhaustive: Reduce dose in hepatic impairment Caution in renal impairment Reduce dose to twice weekly dosing with concomitant use of itraconazole, ketoconazole, posaconazole, voriconazole, telithromycin, and clarithromycin Reduce to once daily dose with concomitant use of fluconazole and erythromycin Rifampicin plasma concentration of ivacaftor reduced; avoid concomitant use St John s Wort likely reduces plasma concentration of ivacaftor; avoid concomitant use Grapefruit juice & Seville oranges likely to increase plasma concentration of ivacaftor; avoid concomitant use There is no need to adjust ivacaftor dose when a child is prescribed ciprofloxacin. Please note the manufacturer s recommendations on dose adjustments are based on modelled data as opposed to pharmacokinetic studies in humans. Therefore, if changes are made to dose, clinical status including lung function should be monitored closely and consideration should be given to measuring sweat chloride and titrating ivacaftor dose to effect. See also Section 6, Monitoring. 5
5. Preparing to commence treatment The following should be carried out prior to commencing treatment: Up to date height, weight & BMI Spirometry (unless too young to do) Ophthalmological examination to exclude existing cataracts Consider sweat test to establish baseline sweat chloride Urea & creatinine Liver function tests including AST, ALT, GGT Review most recent annual review liver ultrasound Consider CFQ-R questionnaire 6. Monitoring Body mass index Spirometry Eyes Sweat chloride BMI must be closely monitored as standard care and dietary advice tailored accordingly. Measures of fat free mass (FFM) may be useful in the future but are not yet validated in children with CF. As per standard care Annual ophthalmological examination. Non-visually significant cataracts have been detected in a small number of paediatric patients treated with ivacaftor. These children had other risk factors (e.g. corticosteroid exposure) but a possible association with ivacaftor cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in paediatric patients initiating treatment. We advise referral to for this to be done prior to commencing treatment and annually thereafter, or earlier if concerns re vision arise. See table 1 for expected reduction in sweat chloride. CF teams may choose to repeat this test for comparison with baseline sweat chloride, especially if concerns arise re compliance. As noted in Section 4, Interactions & dose adjustments, teams may also wish to consider measuring sweat chloride 2-4 weeks after any mediumlong term reductions in ivacaftor (e.g. ivacaftor reduced to twice weekly because child commencing itraconazole) to guide titration of ivacaftor dose. 6
Liver function tests The following is a guide and tests should be done more frequently if deranged at outset or abnormal ultrasound. 6 years: 3 monthly during first year of treatment then annually if stable 2-5 years: 1 month, 3 months, 6 months, 9 months, 12 months then annually if stable. If transaminases increase they should be monitored until the abnormalities resolve. Other causes should be explored. Dosing should be interrupted in patients with ALT or AST > 5x upper limit of normal. Following resolution of transaminase elevations, the benefits and risks of resuming treatment with ivacaftor should be considered. Pancreatic function We have observed a reduced need for pancreatic enzyme replacement therapy (PERT) in some children on ivacaftor. Consideration should be given to baseline measurement and continued monitoring of faecal elastase (we suggest 2-4 monthly for first year then annual). CFQ-R The Cystic Fibrosis Questionnaire (Revised) is an instrument designed to measure impact of CF disease on overall health, daily life, perceived well-being and symptoms. Clinical psychologists may be able to supply/administer the questionnaire. Alternatively it can be obtained from aquittner@miami.edu 7
7. Summary Baseline Monitoring Notes BMI At each clinic visit FEV1 At each clinic visit Unless too young to do Ophthalmology Annual review Sweat chloride 3 months Clinician s discretion Urea & creatinine Annual Liver function tests (inc. AST, ALT, GGT) 6 years: 3 monthly for first year then annual 2-5 years: 1 month, 3 months, 6 months, 9 months, 1 year then annual Faecal elastase 2 4 monthly for first CFQ-R questionnaire More frequently if deranged LFT at outset Suggested year then annual Consider Consider Clinical Pyschology 8. Future audit We will continue to audit the impact and safety of ivacaftor on paediatric patients nationally. This guideline will be updated accordingly. 8
References 1. Davies JC, Wainwright CE, Canny GJ, et al. Efficacy and safety of Ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Respir Crit Care Med 2013;187(11):1219-25. 2. Ramsey BW, Davies J, McElvaney G, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. NEJM 2011;365(18):1663-72. 3. Rowe SM, Heltshe SL, Gonska T, et al. Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator Ivacaftor in G551D-mediated cystic fibrosis. Am J Respir Crit Care Med 2014;190(2):175-84. 4. Ronan NJ, O'Callaghan D, Mooney G, et al. Clinical outcomes of Real- World Kalydeco (CORK) study-a prospective 12 month analysis addressing the impact of CFTR modulation on the cystic fibrosis lung [abstract]. J Cyst Fibros 2015;14(Suppl 1):S37. 5. Davies J, Cunningham S, Harris W et al. Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2 5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study. Lancet Respir Med 2016 6. Dryden C, Wilkinson J, Young D, Brooker RJ. The impact of 12 months treatment with ivacaftor on Scottish paediatric patients with cystic fibrosis with the G551D mutation: a review. Arch Dis Child 2016 (in press) 7. Prosser A, Proud D, Guhaniyogi L, et al. Transformational care at the All Wales Adult CF Centre (AWACFC)-is ivacaftor making us fat? The impact of ivacaftor (Kalydeco) on body composition [abstract]. J Cyst Fibros 2015;14(Suppl 1):S129. 8. King S, Nyulasi I, Strauss B, et al. Fat free mass depletion in cystic fibrosis: Associated with lung disease severity but poorly detected by body mass index. Nutrition 2010:26:753-759. 9. Ivacaftor Summary of Product Characteristics https://www.medicines.org.uk/emc/medicine/27586 10. British National Formulary for Children 2015-2016 (updated annually) Dr Carol Dryden, NHS Lanarkshire: carol.dryden@lanarkshire.scot.nhs.uk Dr Jane Wilkinson, NHS Greater Glasgow & Clyde: jane.wilkinson@ggc.scot.nhs.uk Miss Julie Crocker, NHS Greater Glasgow & Clyde: julie.crocker@nhs.net Miss Katharine Fok, NHS Lothian Dr Richard Brooker, NHS Grampian: rbrooker@nhs.net 9