Objectives

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 Recognize newly approved respiratory products Respiratory Medication Update and significant new dosage forms

 Discuss the indications and side effect potential Mark Malesker, Pharm.D., FCCP, FCCP, FCCM, FASHP, BCPS Professor of Pharmacy Practice and Medicine for each agent Creighton University  Identify updated evidence based respiratory treatment guidelines

2019 Pulmonary Symposium Nebraska Methodist College March 15, 2019

Faculty Disclosure Audience Question #1

3 4 Mark A. Malesker, Pharm.D.  How many new novel medications were FDA approved in 2018 ? Dr. Malesker has listed no financial interest/arrangement that would be  A. 22

considered a conflict of interest  B. 33

 C. 59

 D. 67

Audience Question #2 Audience Question #3

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 What is the dose for Glycopyrrolate  What is the indication for cannabidiol (Lonhala Magnair) ? (Epidiolex)?

 A. 25 mcg one daily  A. Seizures

 B. 25 mcg twice daily  B. Pain

 C. 25 mcg three times daily  C. End stage COPD

 D. 25 mcg every 4 hours PRN  D. Obstructive sleep apnea

1 2018 Drug Approvals 2018 Drug Approvals

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 The FDA approved 59 novel new drugs and biologics,  Fast track (24/59) 41%  Average of 33 for 2009-2017  Drugs that can treat unmet medical needs  First in class (19/59) 32%   Drugs with a new and unique mechanism for treating a medical Priority review (43/59) 73% condition  A drug is given priority review if there is a potential  Orphan drugs (34/59) 58% to provide a significant advance in existing medical  Drugs approved for small populations of patients with rare care and set a target to review within six months diseases (200,000 or fewer Americans)   6800 rare diseases identified affecting 30 million people Accelerated approval (4/59) 7%

 Breakthrough (14/59) 24%  Early approval based on markers that predict a  A drug with preliminary clinical evidence demonstrating that it reasonable benefit, with more testing to confirm may result in substantial improvement on at least one clinically clinical benefit after approval significant endpoint over other available therapies www.fda.gov/drugs www.fda.gov/drugs

2017 Drug Approvals Novel Drug Approvals 2009-2018

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 First cycle (56/59) 45%  Drugs that were approved without additional information that could delay approval and lead to another cycle of review

 First approved in U.S. (42/59) 71%  Drugs that were approved in the United States before approved in other country

www.fda.gov/drugs

Respiratory Pharmacology Correct Inhaler Technique Inhalation Therapy 11 12

 Center for Disease Control and Prevention (CDC)  Beta2-agonists  https://www.cdc.gov/asthma/inhaler_video/  Short-acting beta-agonists (SABA)  Allergy and Asthma Network  Long-acting beta-agonists (LABA)

 https://www.youtube.com/playlist?list=PLC39F35D440D  Anticholinergics 0F155&feature=view_all  Short-acting antimuscarinic agent (SAMA)  Institute for Safe Medication Practices (ISMP)  Long-acting antimuscarinic agent (LAMA)  https://www.ismp.org/newsletters/acutecare/showarticle.  Combined SABA/SAMA aspx?id=1143  Combined LABA/LAMA  http://use-inhalers.com/  Inhaled corticosteroids (ICS)  Product specific websites  Combined LABA/ICS

 Combined LABA/LAMA/ICS

2 Albuterol Short-Acting Beta-Agonists (SABA) (ProAir Digihaler) 13 14

Agent Formulation Dose  Shake before use? Albuterol generic Nebulizer 1.25-5 mg q4-6h PRN  No

Albuterol HFA MDI MDI 2 inhalations q4-6h PRN  Priming (ProAir, Proventil, Ventolin)  No Albuterol (ProAir RespiClick) DPI 1-2 inhalations q4-6h PRN  Cleaning Albuterol (ProAir Digihaler) DPI 1-2 inhalations q4-6h PRN  Wipe mouthpiece as needed Levalbuterol generic Nebulizer 0.31-1.25 mg tid q6-8h  Dose counter Levalbuterol (Xopenex HFA) MDI 2 inhalations q4-6h PRN  Yes  Beyond use date  13 months after removal MDI = metered dose inhaler, DPI = dry powder inhaler from foil pouch

Contains built-in electronic module which detects, records, and stores data on inhaler events for https://www.proairdigihaler.com/ transmission to the mobile App

Generic Albuterol Inhaler Epinephrine (Primatene Mist)

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 On January 17, 2019, Teva launched an  2011  2018 authorized generic version of ProAir HFA (albuterol) inhalation aerosol

 Teva also markets branded ProAir

Epinephrine (Primatene Mist HFA) Long-Acting Beta Agonists (LABA)

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 Returns to market in 2018 after 7 year absence Agent Formulation Dose  OTC for intermittent asthma (≥ 12 years) Salmeterol (Serevent Diskus) DPI 1 inhalation bid  Racemic epinephrine is not recommended treatment Formoterol (Perforomist) Nebulizer 20 mcg bid  Each dose delivers 0.125 mg of epinephrine (160 doses) Arformoterol (Brovana) Nebulizer 15 mcg bid  Dosage is 1-2 inhalations every 4 hours, max 8 puffs/24° Indacaterol (Arcapta) DPI 75 mcg capsule once daily  AAN, ACAAI, ACCP, ALA, ATS all oppose approval Olodaterol (Striverdi Respimat) ISI 2 inhalations daily  Activate before use, clean every day  Shake and spray once into air before each use  Seek medical attention if no relief in 20 minutes, symptoms get worse, use more than 8 puffs in 24 hours or more than 2 attacks per week DPI = dry powder inhaler, ISI = inhalation spray inhaler  Cost $29.99

https://www.primatene.com

3 Short-Acting Anticholinergic (SAMA) Long-Acting Anticholinergic (LAMA)

19 20 Agent Formulation Dose Agent Formulation Dose Ipratropium generic Nebulizer 500 mcg qid PRN Tiotropium (Spiriva HandiHaler) DPI 18 mcg capsule once Ipratropium (Atrovent HFA) MDI 2 inhalations qid PRN daily Tiotropium (Spiriva Respimat) ISI 2.5 mcg 2 inhalations (5 mcg) once daily for COPD Tiotropium (Spiriva Respimat) ISI 1.25 mcg 2 inhalations (2.5 mcg) once daily for Asthma Aclidinium (Tudorza Pressair) DPI 400 mcg twice daily Umeclidinium (Incruse Ellipta) DPI 1 inhalation daily Glycopyrrolate (Seebri Neohaler) DPI 15.6 mcg capsule twice daily

DPI = dry powder inhaler, ISI = inhalation spray inhaler

Long-Acting Anticholinergic (LAMA) Glycopyrrolate (Lonhala Magnair)

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Agent Formulation Dose  First nebulized LAMA for long term maintenance of Glycopyrrolate (Lonhala Magnair) Nebulizer • 25 mcg/1 ml vial COPD twice daily  Dose is one vial (25 mcg) twice daily • Used in portable, handheld, electronic  Magnair eFlow system, developed by Pari Pharma nebulizer  Portable, virtually silent, delivers drug in 2-3 minutes

Revefenacin (Yupelri) Nebulizer • 175 mcg/3ml once  Approval based upon GOLDEN trials which compared daily glycopyrrolate to placebo in moderate to severe COPD • Used in standard jet nebulizer  Improved lung function and health status regardless of lung function or age (pooled analysis)

 Side effects (≥2%) were dyspnea and UTI

 Drug interactions with other anticholinergics

https://www.lonhalamagnair.com

Glycopyrrolate (Lonhala Magnair) Revefenacin (Yupelri)

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 LAMA given once daily 175 mcg (3 ml) over 8-10 minutes by standard jet nebulizer for maintenance treatment of COPD

 Can cause dry mouth, urinary retention

 Avoid concurrent use of rifampin, cyclosporine, anticholinergics

 Avoid with hepatic impairment

https://www.lonhalamagnair.com https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=6dfebf04-7c90-436a-9b16-750d3c1ee0a6&type=display

4 SABA/SAMA Combination LAMA/LABA Combination

25 26 Agent Formulation Dose Agent Formulation Delivery Dosage Albuterol/ipratropium ISI 1 inhalations q 6 hrs Device (Combivent Respimat) Umeclidinium/vilanterol 62.5 mcg/25 mcg DPI 1 inhalation Albuterol/ipratropium (DuoNeb) Nebulizer 2.5 mg/0.5 mg qid PRN (Anoro Ellipta) daily Tiotropium/olodaterol 2.5 mcg/2.5 mcg ISI 2 inhalations (Stiolto Respimat) once daily Glycopyrrolate/indacaterol 15.6 mcg/27.5 DPI 1 capsule daily (Utibron Neohaler) mcg capsule Glycopyrrolate/formoterol 9 mcg/4.8 mcg MDI 2 inhalations (Bevespi Aerosphere) twice daily

DPI = dry powder inhaler, ISI = inhalation spray inhaler

Beclomethasone Dipropionate Inhaled Corticosteroids (ICS) (1) (QVAR) 27 28

Agent Delivery Dose  Shake well before use? Beclomethasone (QVAR HFA) MDI 40-320 mcg bid  No 40, 80 mcg/inhalation  Priming Beclomethasone (QVAR MDI 40-320 mcg bid Redihaler)  Before the first use, or if not used for more than 10 Budesonide (Pulmicort Respules) Nebulizer 250-500 mcg 1x/d or bid or 1 mg 1x/d days: 2 sprays Budesonide (Pulmicort Flexhaler) DPI 180-720 mcg bid 90, 180 mcg/inhalation  Cleaning Ciclesonide (Alvesco) MDI 80-320 mcg bid  At least weekly 80, 160 mcg/inhalation  Dose counter: Yes Flunisolide (Aerospan HFA) MDI 160-320 mcg bid 80 mcg/inhalation  Beyond use date  Exp date on package  Product discontinued in Aug 2017, available till March 2018

www.qvar.com

Beclomethasone Dipropionate HFA (QVAR RediHaler) Inhaled Corticosteroids (ICS) (2) 29 30

 Shake well before use? Agent Delivery Dose Fluticasone propionate DPI 100-1000 mcg bid  No (Flovent Diskus)  Priming 50, 100, 250 mcg/blister Fluticasone propionate MDI 88-880 mcg bid  No (Flovent HFA) 44, 110, 220 mcg/inhalation  Cleaning Fluticasone propionate DPI 55-232 mcg bid  At least weekly (ArmonAir RespiClick) 55, 113, 232 mcg/inhalation  Dose counter: Yes  FDA approved in August 2017  Beyond use date  Only breath activated ICS  Exp date on package

https://www.qvar.com/

5 Inhaled Corticosteroids (ICS) (3) ICS/LABA Combination

31 32 Agent Delivery Dose Agent Formulation Delivery Dosage Fluticasone furoate DPI 100-200 mcg once daily Device (Arnuity Ellipta) Fluticasone 100, 250, DPI 1 inhalation bid 100, 200 mcg/inhalation propionate/salmeterol 500/50 mcg Mometasone DPI 220-880 mcg once/day in evening (Advair Diskus) (Asmanex Twisthaler) or 220 mcg bid Fluticasone 45, 115, 230 MDI 2 inhalations bid 110, 220 mcg/inhalation propionate/salmeterol mcg/21 mcg Mometasone (Asmanex HFA) MDI 200-400 mcg twice daily (Advair HFA) 100, 200 mcg/inhalation Fluticasone/salmeterol 55, 113, 232 DPI 1 inhalation bid (AirDuo RespiClick) mcg/14 mcg Fluticasone furoate/vilanterol 100 mcg/25 mcg DPI 1 inhalation daily (Breo Ellipta) Budesonide/formoterol 80, 160 mcg/ MDI 2 inhalations bid (Symbicort) 4.5 mcg Mometasone/formoterol 100, 200 mcg/ MDI 2 inhalations bid (Dulera) 5 mcg

Fluticasone/Salmeterol (Wixela Inhub) ICS/LAMA/LABA Combination

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 Mylan generic Advair Agent Formulation Delivery Dosage Diskus approved Jan Device Fluticasone furoate/ 100 mcg, DPI 1 inhalation daily 30, 2019 umeclidinium/ vilanterol 62.5 mcg, (Trelegy Ellipta) 25 mcg  GSK generic Advair launched Feb 8, 2019

 100/250/500 mcg/50 mcg

 WAC 70% less than Advair and 67% less than GSK generic

https://www.drugstorenews.com/news/mylan-gets-fdas-approval-for-first-generic-advair-diskus/

Fluticasone Furoate/Umeclidinium/Vilanterol Amikacin Liposome Inhalation (Trelegy Ellipta) Suspension (Arikayce) 35 36

 Shake before use?  Aminoglycoside indicated in adults who have limited or  No no alternative treatments options for Mycobacterium avium complex (MAC) as part of a combination drug regimen  Priming  Only studied in refractory MAC  No  Dose is 590 mg/8.4 ml once daily  Cleaning  Use with Lamira Nebulizer System over 14-20 minutes  If desired  Use pretreatment with inhaled bronchodilator  Dose counter   Yes Boxed warning for increased respiratory adverse reactions including hypersensitivity pneumonitis,  Beyond use date hemoptysis, bronchospasm, and exacerbation of  6 weeks after removal from underlying pulmonary disease that have led to foil pouch or when counter hospitalizations in some cases reads 0 FDA approved 9-18-17

https://www.trelegy.com https://www.arikayce.com/pdf/full-prescribing-information.pdf

6 Amikacin (Arikayce) Levodopa (Inbrija)

37 38  Inhalation powder for Parkinson’s disease  Inhale contents of two capsules (84 mg) as need for OFF symptoms up to 5 times daily  Use only with Inbrija breath-actuated inhaler  Whirl sound with inhalation  Side effects ≥5%: cough, nausea, URI, sputum discolored

https://www.inbrija.com/prescribing-information.pdf

Baloxavir Marboxil (Xofluza) Tezacaftor/Ivacaftor (Symdeko)

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 Endonuclease inhibitor indicated for the treatment  Fixed dose combination for oral treatment of cystic of acute uncomplicated influenza in patients 12 fibrosis in patients ≥ 12 years old who are years and older who have been symptomatic for homozygous for the F508del (also called Phe508del no more than 48 hours or F508) mutation or have at least one mutation in the fibrosis transmembrane conductance regulator  Single dose: (80 kg and above) 80 mg (CFTR) gene that is responsive to the combination  Avoid co-administration with dairy products,  About 50% of CF patients in USA are homozygous cations for the F508del mutation

 Combination improves pulmonary function

 Expensive

https://www.gene.com/download/pdf/xofluza_prescribing.pdf https://pi.vrtx.com/files/uspi_tezacaftor_ivacaftor.pdf

Global Initiative for Asthma (GINA) Monoclonal Antibodies for Asthma Guidelines 41 42 Benralizumab Mepoluzimab Reslizumab Dupilumab  What factors may predict good response to anti- (Fasenra) (Nucala) (Cinqair) (Dupixent) Mechanism of IL-5 receptor IL-5 antagonist IL-5 antagonist IL-4 receptor IL5/5R? action antagonist alpha subunit  Higher blood eosinophils (≥300/μl) antagonist Formulation Prefilled Single dose Single use Prefilled  More exacerbations in previous year syringe vials vials syringe  Adult-onset of asthma Dosage 30 mg SC q4 100 mg SC q4 3 mg/kg IV q4 400 mg SC weeks x 3, weeks weeks then 200 mg  Nasal polyposis then q8 weeks q2 weeks, or 600 mg SC then 300 mg a 2 weeks FDA approved ≥ 12 years ≥ 12 years ≥ 18 years ≥ 12 years Age

https://www.regeneron.com/sites/default/files/Dupixent_FPI.pdf https://ginasthma.org/wp-content/uploads/2018/11/GINA-SA-FINAL-wms.pdf

7 Stepwise Management - Pharmacotherapy

Diagnosis Symptom control & risk factors (including lung function) Inhaler technique & adherence Patient preference Symptoms Exacerbations Side-effects Asthma medications Patient satisfaction Non-pharmacological strategies Lung function Treat modifiable risk factors

STEP 5

STEP 4 Refer for STEP 3 add-on *Not for children <12 years treatment PREFERRED STEP 1 STEP 2 **For children 6-11 years, the CONTROLLER e.g. Med/high tiotropium,* preferred Step 3 treatment is CHOICE ICS/LABA anti-IgE, medium dose ICS Low dose anti-IL5* # Low dose ICS ICS/LABA** For patients prescribed BDP/formoterol or BUD/ formoterol maintenance and Other Consider low Leukotriene receptor antagonists (LTRA) Med/high dose ICS Add tiotropium* Add low reliever therapy controller dose ICS Low dose theophylline* Low dose ICS + LTRA Med/high dose dose OCS options (or + theoph*) ICS + LTRA  Tiotropium by mist inhaler is (or + theoph*) an add-on treatment for patients ≥12 years with a As-needed short-acting beta2-agonist (SABA) As-needed SABA or history of exacerbations RELIEVER low dose ICS/formoterol# © 2019 Global Initiative for Chronic Obstructive Lung Disease GINA 2018, Box 3-5 (2/8) (upper part) © Global Initiative for Asthma www.ginasthma.org

GOLD Guidelines Smoking Cessation Pharmacologic Therapy 45 ► Smoking cessation has the greatest capacity to influence the natural  Pharmacological therapy for COPD is used to reduce history of COPD. symptoms, reduce the frequency and severity of ► If effective resources and time are dedicated to smoking cessation, exacerbations, and improve exercise tolerance and health long-term quit success rates of up to 25% can be achieved. status  To date, there is no conclusive clinical trial evidence that any existing medications for COPD modify the long-term decline in lung function  The choice within each class depends on the availability and cost of medication and favourable clinical response balanced against side effects  Each treatment regimen needs to be individualized as the relationship between severity of symptoms, airflow limitation, and severity of exacerbations can differ between patients

© 2017 Global Initiative for Chronic Obstructive Lung Disease © 2019 Global Initiative for Chronic Obstructive Lung Disease

Common Canister Policy Audience Question #4

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 Efforts intended to curb rising costs and waste associated with  A generic equivalent exits for what MDI use, have resulted in a variety of protocols generically referred to as CCPs ICS/LABA combination product ?

 Allows a single MDI canister to be shared among patient in a designated care area (hospital ward) with each individual  A. Budesonide/formoterol (Symbicort) having his/her own one-way valve holding chamber or spacer   The safety of CCP hinges on proper cleaning of the MDI B. Mometasone/formoterol (Dulera) between users  C. Fluticasone proprionate/salmeterol (Advair)  Before initiating CCP, communication should occur among risk managers, the P&T committee, pulmonologists, respiratory  D. Fluticasone furoate/vilanterol (Breo Ellipta) therapists, the medical executive committee, infection control personnel, and the professional liability insurance provide

https://www.mdedge.com/chestphysician/article/113875/critical-care/common-canister-policy-devil-details/page/0/1

8 Audience Question #5 Audience Question #6

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 Where is revefenacin (Yupelri) best utilized ?  What is the dose for amikacin (Arikayce) for the treatment of MAC?

 A. Acute treatment of asthma  A. Once daily  B. Acute treatment of COPD  B. Twice daily  C. Chronic treatment of asthma  C. Three times daily  D. Chronic treatment of COPD  D. Four times daily

The End Outstanding Presentation

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