methacholine inhaled (Rx)

Frequency Not Defined

Bronchospasm, includes symptoms such as chest tightness, cough, or wheezing

Adverse reactions less commonly associated include headache, throat irritation, light-headedness, and itching

Contraindications

Hypersensitivity to methacholine or other parasympathomimetic agents; reactions have included rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing

Baseline FEV1 <60% predicted (adults or pediatric patients) or <1.5 L (adults)

Cautions

Severe bronchoconstriction can result from methacholine administration (including the lowest dose); see Black Box Warnings

Risk to clinicians administering test

• Supplied powder or nebulized aerosol may cause bronchoconstriction in healthcare providers administering the test

• Precautionary steps include

  • Do not inhale the supplied methacholine powder
  • Do not handle powder with history or asthma or hay fever
  • Apply a low resistance filter to expiratory ports of dosing apparatus, as necessary, to prevent release in room air

Coexisting diseases and conditions

• Not recommended for patients with uncontrolled hypertension, aortic aneurysm, or history of myocardial infarction or stroke diseases
• Patients with epilepsy, vagotonia, peptic ulcer disease, thyroid disease, urinary tract obstruction or other condition that could be adversely affected by a cholinergic agent should undergo methacholine challenge only if benefits to the individual outweighs potential risks

Drug interaction overview

• Beta-adrenergic blockers

  • Beta-adrenergic blockers may impair reversal of methacholine-caused bronchoconstriction by inhaled beta-agonists

• Beta-agonists, anticholinergics, and theophylline

  • These drugs inhibit the response of airways to methacholine
  • Hold before methacholine challenge test for the following duration:
  • Short-acting beta-agonists (eg, albuterol): 6 hr
  • Long-acting beta-agonists (eg, salmeterol): 36 hr
  • Short-acting anticholinergics (eg, ipratropium): 12 hr
  • Long-acting anticholinergics (eg, tiotropium): ≥168 hr
  • Oral theophylline: 12-48 hr

• Oral or inhaled corticosteroids, and inhaled cromoglycates

  • Regular use of oral or inhaled corticosteroids and inhaled cromoglycates (eg, cromolyn sodium, nedocromil) may acutely decrease bronchial responsiveness to methacholine
  • However, these drugs may be continued with methacholine use

Pregnancy

Data regarding use in pregnant females are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes

Animal reproduction studies have not been conducted

Clinical considerations

• Diagnosis of bronchial airway hyperreactivity with broncho-provocation challenge is not recommended during pregnancy because of the potential for hypoxia in the fetus
• If bronchial airway hyperreactivity suspected, consider trial of empiric treatment

Lactation

Data are not available regarding the presence of methacholine in human milk, effect on breastfed infants, or effect on milk production

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Cholinergic agonist

Bronchial smooth muscle contains significant parasympathetic (cholinergic) innervation

Methacholine agonizes muscarinic receptors, which eventually induce bronchoconstriction

Inhalation Preparation

Powder

• Reconstitution

  • Add 6.25 mL of 0.9% NaCl or 0.9% NaCl with 0.4% phenol to supplied vials containing 100 mg of powder
  • Shake vial to obtain a clear solution

• Dilute reconstituted solution

  • Using sterile, empty USP Type 1 borosilicate glass vials, dilute reconstituted solution with 0.9% NaCl or 0.9% NaCl with 0.4% phenol either by doubling the concentration or quadrupling the concentration (see prescribing information for chart)
  • After adding diluent, shake each vial to obtain a clear solution
  • Use the same diluent to prepare all concentrations
  • Use a sterile bacterial-retentive filter (porosity 0.22 μm) when transferring reconstituted or diluted solution from each vial (at least 2 mL) to a nebulizer
  • Refrigerate reconstituted and diluted solutions at 36-46ºF (2-8ºC) for up to 2 weeks
  • Since solution temperature affects nebulizer output, remove solutions from refrigerator and allowed to equilibrate to room temperature (~30 minutes) before use

Add diluent or base solution to nebulizer to obtain post-diluent FEV1 value

• Used to obtain a baseline FEV1

• Powder for inhalation solution

  • Using 3-mL syringe and needle, draw up 2-3 mL of same diluent used to reconstitute powder (0.9% NaCl or 0.9% NaCl with 0.4% phenol) and dispense into nebulizer using a sterile bacterial-retentive filter (porosity 0.22 μm)

• Ready-to-use solution

  • Dispense the contents of a vial containing the base solution (contains no methacholine) into nebulizer

Add methacholine to nebulizer for challenge test

• Used for actual methacholine challenge test

• Powder for inhalation solution

  • Using a 3-mL syringe and needle, draw up recommended methacholine concentration that was prepared using either the doubling or quadrupling dose method and dispense into the nebulizer using a sterile bacterial-retentive filter (porosity 0.22 μm)

• Ready-to-use solution

  • Dispense contents of a vial of the appropriate methacholine concentration, starting with the lowest dose, into the nebulizer
  • Ready-to-use solution concentrations: 0.0625 mg/mL, 0.25 mg/mL, 1 mg/mL, 4 mg/mL, and 16 mg/mL
  • No further dilution required

Inhalation Administration

Before starting a challenge test, baseline spirometry must be performed; for a patient to be able to undergo the test, he or she must present with baseline FEV 1 (Forced Expiratory Volume in 1 second) ≥60% of predicted value (in adults and children) and ≥1.5 L (in adults)

At commencement of methacholine challenge test and prior to nebulization, FEV 1 must be measured following exposure to nebulized diluent or base solution (contains no methacholine chloride) to obtain the post-diluent FEV1

Post diluent FEV1

• Instruct patient to relax and breathe the aerosol quietly (tidal breathing) for 2 minutes of inhalation time
• Place nebulizer facemask loosely over nose and mouth or the mouthpiece in the mouth (with a nose clip) of the patient; hold nebulizer to avoid warming the solution
• Keep nebulizer upright and vertical
• Start nebulizer by adjusting flow meter so that nebulizer is operating at calibrated output (0.13 mL/minute for the English Wright nebulizer)
• Start stopwatch immediately
• After exactly 2 minutes, turn off the flow meter, remove facemask (or mouthpiece) and discard any remaining solution
• Perform spirometry and measure the FEV1 30 and 90 seconds after end of the inhalation to obtain the post-diluent FEV1
• These values may be left at ambient (spirometer) temperature pressure saturated (ATPS). If the FEV1 value is not of acceptable quality, repeat the procedure
• If the post-diluent FEV1 falls by ≥20% from baseline FEV1, do not give further inhalations and proceed to administer inhaled beta-agonist to expedite return of FEV1 to within 90% of baseline and relive any discomfort
• If the post-diluent FEV1 falls by <20% from baseline FEV1, continue to methacholine challenge test

Methacholine challenge test

• Repeat above steps for each methacholine dose, emptying the nebulizer between each dose
• Stop dosing if FEV1 falls by ≥20% from the post-diluent FEV1 or the highest methacholine concentration (16 mg/mL) has been administered (whichever comes first)
• Do not administer additional methacholine doses if severe bronchoconstriction occurs
• At end of test, administer inhaled beta-agonist to expedite return of FEV1 to within 90% of baseline and relive any discomfort

Storage

Inhalation solution kit

• Powder for reconstitution and dilution
• Store at 59-86ºF (15-30ºC)

• Reconstituted and diluted solutions

  • Refrigerate 36-46ºF (2-8ºC) for up to 2 weeks

Inhalation solution, ready-to-use

• Store at 59-86ºF (15-30ºC)