Asthma Medications and Management

IL-5/5Rα Inhibitors

IL-5 Inhibitor: Suppresses eosinophils.
- Mepolizumab (Nucala®): 100mg subcutaneous monthly, for individuals ≥ 12 years old with eosinophil levels ≥ 150 or 300 cells/mcL.
- Reslizumab (Cinqair®): 3mg/kg intravenous monthly, for individuals ≥ 12 years old with eosinophil levels ≥ 400 cells/mcL.
IL-5Rα Inhibitor:
- Benralizimab (Fasenra®): 30mg subcutaneous monthly for 3 months, then every 2 months; for individuals ≥ 18 years old (≥ 12 years in the US) with eosinophil levels ≥ 150 or 300 cells/mcL.
Mechanism of Action (MOA): Inhibition of IL-5/5Rα suppresses eosinophils.
Indication: Add-on maintenance treatment for severe eosinophilic asthma in adults.
- For asthma inadequately controlled by medium- to high-dose inhaled corticosteroids (ICS) plus an additional controller (e.g., LABA).
- Eligibility is based on elevated serum eosinophil levels.
Efficacy: Reduces exacerbation rate and oral steroid dose, improves FEV1, asthma control, and quality of life.
Responders: Typically have higher blood eosinophils, more exacerbations, adult-onset asthma, and nasal polyposis.

IL-4Rα Inhibitor

Dupilumab (Dupixent®): 200 mg subcutaneous every 2 weeks, for individuals ≥ 12 years old.
MOA: Inhibition of IL-4Rα suppresses eosinophils.
Indication: Add-on maintenance treatment for severe asthma with type 2/eosinophilic phenotype or OCS-dependent asthma.
Eligibility: Elevated serum eosinophils (≥ 300 cells/mcL) or OCS-dependent, and frequent exacerbations in the last year.
Efficacy: Reduces exacerbation rate and oral steroid dose and improves FEV1, asthma control, and quality of life.

Anti-TSLP

Tezepelumab (Tezspire®): 210 mg subcutaneous every 4 weeks.
MOA: Blocks thymic stromal lymphopoietin (TSLP), an epithelial cytokine upstream in the inflammatory cascade.
Indication: Add-on therapy for individuals ≥ 12 years old with severe asthma uncontrolled on current treatment, regardless of Th2 biomarkers.
Efficacy: Reduces eosinophils, FeNO, IgE, and exacerbations; increases QoL and FEV1.
- A reduction in exacerbations occurred in high-eosinophil, high FeNO.
- An increase in Th2 markers is not a requirement for use.
- Reduction on oral corticosteroid dose not demonstrated.

Effect of Biologics on Type 2 Biomarkers

Benralizumab: Targets IL-5 Rα.
- Total serum IgE: Not affected.
- FeNO: No change.
- Blood eosinophils: Depleted ( $\downarrow \downarrow \downarrow$ ).
- Airway eosinophils: Decreased ( $\downarrow \downarrow$ ).
Mepolizumab: Targets IL-5.
- Total serum IgE: Not affected.
- FeNO: No change.
- Blood eosinophils: Decreased ( $\downarrow \downarrow$ ).
- Airway eosinophils: Decreased ( $\downarrow \downarrow$ ).
Reslizumab: Targets IL-5.
- Total serum IgE: Not affected.
- FeNO: No change.
- Blood eosinophils: Decreased ( $\downarrow \downarrow$ ).
- Airway eosinophils: Decreased ( $\downarrow \downarrow$ ).
Dupilumab: Targets IL-4 Rα.
- Total serum IgE: Decreased (gradual reduction over 12 months).
- FeNO: Decreased ( $\downarrow$ to $\downarrow \downarrow$ ).
- Blood eosinophils: Not affected or temporarily increased $\uparrow$ .
- Airway eosinophils: Unknown.
Omalizumab: Targets IgE.
- Total serum IgE: Decreased free IgE; no reduction in total IgE (due to anti-IgE complexes).
- FeNO: Slightly decreased ($\pm \downarrow$).
- Blood eosinophils: Not affected.
- Airway eosinophils: Decreased ( $\downarrow$ ).
Tezepelumab: Targets Thymic stromal lymphopoietin (TSLP).
- Total serum IgE: Decreased (gradual reduction over 12 months).
- FeNO: Decreased ( $\downarrow$ ).
- Blood eosinophils: Decreased ( $\downarrow$ ).
- Airway eosinophils: Decreased ( $\downarrow \downarrow$ ).

Macrolides (Azithromycin and Clarithromycin)

Azithromycin: 250mg daily or 3 days/week.
MOA: Antimicrobial and anti-inflammatory effects.
- Effective in neutrophilic airway disease.
Efficacy in severe asthma (≥2 exacerbations/yr):
- May reduce exacerbation rate and oral steroid dose.
- May improve FEV1, asthma control, and quality of life.
Safety: Potential for antibiotic resistance, QTc prolongation, and hearing loss.
GINA recommendation: May add to high-dose ICS/LABA for a 6-week trial in those without markers of Th2 inflammation (eosinophilia).

Oral Corticosteroids

Oral Prednisone: Avoid long-term use due to side effects.
- Short term: Increased blood glucose levels, sodium and water retention, and elevation of blood pressure.
- Long term: Osteoporosis, cataracts, and thinning of the skin.
Maintenance treatment only in severe asthma.
For acute exacerbations:
- Onset occurs in 4-6 hours.
- Dosage: 40-50mg daily x 5-7 days.
- No need to taper if ICS continues.

Key Points

LTRAs are more effective in the elderly than in younger adults.
LTRAs may be a less effective option than low-dose ICS but may be desirable in elderly patients with poor inhaler technique.
Montelukast has modest bronchodilator efficacy; a SABA is required for acute symptom relief.
Theophylline can be added to ICS or ICS/LABA to improve symptoms if an inexpensive oral therapy is desired. Theophylline is not used routinely.
A LAMA (tiotropium) can be added to medium- or high-dose ICS/LABA to control symptoms (Step 4 or 5).
Omalizumab is indicated for severe allergic asthma with elevated IgE levels.
Mepolizumab & reslizumab inhibit IL-5; benralizumab inhibits IL-5Rα. All suppress eosinophils and are indicated for severe asthma (frequent exacerbations or OCS dependent).
Dupilumab inhibits IL-4 and IL-13, same indications as #7.
Tezepelumab inhibits TSLP, same indications as above, but the OCS-sparing effect is uncertain. Efficacy is independent of Th2 status.
Macrolides may reduce asthma attacks in severe asthma.
Prednisone is only recommended for short-term treatment of asthma attacks, not chronic use.

Goals of Asthma Management

Control symptoms.
Enable normal activities.
Maintain pulmonary function near normal.
Reduce risk.
- Prevent exacerbations.
- Avoid airway damage.
- Avoid adverse effects from medications.
- Prevent mortality.
Develop patient/clinician partnership.
- Using communication skills.
- Considering patient preferences.
Assess knowledge and skills for self-management.
- Health literacy.
Identify & reduce exposure to risk factors.
Assess, treat, and monitor.
Manage exacerbations.

Non-Pharmacological Strategies

Smoking cessation and tobacco avoidance.
Avoid occupational sensitizers.
Avoid known food allergens.
Allergen avoidance (if possible).
Encourage physical activity.
Guided self-management and written action plan.

The Control-Based Asthma Management Cycle

Assess:
- Symptoms.
- Exacerbations.
- Side effects.
- Lung function.
- Patient satisfaction.
- Alternative strategies.
- Inflammatory markers (Eosinophils in sputum, Exhaled FeNO).
- Confirmation of diagnosis if necessary.
- Symptom control & modifiable risk factors (including lung function).
- Comorbidities.
- Inhaler technique & adherence.
- Patient preferences and goals.
Treatment of modifiable risk factors and comorbidities.
Non-pharmacological strategies.
Asthma medications (adjust down/up between tracks).
Education and skills training.

Options for Initial Asthma Treatment

Infrequent asthma symptoms, e.g.,
Asthma symptoms or need for reliever twice a month or more
- Preferred INITIAL treatment (Track 1): As-needed low dose ICS-formoterol
- Alternative INITIAL treatment (Track 2): Low dose ICS with as-needed SABA. Consider likely adherence with daily ICS
Troublesome asthma symptoms most days; or waking due to asthma once a week or more, especially if any risk factors exist.
- Preferred INITIAL treatment (Track 1): Low dose ICS-formoterol maintenance and reliever therapy
- Alternative INITIAL treatment (Track 2): Low dose ICS-LABA with as needed SABA, OR Medium dose ICS with as needed SABA. Consider likely adherence with daily controller
Initial asthma presentation is with severely uncontrolled asthma, or with an acute exacerbation
- Preferred INITIAL treatment (Track 1): Medium dose ICS-formoterol maintenance and reliever therapy. A short course of OCS may also be needed
- Alternative INITIAL treatment (Track 2): Medium or high dose ICS-LABA with as needed SABA. Consider likely adherence with daily controller. A short course of OCS may also be needed. High dose ICS with as needed SABA is another option, but adherence is poor compared to ICS-LABA

Initial Asthma Treatment, continued

Before starting treatment:
- Record evidence of asthma diagnosis.
- Record level of symptom control and risk factors including lung function.
- Consider factors influencing choice of therapy.
- Ensure proper use of inhaler(s).
- Schedule a follow-up visit.
After starting treatment:
- Review patient’s response after 2-3 months (or earlier).
- Adjust treatment to achieve control.
- Check adherence and inhaler technique frequently.
- Step down once good control achieved for 3 months.

Selecting initial controller treatment in adults and adolescents with a diagnosis of asthma

First Assess:
- Confirmation of diagnosis
- Symptom control & modifiable risk factors (including lung function)
- Comorbidities
- Inhaler technique
- Patient preferences & goals
If:
- Daily symptoms, waking at night once a week or more and low lung function? Yes
  - Start With
    - Track 1 (preferred): Medium dose ICS-formoterol maintenance and reliever (MART) (Step 4)
    - Track 2: Medium/high dose ICS-LABA + as needed SABA (High dose ICS)
- Symptoms most days, or waking at night once a week or more? Yes
  - Start With
    - Track 1 (preferred): Low dose ICS-formoterol maintenance and reliever (MART) (Step 3)
    - Track 2: Low dose ICS-LABA + as needed SABA
- Symptoms twice a month or more? Yes
  - Start With
    - Track 1 (preferred): As-needed low dose ICS-formoterol (Step 2)
    - Track 2: Low dose ICS + as needed SABA
- Daily symptoms, waking at night once a week or more and low lung function? No, Symptoms most days, or waking at night once a week or more? No, Symptoms twice a month or more? No
  - Start With
    - Track 1 (preferred): As-needed low dose ICS-formoterol (Step 1)
    - Track 2: Take low dose ICS whenever SABA taken

Personalized management for adults and adolescents to control symptoms and minimize future risk

Controller & Preferred Reliever Track 1: Using ICS-formoterol as reliever reduces the risk of exacerbations compared with using SABA reliever
- Steps 1-2: As-needed low dose ICS-formoterol
- Step 3: Low dose maintenance ICS-formoterol
- Step 4: Medium dose maintenance ICS-formoterol
- Step 5: Add-on LAMA, Refer for assessment of phenotype. Consider high dose ICS-formoterol ± anti-IgE, anti-IL-5/5R, anti-IL4R, anti-TSLP
- Reliever: As needed low dose ICS-formoterol
Controller & Alternative Reliever Track 2: Before considering a regimen with SABA reliever, check if the patient is likely to be adherent with daily controller
- Step 1: Take ICS whenever SABA taken
- Step 2: Low dose maintenance ICS
- Step 3: Low dose maintenance ICS-LABA
- Step 4: Medium/high dose maintenance ICS-LABA
- Step 5: Add-on LAMA Refer for assessment of phenotype. Consider high dose maintenance ICS-LABA ± anti-IgE, anti-IL-5/5R, anti-IL4R, anti-TSLP
- Reliever: As needed SABA
Other options for either track
- Low dose ICS whenever SABA taken or daily LTRA or add HDM SLIT
- Medium dose ICS or add LTRA or add HDM SLIT
- Add LAMA or LTRA or HDM SLIT, or switch to high dose ICS
- Add azithromycin (adults) or LTRA. As a last resort consider adding low dose OCS, but consider S/E

Management of Very Mild and Mild Asthma- CTS 2021

Patient currently on PRN SABA OR no medication
- YES Does the patient have well-controlled asthma?
  - NO Is the patient at higher risk* for asthma exacerbation?
    - NOT at higher risk
      - All ages—stay on PRN SABA Or start daily ICS + PRN SABA** OR If ≥ 12 years of age, alternative additional option PRN bud/form**
    - YES, at higher risk*
      - All ages—stay daily ICS + PRN SABA OR If ≥ 12 years of age, alternative additional option PRN bud/form**
  - YES Does the patient have well-controlled asthma?
    - If ≥ 18 years of age + unable to take daily ICS or PRN bud/form, consider PRN ICS-SABA Review with patient • Optimize technique, • Trigger avoidance, and • Co-morbidities
- YES Does the patient have well-controlled asthma?
  - YES, at higher risk*
    - All ages—stay daily ICS + PRN SABA OR If ≥ 12 years of age and poor adherence despite substantial asthma education and support, start PRN bud/form instead of daily ICS + PRN SABA
  - YES Does the patient have well-controlled asthma?
    - If ≥ 18 years of age at higher risk* for asthma exacerbation And unable to take ICS + PRN SABA or PRN bud/form, consider PRN ICS-SABA
*Higher risk if patient had any of the following: 1) any history of previous severe asthma exacerbation requiring systemic steroids, ED visit or hospitalization 2) poorly-controlled asthma as per CTS criteria 3) overuse of SABA (≥2 inhalers of SABA in a yr) 4) current smoker
** Based on patient preference —the decision to switch from PRN SABA to daily ICS + PRN SABA or PRN bud/form is for those that want better asthma control and to decrease their risk of exacerbation

Reviewing response and adjusting treatment (GINA)

How often should asthma be reviewed?
- 1-3 months after treatment started, then every 3-12 months
- After an exacerbation, within 1 week
Stepping up asthma treatment
- Sustained step-up, for at least 2-3 months if asthma is poorly controlled
  - Important: first check for common causes (symptoms not due to asthma, incorrect inhaler technique, poor adherence)
Stepping down asthma treatment
- After good control is maintained for 3 months
- Aim to find each patient’s minimum effective dose that controls both symptoms and exacerbations
- Reducing ICS dose by 25–50% at 3-month intervals is feasible and safe for most patients
- Monitor

Options for stepping down asthma therapy

Step 5
- Current medication and dose: High dose ICS-LABA + prednisone
- Options for stepping down
  - Continue HD ICS-LABA, reduce OCS dose
  - Use sputum-guided approach ↓ OCS
  - Reduce the OCS or alternate day
  - Replace OCS with high-dose ICS
- Current medication and dose: High dose ICS-LABA + other agents
  - Options for stepping down
    - Refer for expert advice
Step 4
- Current medication and dose: Mod or high dose ICS-LABA Medium dose ICS-form as MART High dose ICS + second controller
- Options for stepping down
  - Reduce ICS component by 50%
  - Stopping LABA deterioration
  - Reduce to low dose ICS-form & continue low dose ICS-form as reliever
  - Reduce ICS dose by 50% and continue 2nd controller
Step 3
- Current medication and dose: Low dose ICS-LABA Low dose ICS-formoterol as MART Medium or high dose ICS
- Options for stepping down
  - Reduce ICS-LABA to once daily.
  - Stopping LABA deterioration.
  - Reduce low dose ICS-formoterol to once daily and continue as needed low dose ICS-form as reliever.
  - Reduce ICS dose by 50%
  - Adding LTRA may allow ICS dose to be stepped down.
Step 2
- Current medication and dose: Low dose ICS
- Options for stepping down
  - Once daily (budesonide, ciclesonide, mometasone)
  - ∆ to as needed low dose ICS-formoterol
  - ∆ to taking ICS whenever SABA is taken
- Current medication and dose: Low dose ICS or LTRA
- Options for stepping down
  - ∆ to as needed low dose ICS-formoterol. Complete cessation of ICS is not advised due to risk of SABA-only treatment.

Recall Case

A 70-year-old male with newly diagnosed asthma who has wheezing episodes 2 times per week and waking at night ≥ 2 /month should begin treatment.
- Initiate:
  - Track 1: low-dose ICS/formoterol PRN (preferred)
  - Track 2: low-dose ICS + SABA PRN (Step 2)
- Reassess and adjust: if uncontrolled
  - Track 1: low-dose ICS/formoterol BID + Symbicort PRN
  - Track 2: low-dose ICS/LABA + SABA PRN (Step 3) or medium dose ICS + SABA PRN
- Reassess after 3 months or earlier if necessary
Reassess and adjust: if uncontrolled
- Track 1: medium-dose ICS/formoterol BID + Symbicort PRN (Step 4)
- Track 2: medium-dose ICS/LABA + SABA PRN
If asthma remains uncontrolled:
- Track 1: Add LAMA in a separate inhaler (Step 5)
- Track 2: Add LAMA in a separate inhaler or switch to a triple inhaler
If asthma remains uncontrolled, refer to a specialist for consideration of biologic therapy based on biomarkers of inflammation.

Action Plan

Recognition of worsening symptoms
Instructions for increasing medications
Instructions for when to seek medical attention
to manage chronic worsening
- Increase controller for 2-3 months and reassess or
to manage acute worsening due to respiratory infection or trigger exposure
- Increase controller temporarily (7-14 days)

Acute Exacerbations

Increase usual reliever
- If ICS-formoterol: inc dose, max 8 puffs/day
- If SABA: increase dose as needed
- If relief lasts < 3 or 4 hrs, seek medical help
Increase controller x 1-2 weeks
- Maintenance therapy is PRN ICS- formoterol
  - Increase PRN doses up to 8 inhalations/day
- Maintenance and reliever ICS-formoterol (MART)
  - Continue maintenance, inc PRN doses (max 8/day)
- Maintenance ICS + SABA
  - Quadruple ICS dose
- Maintenance ICS-formoterol + SABA
  - Quadruple ICS-formoterol (ie, 4 puff bid)
- Maintenance ICS-LABA (Advair, Zenhale, Atectura) + SABA
  - Step up to higher strength ICA-LABA
  - Consider adding separate ICS inhaler to quadruple dose
  - If using fluticasone furoate-vilanterol 100/25 → 200/25
If treatment is ineffective over 48 hours:
- Prednisone 40 to 50 mg/day for 5 to 7 days
- Tapering not necessary if < 2 weeks of use

Recap of Therapeutic Principles in the Treatment of Adults and the Elderly

Select initial controller (based on symptom severity)
- Track 1 (ICS-formoterol PRN) is preferred. Or Track 2 (SABA PRN). LTRA if refusing ICS
Reassess in 2-3 months, adjust dose based on:
- symptoms, exacerbations and side effects
- aim for the lowest effective dose
Step down if well-controlled ≥ 3 months
An action plan is in place to manage loss of asthma control
- 25 to 50% reduction in ICS (ie, once daily)
- Stopping ICS is not recommended in adults
- Intermittent therapy if only symptomatic seasonally
Stepping up
- At any time, if not well-controlled on the existing therapy
- Use Track 1 or Track 2 recommendations, or switch between tracks
- Select the most appropriate step based on current symptoms
- Maintain dose until sustained control is achieved
Biologic therapies are available for severe asthma, specialist referral.
A written asthma action plan to manage exacerbations

Special Populations

Pregnancy
- ICS, β2-agonists, LTRA (montelukast), theophylline are not associated with fetal abnormalities
Rhinitis
- The majority of asthmatics have rhinitis
- 30% with rhinitis develop asthma
- Nasal steroid use improves asthma
GERD
- 3x more prevalent in asthmatics
Occupational asthma
- Avoid irritants
- Seek specialist care
ASA-induced asthma
- 28% of adults with asthma
- Avoid ASA
- Use LTRA
Elderly
- Goals of care as usual, but may lack self-management skills
- Decline in cognition, function & physiology
- More prone to S/E beta-agonists, ICS
- Comorbidities may Impair response
  - airway fibrosis (e.g., Asthma-COPD overlap), age-related decline in FEV1, ↓ Beta-2 response
  - Muscle weakness, arthritis, weak inspiration affected inhaler device
  - Difficulty with instructions, action plan decisions

Monitoring

Symptoms (green, yellow, red) www.asthmaactionplan.com, ginasthma.com, lung.ca
response to β2-agonist
peak expiratory flow in selected individuals
- poor perceivers, near fatal attack, nighttime sx only
adherence to treatment, inhaler technique
environmental control

Strategies to Avoid Triggers

Dust mites
- Encase mattress and pillows, launder bed linen in hot water remove carpeting where possible
Pet dander
- Remove pet from home or bedroom
Molds
- Use a HEPA filter to clean room air, Frequently vacuum furniture, Keep house humidity < 50%
Environment
- Avoid outdoor activity during high pollution or high pollen days, and avoid noxious fumes
Common cold
- Wash hands frequently, flu vaccination

Concepts in Asthma Education

Cognition
- What has to be learned and its importance, elicit shared goals
Beliefs
- That lead to adopting health behaviors
Attitudes
- Acquire a positive attitude, give encouragement/praise
Emotions
- Be a supportive resource- empathy, relieve what is threatening, provide information in small doses
Values
- Appeal to what a person believes to be right

Asthma Education

Prominent role for pharmacists
- understanding of the disease (cognition)
- treatment goals
- asthma triggers and avoidance strategies
- difference between “relievers” and “controllers”
- use of medications, including inhaler technique
- criteria for recognition of deterioration
- action plan for self-administered increases in therapy
- follow-up for monitoring purposes

Asthma in the Elderly

Lisa is 70-year-old female, diagnosed with asthma 1 year ago.
Meds: Budesonide 200 mcg 1 puff BID and salbutamol 2 puffs PRN (Track 2)
Sym: over last 3 months, uses salbutamol 2x/d on most days and prior to cold air exposure; exercise is limited by wheezing; sleep is interrupted at least 1/week
Plan: check inhaler technique, adherence, environmental control, asthma action plan and continue current therapy or
- Switch to Track 1: Symbicort 200/6 1 puff BID + Symbicort 200/6 PRN
- Identify and avoid environmental triggers
- Monitor symptoms over 2-3 months. If well controlled, attempt to lower ICS dose (100/6 BID or 200/6 daily + Symbicort PRN) or Symbicort PRN only
- Monitor use of reliever. Increased reliever use may require increased controller (e.g., increase to medium-dose ICS/formoterol or add a LAMA)

Summary

Consider the impact of aging on asthma
Aim for asthma control, assess regularly
Encourage environmental control
ICS-based treatment is the mainstay of therapy
- Track 1: Symptom-driven PRN ICS-containing controller therapy (budesonide/formoterol) for mild asthma (preferred). Step up therapy to maintenance and reliever (MART).
- Track 2: ICS + SABA PRN.
  - Mildest asthma- may take low-dose ICS with each SABA PRN dose*
  - Step up to low-dose maintenance ICS + SABA PRN.
  - If ineffective, add LABA to low-dose ICS before  ICS dose.
Once controlled, taper to the lowest effective dose (ie., no symptoms or exacerbations)
*Canadian guidelines permit SABA PRN alone in mildest asthma, where there is a low risk of exacerbation

Summary - Continued

LTRA monotherapy or add-on to ICS or ICS/LABA
Options for severe asthma, add-on therapy
- LAMA added to ICS-LABA (i.e., ICS-LABA+tiotropium, or triple therapy inhaler)
- Chronic macrolide added to maintenance therapies
Anti-IgE: Omalizumab for severe allergic asthma (↑ IgE)
Anti IL-5/ 5Rα : Mepolizumab, reslizumab/ benralizumab for severe eosinophilic asthma
Anti-IL-4Rα: Dupilumab for eosinophilic asthma or if OCS- dependent
Anti-TSLP: Tezepelumab for severe asthma regardless of Th2 status
Empower the patient
- Patient education & instructions for self-management of exacerbations

Summary - Continued

Evaluate the route of medication delivery, adherence, and safety
Monitor for progression of comorbidities that may mimic or worsen asthma or the patient’s ability to manage asthma.
Consider oral therapy options if inhaler technique is poor.
Adjust therapy if S/E occur due to ICS, Beta-agonists or muscarinic antagonists
Once controlled, taper to the lowest effective dose
Stopping ICS-containing therapy completely is not recommended