This Supplement Has Been Developed In Partnership With Boehringer .
This supplement has been developed in partnership with Boehringer Ingelheim LtdProductUpdateRespiratoryThe re-usable Respimat Soft Mist inhalerThis supplement has been commissioned and funded by Boehringer Ingelheim Ltdand developed in partnership with Guidelines in Practice. Boehringer IngelheimLtd suggested the topic and authors, and carried out full medical approval on allmaterials to ensure factual accuracy and compliance with the ABPI Code of Practice.The sponsorship fee included honoraria for the authors. The views and opinions ofthe authors are not necessarily those of Boehringer Ingelheim Ltd, or of Guidelinesin Practice, its publisher, advisers, or advertisers. No part of this publication maybe reproduced in any form without the permission of the publisher. Prescribinginformation can be found on the outside back cover.PC-GB-100146 V2 MGP Ltd 2020September 2020
THE RE-USABLE RESPIMAT SOFT MIST INHALERForewordDr Steve Holmes, GP, Shepton Mallet; Educational Lead, Primary Care Respiratory Society UKThe NHS long term plan published in January 2019 set a challenging agenda for the whole NHS to develop bettercare and outcomes for patients, while recognising its responsibility to use resources mindfully.1 The respiratorycommunity is delighted that the needs of respiratory patients have been recognised in the long term plan; one ofthe important aspects we support is the focus on improved outcomes in terms of quality of life, reduced hospitaladmissions, and reduced mortality.1A point highlighted in several areas of the long term plan is the NHS’ responsibility to look beyond healthcareprovision and address some of the environmental issues linked to its global impact, supported by the rising profile ofthe NHS Sustainability Unit looking at the impact of the NHS on the environment. The Unit has published a reportentitled ‘Identifying high greenhouse gas intensity procured items for the NHS in England’, which identifies 25 items withhigh carbon footprint needing further investigation;2 they also reported that anaesthetic gases account for 5% of thecarbon footprint in acute organisations, equivalent to around half the emissions from the gas used to heat buildingsand water;3 finally, they have also looked into inhaler devices, suggesting that 3.5% of the total NHS carbon footprintis associated with their use.4We know that the NHS spending on medicines is growing on average 5% every year, 5 and we have the duty to usethese medicines in the most effective way. The re-usable Respimat Soft Mist inhaler is a welcomed innovation thatcan be used by patients; it has a patient-friendly delivery system (with improved dose counter and new cartridgecounters and easy-to-change cartridges), and a lower environmental impact compared to traditional pressurisedmetered dose inhalers, thanks to the lack of propellants and to its re-usability. 6Our responsibilities as commissioners include helping clinicians supporting their patients; we have an overridingcommitment to commend inhalers that patients can use properly, because with optimal inhaler use it is possible toimprove outcomes and reduce admissions.7–9 Furthermore, we have a responsibility towards our environment anda responsibility to use the NHS’ financial resources efficiently. The re-usable Respimat inhaler appears to go in theright direction and is worth careful consideration when prescribing the medications for which Respimat is an option.References1.2.3.4.5.6.7.8.9.NHS England. NHS long term plan 2019. Available at: www.longtermplan.nhs.ukNHS Sustainability Unit. Identifying high greenhouse gas intensity procured items for the NHS in England. Available at:www.sduhealth.org.uk/NHS Sustainability Unit. Anaesthetic gases. s/anaesthetic-gases.aspx (Accessed 6November 2019)House of Commons Environmental Audit Committee. UK progress on reducing F-gas emissions. House of Commons, 2018. Available cmselect/cmenvaud/469/469.pdfThe King’s Fund. The rising cost of medicines to the NHS. What’s the story? Available at ising-cost-of-medicines.pdfHänsel M et al. Adv Ther 2019; doi.org/10.1007/s12325-019-01028-yMaricoto T et al. JAGS 2019; 67: 57–66.Al-Jahdali H et al. Allergy Asthma Clin Immunol 2013; 9: 8.Molimard M et al. Eur Resp J 2017; 49: doi 10.1183/13993003.01794-20162
THE RE-USABLE RESPIMAT SOFT MIST INHALERThe re-usable Respimat Soft Mist inhalerDr Kevin Gruffydd-Jones FRCGP, GP, Box, WiltshireIntroductionKey pointsThe Respimat Soft Mist inhaler (SMI) is a handheldpropellant-free device that produces a slow-moving,long-lasting mist of drug for inhalation. The originalRespimat inhaler has been available since 2007, butin September 2019 it became available in the UK as are-usable device.›This article highlights the main features of theRespimat SMI, compares it with other inhaler types,describes the key features of the re-usable device, anddiscusses the environmental impact of its use.››The Respimat SMI delivers a propellant-free,slow-moving, long-lasting soft mist aerosolof drug with high lung deposition, and lowerenvironmental impact than traditional MDIsThe re-usable Respimat SMI has an improveddesign, allowing greater ease of loading of thedrug cartridge, and an improved dose counterUse of up to six cartridges with each inhalerincreases patient convenience and furtherreduces the environmental impact of inhaleruse.Mechanism of action of the Respimat SMIThe active drug used with the Respimat inhaler isformulated in aqueous solution with benzalkoniumchloride as a preservative.1 When a cartridge containingthe drug is inserted into the base of the inhaler, thedevice needs to be primed to expel air from the drugsolution flow path. To load a dose, the patient hasto turn the base of the device by half a turn. Thistightens the helical spring that lowers and opens upthe non-return valve, drawing a metered volume of thedrug solution via the capillary tube into the loadingchamber. The drug is delivered when the patient pressesthe dose-release button, which uncoils the spring.1Figure 1 shows the internal design of the Respimatinhaler.nozzles of the uniblock. These fine jets converge on eachother at such an angle that a slow-moving aerosol, ‘softmist’, is produced.1The soft mist is delivered with a high fine particlefraction of 75% (nearly double the value reported foraerosols emitted by a standard pressurised metered doseinhaler [pMDI] or dry powdered inhaler [DPI]) andwith a slow velocity (3–10 times slower than the aerosolemitted from a pMDI).1 This allows low oropharyngealdeposition and high lung deposition, minimisingoropharyngeal side-effects and reducing the dose ofdrug that needs to be used to be effective. In addition,the spray duration of the Respimat SMI is considerablylonger than for pMDIs (1.2 seconds vs. 0.15–0.36seconds, respectively), allowing a longer time for thepatient to coordinate their inhalation with the releaseof the drug.1The mechanical power of this action drives the drugsolution through a series of fine channels of siliconwafer enclosed in a ‘uniblock’ (see Figure 2), causingtwo fine jets of liquid to emerge through the twin3
THE RE-USABLE RESPIMAT SOFT MIST INHALERFigure 1: Schematic diagram of the internalmechanism of the Respimat inhaler.2Figure 2: Schematic diagram of Respimatuniblock nozzle3Figure 3 highlights the differences and retained featuresbetween the disposable and re-usable inhalers.Key features of the re-usable device compared to thedisposable are:Respimat SMI vs other devices›A study analysing lung and oropharyngeal depositionof fenoterol[A] (a short-acting beta 2- agonist) whenadministered via the Respimat SMI comparedto when administered via a pMDI or pMDI plusspacer in healthy volunteers, showed that the meanoropharyngeal deposition of fenoterol was significantlylower via Respimat SMI than via pMDI (37.1% vs71.1%, respectively). Lung deposition was significantlyhigher via Respimat SMI than via pMDI (39.2% vs 11%,respectively).4 Comparable results were obtained in asimilar study performed on patients with asthma. 5››The re-usable Respimat SMIIn the UK, the re-usable version of the Respimat inhalerwas launched in September 2019. The original Respimatinhaler was updated to simplify assembly, improvehandling, and make it re-usable.a locking device attached to the cartridge ratherthan to the device, which prevents further useof the device when the cartridge is empty andreleases a safety catch allowing the clear base to bepushed away, alerting the user that the cartridgeneeds replacingan improved dose counter on the cartridge, withthe number of doses left clearly displayed; thedose counter changes colour when only 10 dosesare left, clearly indicating to the patient that thecartridge will need to be replaced soon (Figure 4)a longer base to improve grip and to make twistingthe device easier.Comparative studies performed by Dhand et al. showedthat the re-usable Respimat inhaler has improvedusability compared to the disposable device, but nodifferences in drug delivery, aerosol particle size, andrequired inhalation method across multiple cartridge[A] Fenoterol is not licensed in the UK.4
THE RE-USABLE RESPIMAT SOFT MIST INHALERFigure 3: Differences between the disposable (left) and the re-usable (right, front and back)Respimat SMI; features that have been added or changed in the re-usable version are labelledin red.Environmantal benefits of the re-usableRespimat SMIuse. 6 Performance of the re-usable Respimat inhaler hasbeen shown to be comparable to that of the disposableinhaler, so lung deposition and clinical data establishedon the disposable inhaler can be applied to the re-usableone. 6The NHS Long Term Plan for England 2019 7 hascommitted the NHS to reducing greenhouse gasemissions from inhalers. Traditional pMDIs usehydrofluoroalkane (HFA) propellants, which have ahigh global warming potential.Moreover, small-scale studies in patients with asthmasand/or COPD (n 16) showed that 4 people out of 16felt that the process was ‘equally easy’ in both inhalers,while the remaining 12 people considered the cartridgeinsertion process to be ‘easier’ or ‘much easier’ with theThe re-usable Respimat SMI is propellant-free, and, dueto its re-usability, is potentially more environmentallyreusable Respimat than with the disposable Respimat.Patients particularly liked the easily readable dosecounter. 6friendly. In fact, re-using the inhaler with more than onecartridge further reduces its product carbon footprint(PCF).These potential environmental benefits were examinedin a study which compared the PCF of Respimatwith that of pMDIs. 8 The PCF looks at the carbonfootprint of the product during its life cycle, includingproduction, packaging, usage, and disposal, and isexpressed in kg CO2 equivalent (eq). This study foundFigure 4: New cartridge dose counterthat the PCF of the Respimat was approximately 20times lower than a pMDI (0.78 kgCO2eq vs. 14.59kgCO2eq, respectively), mainly due to the lack ofpropellant in the Respimat, and found a furtherreduction of 73% in the PCF after 6 months’ use ofthe re-usable versus disposable Respimat when sixcartridges are used with one inhaler (due to the lowercarbon impact of using less material in manufacturingthe device). 85
THE RE-USABLE RESPIMAT SOFT MIST INHALERFigure 5: How to use the re-usable Respimat SMIUse of the re-usable Respimat SMI in clinicalpracticeshown to have high patient acceptability,1 a distinctcartridge counter, a clear dose indicator, 6 and lowercarbon footprint compared to pMDIs. 8International9,10 and national11,12 asthma and COPDguidelines emphasise the importance of inhaler choiceand technique linked to outcomes. It is generallyInstructions on how to use the re-usable Respimat SMIare shown in Figure 5.acknowledged that there is no one inhaler type that‘fits all’ and inhaler prescription should be tailoredto the individual patient. The National Institute forHealth and Care Excellence (NICE) produced a clinicaldecision aid for patients with asthma to help them andthe prescriber to come to a decision on which inhaler toprescribe.13SummaryThe re-usable Respimat SMI was introduced in theUK in September 2019. It incorporates many ofthe features of the original Respimat device, whichdelivers a propellant-free slow-moving, long-lastingsoft mist aerosol with improved lung deposition, lowerenvironmental impact, and more time for co-ordinatedinhalation with release of drug, than traditional pMDIs.The re-usable inhaler has the additional advantage of anupdated design to to improve cartridge exchange and aclearer dose counter.The ability to use the same device with up to sixcartridges increases convenience for the patients andfurther reduces the environmental impact of inhaleruse.The key features that a patient is asked to consider are:›››››being able to use the inhaler correctly and easilybeing able to tell how many doses are left in theinhalerhaving to clean the inhaler frequentlybeing able to carry the inhaler aroundthat the inhaler has a low carbon footprint.In line with this, the re-usable Respimat SMI has been6
THE RE-USABLE RESPIMAT SOFT MIST INHALERReferencesConflicts of interest1. Dalby R, Eicher E, Zierenberg B. Development ofRespimat Soft MistTM Inhaler and its clinical utilityin respiratory disorders. Med Devices (Auckl) 2011; 4:145–155.2. Boehringer Ingelheim Ltd. Data on file. Pharmaceuticaldevelopment report for Respimat ReUsable 2017; documentnumber: q00240658-01.3. Watchel H, Kattenbeck S, Dunne S et al. The Respimat development story: patient-centered innovation. Pulm Ther2017; 3: 19–30.4. Newman S, Brown J, Steed K et al. Lung Deposition offenoterol and flunosolide delivered using a novel device forinhaled medicines. Chest 1998; 113: 957–963.5. Pitcairn G, Reader S, Pavia D et al. Deposition ofcorticosteroid aerosol in the human lung by RespimatSoft Mist inhaler compared to deposition by metered doseinhaler or by Turbohaler dry powder inhaler. J Aerosol Med2005; 18: 264–272.6. Dhand R, Eicher J, Hansel M et al. Improving usability andmaintaining performance: human-factor and aerosol—performance studies evaluating the new reusable Respimatinhaler. Int J COPD 2019; 14: 509–523.7. NHS England. NHS Long Term Plan 2019. Available at:www.longtermplan.nhs.uk (accessed 26 November 2019).8. Hänsel M, Bambach T, Wachtel H. ReducedEnvironmental Impact of the reusable Respimat SoftMistTM Inhaler compared with pressurised metered-doseinhalers. Adv Ther 2019; doi.org/10.1007/s12325-01901028-y9. Global Initiative for Chronic Obstructive Lung Disease(GOLD). Global strategy for the diagnosis, management, andprevention of chronic obstructive pulmonary disease. 2019report. Available at: https://goldcopd.org/gold-reports/(accessed 26 November 2019).10. Global Strategy for Asthma Management and Prevention2019. Global Initiative for Asthma (GINA) 2019. Availableat: www.ginasthma.org (accessed 26 November 2019).11. NICE. Chronic obstructive pulmonary disease in over 16s:diagnosis and management. NICE guideline 115. NICE,2019. Available at: www.nice.org.uk/NG115 (accessed 26November 2019).12. British Thoracic Society/Scottish IntercollegiateGuidelines Network. British guideline on the management ofasthma. SIGN 158. Available at: www.sign.ac.uk/assets/sign158.pdf (accessed 26 November 2019).13. NICE. Asthma: diagnosis, monitoring and chronic asthmamanagement. Tools and resources. NICE guideline 80.NICE, 2017 www.nice.org.uk/ng80/resourcesKevin Gruffydd-Jones has acted as a consultant andspoken on behalf of GlaxoSmithKline, AstraZeneca,Teva, Napp, Boehringer Ingelheim, Novartis, andChiesi. He is a member of the NHS England SustainableInhaler Committee.Steve Holmes has undertaken work for five CCG areasin the last two years, he has involvements with the NHScardiovascular and respiratory board, and works withthe Primary Care Respiratory Society and the RoyalCollege of General Practitioners. He has receivedadvisory board honoraria, lecture fees or travel grantsfrom most of the respiratory orientated pharmaceuticalcompanies (including Boehringer Ingelheim) and hasworked for several publishers/medical communicationagencies (including Guidelines in Practice/MGP).7
Prescribing Information (UK)SPIOLTO RESPIMAT (tiotropium and olodaterol)Inhalation solution containing 2.5 microgram tiotropium (asbromide monohydrate) and 2.5 microgram olodaterol (ashydrochloride) per puff. Action: Inhalation solution containinga long acting muscarinic receptor antagonist, tiotropium, anda long acting beta2-adrenergic agonist, olodaterol. Indication:Maintenance bronchodilator treatment to relieve symptomsin adult patients with chronic obstructive pulmonary disease(COPD). Dose and Administration: Adults only aged 18years or over: 5 microgram tiotropium and 5 microgramof olodaterol given as two puffs from the Respimat inhaleronce daily, at the same time of the day. Contraindications:Hypersensitivity to tiotropium or olodaterol or any of theexcipients; benzalkonium chloride, disodium edetate,purified water, 1M hydrochloric acid (for pH adjustment);atropine or its derivatives e.g. ipratropium or oxitropium.Warnings and Precautions: Not for use in asthma or forthe treatment of acute episodes of bronchospasm, i.e. asrescue therapy. Inhaled medicines may cause inhalationinduced paradoxical bronchospasm. Caution in patients withnarrow-angle glaucoma, prostatic hyperplasia or bladderneck obstruction. Patients should be cautioned to avoidgetting the spray into their eyes. They should be advisedthat this may result in precipitation or worsening of narrowangle glaucoma, eye pain or discomfort, temporary blurringof vision, visual halos or coloured images in association withred eyes from conjunctival congestion and corneal oedema.Should any combination of these eye symptoms develop,patients should stop using Spiolto Respimat and consult aspecialist immediately. In patients with moderate to severerenal impairment (creatinine clearance 50ml/min) useonly if the expected benefit outweighs the potential risk.Caution in patients with a history of myocardial infarctionduring the previous year, unstable or life-threateningcardiac arrhythmia, hospitalised for heart failure during theprevious year or with a diagnosis of paroxysmal tachycardia( 100 beats per minute) as these patients were excludedfrom the clinical trials. In some patients, like other betaadrenergic agonists, olodaterol may produce a clinicallysignificant cardiovascular effect as measured by increasesin pulse rate, blood pressure and/or symptoms. Caution inpatients with: cardiovascular disorders, especially ischaemicheart disease, severe cardiac decompensation, cardiacarrhythmias, hypertrophic obstructive cardiomyopathy,hypertension, and aneurysm; convulsive disorders orthyrotoxicosis; known or suspected prolongation of the QTinterval (e.g. QT 0.44 s); patients unusually responsive tosympathomimetic amines; in some patients beta2-agonistsmay produce significant hypokalaemia; increases in plasmaglucose after inhalation of high doses. Caution in plannedoperations with halogenated hydrocarbon anaestheticsdue to increased susceptibility of adverse cardiac effects.Should not be used in conjunction with any other longacting beta2-adrenergic agonists. Immediate hypersensitivityreactions may occur after administration. Should not be usedmore frequently than once daily. Benzalkonium chloridemay cause wheezing and breathing difficulties; patientswith asthma are at an increased risk for these adverseevents. Interactions: Although no formal in vivo druginteraction studies have been performed, inhaled SpioltoRespimat has been used concomitantly with other COPDmedicinal products, including short acting sympathomimeticbronchodilators and inhaled corticosteroids without clinicalevidence of drug interactions. The co-administrationof the component tiotropium with other anticholinergiccontaining drugs has not been studied and therefore isnot recommended. Concomitant administration of otheradrenergic agents (alone or as part of combination therapy)may potentiate the undesirable effects of Spiolto Respimat.Concomitant treatment with xanthine derivatives, steroids,or non-potassium sparing diuretics may potentiate anyhypokalaemic effect of adrenergic agonists. Beta-adrenergicblockers may weaken or antagonise the effect of olodaterol.Cardioselective beta-blockers could be considered, althoughthey should be administered with caution. MAO inhibitors,tricyclic antidepressants or other drugs known to prolong theQTc interval may potentiate the action of Spiolto Respimaton the cardiovascular system. Fertility, pregnancy andlactation: There is a very limited amount of data from theuse of tiotropium in pregnant women. For olodaterol noclinical data on exposed pregnancies are available. As aprecautionary measure, avoid the use of Spiolto Respimatduring pregnancy. Like other beta2-adrenergic agonists,olodaterol may inhibit labour due to a relaxant effect onuterine smooth muscle. It is not known whether tiotropiumand/or olodaterol pass into human breast milk. A decisionon whether to continue/discontinue breast-feeding or tocontinue/discontinue therapy with Spiolto Respimat shouldbe made taking into account the benefit of breast-feedingto the child and the benefit of therapy for the woman.Clinical data on fertility are not available for tiotropium orolodaterol or the combination of both components. Effectson ability to drive and use machines: No studies havebeen performed. The occurrence of dizziness or blurredvision may influence the ability to drive and use machinery.Undesirable effects: Uncommon ( 1/1,000 to 1/100):Dizziness, headache, tachycardia, cough, dysphonia, drymouth. Rare ( 1/10,000 to 1/1,000): Insomnia, visionblurred, atrial fibrillation, palpitations, supraventriculartachycardia, hypertension, laryngitis, pharyngitis, epistaxis,bronchospasm, constipation, oropharyngeal candidiasis,gingivitis, nausea, stomatitis, hypersensitivity, angioedema,urticaria, pruritus, rash, arthralgia, back pain, joint swelling,urinary retention, urinary tract infection, dysuria. Notknown (cannot be estimated from the available data):Nasopharyngitis, dehydration, glaucoma, intraocular pressureincreased, sinusitis, intestinal obstruction ileus paralytic,dysphagia, gastrooesophageal reflux disease, glossitis,dental caries, anaphylactic reaction, skin infection and skinulcer, dry skin. Serious undesirable effects consistent withanticholinergic effects: glaucoma, constipation, intestinalobstruction including ileus paralytic and urinary retention. Anincrease in anticholinergic effects may occur with increasingage. The occurrence of undesirable effects related to betaadrenergic agonist class should be taken into considerationsuch as, arrhythmia, myocardial ischaemia, angina pectoris,hypotension, tremor, nervousness, muscle spasms, fatigue,malaise, hypokalaemia, hyperglycaemia and metabolicacidosis. Prescribers should consult the Summary of ProductCharacteristics for further information on side effects. Packsizes and NHS price: Single pack: 1 Respimat re-usableinhaler and 1 cartridge providing 60 puffs (30 medicinaldoses) 32.50; Single refill pack: 1 cartridge providing 60puffs (30 medicinal doses) 32.50 Legal category: POMMA numbers: PL 14598/0101 Marketing AuthorisationHolder: Boehringer Ingelheim International GmbH, D-55216Ingelheim am Rhein, Germany. Prescribers should consultthe Summary of Product Characteristics for full prescribinginformation. Prepared in September 2020Adverse events should be reported. Reporting formsand information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reportedto Boehringer Ingelheim Drug Safety on 0800 328 1627(freephone).
inhaler [pMDI] or dry powdered inhaler [DPI]) and with a slow velocity (3-10 times slower than the aerosol emitted from a pMDI).1 This allows low oropharyngeal deposition and high lung deposition, minimising oropharyngeal side-effects and reducing the dose of drug that needs to be used to be effective. In addition,
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