Methacholine

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)

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.

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 Preparation and Administration Overview Provocholine powder for inhalation solution requires reconstitution and dilution prior to use [see Dosage and Administration (2.2)]. Provocholine inhalation solution in a ready-to-use kit does not require reconstitution and/ or silution prior to use. Provocholine inhalation solution 16 mg/mL in a single-dose vial requires dilution prior to use [see Dosage and Administration (2.2)] . For safety and accuracy, administer Provocholine during 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. 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 FEV 1 (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). Provocholine is contraindicated in adult and pediatric patients with baseline FEV1 < 60% predicted or in adults with FEV 1 < 1.5 L [see Contraindications (4) and Warnings and Precautions (5.1)]. At commencement of the methacholine challenge test and prior to administration of Provocholine, a post-diluent FEV 1 must be measured following nebulization of the diluent or base solution (contains no methacholine chloride) [ see Dosage and Administration (2.4, 2.5)]. Administer Provocholine by oral inhalation, with or without food, using either the 5-Breath Dosimeter Dosing Method or the 1-Minute Tidal Breathing Dosing Method with the dose doubling or quadrupling protocols [see Dosage and Administration (2.3, 2.4, 2.5)]. Discard any unused solution from the nebulizer after each administration. The methacholine challenge test is considered positive if there is a reduction of FEV 1 of 20% or more from the post-diluent FEV 1 . The test should be stopped at this point. Calculate and record the FEV 1 reduction value before starting the test [see Dosage and Administration (2.3, 2.4, 2.5)]. After the methacholine challenge test with Provocholine, administer an inhaled β-agonist to expedite the return of the FEV 1 to baseline and to relieve any discomfort the patient may experience. Most patients revert to normal pulmonary function within 10 to 20 minutes following administration of an inhaled β-agonist [see Dosage and Administration (2.6)]. 2.2 Reconstitution and/or Dilution Instructions for Provocholine Powder for Inhalation Solu

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. Respiratory System: Bronchospasm (includes symptoms such as chest tightness, cough or wheezing). Less Common Adverse Reactions: 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

5 WARNINGS AND PRECAUTIONS . Healthcare provider and any other personnel involved in the administration of the methacholine challenge test should take precautions to minimize inhalation of Provocholine powder and nebulized aerosol (5.2) 5.1 Risk of Severe Bronchoconstriction Severe bronchoconstriction can result from Provocholine administration (including the lowest dose). The use of Provocholine is contraindicated in pediatric and adult patients with baseline FEV 1 < 60% predicted or adults with FEV 1 < 1.5 L. Emergency equipment and medication should be immediately available to treat acute respiratory distress. Because of the potential for severe bronchoconstriction, the use of Provocholine in patients with clinically apparent asthma or wheezing is not recommended. If severe bronchoconstriction occurs, reverse immediately by the administration of a rapid-acting inhaled β-agonist. If baseline spirometry is not performed or is measured inaccurately, the initial FEV 1 may be underestimated. In this situation, decreases in FEV 1 may not be detected after escalating Provocholine doses, which may result in administration of unnecessary higher doses and an increase in the risk for excessive bronchoconstriction. 5.2 Risks to Healthcare Providers Administering Provocholine The supplied Provocholine powder or the Provocholine nebulized aerosol may cause bronchoconstriction in healthcare providers administering Provocholine in a methacholine challenge test. Healthcare providers and any other personnel involved in the administration of Provocholine should take the following precautionary steps: Do not inhale the supplied Provocholine powder Do not handle the Provocholine powder if you have asthma or hay fever. Apply a low resistance filter to expiratory ports of dosing apparatus, as necessary, to prevent Provocholine release in the room air 5.3 Coexisting Diseases and Conditions Provocholine is 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 the healthcare practitioner considers the benefit to the individual outweighs the potential risks.

4 CONTRAINDICATIONS Provocholine is contraindicated in patients with: Hypersensitivity to methacholine or other parasympathomimetic agents. Reactions have included rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing. Baseline FEV 1 < 60% predicted (adults or pediatric patients) or <1.5 L (adults) Known hypersensitivity to methacholine chloride or other parasympathomimetic agents (4) Baseline FEV 1 <60% predicted (adults or children) or <1.5 L (adults) (4)