PART VI: SUMMARY OF THE RISK MANAGEMENT PLAN VI.1 Summary of risk management plan for RELVAR ELLIPTA (fluticasone furoate/vilanterol) This is a summary of the risk management plan (RMP) for RELVAR ELLIPTA. The RMP details important risks of RELVAR ELLIPTA, how these risks can be minimised, and how more information will be obtained about RELVAR ELLIPTA risks and uncertainties (missing information). RELVAR ELLIPTA 's summary of product characteristics (SmPC) and its package leaflet give essential information to healthcare professionals and patients on how RELVAR ELLIPTA should be used. This summary of the RMP for RELVAR ELLIPTA should be read in the context of all this information including the assessment report of the evaluation and its plain-language summary, all which is part of the European Public Assessment Report (EPAR). Important new concerns or changes to the current ones will be included in updates of RELVAR ELLIPTA 's RMP. I The medicine and what it is used for RELVAR ELLIPTA is authorised for the regular treatment of asthma in adults and adolescents aged 12 years and older where use of a combination medicinalproduct (long-acting beta-2- agonist and inhaled corticosteroid) is appropriate (i.e. patients not adequately controlled with inhaled corticosteroids and 'as needed' inhaled short acting beta-2-agonist) and patients already adequately controlled on both inhaled corticosteroid and long-acting beta2-agonist. Relvar Ellipta is indicated for the symptomatic treatment of adults with COPD with a FEV1<70% predicted normal (post-bronchodilator) with an exacerbation history despite regular bronchodilator therapy. (see SmPC for the full indication). It contains fluticasone furoate/ vilanterol as the active substance and it is given by inhalation. For Asthma: FF/VI 100/25mcg (delivered dose 92/22mcg), FF/VI 200/25mcg (delivered dose 184/22mcg) once daily and for COPD: FF/VI 100/25mcg (delivered dose 92/22mcg) once daily. Further information about the evaluation of RELVAR ELLIPTA s benefits can be found in RELVAR ELLIPTA s EPAR, including in its plain-language summary, available on the EMA website, under the medicine s webpage: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002673/hu man_med_001708.jsp&mid=wc0b01ac058001d124
II Risks associated with the medicine and activities to minimise or further characterise the risks Important risks of RELVAR ELLIPTA together with measures to minimise such risks and the proposed studies for learning more about RELVAR ELLIPTA's risks, are outlined below. Measures to minimise the risks identified for medicinal products can be: Specific information, such as warnings, precautions, and advice on correct use, in the package leaflet and SmPC addressed to patients and healthcare professionals; Important advice on the medicine s packaging; The authorised pack size the amount of medicine in a pack is chosen so to ensure that the medicine is used correctly; The medicine s legal status the way a medicine is supplied to the patient (e.g. with or without prescription) can help to minimise its risks. Together, these measures constitute routine risk minimisation measures. In addition to these measures, information about adverse reactions is collected continuously and regularly analysed, including PSUR assessment - so that immediate action can be taken as necessary. These measures constitute routine pharmacovigilance activities. If important information that may affect the safe use of RELVAR ELLIPTA is not yet available, it is listed under missing information below. II.A List of important risks and missing information Important risks of RELVAR ELLIPTA are risks that need special risk management activities to further investigate or minimise the risk, so that the medicinal product can be safely taken. Important risks can be regarded as identified or potential. Identified risks are concerns for which there is sufficient proof of a link with the use of RELVAR ELLIPTA. Potential risks are concerns for which an association with the use of this medicine is possible based on available data, but this association has not been established yet and needs further evaluation. Missing information refers to information on the safety of the medicinal product that is currently missing and needs to be collected (e.g. on the long-term use of the medicine); List of important risks and missing information Important identified risks Pneumonia in patients with COPD and asthma Serious cardiovascular events Growth retardation in children and adolescents Decreased bone mineral density and associated
fractures Corticosteroid-associated eye disorders Missing information Safety in pregnancy and lactation II.B Summary of important risks Important Identified Risk: Pneumonia in patients with COPD and asthma Evidence for linking the risk to the medicine In two replicate 12 month studies (HZC102871 and HZC102970) in a total of 3,255 patients with COPD who had experienced a COPD exacerbation in the previous year, there was a higher incidence of pneumonia (6%- 7%) reported in patients receiving the fluticasone furoate (at strengths of 50, 100, and 200 micrograms)/vilanterol 25 micrograms combination than in those receiving vilanterol 25 micrograms alone (3%). Pneumonia which required hospitalisation occurred in 3% of patients receiving fluticasone furoate/vilanterol (all strengths) and in <1% of patients receiving vilanterol. In these studies, nine fatal cases of pneumonia were reported. Of these, seven were reported during treatment with fluticasone furoate/vilanterol 200/25 micrograms, one during treatment with fluticasone furoate/vilanterol 100/25 micrograms and one post-treatment with vilanterol monotherapy. Risk factors for pneumonia observed in these studies included current smokers, patients with a history of prior pneumonia, patients with a body mass index <25 kg/m 2 and patients with an FEV 1<50% predicted There was no significant evidence in SLS-COPD of any difference in pneumonia risk between FF/VI and usual care which included FP/salmeterol and other ICS/LABAs. The data in SLS-COPD are consistent with the PRAC review (EMA: EMA/H/A-31/1415, 2016), which did not find any conclusive evidence of differences in pneumonia risk for different inhaled corticosteroid medicines in the treatment of COPD. In SUMMIT, when FF/VI was compared with placebo, there was no meaningful difference in the incidence of pneumonia. Recent evidence suggests that asthma is an
independent risk factor for pneumonia. In asthma, an integrated analysis of all FF/VI clinical studies regardless of duration and patient population showed that the incidence of pneumonia was low (<1%) in all treatment groups (ISS V2 Doc Ref 2013N187157). The calculated incidence of pneumonia (adjusted for exposure) for FF/VI 100/25 mcg of 8.5/1000 subject years was similar to placebo (9.3/1000 subject years). This is in line with literature evidence of the incidence of pneumonia reported in the general population. A slightly higher incidence in the FF/VI 200/25 mcg arm was observed (18.3/ 1000 subject years). For both pneumonia and serious pneumonia incidences calculated, confidence intervals were wide and overlapped across all treatment groups including placebo. In SLS-Asthma, when analysed by current treatment, the incidence of Pneumonia was similar between FF/VI and other asthma maintenance therapy (usual care) Risk factors and risk groups A detailed analysis of potential risk factors demonstrates increased hazard ratios with FF/VI compared with VI for BMI<25 kg/m 2, current smoker, history of pneumonia at screening and FEV 1<50% predicted). A BMI 21 kg/m 2, also shows a strong relationship with event of pneumonia. Both lower BMI and low FEV 1 are known risks for pneumonia and worse outcomes with pneumonia. Routine risk minimisation measures SmPC section 4.4 and 4.8, PIL section 2, 4 (see Approved Product Information) This is a prescription only medicine Additional Pharmacovigilance activities Additional pharmacovigilance activities: None
Important Potential Risk: Serious cardiovascular events Evidence for linking the risk to the medicine Cardiovascular events occurred at a similar incidence to placebo (in controlled studies). In SUMMIT (HZC113782), the risk of an on-treatment CV composite event was similar among all treatment groups. These data support the lack of a significant effect of FF/VI on all-cause mortality, which is primarily driven by CV mortality. In this population with history and/or risk of CV disease, subjects treated with VI (as VI alone or FF/VI) did not report a higher incidence or exposure-adjusted rate of cardiovascular events (assessed by all terms in MedDRA SMQs of hypertension, cardiac arrhythmia, cardiac failure, ischemic heart disease, and central nervous system hemorrhages and cerebrovascular conditions. Risk factors and risk groups In asthma, there were very few adverse events within the cardiac system disorder class. Older age, a history of previous cardiac disease and worse lung function were predictive of increased risk of cardiovascular events in the COPD population. Routine risk minimisation measures: SmPC section 4.4, PIL section 2, 3, 4 (see Approved Product Information) This is a prescription only medicine Additional pharmacovigilance activities None Important Potential Risk: Growth retardation in children and adolescents Evidence for linking the risk to the medicine The risk is a class risk for corticosteroid products. Inhaled corticosteroids have low oral bioavailability. Children with asthma may experience growth retardation, which has been attributed to the delayed
onset of puberty seen in asthmatics relative to nonasthmatics). A systematic review of 25 trials involving 8471 (5128 ICS-treated and 3343 control) children with mild to moderate persistent asthma showed that regular use of ICS at low or medium daily doseswas associated with a statistically significant reduction in linear growth velocity (14 trials including 5717 participants; MD - 0.48 cm/y, 95% confidence interval (CI) -0.65 to -0.30, P value <0.0001) and in change from baseline in height (15 trials including 3275 participants; MD-0.61 cm/y, 95% CI -0.83 to -0.38, p value <0.00001) during a one-year treatment period. The effect size of ICS on linear growth velocity appeared to be associated more strongly with the ICS molecule than with the device or dose. ICS induced growth suppression seemed to be maximal during the first year of therapy and less pronounced during subsequent years of treatment. This review did not find an overall effect of ICS during the first three months of treatment A recent study demonstrated a reduced mean adult height of 1.2cm (95% CI: -1.9 to -0.5) in subjects who received inhaled budesonide compared to placebo, after use of 4 to 6 years. For FF, a completed knemometry study did not show a clinically significant effectof FF on short term leg growth compared with placebo (HZA107112). Risk factors and risk groups Although not studied, patients with concurrent genetic, medical, environmental or nutritional causes of growth retardation may be at greater risk of this effect. However, given the minimal effect, these other risks are likely to be of greater importance. Routine risk minimisation measures SmPC section 4.4 (see Approved Product Information) This is a prescription only medicine
Additional Pharmacovigilance activities Additional pharmacovigilance activities: HZA114971: A Randomized, Double-Blind, Active- Controlled, Parallel-Group, Multi-Centre Study to Evaluate the Effects of a One-Year Regimen of Inhaled Fluticasone Furoate on Growth Velocity in Pre- Pubescent, Paediatric Subjects with Persistent Asthma See section II.C of this summary for an overview of the post-authorisation development plan. Important Potential Risk: Decreased Bone mineral density and associated fractures Evidence for linking the risk to the medicine This is considered a class risk for ICS products in COPD patients. In two replicate 12 month studies in a total of 3,255 patients with COPD the incidence of bone fractures overall was low in all treatment groups, with a higher incidence in all fluticasone furoate/vilanterol groups (2%) compared with the vilanterol 25 micrograms group (<1%). Although there were more fractures in the fluticasone furoate/vilanterol groups compared with the vilanterol 25 micrograms group, fractures typically associated with corticosteroid use (e.g., spinal compression/thoracolumbar vertebral fractures, hip and acetabular fractures) occurred in <1% of the fluticasone furoate/vilanterol and vilanterol treatment arms. In SUMMIT, the exposure-adjusted rate of AEs of special interest for decreased bone mineral density and associated fractures was similar for FF containing treatment groups (1.5 and 1.6 per 100 treatment years) compared with the other treatment groups (1.3 and 1.6 per 100 treatment years). In an integrated analysis of 11 studies in asthma (7,034 patients), the incidence of fractures was <1%, and usually associated with trauma. Risk factors and risk groups Prolonged immobilization, family history of osteoporosis, post-menopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids). These are likely to be of greater relevance to the COPD population, than for the asthma population. Routine risk minimisation measures
SmPC section 4.4; 4.8, PIL section 4 (see Approved Product Information) This is a prescription only medicine Additional Pharmacovigilance activities Additional pharmacovigilance activities: HZC102972: Multi-centre, randomized, doubleblind, parallel-group study evaluating the effect of Fluticasone Furoate/ Vilanterol (FF/VI) Inhalation Powder once daily compared with Vilanterol (VI) Inhalation Powder Once Daily on Bone Mineral Density (BMD) in subjects with Chronic Obstructive Pulmonary Disease (COPD) See section II.C of this summary for an overview of the post-authorisation development plan. Important Potential Risk: Corticosteroid-associated eye disorders Evidence for linking the risk to the medicine This is consided a class risk for ICS-containing products. There were few ocular associated adverse events reported during clinical studies. In the COPD placebo controlled lung function studies these were few events, and these were distributed across the treatment arms, including placebo. In the COPD one year exacerbation studies, the incidence of events was similar across treatment arms, and there was no clear difference between events on arms containing FF, than in the VI monotherapy treatment arm. These events are likely to represent the background rate in this population. In the SUMMIT study, the incidence of corticosteroid associated eye disorders was similar across treatment arms including placebo. The proportion of subjects experiencing at least one ADR/ one serious AE of special interest of corticosteroid associated eye disorders was similar between the two treatment arms. There were few ocular associated adverse events reported during the Asthma studies. In the one year safety study (HZA106839) Ophthalmic examinations, including Lens Opacities Classification System, Version III (LOCS III) lens grades, intraocular pressure (IOP), horizontal cup-to-disc ratio, and visual acuity using Logarithm of the Minimum Angle of Resolution (LogMAR), were performed at Screening,
Week 28 and Week 52. Of these ophthalmic measures, the posterior subcapsular opacity (P) lens grade is considered to be the most relevant assessment of drugrelated cataract formation. The results of this study showed that FF/VI 100/25 and FF/VI 200/25 had no apparent ophthalmic effects, including lens opacification and IOP. Risk factors and risk groups As a clear association with glaucoma and cataract has not been demonstrated with inhaled corticosteroids, it is not possible to determine any specific risk factors. It can be assumed that those patients with a predisposition for glaucoma or cataract may be more at risk from any additional influences. Routine risk minimisation measures: SmPC section 4.4, PIL section 2, 4 (see Approved Product Information) This is a prescription only medicine Additional pharmacovigilance activities None Missing information: Safety in pregnancy and lactation Routine risk minimisation measures SmPC section 4.6 and PIL section 2 (see Approved Product Information)
This is a prescription only medicine. II.C Post-authorisation development plan II.C.I Studies which are conditions of the marketing authorisation There are no studies that are conditions of the marketing authorisation. II.C.2 Other studies in post-authorisation development plan Growth velocity study in children (HZA114971) Purpose of the study: Growth impairment is a well-established adverse effect of glucocorticosteroids in children. Due to significantly reduced systemic exposure the potential impact of inhaled corticosteroids (ICS) on growth is small when compared with the effect observed with the use of oral corticosteroid treatments. ICS-induced growth suppression seems to be maximal in the first year of therapy and less pronounced in the subsequent years of treatment. The purpose of the study is to evaluate the magnitude of effect (with a level of precision) on growth velocity of prepubertal asthmatic paediatric subjects (aged 5 to <9 years) following administration of once daily (OD) inhaled fluticasone furoate (FF) 50 mcg for one year. Study of bone mineral density in COPD (HZC102972) Purpose of the study: Although inhaled corticosteroids have demonstrated utility in patients with COPD, there is a potential safety concern with long-term use on bone demineralization. These concerns, for the most part, are derived from the well-documented effects of oral corticosteroids on bone density and fracture; however, the actual effects of inhaled corticosteroids are not clear and require further study. Study HZC102972 will prospectively assess the effects of 3 years (156 weeks) exposure to fluticasone furoate/vilanterol (FF/VI) Fluticasone Furoate /Vilanterol (FF/VI) inhalation powder once daily versus VI once daily on bone mineral density in adult subjects with COPD at approximately 40 centres. The primary objective of this study is to evaluate the effect of the inhaled corticosteroid FF on bone mineral density (BMD) assessed at the total hip by comparing FF/VI treatment with VI treatment in subjects with moderate COPD. A secondary objective is to evaluate the effect of the inhaled corticosteroid FF on bone mineral density by gender by comparing FF/VI treatment with VI treatment in subjects with moderate COPD. Another secondary objective is to evaluate
the effect of FF on bone mineral density as assessed at the lumbar spine (L1-L4) by comparing FF/VI treatment with VI treatment in subjects with moderate COPD.