Fluticasone Furoate,Umeclidinium,Vilanterol

Coventry & Warwickshire Area Prescribing Committee

Drug Positioning Statement DPS091 Fluticasone with umeclidinium and vilanterol (Trelegy Ellipta®q) July 2018

VERDICT Trelegy® (fluticasone/vilanterol/umeclidinium)

The Coventry and Warwickshire APC advises prescribers that Trelegy® is the second licensed triple therapy presented in one inhaler for use in adult patients with moderate to severe COPD who require triple therapy. Patients on current triple therapy receiving 2 separate inhalers may benefit from a simplification of their treatment and reduction in number of inhalers. Specialist Drugs Status: This is not classed as a specialist medication and is suitable for primary care prescribing.

SUMMARY NOTES

Indication: Trelegy® is indicated as a maintenance treatment in adult patients with moderate to severe chronic obstructive pulmonary 1 disease (COPD) who are not adequately treated by a combination of an inhaled corticosteroid and a long-acting β2-agonist . Presentation: Trelegy® is available in the Ellipta device. Each single inhalation provides a delivered dose (the dose leaving the mouthpiece) of 92 micrograms fluticasone furoate (ff), 65 micrograms umeclidinium bromide (umec) equivalent to 55 micrograms umeclidinium and 22 micrograms vilanterol (as trifenatate)1. Pharmacological action: Fluticasone furoate is an inhaled corticosteroid (ICS) with potent anti-inflammatory activity. The precise mechanism through which fluticasone furoate affects COPD symptoms is not known. Corticosteroids have been shown to have a wide range of actions on multiple cell types (e.g. eosinophils, macrophages, lymphocytes) and mediators (e.g. cytokines and chemokines) involved in inflammation1. Umeclidinium is a long-acting muscarinic receptor antagonist (LAMA). Umeclidinium exerts its bronchodilatory activity by competitively inhibiting the binding of acetylcholine with muscarinic receptors on airway smooth muscle. It demonstrates slow reversibility at the human M3 muscarinic receptor subtype in vitro and a long duration of action in vivo when administered directly to the lungs in pre-clinical models1.

Vilanterol is a selective long-acting, beta2-adrenergic receptor agonist (LABA). The pharmacologic effects of beta2-adrenergic agonists, including vilanterol, are at least in part attributable to stimulation of intracellular adenylate cyclase, the enzyme that catalyses the conversion of adenosine triphosphate (ATP) to cyclic-3',5'-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells1. Dose: The recommended and maximum dose is one inhalation of Trelegy Ellipta® 92/55/22 micrograms once daily, at the same time each day1. Cost comparison 2: Cost of 30 days (N.B. these doses are for general comparison and do not imply therapeutic equivalence) Prices sourced from DM and D browser (NHSBSA) on 8th February 2018.

Key to table: DPI = dry powder inhaler, pMDI – pressurised metered dose inhaler, SMI = soft mist inhaler

Inhaler Strength Dose Price ICS/LABA/LAMA 92 micrograms fluticasone furoate/ Trelegy Ellipta® (DPI) 55 micrograms umeclidinium/ 1 inhalation once daily £44.50 22 micrograms vilanterol 87 micrograms beclometasone/ Trimbow® MDI (pMDI) 5 micrograms formoterol/ 2 inhalations twice daily £44.50 9 micrograms glycopyrronium/dose

Not to be used for commercial purposes The information in this review is believed to be true and accurate. It is issued on the understanding that it is the best available from the resources at our disposal at the time of issue DPS091 Published: July 2018 Version 1.0 Page 1 SUMMARY NOTES cont’d

Inhaler Strength Dose Price LAMA Umeclidinium (Incruse® 55 micrograms 1 inhalation daily £27.50 Ellipta®) (DPI) Aclidinium 322 micrograms 1 inhalation twice daily £28.60 (Eklira® Genuair®) (DPI) Glycopyrronium 44 micrograms 1 inhalation daily £27.50 (Seebri® Breezhaler®) (DPI)

18 micrograms for Spiriva / Spiriva ®£33.50 Tiotropium powder capsules Contents of one capsule (N.B handihaler with capsules £34.87) 13 micrograms for Braltus for inhalation via inhaler (DPI) inhaled daily Braltus®with Zonda® inhaler (delivered dose 10 micrograms) £25.80

Tiotropium (Spiriva® 2.5 micrograms 2 puffs daily £23 Respimat®) (SMI) ICS/LABA 92 micrograms fluticasone furoate / Relvar® Ellipta® (DPI) 1 inhalation daily £22 22 micrograms vilanterol

DuoResp® Spiromax® 320 micrograms budesonide / 1 inhalation twice daily £27.97 (DPI) 9 micrograms formoterol 400 micrograms budesonide / Symbicort® Turbohaler® (DPI) 1 inhalation twice daily £28 12 micrograms formoterol Fostair® NEXThaler® 100 micrograms beclomethasone 2 inhalations twice daily £29.32 (DPI) extrafine / 6 micrograms formoterol 100 micrograms beclomethasone Fostair® MDI (pMDI) 2 inhalations twice daily £29.32 extrafine / 6 micrograms formoterol 500 micrograms fluticasone Seretide® Accuhaler® propionate / 50 micrograms 1 inhalation twice daily £40.92 (DPI) formoterol

DRUG PROFILE

Clinical Effectiveness: The FULFIL (Lung Function and Quality of Life Assessment in Chronic Obstructive Pulmonary Disease with Closed Triple Therapy) trial was a randomised, double-blind, double-dummy study comparing 24 weeks of once-daily triple therapy (fluticasone furoate/umeclidinium/vilanterol 100 mg/62.5 mg/25 mg; ELLIPTA inhaler, n=911) with twice-daily budesonide/formoterol 400 mg/12 mg; Turbohaler (n=899). A patient subgroup remained on blinded treatment for up to 52 weeks. Co–primary endpoints were change from baseline in trough FEV1 and in St. George’s Respiratory Questionnaire (SGRQ) total score at Week 24. Inclusion criteria included patients with COPD aged 40 years or older who were defined as being in Global Initiative for Chronic Obstructive Lung Disease group D: (1) FEV1 less than 50% and COPD Assessment Test score greater than or equal to 10, or (2) patients with FEV1 less than or equal to 50% to less than 80% and COPD Assessment Test score greater than or equal to 10, and either at least two moderate exacerbations or at least one severe exacerbation in the past year. Patients were required to be receiving daily maintenance therapy for COPD for at least 3 months. Patients were excluded if they had a current diagnosis of asthma causing their symptoms or if they had unresolved pneumonia or severe COPD exacerbation. Demographic and disease characteristics were recorded at screening3.

The mean changes from baseline in FEV1 were 142 ml (95% confidence interval [CI], 126 to 158) and minus (-) 29 ml (95% CI, -46 to -13) for fluticasone furoate/umeclidinium/vilanterol and budesonide/formoterol respectively. The mean changes from baseline in SGRQ scores were minus (-) 6.6 units (95% CI, - 7.4 to -5.7) and minus (-) 4.3 units (95% CI, 25.2 to 23.4), respectively. For both endpoints, the between-group differences were statistically significant (P < 0.001)3. There was a statistically significant reduction in moderate/severe exacerbation rate with triple therapy versus dual ICS/LABA therapy up to 24 weeks (35% reduction; 95% CI, 14–51; P = 0.002)3. In the extension study, a 44% reduction in moderate to severe exacerbations was achieved in the subset of patients that received treatment for up to 52 weeks3. The authors have noted that the study compared different dosing regimens (once daily vs. twice daily), different inhaler devices and different individual components and combinations. These study design characteristics have been noted as limitations and the need for further studies has been acknowledged in the discussion. In a PIII IMPACT study (n=10,355), once-daily Trelegy® Ellipta reduced annual rate of on-treatment moderate/severe exacerbations compared with Relvar® Ellipta (FF/VI 100/25micrograms; 0.91 vs 1.07 per year; p<0.001) and Anoro® Ellipta (UMEC/VI, 62.5/25micrograms; 4 0.91 vs 1.21 per year; p<0.001). This study is to be published.

NNoott ttoo bbee uusseedd ffoorr ccoommmmeerrcciiaall ppuurrppoosseess TThhee iinnffoorrmmaattiioonn iinn tthhiiss rreevviieeww iiss bbeelliieevveedd ttoo bbee ttrruuee aanndd aaccccuurraattee.. IItt iiss iissssuueedd oonn tthhee uunnddeerrssttaannddiinngg tthhaatt iitt iiss tthhee bbeesstt aavvaaiillaabbllee ffrroomm tthhee rreessoouurrcceess aatt oouurr ddiissppoossaall aatt tthhee ttiimmee ooff iissssuuee DPS091 Published: July 2018 Version 1.0 Page 2 DRUG PROFILE cont’d

Adverse effects (AEs): The safety profile of triple therapy reflected the known profiles of the components. The incidence rates of on- treatment AEs in the ITT population up to Week 24 were 38.9% in the FF/UMEC/VI group and 37.7% in the BUD/FOR group. The most common AEs were nasopharyngitis (7% and 5% for FF/UMEC/VI and BUD/FOR, respectively) and headache (5% and 6% for FF/UMEC/VI and BUD/FOR, respectively).3 Cautions: Cardiovascular effects - arrhythmias may be seen after the administration of muscarinic receptor antagonists and sympathomimetics, including umeclidinium and vilanterol, respectively. Therefore, Trelegy® Ellipta should be used with caution in patients with unstable or life-threatening cardiovascular disease. Visual disturbance - may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids. Coexisting conditions - Use with caution in patients with convulsive disorders or thyrotoxicosis, and in patients who are unusually responsive to beta2-adrenergic agonists. Use with caution in patients with pulmonary tuberculosis or in patients with chronic or untreated infections. Anticholinergic activity - Use with caution in patients with narrow-angle glaucoma or urinary retention. Patients should be informed about the signs and symptoms of acute narrow-angle glaucoma and should be informed to stop and to contact their doctor immediately should any of these signs or symptoms develop. Pneumonia in patients with COPD - An increase in the incidence of pneumonia, including pneumonia requiring hospitalisation, has been observed in patients with COPD receiving inhaled corticosteroids. There is some evidence of an increased risk of pneumonia with increasing steroid dose but this has not been demonstrated conclusively across all studies. There is no conclusive clinical evidence for intra-class differences in the magnitude of the pneumonia risk among inhaled corticosteroid products. Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections overlap with the symptoms of COPD exacerbations. Risk factors for pneumonia in patients with COPD include current smoking, older age, low body mass index (BMI) and severe COPD.

Hypokalaemia - Beta2-adrenergic agonists may produce significant hypokalaemia in some patients, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. 1 Hyperglycaemia - Beta2-adrenergic agonists may produce transient hyperglycaemia in some patients . No dosage adjustments - are required in elderly 65 years or in patients with renal impairment. Trelegy® should only be used with caution in patients with moderate to severe hepatic impairment1

Interactions: Clinically significant drug interactions mediated by fluticasone furoate/umeclidinium/vilanterol at clinical doses are considered unlikely due to the low plasma concentrations achieved after inhaled dosing.

Interaction with beta-blockers - Beta2-adrenergic blockers may weaken or antagonise the effect of beta2-adrenergic agonists, such as vilanterol. If beta-blockers are required, cardioselective beta-blockers should be considered, however, caution should be exercised during concurrent use of both non-selective and selective beta-blockers. Interaction with CYP3A4 inhibitor - Fluticasone furoate and vilanterol are rapidly cleared by extensive first pass metabolism mediated by enzyme CYP3A4. Caution is advised when co-administering with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir, cobicistat-containing products) as there is potential for increased systemic exposure to both fluticasone furoate and vilanterol, which could lead to an increased potential for adverse reactions. Hypokalaemia - Concomitant treatment with methylxanthine derivatives, steroids, or non-potassium-sparing diuretics may potentiate the possible hypokalaemic effect of beta2-adrenergic agonists, therefore caution should be exercise CURRENT PLACE IN THERAPY

National Institute for Health and Care Excellence (NICE) NICE CG 101 recommends adding a LAMA in addition to ICS/LABA in people with 5 COPD who remain breathless or have exacerbations despite taking ICS/LABA, irrespective of FEV1 . The evidence for this guidance was reviewed in 2016 and is being updated. The expected publication date is November 2018. However, Trelegy® is not expected to be reviewed. Global Initiative for Chronic Obstructive Lung Disease (GOLD) The GOLD report (2017) states that “adding a LAMA to existing LABA/ICS improves lung function and patient reported outcomes, in particular exacerbation risk”. The reports also state, that “The step up in inhaled treatment to triple therapy can occur by various approaches. A RCT did not demonstrate any benefit of adding ICS to LABA plus LAMA on exacerbations. Altogether, more evidence is needed to draw conclusions on the benefits of triple therapy LABA/LAMA/ ICS compared to LABA/LAMA”.

For Group D patients (high symptoms and 2 exacerbations or 1 exacerbation leading to hospital), who develop further exacerbations on LABA/LAMA therapy, GOLD suggests two alternative pathways:  Escalation to LABA/LAMA/ICS. Studies are underway comparing the effects of LABA/LAMA vs. LABA/LAMA/ICS for exacerbation prevention.  Switch to LABA/ICS. However, there is no evidence that switching from LABA/LAMA to LABA/ICS results in better exacerbation prevention. If LABA/ICS therapy does not positively impact exacerbations/symptoms, a LAMA can be added6. Scottish Medicines consortium (SMC) Accepted for restricted use within NHS Scotland in patients with severe COPD (forced expiratory volume in one second [FEV1] <50% predicted normal) 7.

Summary  Trelegy® is a once daily triple therapy (presented in one inhaler) suitable for use in adult patients with moderate to severe COPD who require triple therapy.  The FULFIL study met its two co-primary endpoints, showing statistically significant improvements compared to budesonide/formoterol in both lung function and health-related quality of life as measured by the St. George´s Respiratory Questionnaire (SGRQ: -6.6 versus - 4.3, respectively).  The IMPACT study to show effect on exacerbations of ICS/LAMA/LABA vs. LABA/ICS vs. LAMA/LABA is soon to be published.  Patients currently receiving triple therapy in two separate inhalers may benefit from a simplification of their treatment and reduction in number of inhalers, thereby potentially aiding adherence4. Trelegy would fit in to the COPD prescribing guidelines CG020 (Coventry and Warwickshire APC)8 as a triple therapy but it would need to be ensured inhaler devices remain the same or patients are adequately educated, when inhalers are switched to aid understanding and adherence.  There are potential cost savings of using Trelegy® compared to using an ICS/LABA and LAMA in separate inhalers. The annual savings vary from £39-£300 depending on the ICS/LABA and LAMA used.

References

1. Summary of product characteristics (Trelegy). Last updated 23/11/17. Accessed 8/2/18 via www.medicines.org.uk 2. Dictionary of medicines and Devices. NHS Business Services Authority. Available at https://apps.nhsbsa.nhs.uk/DMDBrowser/DMDBrowser.do accessed 8/2/18 3. Lipson D, Barnacle H, Birk R et al. FULFIL Trial: Once-Daily Triple Therapy for Patients with Chronic Obstructive Pulmonary Disease. American Journal of respiratory and critical Care. Vol 196, no. 4. Aug 2017. Accessed at https://www.atsjournals.org/doi/abs/10.1164/rccm.201703-0449OC?url_ver=Z39.88- 2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed 8/2/18 4. Specialist Pharmacy services. Fluticasone furoate+umeclidinium+vilanterol. Available at https://www.sps.nhs.uk/medicines/fluticasone-furoate-umeclidinium-vilanterol/ accessed 8/ 2/18 5. NICE Clinical Guideline 101. Chronic obstructive pulmonary disease in over 16s: diagnosis and management (partial update April 2016). June 2010. Available from www.nice.org.uk accessed 8/2/18. 6. From the Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017. Available from: http:// goldcopd.org/gold-2017-global-strategy-diagnosis-management-prevention-copd/ accessed 8/2/18 7. Scottish Medicines Consortium. SMC ID 103/18. January 2018. Available from https://www.scottishmedicines.org.uk/files/advice/ fluticasone_furoate_Trelegy_Ellipta_Abbreviated_FINAL_Jan_2018_for_website.pdf accessed 13/2/18 8. Coventry and Warwickshire Area Prescribing Committee Clinical Guideline CG020 COPD Prescribing Guidelines. January 2018. Available from: http://www.coventrywarksapc.nhs.uk/ DocLib/6377a8a8-d730-4656-b99d-0f5b7c99797d accessed 20/2/18

DPS091 Published: July 2018 Version 1.0 Page 4