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MEDICATION COVERAGE POLICY PHARMACY AND THERAPEUTICS ADVISORY COMMITTEE POLICY: /COPD P&T DATE 12/14/2016 CLASS: Respiratory Disorders REVIEW HISTORY 9/15, 5/15, 9/14, 2/13, LOB: Medi-Cal, SJHA (MONTH/YEAR) 5/12 This policy has been developed through review of medical literature, consideration of medical necessity, generally accepted medical practice standards, and approved by the HPSJ Pharmacy and Therapeutic Advisory Committee.  OVERVIEW Asthma is a reversible, chronic, inflammatory disorder that involves narrowing of the respiratory airways leading to wheezing, chest tightness, and shortness of breath. Inhaled corticosteroids are the mainstay of therapy and the goal of treatment is to reverse airway obstruction and maintain respiratory control. Chronic obstructive pulmonary disease (COPD) is another chronic airway disorder. Unlike asthma, COPD is not reversible. The goal of COPD management is to slow disease progression. COPD is managed with a combination of inhaled corticosteroids and . Some patients exhibit both features of asthma and COPD; this is called Asthma-COPD Overlap Syndrome (ACOS). The below criteria, limits, and requirements for asthma & COPD agents are in place to ensure appropriate use and to help members achieve control of their Asthma or COPD.

Table 1: Available Asthma/COPD Medications (Current as of 9/2016) Average Therapeutic Generic Name Strength & Dosage Formulary Cost per Limits Notes/Restriction Language Class (Brand Name) form 30 days* Single Agents Limit 2 inhalers per 30 days; Limit 7 inhalers per 180 days. Albuterol (Ventolin 90 mcg/act QL $57.07 Overuse of Short Acting HFA) may indicate poor Asthma/COPD control. ProAir: Albuterol (ProAir HFA, $55.81 Non-Formulary: Alternative is 90 mcg/act NF Proventil HFA) Proventil: Ventolin $96.71 Short Acting Non-Formulary: Alternatives are Beta Agonist Albuterol Syrup 2 mg/5 mL Syrup NF $10.13 Ventolin, Albuterol nebulizer (SABA) solution IR Tab: Non-Formulary: Alternatives are $462.55 Albuterol Sulfate 2 mg, 4 mg Tablet NF Ventolin, Albuterol nebulizer 4 mg, 8 mg ER Tablet ER Tab: solution $129.04 Reserved for treatment failure or intolerance of albuterol sulfate HFA. Levalbuterol (Xopenex 45 mcg/act PA $73.81 Overuse of Short Acting HFA) Bronchodilators may indicate poor Asthma/COPD control. Limit 2 packages per 30 days. Short Acting Ipratropium (Atrovent Overuse of Short Acting 17 mcg/act QL $284.24 HFA) Bronchodilators may indicate poor Asthma/COPD control. Furoate 100 mcg/act Restricted to patients 12 years and AL; QL $172.65 (Arnuity Ellipta) 200 mcg/act older. Limit 1 device per 30 days. Diskus: Inhaled 50 mcg/act Corticosteroid 100 mcg/act Diskus: 250 mcg/act $171.34 (ICS) QL Limit 1 package per 30 days (Flovent HFA/Diskus) HFA: HFA: 44 mcg/act $201.70 110 mcg/act 220 mcg/act

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Therapeutic Generic Name Strength & Dosage Formulary Average Notes/Restriction Language Class (Brand Name) form Limits Cost per 30 days* Limit 1 package per 30 days. Furoate 110 mcg/act (30 doses) AL (110 220 mcg/act (30, 60, or $195.61 110 mcg: Restricted to patients (Asmanex Twisthaler) mcg); QL 120 doses) under the age of 12. Non-Formulary: Alternatives are Mometasone Furoate Pulmicort Flexhaler, Asmanex 100 mcg/act NF $233.30 (Asmanex HFA) 200 mcg/act Twisthaler, Qvar, Flovent HFA/Diskus Beclomethasone 40 mcg/act QL $178.76 Limit 1 package per 30 days Dipropionate (Qvar) 80 mcg/act Non-Formulary: Alternatives are (Pulmicort Flovent HFA 44 mcg, Flovent Diskus 90 mcg/act NF $159.94 Flexhaler) 50 mcg, Asmanex Twisthaler 110 mcg, Qvar 40 mcg Budesonide (Pulmicort 180 mcg/act QL $192.23 Limit 1 package per 30 days Flexhaler) Non-Formulary: Alternatives are Pulmicort Flexhaler, Asmanex (Aerospan) 80 mcg/act NF $235.31 Twisthaler, Qvar, Flovent HFA/Diskus Non-Formulary: Alternatives are 80 mcg/act Pulmicort Flexhaler, Asmanex (Alvesco) NF $186.62 160 mcg/act Twisthaler, Qvar, Flovent HFA/Diskus, Arnuity Ellipta Xinafoate Non-Formulary: Alternative is 50 mcg/act NF $314.79 (Serevent Diskus) Striverdi Respimat Fumarate Concurrent use of ICS is required. 12 mcg Inhalation ST; QL $246.66 (Foradil) Capsule Limit 1 package per 30 days. Long Acting Maleate Non-Formulary: Alternative is Beta Agonist 75 mcg/act NF $256.33 (LABA) (Arcapta Neohaler) Striverdi Respimat Concurrent use of ICS is required. Hydrochloride 2.5 mcg/act ST; QL $201.79 Limit 1 package per month. (Striverdi Respimat) Documentation of diagnosis of Handihaler: Handihaler: GOLD Grade II COPD is required for 18 mcg Inhalation PA; QL $332.65 Capsule approval. Respimat: (Spiriva) Respimat: (Respimat) $340.95 Respimat: Limit 1 package per 30 2.5 mcg/act days. Step therapy to AND one of the following: Symbicort (160 Tiotropium Bromide 1.25mcg/act ST $348.85 mcg/4.5 mcg), Advair (500 mcg/50 Long Acting (Spiriva Respimat) mcg), or Dulera (200 mcg/5 mcg) Anticholinergic within the last 30 days. Documentation of diagnosis of GOLD Grade II COPD is required for 400 mcg/act PA; QL $290.32 (Tudorza Pressair) approval. Limit 1 package per 30 days. Non-Formulary: Alternatives are 62.5 mcg/act NF $327.30 Spiriva Handihaler, Spiriva Respimat (Incruse Ellipta) 2.5 mcg, Tudorza 4 mg Oral Granules Montelukast Sodium 4 mg, 5 mg Chewable QL $12.39 Limit 30 tablets per 30 days (Singulair) Tablet Receptor 10 mg Tablet Antagonist Non-Formulary: Alternative is (Accolate) 10 mg, 20 mg Tablet NF $98.93 montelukast 5-Lipoxygenase Zileuton (Zyflo, Zyflo 600 mg Tablet NF $2,980.00 Indicated for Asthma only Inhibitor CR) 600 mg ER Tablet

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Therapeutic Generic Name Strength & Dosage Formulary Average Notes/Restriction Language Class (Brand Name) form Limits Cost per 30 days* 80mg/15mL Oral Elixophyllin: Elixir/Solution $378.39 100 mg, 200 mg, 300 mg, Theo-24: ER Cap (Theo-24) $116.07 (Theo- 100 mg, 200 mg, 300 mg Theochron: Narrow therapeutic window. Should /Phos 24, Elixophyllin, ER Tab (Theochron, 12- -- $17.24 be reserved as last line therapy. phodiesterase Theochron) hr) 400 mg, 600 mg ER Tab 24-hr tabs (400 mg, Inhibitor, (24-hr) 450 mg ER Tab 600 mg): Nonselective (Theochron, 12-hr) $42.57 Theophylline (Theo- Non-Formulary: Alternative is 400 mg ER Cap NF $131.51 24) theophylline 400 mg ER tablet Theophylline 400 mg, 800 mg IV NF $21.02 Solution Indicated for COPD only. Reserved for GOLD Grade III COPD PDE-4 Inhibitor (Daliresp) 500 mcg Tablet PA; ST $278.08 in patients compliant on ICS/LABA and Spiriva/Tudorza. Reserved for inadequate asthma (Xolair) 150 mg Vial PA $2,014.88 control or uncontrolled chronic idiopathic urticaria Monoclonal Reserved for patients with Antibody, Anti- Mepolizumab (Nucala) 100 mg Vial PA $3,090.00 poorly controlled, severe Asthmatic eosinophilic asthma 100 mg/10 mL IV $100.20 Indicated for Asthma only. Dose is Reslizumab (Cinqair) NF Solution per vial weight-dependent (3 mg/kg). Combination Agents Short Acting Ipratropium/Albuterol Limit 1 package per 30 days. Should 20 mcg-100 mcg QL $312.42 Combination (Combivent Respimat) not be used with Tiotropium. Budesonide/ 80 mcg-4.5mcg Formoterol 160 mcg-4.5 mcg QL $277.37 Limit 1 package per 30 days (Symbicort) Mometasone/ 100 mcg-5mcg QL $265.98 Limit 1 package per 30 days Formoterol (Dulera) 200 mcg-5mcg Diskus: 100 mcg-50 mcg Diskus: Fluticasone/ 250 mcg-50 mcg $337.11 Salmeterol (Advair 500 mcg-50 mcg QL Limit 1 package per 30 days HFA: HFA: Diskus or HFA) 45 mcg-21mcg $340.58 115 mcg-21mcg 230 mcg-21 mcg Non-Formulary: Alternatives include Fluticasone/ 100 mcg-25 mcg NF $272.74 Advair, Symbicort, Dulera, Long Acting (Breo Ellipta) 200 mcg-25 mcg Combination Combivent Reserved for patients with at least Tiotropium/ Grade II (moderate) COPD Otodaterol (Stiolto 2.5 mcg-2.5 mcg PA; QL $318.49 confirmed by PFTs. Limit 1 inhaler Respimat) per 30 days. Umeclidinium/ Non-Formulary: Alternatives include Vilanterol (Anoro 62.5 mcg-25 mcg NF $378.82 Advair, Symbicort, Dulera, Ellipta) Combivent, Stiolto Respimat Glycopyrrolate/ Non-Formulary: Alternatives include Indacaterol (Utibron 27.5 mcg-15.6 mcg NF $357.37 Advair, Symbicort, Dulera, Neohaler) Combivent, Stiolto Respimat Glycopyrrolate/ Non-Formulary: Alternatives include Formoterol (Bevespi 9 mcg-4.8 mcg NF $378.82 Advair, Symbicort, Dulera, Aerosphere) Combivent, Stiolto Respimat

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Therapeutic Generic Name Strength & Dosage Formulary Average Notes/Restriction Language Class (Brand Name) form Limits Cost per 30 days* Solution for Nebulization 0.63 mg/3 mL 1.25 mg/3 mL Albuterol Sulfate 2.5 mg/0.5 mL (0.083%) QL $19.85 Limit 375 mL per 30 days Short Acting 2.5 mg/3 mL Beta Agonist 5 mg/mL (0.5%) (SABA) 0.31 mg/3 mL Reserved for patients with Levalbuterol 0.63 mg/3 mL PA $292.60 intolerance/contraindication to Hydrochloride 1.25 mg/3 mL 1.25 mg/0.5 mL Albuterol Short Acting 0.02% Nebulization -- $15.16 Anticholinergic Solution Short Acting Ipratropium/ 0.5 mg-3 mg(2.5 mg QL $33.08 Limit 375 mL per 30 days Combination Albuterol (Duoneb) Base)/3 mL Inhaled 0.25 mg/2 mL Limit 120 mL per 30 days. Budesonide 0.5 mg/2 mL AL; QL $297.51 Corticosteroid 1 mg/2 mL Restricted to members ≤ 4 years old. Formoterol Fumarate Non-Formulary: Formulary Dihydrate 20 mcg/2 mL NF $666.42 Long Acting alternative is Serevent Diskus (Perforomist) Beta Agonist Non-Formulary: Formulary 15 mcg/2 ml NF $612.39 (Brovana) alternative is Serevent Diskus Mast Cell Cromolyn Sodium 20 mg/2 mL ------Stabilizer Medical Equipment Peak Air Peak Flow Meter QL $17.89 Limit 1 per lifetime Limit 1 per lifetime. Submit PA for Bubbles the Fish II Pedi Mask QL $1.65 lost/broken. Optichamber Adult Mask (Large) QL $30.03 Limit 2 per year Optichamber Diamond Large Medium QL $28.51 Limit 2 per year with mask Small Vortex Holding Chamber with + Child Mask (Frog) QL $24.70 Limit 2 per year Toddler Mask (Ladybug) without mask Flow-VU: Mask/Spacer $45.81 Aerochamber Plus Large Plus Z-Stat: Non-Formulary: Alternatives are Flow-VU/Plus Z-Stat/ Medium NF $34.20 Small Optichamber, Vortex Z-stat Plus with mask Z-Stat Plus: $28.50 Inspirachamber with Large Non-Formulary: Alternatives are Medium NF $53.42 mask Small Optichamber, Vortex Easivent Holding Large Non-Formulary: Alternatives are Medium NF $57.78 Chamber with mask Small Optichamber, Vortex Limit 1 per lifetime. Nebulizer QL -- Max amount = $100. PA = Prior Authorization; QL = Quantity Limit; AL = Age Limit; NF = Non-formulary *Cost/Rx based on HPSJ Medi-Cal utilization historical data from September 2015 through August 2016  EVALUATION CRITERIA FOR APPROVAL/EXCEPTION CONSIDERATION Below are the coverage criteria and required information for each agent. These coverage criteria have been reviewed approved by the HPSJ Pharmacy & Therapeutics (P&T) Advisory Committee. For conditions not covered under this Coverage Policy, HPSJ will make the determination based on Medical Necessity as described in HSPJ Medical Review Guidelines (UM06).

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Short Acting Beta Agonists Albuterol sulfate (Ventolin HFA, ProAir HFA, Proventil HFA, albuterol syrup, albuterol tablets), Levalbuterol tartrate (Xopenex HFA)

Albuterol Sulfate (Ventolin HFA)  Coverage Criteria: None  Limits: 2 inhalers per 30 days; 7 inhalers per 180 days  Required Information for Approval: N/A  Other Notes: Ventolin HFA is the preferred Albuterol formulation. Use of more than 7 inhalers per 180 day period may indicate uncontrolled asthma. Consider starting or titrating a controller agent.  Non-Formulary: ProAir, Proventil, Albuterol syrup, Albuterol tablets

Levalbuterol Tartrate (Xopenex HFA)  Coverage Criteria: Xopenex HFA is step therapy to treatment failure or intolerance of Albuterol Sulfate HFA.  Limits: None  Required Information for Approval: Chart notes with clinical documentation describing intolerance to Albuterol HFA.  Other Notes: Use of more than 7 inhalers per 180 day period may indicate uncontrolled asthma. Consider starting or titrating a controller agent.

Short Acting Anticholinergics Ipratropium bromide (Atrovent HFA)  Coverage Criteria: None  Limits: 2 inhalers per 30 days  Required Information for Approval: N/A  Other Notes: Usage above the quantity limit may indicate uncontrolled disease. Consider adding or titrating a controller agent.

Inhaled Corticosteroid Fluticasone Propionate (Flovent HFA/Diskus), Fluticasone Furoate (Arnuity Ellipta), Mometasone Furoate (Asmanex Twisthaler/HFA), Beclomethasone Dipropionate (Qvar), Budesonide (Pulmicort Flexhaler), Flunisolide (Aerospan), Ciclesonide (Alvesco)

Fluticasone Propionate (Flovent HFA/Diskus), Beclomethasone Dipropionate (Qvar)  Coverage Criteria: None  Limits: 1 inhaler/device per 30 days  Required Information for Approval: N/A  Other Notes: None  Non-Formulary: Flunisolide (Aerospan), (Ciclesonide (Alvesco)

Fluticasone Furoate (Arnuity Ellipta)  Coverage Criteria: Fluticasone Furoate (Arnuity Ellipta) is reserved for patients 12 years and older.  Limits: 1 inhaler per 30 days  Required Information for Approval: N/A  Other Notes: None

Mometasone Furoate (Asmanex Twisthaler), Budesonide (Pulmicort Flexhaler 180 mcg)  Coverage Criteria: Mometasone Furoate (Asmanex Twisthaler) 110 mcg and Budesonide (Pulmicort Flexhaler) 180 mcg are reserved for patients under the age of 12.  Limits: 1 inhaler/device per 30 days  Required Information for Approval: N/A  Other Notes: Asmanex Twisthaler 220 mcg has no age restriction.  Non-Formulary: Asmanex HFA, Pulmicort Flexhaler 90 mcg

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Long Acting Beta Agonist Salmeterol Xinafoate (Serevent Diskus), Formoterol Fumarate (Foradil Aerolizer), Indacaterol Maleate (Arcapta Neohaler), Olodaterol Hydrochloride (Striverdi Respimat)

Olodaterol HCl (Striverdi Respimat) and Formoterol Fumarate (Foradil Aerolizer)  Coverage Criteria: Olodaterol HCl (Striverdi Respimat) and Formoterol Fumarate (Foradil Aerolizer) are step therapy to Inhaled Corticosteroid use.  Limits: 1 inhaler/package per 30 days. Concurrent use of Inhaled Corticosteroid required.  Required Information for Approval: N/A  Other Notes: Due to an increased risk of asthma related death, LABAs are not recommended for monotherapy in asthma. Foradil Aerolizer was discontinued by the manufacturer in October 2015. Marketing end date is scheduled for 1/31/17.  Non-Formulary: Indacaterol Maleate (Arcapta Neohaler), Salmeterol Xinafoate (Serevent Diskus)

Long Acting Anticholinergic Tiotropium Bromide (Spiriva, Spiriva Respimat), Aclidinium Bromide (Tudorza Pressair), Umeclidinium Bromide (Incruse Ellipta)

For COPD Tiotropium Bromide (Spiriva/Spiriva Respimat 2.5mcg), Aclidinium Bromide (Tudorza Pressair)  Coverage Criteria: Spiriva, Spiriva Respimat 2.5mcg, and Tudorza Pressair are reserved for patients with at least GOLD Grade II (moderate airflow limitation) COPD confirmed by PFTs.  Limits: Spiriva Respimat 2.5 mcg and Tudorza Pressair: 1 package per 30 days  Required Information for Approval: Chart notes with clinical documentation of Moderate (Grade II) COPD diagnosis (i.e., numerical values of PFT results). 2016 GOLD guidelines define Moderate (Grade II) COPD as FEV1/FVC <0.70 and postbronchodilator FEV1 between 50-80% predicted.  Other Notes: Long-Acting Anticholinergics should not be used in combination with Combivent Respimat due to the increased risk of anticholinergic side effects.  Non-Formulary: Umeclidinium Bromide (Incruse Ellipta)

For Asthma Tiotropium Bromide (Spiriva Respimat 1.25mcg)  Coverage Criteria: Spiriva Respimat 1.25mcg is step therapy to Montelukast AND one of the following: Symbicort (160 mcg/4.5 mcg), Advair (500 mcg/50 mcg), or Dulera (200 mcg/5 mcg) within the last 30 days.  Limits: None  Required Information for Approval: Fills of Montelukast and one of the following: Symbicort (160 mcg/4.5 mcg), Advair (500 mcg/50 mcg), or Dulera (200 mcg/5 mcg) within the last 30 days.  Other Notes: Criteria applies only to Spiriva Respimat 1.25 mcg. Spiriva Respimat and Spiriva Handihaler are restricted for COPD use only.

Leukotriene Receptor Antagonist Montelukast Sodium (Singulair), Zafirlukast (Accolate)

Montelukast Sodium (Singulair)  Coverage Criteria: None  Limits: 30 tablets per 30 days  Required Information for Approval: N/A  Other Notes: None  Non-Formulary: Zafirlukast (Accolate)

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Xanthine/Phosphodiesterase , Nonselective Theophylline (Theo-24, Elixophyllin, Theochron)

Theophylline 80mg/15mL Oral Elixir/Solution; 100 mg, 200 mg, 300 mg, ER capsules (Theo-24); 100 mg, 200 mg, 300 mg ER tablets (Theochron, 12-hour); 600 mg ER tablets (24-hour); 450 mg ER tablets (Theochron, 12-hour)  Coverage Criteria: None  Limits: None  Required Information for Approval: N/A  Other Notes: Theophylline should be initiated and monitored by an experienced physician, due to the narrow therapeutic window.  Non-Formulary: Theophylline IV Solution, Theo-24 400 mg ER capsules

PDE-4 Inhibitor Roflumilast (Daliresp)  Coverage Criteria: Daliresp is reserved for patients with GOLD Grade III COPD (post FEV1/FVC < 0.70 and FEV1 of 30-50% predicted) or higher who are compliant with, or intolerant to, use of [1] Long acting anticholinergics (Spiriva) AND [2] ICS (Qvar/Flovent/Arnuity Ellipta/Pulmicort) + Long acting beta agonists (Serevent/Foradil) or ICS/LABA combination (Advair/Symbicort/Dulera).  Limits: None  Required Information for Approval: Evidence of compliant use of all other controller medications, in the form of pharmacy fill history. Chart notes detailing a diagnosis of GOLD Grade III COPD, evidenced by Pulmonary Function Testing.  Other Notes: None

Monoclonal Antibody Omalizumab (Xolair), Mepolizumab (Nucala), Reslizumab (Cinqair)

Omalizumab (Xolair)  Coverage Criteria: For asthma, Xolair is reserved for poorly controlled moderate-severe allergic asthma patients with baseline serum IgE levels between 30-700 IU/ml, with FEV1 < 80% predicted, despite being compliant with dose-optimized [1] Inhaled Corticosteroids (ICS) + Long-Acting Beta-2 Agonist (LABA), [2] Spiriva Respimat, and [3] leukotriene modifier or theophylline.  Limits: None  Required Information for Approval: Patients must meet all of the following criteria: o Asthma classified as moderate to severe persistent asthma o Pretreatment level of IgE ≥30IU/ml and <700IU/ml o Positive skin test of in vitro reactivity to at least 1 perennial aeroallergen o Dose optimized inhaled corticosteroids without adequate asthma control (as evidenced by fill history and clinic documentation) o Dose optimized combination inhaled corticosteroid/long-acting beta2-agonist and leukotriene modifier or theophylline.  Other Notes: Initial approval is 6 months. Continuing Approval will require updated clinic notes with documented therapeutic response in the form of improved symptomology. Perennial aeroallergens include: cat or dog dander, house-dust mites, and pollens. Evidence is limited for molds and cockroaches.2

Mepolizumab (Nucala)  Coverage Criteria: Nucala is reserved for patients with poorly controlled, severe eosinophilic asthma with baseline serum eosinophil counts of either ≥ 150 cells/µL at initiation of treatment or ≥ 300 cells/µL in the past 12 months AND 2 or more exacerbations in the past 12 months, despite being compliant with dose-optimized [1] Inhaled Corticosteroids (ICS) + Long-Acting Beta-2 Agonist (LABA), [2] Spiriva Respimat, and [3] leukotriene modifier or theophylline. Must be prescribed by an allergist.  Limits: None

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 Required Information for Approval: Patients must meet all of the following criteria: o Diagnosis of asthma o Eosinophil level of either ≥ 150 cells/µL at initiation of treatment or ≥ 300 cells/µL in the past 12 months o 2 or more exacerbations in the past 12 months, despite being compliant with dose-optimized [1] Inhaled Corticosteroids (ICS) + Long-Acting Beta-2 Agonist (LABA), [2] Spiriva Respimat, and [3] leukotriene modifier or theophylline.  Other Notes: Initial approval is 6 months. Continuing Approval will require updated clinic notes with documented therapeutic response in the form of improved symptomology.  Non-Formulary: Reslizumab (Cinqair)

Short Acting Combination Ipratropium/Albuterol (Combivent Respimat)  Coverage Criteria: None  Limits: 1 Inhaler per 30 days  Required Information for Approval: None  Other Notes: Should not be used with Tiotropium (Spiriva).

Long Acting Combination Fluticasone/Salmeterol (Advair), Budesonide/Formoterol (Symbicort), Mometasone/Formoterol (Dulera), Fluticasone/Vilanterol (Breo Ellipta), Tiotropium/Otodaterol (Stiolto Respimat), Umeclidinium/ Vilanterol (Anoro Ellipta), Glycopyrrolate/ Indacaterol (Utibron Neohaler), Glycopyrrolate/ Formoterol (Bevespi Aerosphere)

Fluticasone/Salmeterol (Advair), Budesonide/Formoterol (Symbicort), Mometasone/Formoterol (Dulera)  Coverage Criteria: None  Limits: 1 Inhaler per 30 days  Required Information for Approval: None  Other Notes: None  Non-Formulary: Fluticasone/Vilanterol (Breo Ellipta)

Tiotropium/Otodaterol (Stiolto Respimat)  Coverage Criteria: Stiolto Respimat is reserved for patient with at least Grade II (moderate) COPD confirmed by pulmonary function testing (PFTs).  Limits: 1 Inhaler per 30 days  Required Information for Approval: PFTs showing post-bronchodilator FEV1/FVC is <0.7 and FEV1 between 50-80% predicted.  Other Notes: None  Non-Formulary: Umeclidinium/ Vilanterol (Anoro Ellipta), Glycopyrrolate/ Indacaterol (Utibron Neohaler), Glycopyrrolate/ Formoterol (Bevespi Aerosphere)

Solution for Nebulization Albuterol Sulfate, Ipratropium-Albuterol (Duoneb), Ipratropium Bromide, Levalbuterol Hydrochloride, Budesonide, Cromolyn Sodium, Formoterol Fumarate Dihydrate (Perforomist), Arformoterol (Brovana)

Albuterol Sulfate, Ipratropium-Albuterol (Duoneb)  Coverage Criteria: None  Limits: 375mL per 30 days  Required Information for Approval: N/A  Other Notes: None

Ipratropium Bromide  Coverage Criteria: None  Limits: None  Required Information for Approval: N/A  Other Notes: None

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Levalbuterol Hydrochloride  Coverage Criteria: Step Therapy to treatment failure of or intolerance to Albuterol Sulfate  Limits: None  Required Information for Approval: Chart notes with clinical documentation explaining intolerance to Albuterol.  Other Notes: Formoterol Fumarate Dihydrate (Perforomist), Arformoterol (Brovana)

Budesonide  Coverage Criteria: Restricted to members less than or equal to 4 years of age.  Limits: 120 mL per 30 days  Required Information for Approval: N/A  Other Notes: Members older than 4 should use a mask and spacer to facilitate delivery of ICS products. Formulary agents include Qvar, Flovent HFA/Diskus, and Asmanex Twisthaler.

Cromolyn Sodium  Coverage Criteria: None  Limits: None  Required Information for Approval: N/A  Other Notes: None

Medical Equipment Peak Flow Meter, Mask/Spacer, Nebulizer

Peak Flow Meter, Bubbles the Fisk II Pedi Mask, Nebulizer  Coverage Criteria: None  Limits: 1 per lifetime  Required Information for Approval: N/A  Other Notes: Nebulizers will be paid at a maximum of $100 per machine.

Optichamber Adult Mask (Large), Optichamber Diamond with Mask, Vortex Holding Chamber with/without mask  Coverage Criteria: None  Limits: 2 per year  Required Information for Approval: N/A  Other Notes: None  Non-Formulary: Aerochamber Plus Flow-VU/Plus Z-Stat/Z-stat Plus with mask, Inspirachamber with mask, Easivent Holding Chamber with mask

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Clinical Justification: Figure 1: Global Initiative for Asthma Management and Prevention Strategy 20161

*Not for children <12 years. **For children 6–11 years, the preferred Step 3 treatment is medium dose ICS. # Low dose ICS/formoterol is the reliever medication for patients prescribed low dose budesonide/formoterol or low dose /formoterol for maintenance and reliever therapy. Tiotropium by mist inhaler is an add-on treatment for patients with a history of exacerbations*.

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Figure 2: National Asthma Education and Prevention Program Asthma Treatment Guidelines 20122

Abbreviations: EIB, exercise-induced † Treatment options are listed in alphabetical order, if more than one. ‡ If alternative treatment is used and response is inadequate, discontinue and use preferred treatment before stepping up. § Theophylline is a less desirable alternative because of the need to monitor serum concentration levels. Based on evidence for dust mites, animal dander, and pollen; evidence is weak or lacking for molds and cockroaches. Evidence is strongest for immunotherapy with single allergens. The role of allergy in asthma is greater in children than in adults. †† Clinicians who administer immunotherapy or omalizumab should be prepared to treat anaphylaxis that may occur. ‡‡ Zileuton is less desirable because of limited studies as adjunctive therapy and the need to monitor function. §§ Before oral corticosteroids are introduced, a trial of high-dose ICS + LABA + either LTRA, theophylline, or zileuton, may be considered, although this approach has not been studied in clinical trials.

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Asthma is a dynamic condition requiring constant assessment in order to provide optimal control of symptoms. The HPSJ formulary is designed to make controller agents accessible, as these are the mainstay of therapy according to NAEPP and GINA guidelines. Controller medications for asthma include inhaled corticosteroids, long-acting beta-2 agonists, leukotriene antagonists, theophylline, cromolyn, and zileuton. New classes of agents have also entered the market in recent years: long-acting anticholinergics (Spiriva Respimat 1.25 mcg) and monoclonal antibodies (Xolair). Since NAEPP and GINA guidelines list these agents as add-on therapies for patients with severe, uncontrolled disease, they are reserved for patients who have failed ICS, LABA, and leukotriene antagonists. Xolair is specifically indicated in patients with allergic asthma, and therefore requires additional lab testing to establish medical necessity.

Combination ICS/LABA products such as Advair, Symbicort, and Dulera, are available with quantity limits to ensure appropriate use. Short acting-inhalers should only be used on an as-needed basis, and therefore have quantity limits to prevent overuse. Frequent use of short-acting inhalers can be an indicator of poorly controlled asthma.

Short-acting beta-2 agonists (SABAs) are commercially available as oral syrups or tablets. However, these formulations are not on HPSJ’s formulary due to NAEPP guideline recommendations, which state inhaled route is preferred because they cause fewer systemic side effects than oral agents. Additionally, oral extended-release tablets have not been adequately studied as adjunctive therapy with ICS.2

Figure 3: Adapted from Global Initiative for Chronic Obstructive Lung Disease 20163 Patient GOLD FEV1 Exacer Hospital CAT mMRC Recommended Other Possible Alternative Choice Group Grade bation ization Score Grade First Choice Treatments** LA anticholinergic ≥80% SA or 1 or 2 predicted anticholinergic LA beta2-agonist (mild- or 0-1 per A No <10 0-1 prn or or Theophylline moderate 50%≤FEV year SA beta2- SA beta2-agonist airflow 1<80% agonist prn and SA limitation) predicted anticholinergic ≥80% SA beta2- 1 or 2 LA predicted agonist and/or (mild- anticholinergic LA anticholinergic or 0-1 per SA B moderate No ≥10 ≥2 or and LA beta2- 50%≤FEV year anticholinergic airflow LA beta2- agonist 1<80% limitation) agonist predicted Theophylline LA anticholinergic and LA beta2- agonist 3 or 4 30%≤FEV SA beta2- or (severe- 1<50% ICS + LA beta2- agonist and/or LA anticholinergic very predicted agonist or SA C ≥2 ≥1 <10 0-1 and PDE-4 severe or LA anticholinergic Inhibitor airflow <30% anticholinergic or limitation) predicted Theophylline LA beta2-agonist and PDE-4 Inhibitor ICS + LA beta2- agonist and LA Carbocysteine anticholinergic or

ICS + LA beta2- N- 3 or 4 30%≤FEV agonist and PDE-4 acetylcysteine (severe- 1<50% ICS + LA beta2- inhibitor

very predicted agonist and/or or D ≥2 ≥1 ≥10 ≥2 SA beta2- severe or LA LA anticholinergic agonist and/or airflow <30% anticholinergic and LA beta2- SA limitation) predicted agonist anticholinergic or

LA anticholinergic Theophylline and PDE-4 inhibitor **Medications in this column can be used alone or in combination with other options in the First and Alternative Choice columns

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The mainstay of therapy for COPD is ICS, LABA, and long-acting anticholinergics. Spiriva Handihaler, Spiriva Respimat 2.5 mcg, Tudorza, Stiolto Respimat, and Daliresp have only been approved for COPD. According to the GOLD Guidelines, the diagnosis and grading of COPD is determined by pulmonary function test results. These agents are reserved for patients with GOLD Grade II COPD or higher. Therefore, HPSJ requires pulmonary function testing to ensure appropriate use based on members’ GOLD Grading.  REFERENCES 1. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2016. Available from: www.ginasthma.org. 2. National Heart, Lung, and Blood Institute. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. 2007. Available from: http://www.nhlbi.nih.gov/files/docs/guidelines/asthgdln.pdf. 3. Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. 2016. Available from: www.goldcopd.org. 4. Global Initiative for Chronic Obstructive Lung Disease. Diagnosis of Diseases of Chronic Airflow Limitation: Asthma COPD and Asthma-COPD Overlap Sndrome (ACOS). 2016. Available from: www.goldcopd.org. 5. Chung KF, Wenzel SE, Brozek JL, et al. International ERA/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43 (2): 343-373. 6. Food and Drug Administration. FDA News Release: FDA approves Nucala to treat severe asthma. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm471031.htm. Updated November 6, 2015. Accessed September 18, 2016. 7. Nucala [Package Insert]. Philadelphia, PA: GlaxoSmithKline LLC; 2015. 8. Food and Drug Administration. FDA News Release: FDA approves Cinqair to treat severe asthma. http://www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm491980.htm. Updated March 23, 2016. Accessed September 23, 2016. 9. Cinqair [Package Insert]. Frazer, PA: Teva Respiratory, LLC; 2016. 10. Donohue JF. Systematic review comparing LABA, olodaterol, and indacaterol: limitations. Int J Chron Obstruct Pulmon Dis. 2014;9:1331-1335. 11. Cazzola M, Calzetta L, Matera MG. Beta2-adrenoreceptor agonists: current and future direction. Br J Pharmacol. 2011;163(1):4-17. 12. Roskell NS, Anzueto A, Hamilton A, Disse B, Becker K. Once-daily long-acting beta-agonists for chronic obstructive pulmonary disease: an indirect comparison of olodaterol and indacaterol. Int J Chron Obstruct Pulmon Dis. 2014;9:813-824. 13. Schurmann W, Schmidtmann S, Moroni P, Massey D, Qidan M. Respimat Soft Mist Inhaler versus Hydrofluoroalkane Metered Dose Inhaler: Patient Preference and Satisfaction. 2005;4(1):53-61. 14. Hodder R, Price D. Patient preferences for inhaler devices in chronic obstructive pulmonary disease: experience with Respimat Soft Mist Inhaler. Int J Chorn Obstruct Pulmon Dis. 2009;4:381-390. 15. Cazzola M, Beeh KM, Price D, Roche N. Assessing clinical value of fast onset and sustained duration of action of long- acting bronchodilators for COPD. Pulmonary Pharmacology and Therapeutics. 2015;31:68-78. 16. Hannaway PJ, Hooper GD. Comparison study of sustained-release theophylline products: Slo-bid capsules versus Theo-DUR tablets in 20 children and young adults with asthma. J Allergy Clin Immunol. 1986;77(3):456-464. 17. Food and Drug Administration. FDA Drug Shortages: Current and Resolved Drug Shortages and Discontinuations Reported to FDA. http://www.accessdata.fda.gov/scripts/drugshortages/ dsp_ActiveIngredientDetails.cfm?AI=Theophylline%20Extended%20Release%20Tablets%20and%20Capsules&st=c &tab=tabs-1. Updated August 16, 2016. Accessed September 26, 2016. 18. American Society of Health-System Pharmacists. Theophylline Extended-Release Tablets. http://www.ashp.org/ menu/DrugShortages/CurrentShortages/bulletin.aspx?id=1221. Updated August 15, 2016. Accessed September 26, 2016.  REVIEW & EDIT HISTORY

Document Changes Reference Date P&T Chairman Creation of Policy Singulair Survey 7-06.doc 7/2006 Allen Shek PharmD BCPS Update to Policy ICS Review 9-06.doc 9/2006 Allen Shek PharmD BCPS Update to Policy Albuterol HFA 11-06.doc 11/2006 Allen Shek PharmD BCPS Update to Policy ICS-LABA combo status 9-07.doc 9/2007 Allen Shek PharmD BCPS Update to Policy Symbicort 9-11-07.doc 9/2007 Allen Shek PharmD BCPS Update to Policy Asthma_Xopenex 9-08.doc 9/2008 Allen Shek PharmD BCPS Update to Policy ICS Review 9-16-08.doc 9/2008 Allen Shek PharmD BCPS Update to Policy Spacer utilization.doc 3/2009 Allen Shek PharmD BCPS Update to Policy ICS post P&T Survey recap.doc 3/2009 Allen Shek PharmD BCPS

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Update to Policy Daliresp Monograph 11-20-12.doc 11/2012 Allen Shek PharmD BCPS Update to Policy Tudorza 5-21-2013.docx 5/2013 Allen Shek PharmD BCPS Update to Policy HPSJ Coverage Policy – Respiratory – 9/2015 Jonathan Szkotak, PharmD, Asthma & COPD 2015-05.docx BCACP Update to Policy HPSJ Coverage Policy – Respiratory – 12/2016 Johnathan Yeh, PharmD Asthma & COPD 2016-12.docx Note: All changes are approved by the HPSJ P&T Committee before incorporation into the utilization policy

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