Methacholine

12.1 Mechanism of Action Methacholine chloride is a cholinergic agonist. Bronchial smooth muscle contains significant parasympathetic (cholinergic) innervation. Methacholine chloride agonizes the muscarinic receptors which eventually induce bronchoconstriction.

1 INDICATIONS AND USAGE Provocholine, used in a methacholine challenge test, is indicated for the diagnosis of bronchial airway hyperreactivity in adults and pediatric patients five years of age and older who do not have clinically apparent asthma. Provocholine, a cholinergic agonist used in a methacholine challenge test, is indicated for the diagnosis of bronchial airway hyperreactivity in adults and pediatric patients five years of age and older who do not have clinically apparent asthma (1)

2 DOSAGE AND ADMINISTRATION The methacholine challenge test should be conducted in a pulmonary function laboratory or clinic, by adequately trained personnel, for safety and accuracy (2.1) Determine baseline FEV1 values to assess whether a patient is able to undergo the methacholine challenge test (2.1) Recommended dosage(s) of Provocholine in the Methacholine Challenge Test is administration of increasing concentrations of Provocholine solution via nebulization (2.2) Administer using either the 5-Breath Dosimeter Dosing Method or the 2-Minute Tidal Breathing Dosing Method with the doubling or quadrupling stepwise protocols (2.4, 2.5) See the Full Prescribing Information for the required reconstitution and dilution procedures prior to use (2.3) See the Full Prescribing Information for the calculation and interpretation of the results (2.6) 2.1 Methacholine Challenge Test Overview Provocholine should be administered in a methacholine challenge test in a pulmonary function laboratory or clinic, by adequately trained personnel, for safety and accuracy, and should be performed only under the responsibility of a healthcare practitioner trained in and thoroughly familiar with all aspects of the technique of the test and the management of respiratory distress. Emergency medication and equipment should be immediately available to treat acute respiratory distress. Only consider Provocholine use in patients on chronic asthma drugs if the accuracy of the asthma diagnosis is in doubt. In these patients, only administer Provocholine if spirometry is normal after supervised withdrawal of the asthma drugs. Provocholine is not recommended for use in patients with clinically apparent asthma or wheezing. Before starting a methacholine challenge test, baseline spirometry must be performed. For a patient to be able to undergo the test, he or she must present with baseline FEV1 (Forced Expiratory Volume in 1 second) greater than or equal to 60% of the predicted value (in adults and children) and greater than or equal to 1.5 L (in adults). Do not use Provocholine in pediatric and adult patients with baseline FEV1 < 60% predicted or in adults with FEV1 < 1.5 L [ see Contraindications (4) and Warnings and Precautions (5.1) ]. At commencement of the methacholine challenge test and prior to nebulization with Provocholine dose(s), FEV1 must be measured following exposure to nebulized diluent or base solution (contains no methacholine chloride) to obtain the post-diluent FEV1 [ see Dosage and Administration (2.4, 2.5) ]. Provocholine powder for inhalation solution requires reconstitution and dilution before use ( see Reconstitution and Dilution Prior to Administration (2.3) ). Provocholine inhalation solution (in a ready-to-use kit) does not require reconstitution and/or dilution. Administer Provocholine by oral inhalation using either the 5-Breath Dosimeter Dosing Method or the 2-Minute Tidal Breathing Dosing Method with the doubling or quadrupling stepwise protocols [ see Dosage and Administration (2.4, 2.5) ]. Discard any unused solution from the nebulizer after each administration. May use Provocholine with or without meals. The methacholine challenge test is considered positive if there is a reduction in FEV1 of 20% or more from post-diluent FEV1. The test should be stopped at this point. The reduction value must be calculated and recorded before starting the test with Provocholine ( see Calculation and Interpretation of Methacholine Challenge Test Results (2.6) ). An inhaled β agonist must be administered after a methacholine challenge test with Provocholine to expedite the return of the FEV1 to baseline and to relieve any discomfort of the subject. Most patients revert to normal pulmonary function within 10 to 20 minutes following administration of a β agonist.

6 ADVERSE REACTIONS The following adverse reactions associated with the use of Provocholine were identified in clinical studies or post marketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Bronchospasm (includes symptoms such as chest tightness, cough or wheezing). Adverse reactions less commonly associated with Provocholine include headache, throat irritation, light-headedness and itching. Adverse reactions associated with Provocholine include headache, throat irritation, light-headedness and itching (6) To report SUSPECTED ADVERSE REACTIONS, contact Methapharm at 1-866-701-4636 or call FDA at 1-800-FDA-1088 or visit www.fda.gov/medwatch

7 DRUG INTERACTIONS Beta-Adrenergic Blockers The use of beta-adrenergic blockers may impair reversal of Provocholine-caused bronchoconstriction. Beta-Agonists, Anticholinergics, and Theophylline Beta-agonists, anticholinergics, and theophylline inhibit the response of airways to Provocholine; therefore, hold these drugs before Provocholine use for the following duration: • Short-acting β-agonists (e.g., albuterol): 6 hours • Long-acting β-agonists (e.g., salmeterol): 36 hours • Short-acting anti-cholinergics (e.g., ipratropium): 12 hours • Long-acting anti-cholinergics (e.g., tiotropium): ≥168 hours • Oral theophylline: 12-48 hours Oral or Inhaled Corticosteroids, and Inhaled Cromoglycate Regular use of oral or inhaled corticosteroids and inhaled cromoglycate may acutely decrease bronchial responsiveness to Provocholine. However, these drugs may be continued with Provocholine use. Beta-Adrenergic Blockers : May impair reversal of Provocholine-caused bronchoconstriction (7) Beta-Agonists, Anticholinergics, and Theophylline : Inhibit response to Provocholine; therefore, hold these drugs prior to Provocholine use (7) Oral or Inhaled Corticosteroids, and Inhaled Cromyoglycate : May decrease response to Provocholine (7)