Breathe in, Breathe out, How to Pick em Out: Selecting Inhalers for Patients and Institutions

Transcription

1 Breathe in, Breathe out, How to Pick em Out: Selecting Inhalers for Patients and Institutions Nune Zadikian, PharmD Jeff Endicott, PharmD University of Vermont Medical Center April 14, 2016

2 Objectives Differentiate between the mechanisms of action of common inhaled medications Compare and contrast the characteristics of available inhaled products for prescribing Identify key elements involved in selecting medications for formulary addition

3 Asthma Affects ~7% of Americans ~300 million worldwide Improved outcomes in recent decades More widespread preventive use of ICS Introduction of other effective medications Airway obstruction caused by airway smoothmuscle constriction and inflammation of the bronchi Cough, SOB, chest tightness, wheezing New Engl J Med 2009;360:

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5 Pathophysiology of Asthma Nature Reviews Drug Discovery 2004;3:831-44

6 Classifying Asthma Severity Expert panel report 3: guidelines for the diagnosis and management of asthma. Bethesda, MD: NHLBI, Aug 2007

7 Components of Asthma Management Measures of assessment and monitoring Education Control of environmental and comorbid conditions Pharmacologic therapy Expert panel report 3: guidelines for the diagnosis and management of asthma. Bethesda, MD: NHLBI, Aug 2007

8 Stepped-Care Approach to Asthma Treatment New Engl J Med 2009;360:

9 Medications For Asthma Categorized into two general classes Quick-relief PRN Anticholinergics SABAs Systemic corticosteroids Long-term control Taken daily Inhaled corticosteroids Cromolyn sodium and nedocromil Immunomodulators Omalizumab Leukotriene modifiers LABAs Methylxanthines Expert panel report 3: guidelines for the diagnosis and management of asthma. Bethesda, MD: NHLBI, Aug 2007

10 Inhaled Medications Drug Class Short Acting Beta-2 agonists Long Acting Beta-2 agonists Inhaled Corticosteroids Anticholinergic Long-Acting Anticholinergics Medications Albuterol, levalbuterol Formoterol, salmeterol, indacaterol, vilanterol (combination) Ciclesonide, flunisolide, mometasone, fluticasone, beclomethasone, budesonide Ipratropium tiotropium, aclidinium, umeclidinium (combination)

11 INHALED CORTICOSTEROIDS (ICS)

12 Cellular Effects of Corticosteroids Annals of Internal Medicine 2003;139:359-70

13 Inhaled Corticosteroids Most effective long-term therapy in asthma Preventative therapy Multiplicity of anti-inflammatory activities Suppress generation of cytokines, recruit airway eosinophils and other inflammatory mediators Clinical outcomes Fewer asthmatic symptoms Increased lung function Improved asthma specific QOL Fewer asthmatic exacerbations Suppress but do not cure asthmatic inflammation Airway inflammation returns to baseline 2 weeks after stopping Expert panel report 3: guidelines for the diagnosis and management of asthma. Bethesda, MD: NHLBI, Aug 2007

14 Safety of ICS Well tolerated and safe Only small amount available for systemic absorption <20% of delivered dose deposited onto airways Undergo extensive first-pass metabolic inactivation HPA function affected with doses of 88 mcg/day of fluticasone, Not clinically important, long term adverse systemic effects observed with low to medium doses At high doses (>1000 mcg/day of beclomethasone or equivalent), risk of skin bruising, cataracts, elevated intraocular pressure and accelerated loss of bone mass increase Growth retardation in children? Pharyngeal and laryngeal side effects Sore throat, coughing, weak/horse voice, candidiasis High-dose ICS effective for severe persistent asthma However, dose-response curve for treatment begins to flatten at low to medium doses, whereas dose-systemic absorption curve is linear New Engl J Med 2009;360:

15 BRONCHODILATORS: BETA-AGONISTS

16 Molecular Mechanism of Action of Bronchodilators Nature Reviews Drug Discovery 2004;3:831-44

17 Inhaled Long Acting Beta-Agonists Sustained relaxation of airway smooth muscles Stimulating β2-receptors increase camp and antagonize bronchoconstriction Lipophilic molecules Prolonged retention in lung tissue Duration of bronchodilation ~12 h after a dose BID administration No anti-inflammatory activity Expert panel report 3: guidelines for the diagnosis and management of asthma. Bethesda, MD: NHLBI, Aug 2007 New Engl J Med 2009;360:

18 Inhaled Long Acting Beta-Agonists Used as adjunct to ICS for providing long-term control of symptoms Reduce daytime and night-time symptoms, improve lung function, reduce risk of exacerbations, minimize required dose of ICS Not recommended as monotherapy for long-term control of persistent asthma Discontinuation of ICS following LABA initiation results in an increase in asthma exacerbation Use not recommended for acute symptoms or exacerbations Expert panel report 3: guidelines for the diagnosis and management of asthma. Bethesda, MD: NHLBI, Aug 2007 New Engl J Med 2009;360:

19 Chemical Structures Albuterol Indacaterol Salmeterol Formoterol

20 Inhaled B2-Agonists

21 Salmeterol vs Formoterol Salmeterol Partial agonist Onset: 15 min Peak effect: 3 h Duration: 12 h Formoterol Full agonist More rapid onset 3-5 minutes Similar to albuterol Peak effect: 15 min Duration: 12 h Less lipophilic Expert panel report 3: guidelines for the diagnosis and management of asthma. Bethesda, MD: NHLBI, Aug 2007.

22 LABA Adverse Effects Cardiovascular effects seen at doses 4-5 times those recommended Tachycardia QTc prolongation Hypokalemia Tremor Hyperglycemia Expert panel report 3: guidelines for the diagnosis and management of asthma. Bethesda, MD: NHLBI, Aug 2007.

23 Safety of LABAs in Asthma FDA Black Box Warning CT comparing salmeterol vs placebo added to usual asthma therapy Increased risk of asthma-related deaths in patients treated with salmeterol 13/13176 vs 3/13179 treated for 28 weeks LABA should not be used as monotherapy as long-term control in persistent asthma Daily use should not exceed 100 mcg salmeterol or 24 mcg formoterol Expert panel report 3: guidelines for the diagnosis and management of asthma. Bethesda, MD: NHLBI, Aug 2007

24 SABA Relax airway smooth muscle Onset of action 5 min Peak effect in min Duration of action of 4-5 hrs With regular use 4 X per day, potency not affected, duration of action slightly shortened Drug of choice Acute asthma symptoms and exacerbations Exercise induced asthma Exist chemically as racemic mixtures Therapeutic activity resides in the (R)-enantiomer Expert panel report 3: guidelines for the diagnosis and management of asthma. Bethesda, MD: NHLBI, Aug 2007

25 SABA In mild to moderate asthma, regularly scheduled albuterol vs PRN albuterol No difference in level of asthma control No difference in efficacy or side effects Regularly scheduled, daily, long-term use not recommended Administering SABA before ICS to improve delivery to lower airways is unnecessary Use not contraindicated in patients on beta-blockers Effectiveness may be somewhat diminished Expert panel report 3: guidelines for the diagnosis and management of asthma. Bethesda, MD: NHLBI, Aug 2007 New Engl J Med 2009;360:

26 SABA Albuterol (salbutamol), levalbuterol Decision largely based on cost and patient s or physician s preference Levalbuterol Only active enantiomer When delivered by MDI, has efficacy and side-effect profile indistinguishable from racemic albuterol New Engl J Med 2009;360:

27 BRONCHODILATORS: ANTICHOLINERGICS

28 Mechanism of Action of Anticholinergics Anticholinergics

29 Anticholinergics Mechanism of Action Block the action of acetylcholine at parasympathetic sites in bronchial smooth muscle causing bronchodilation Ipratropium bromide Short acting Not FDA approved for asthma Has not demonstrated to be effective in long-term management of asthma Tiotropium bromide Long acting, once daily for COPD Tiotropium Respimat: Has approval for asthma Expert panel report 3: guidelines for the diagnosis and management of asthma. Bethesda, MD: NHLBI, Aug 2007

30 Ipratropium Not recommended routinely for quick relief of asthmatic symptoms Takes longer to start working (15-20 min) and causes less bronchodilation than SABA May be used in patients with SABA intolerance May be used in treatment of severe asthma attacks or attacks induced by beta-blockers New Engl J Med 2009;360:

31 CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)

32 COPD Preventable and treatable disease Characterized by progressive airflow limitation caused by chronic inflammation in the airways and lung parenchyma Main cause: smoking ~25% of adults > 40 years have mild airflow obstruction Fourth leading cause of death 60-85% with mild to moderate disease remain undiagnosed Lancet 2012;379:

33 Pathophysiology of COPD NEJM 2010;362: Lancet 2012;379:

34 Algorithm for Treatment of COPD NEJM 2004; 350:

35 COPD Assessments Symptoms Modified British Medical Research Council (mmrc) Questionnaire Measure of breathlessness COPD Assessment Test (CAT) 8-item unidimensional measure of health status impairment Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) Available from:

36 mmrc Questionnaire Grade Degree of breathlessness related to activities 1 Not troubled by breathlessness except on strenuous exercise 2 Short of breath when hurrying on the level or walking up a slight hill 3 Walks slower than most people on the level, stops after a mile or so, or stops after 15 minutes walking at own pace 4 Stops for breath after walking about 100 yards or after a few minutes on level ground 5 Too breathless to leave the house, or breathless when undressing Stenton C. Occup Med. 2008; 58:

37 COPD Assessment Test Accessed 2/12/2016.

38 COPD Assessments Spirometric assessment Classification of Severity of Airflow Limitation in COPD Classification GOLD 1: Mild GOLD 2: Moderate GOLD 3: Severe GOLD 4: Very severe Spirometric Assessment FEV 1 80% predicted 50% FEV 1 < 80% predicted 30% FEV 1 < 50% predicted FEV 1 < 30% predicted Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) Available from:

39 Risk (GOLD Classification of Airflow Limitation) Risk (Exacerbation History) Combined COPD Assessment 4 (C) (D) 2 Or 1 leading to hospital admission 3 2 (A) (B) 1 not leading to hospital admission 1 CAT < 10 CAT 10 Symptoms mmrc 0-1 mmrc 2 Breathlessness Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) Available from:

40 GOLD Initial Pharmacologic Treatment Patient Group Recommended First Choice A Short-acting anticholinergic prn or Short-acting beta 2-agonist prn B Long-acting anticholinergic or Long-acting beta 2-agonist C Inhaled corticosteroid + long-acting beta 2-agonist or Long-acting anticholinergic D Inhaled corticosteroid + long-acting beta 2-agonist and/or Long-acting anticholinergic Alternative Choice Long-acting anticholinergic or Long-acting beta 2-agonist or Short-acting beta 2-agonist and short-acting anticholinergic Long-acting anticholinergic and long-acting beta 2- agonist Long-acting anticholinergic and long-acting beta 2- agonist or Long-acting anticholinergic and phosphodiesterase- 4 inhibitor or Long-acting beta 2-agonist and phosphodiesterase- 4 inhibitor Inhaled corticosteroid + long-acting beta 2-agonist and long-acting anticholinergic or Inhaled corticosteroid + long-acting beta 2-agonist and phosphodiesterase-4 inhibitor or Long-acting anticholinergic and long-acting beta 2- agonist or Long-acting anticholinergic and phosphodiesterase- 4 inhibitor Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) Available from:

41 Fluticasone (Flovent, Arunity) Beclomethasone (QVAR) Budesonide (Pulmicort) Mometasone (Asmanex) Fluticasone/Salmeterol (Advair) Mometasone/Formoterol (Dulera) Budesonide/Formoterol (Symbicort) Fluticasone/Vilanterol (Breo) Albuterol (ProAir, Ventolin, Proventil) Levalbuterol (Xopenex) Olodaterol (Striverdi) Salmeterol (Serevent) Formoterol (Foradil) Indacaterol (Arcapta) Ipratropium/Albuterol (Combivent) Tiotropium/Olodaterol (Stiolto) Umeclidinium/Vilanterol (Anoro) Glycopyrolate/Indacaterol (Ubitron) Ipratropium (Atrovent) Umeclidinium (Incruse) Tiotropium (Spiriva) Aclidinium bromide (Turdoza) Anticholinergics Glycopyrolate (Seebri)

42 Which drug is best?

43 Trials Olodaterol vs placebo vs formoterol Koch A. Int J Chron Obstruc Pulm Dis. 2014;9:

44 Trials Olodaterol improved lung function (FEV 1 ) over placebo Formoterol also improved lung function over placebo Olodaterol improved health-related quality of life scores compared to placebo(transitional Dyspnea Index and St. George s Respiratory Questionnaire) No significant difference seen when comparing formoterol versus placebo No comparison given for olodaterol versus formoterol Safety similar between formoterol and olodaterol Koch A. Int J Chron Obstruc Pulm Dis. 2014;9:

45 Trials The 24 Hour Lung Function Time Profile of Olodaterol Once Daily Versus Placebo and Tiotropium in Patients with Moderate to Very Severe Chronic Obstructive Pulmonary Disease Outcomes examined change in FEV1 Tiotropium vs placebo (statistically significant) Olodaterol vs placebo (statistically significant) Improvements in FEV1 appeared similar between tiotropium and olodaterol Lange P, et al. J Pulm Respir Med. 2014; 4: 196

46 Trials Umeclidinium/vilanterol (Anoro Ellipta) Improvement in FEV1 compared with vilanterol alone or tiotropium alone Improvement in Transition Dyspnea Index compared to placebo, not to monotherapy Aclidinium Improvement in FEV1 over placebo Improvement in TDI over placebo Decramer M, et al. Lancet Resp Med. 2014; 2: Donohue JF, et al. Resp Res. 2014; 15:78 Kerwin EM, et al. J Chronic Obstruct Pulm Dis. 2012; 9: Jones PW, et al. Eur Resp J. 2012; 40: 830 6

47 Drug Selection Randomized, controlled trials are typically placebo controlled No indicators one more efficacious than another FDA approval does not require a drug to be more efficacious than another Combination therapies typically compare to monotherapy 2 > 1

48 FDA Approved Indications ICS/LABA COPD/Asthma Fluticasone/Salmeterol (Advair) Budesonide/Formoterol (Symbicort) Fluticasone/Vilanterol (Breo) Asthma Mometasone/formoterol (Dulera) Long-acting anticholinergics COPD/Asthma Tiotropium (Spiriva) COPD Different doses Aclidinium bromide (Turdoza) Umeclidinium (Incruse) Glycopyrolate (Seebri)

49 Frequency LABA Twice daily Salmeterol Formoterol Once daily Indacaterol Olodaterol Vilanterol/Fluticasone Long acting anticholinergics Twice daily Glycopyrrolate Aclidinium Once daily Tiotropium Umeclidinium

50 Fluticasone (Flovent, Arunity) Beclomethasone (QVAR) Budesonide (Pulmicort) Mometasone (Asmanex) Fluticasone/Salmeterol (Advair) Mometasone/Formoterol (Dulera) Budesonide/Formoterol (Symbicort) Fluticasone/Vilanterol (Breo) Albuterol (ProAir, Ventolin, Proventil) Levalbuterol (Xopenex) Olodaterol (Striverdi) Salmeterol (Serevent) Formoterol (Foradil) Indacaterol (Arcapta) Ipratropium/Albuterol (Combivent) Tiotropium/Olodaterol (Stiolto) Umeclidinium/Vilanterol (Anoro) Glycopyrolate/Indacaterol (Ubitron) Ipratropium (Atrovent) Umeclidinium (Incruse) Tiotropium (Spiriva) Aclidinium bromide (Turdoza) Anticholinergics Glycopyrolate (Seebri)

51 Types of Inhalers Metered-Dose Inhalers (MDI) Soft-Mist Inhalers (Respimat) Dry-Powder Inhalers (DPI) Single-Dose Aerolizer HandiHaler Neohaler Multidose Diskus Ellipta Flexhaler Pressair RespiClick Twisthaler

52 Device Considerations Device Advantages Disadvantages Pressurized metered-dose inhalers (pmdi s) Portable and compact Independent of inspiratory flow Reproducible dosing Low cost Dry powder inhalers (DPI s) Portable and compact Do not require coordination (no spacer needed) Soft-mist inhalers Slow velocity aerosol Do not require coordination (no spacer needed) Coordination between actuation and inspiration High oropharyngeal deposition Inspiratory flow dependent (less in new devices) Poor dose reproducibility Affected by environmental factors Dose loading into device

53 Survey Recent survey of healthcare providers and patients examined what influences their preferences for inhaler devices 245 patients with COPD from USA, UK, France, and Germany 504 HCPs from US, UK, France, Italy, and Japan Molimard M. J Aerosol Med Pulm Drug Deliv. 2015;28:219-28

54 Survey Ease of use Size of inhaler Dose recording Disposable or recyclable Doses carried Dose confirmation Once vs twice daily dosing Molimard M. J Aerosol Med Pulm Drug Deliv. 2015;28:219-28

55 Survey Molimard M. J Aerosol Med Pulm Drug Deliv. 2015;28:219-28

56 Patient Preference Molimard M. J Aerosol Med Pulm Drug Deliv. 2015;28:219-28

57 Provider Preference Molimard M. J Aerosol Med Pulm Drug Deliv. 2015;28:219-28

58 Inhalational flow Drug deposition Aerosol velocity Inhaled drug particle size Bonini M, et al.copd Res and Prac. 2015; 1:9

59 Deposition Inhalation flow Failure to inhale slow and deep leads to failure with pmdi Greater impaction of drug DPI s require greater inhalation flows Flows > 60 L/min may be necessary for de-aggregation and dispersion Particle size 2-5 micron have greatest deposition in bronchial tree Aerosol velocity Slow-moving velocity achieves greater deposition

60 Deposition Before training After training Respimat pmdi Brand P, et al. Int J of COPD. 2008; 3:763-70

61 Deposition Device selection impacts drug deposition All devices (when used appropriately) should be effective and achieve appropriate clinical response Drug formulation Degree of airway obstruction Inspiratory flow Lung Deposition Device usability Particle size Patient ability Scichilone N, et al. Pulm Pharmacol Ther. 2015; 31:63-7

62 Feedback Seebri Prescribing Information. InspiraChamber prescribing Information. Turdoza Prescribing Information.

63 Patient Considerations Age, physical, and cognitive ability Coordination of breath and actuation (pmdi) Dose loading into device (Respimat) Once vs twice daily dosing Inspiratory flow dependent (DPI) Convenience Single vs multi dose Need for a spacer Cost Adherence Dose counters

64 Patient Preference

65 Formulary Continually updated list of medications and related information Includes List of medications Medication-associated products and devices Medication-use policies Decision support tools Organizational guidelines American Society of Health-System Pharmacists. ASHP guidelines on the pharmacy and therapeutics committee and the formulary system. Am J Health-Syst Pharm. 2008; 65:

66 Formulary System Ongoing process through which an organization establishes policies Use of drug therapies Drug-related products Identify most medically appropriate and costeffective Overseen by Pharmacy & Therapeutics Committee (P&T) American Society of Health-System Pharmacists. ASHP guidelines on the pharmacy and therapeutics committee and the formulary system. Am J Health-Syst Pharm. 2008; 65:

67 Formulary System Evaluating medications for inclusion on formulary Using evidence-based decision making Review, evaluate, and apply the relevant biomedical literature Create a Drug-Evaluation Document or P&T Drug Monograph American Society of Health-System Pharmacists. ASHP guidelines on the pharmacy and therapeutics committee and the formulary system. Am J Health-Syst Pharm. 2008; 65:

68 Monograph Brand/generic FDA approval info FDA approved indications Potential non-fda approved indications Pharmacology/MOA Recommended dosage PK/PD Special populations Pregnancy category Evidence Compare vs alternatives Clinical trials (critique) Medication safety assessment Pharmacoeconomic assessment American Society of Health-System Pharmacists. ASHP guidelines on the pharmacy and therapeutics committee and the formulary system. Am J Health-Syst Pharm. 2008; 65:

69 Need for the drug? Prevalence and importance of condition to be treated Does this drug overcome problems with existing therapies? FDA approved indications? Schiff GD, Galanter WL, Duhig J, et al. PLoS Med. 2012; 9:1-7

70 Efficacy Quality and strength of evidence Design of studies Patient population Conflicting evidence Schiff GD, Galanter WL, Duhig J, et al. PLoS Med. 2012; 9:1-7

71 Safety Look-alike, sound-alike drugs Administration or preparation requirements Long term experience with the drug Patient monitoring or special precautions Schiff GD, Galanter WL, Duhig J, et al. PLoS Med. 2012; 9:1-7

72 Misuse potential Existing marketing to consumers/prescribers for off-label indications Difficulty in accurately diagnosing conditions which the drug is indicated for Experience with similar drugs that may be misused Schiff GD, Galanter WL, Duhig J, et al. PLoS Med. 2012; 9:1-7

73 Cost Product cost Preparation, storage, administration, monitoring Comparative costs/generics available Insurance coverage Schiff GD, Galanter WL, Duhig J, et al. PLoS Med. 2012; 9:1-7

74 Therapeutic interchange Safety Safe to change between products Efficacy Equally efficacious Cost Save some money for the patient

75 Therapeutic interchange Several ICS/LABA combinations available Some have different approvals by the FDA Safety No major concerns switching between ICS/LABAs Efficacy One combination product has not been shown to be superior when inhaler used correctly Cost Inhaler A = $65.70/15 days Inhaler B = $91.40/15 days Inhaler C = $59.52/15 days > $140,000/year

76 Conclusion Inhaled therapies utilize various mechanisms of action to help control asthma and COPD Minor differences between agents exist that afford them their unique characteristics Despite these differences, no drug in the same class has proven to be more efficacious than another in clinical trials Patient and inhaler characteristics need to be considered to appropriately select products for patients Formulary system is in place to ensure the safest, most efficacious and cost effective treatments for our patients in the health care system