ADVERSE REACTIONS SECTION.

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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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.

BOXED WARNING SECTION.

WARNING: 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 FEV1 60% predicted or adults with FEV1 1.5 L. Because of the potential for severe bronchoconstriction, the use of Provocholine in patients with clinically apparent asthma or wheezing is not recommended [see Warnings and Precautions (5.1)].Emergency equipment and medication should be immediately available to treat acute respiratory distress. If severe bronchoconstriction occurs, reverse immediately with rapid-acting inhaled bronchodilator agent (-agonist) [see Warnings and Precautions (5.1)].If baseline spirometry is not performed or is measured inaccurately, the initial FEV1 may be underestimated. In this situation, decreases in FEV1 may not be detected after administration of escalating Provocholine doses, which may result in administration of unnecessary higher doses and an increased risk for excessive bronchoconstriction [see Warnings and Precautions (5.1)]. WARNING: SEVERE BRONCHOCONSTRICTIONSee full prescribing information for complete boxed warning.o Severe bronchoconstriction can result from Provocholine administration (including the lowest dose) (5.1)o Use of Provocholine is contraindicated in pediatric and adult patients with baseline FEV1 <60% predicted or adults with FEV1 <1.5 (5.1)o Use of Provocholine is not recommended in patients with clinically apparent asthma or wheezing (5.1)o If severe bronchoconstriction occurs, reverse immediately with rapid-acting inhaled bronchodilator agent(-Agonist) (5.1).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Methacholine chloride is cholinergic agonist. Bronchial smooth muscle contains significant parasympathetic (cholinergic) innervation. Methacholine chloride agonizes the muscarinic receptors which eventually induce bronchoconstriction.. 12.2 Pharmacodynamics. After oral inhalation of Provocholine, patients with asthma are more sensitive to Provocholine-induced bronchoconstriction than are healthy subjects. This difference in response is the pharmacological basis for Provocholine in the methacholine challenge test.. 12.3 Pharmacokinetics. There are no metabolic and pharmacokinetic data available on methacholine chloride.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Provocholine is contraindicated in the following: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 (adults). 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 (adults). Known hypersensitivity to methacholine chloride or other parasympathomimetic agents (4)Baseline FEV1 <60% predicted (adults or children) or <1.5 (adults) (4). Known hypersensitivity to methacholine chloride or other parasympathomimetic agents (4). Baseline FEV1 <60% predicted (adults or children) or <1.5 (adults) (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Methacholine chloride, the active ingredient of Provocholine, is parasympathomimetic (cholinergic) bronchoconstrictor agent. Provocholine (methacholine chloride) powder for solution is administered by oral inhalation.Chemically, methacholine chloride (the active ingredient) is 1-propanaminium, 2-(acetyloxy)-N,N,N,-trimethyl-, chloride. It is white to practically white deliquescent compound, soluble in water, alcohol and chloroform and insoluble in ether. Aqueous solutions are neutral to litmus.Methacholine chloride has an empirical formula of C8H18ClNO2, molecular weight of 195.69, and the following structural formula:Each vial of Provocholine contains 100 mg of methacholine chloride powder.. structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Provocholine is potent bronchoconstrictor. Do not inhale the powder. Do not handle this material if you have asthma or hay fever(2.1). The methacholine challenge test should be conducted in pulmonary function laboratory or clinic, by adequately trained personnel, for safety and accuracy (2.2)Determine baseline FEV1 values to assess whether patient is able to undergo the methacholine challenge test (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 (2.3, 2.4)See the Full Prescribing Information for the required reconstitution and dilution procedures prior to use (2.5)See the Full Prescribing Information for the calculation and interpretation of the results (2.6). Provocholine is potent bronchoconstrictor. Do not inhale the powder. Do not handle this material if you have asthma or hay fever(2.1). The methacholine challenge test should be conducted in pulmonary function laboratory or clinic, by adequately trained personnel, for safety and accuracy (2.2). Determine baseline FEV1 values to assess whether patient is able to undergo the methacholine challenge test (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 (2.3, 2.4). See the Full Prescribing Information for the required reconstitution and dilution procedures prior to use (2.5). See the Full Prescribing Information for the calculation and interpretation of the results (2.6).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Beta-Adrenergic BlockersThe use of beta-adrenergic blockers may impair reversal of Provocholine-caused bronchoconstriction.Beta-Agonists, Anticholinergics, and TheophyllineBeta-agonists, anticholinergics, and theophylline inhibit the response of airways to Provocholine; therefore, hold these drugs before Provocholine use for the following duration:o Short-acting -agonists (e.g., albuterol): hourso Long-acting -agonists (e.g., salmeterol): 36 hourso Short-acting anti-cholinergics (e.g., ipratropium): 12 hourso Long-acting anti-cholinergics (e.g., tiotropium): >=168 hourso Oral theophylline: 12-48 hoursOral or Inhaled Corticosteroids, and Inhaled CromoglycateRegular 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). 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).

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. How SuppliedProvocholine (methacholine chloride) powder for solution: in amber glass vials that contain 100 mg of methacholine chloride powder, white to off-white in color. Cartons have vials (NDC 64281-100-06).Storage and HandlingPowder for solution: Store the supplied powder at 59oF to 86oF (15oC to 30oC). Refrigerate the reconstituted and diluted solutions at 36oF to 46oF (2oC to 8oC) for up to weeks [see Dosage and Administration (2.5)].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Provocholine, used in 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, cholinergic agonist used in 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).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Risk of Severe BronchoconstrictionInform the patient or caregiver that severe bronchoconstriction can result from Provocholine administration [see Warnings and Precautions (5.1)].Cough, Chest Tightness, or Shortness of BreathInform the patient or caregiver that Provocholine may produce mild cough, chest tightness or shortness of breath.Distributed by Methapharm, Inc. Coral Springs, FL 33065.For more information visit www.provocholine.com, email salesmethapharm.com or call 1-833-887-7686. (R)Provocholine is registered trademark of Methapharm Inc.Revision: December 2020. methapharm.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThe available data from published literature on Provocholine use in pregnant women are insufficient to evaluate for drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal reproduction studies evaluating effects of methacholine chloride on embryofetal development have not been conducted. Diagnosis of bronchial airway hyperreactivity with bronchoprovocation challenge is not recommended for pregnant women because of the potential for hypoxia in the fetus. If bronchial airway hyperreactivity is suspected, consider trial of empiric treatment.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the United States general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.

SPL UNCLASSIFIED SECTION.

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 FEV1 60% predicted or adults with FEV1 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 rapid-acting inhaled -agonist.If baseline spirometry is not performed or is measured inaccurately, the initial FEV1 may be underestimated. In this situation, decreases in FEV1 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Provocholine is not recommended (8.1) 8.1 Pregnancy. Risk SummaryThe available data from published literature on Provocholine use in pregnant women are insufficient to evaluate for drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal reproduction studies evaluating effects of methacholine chloride on embryofetal development have not been conducted. Diagnosis of bronchial airway hyperreactivity with bronchoprovocation challenge is not recommended for pregnant women because of the potential for hypoxia in the fetus. If bronchial airway hyperreactivity is suspected, consider trial of empiric treatment.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the United States general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. 8.2 Lactation. Risk SummaryThere are no available data on the presence of methacholine chloride in human milk, the effect on the breastfed infant, or the effect on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Provocholine and any potential adverse effects on the breastfed infant from Provocholine or from the underlying maternal condition.. 8.4 Pediatric Use. Provocholine is used in methacholine challenge test for the diagnosis of bronchial airway hyperreactivity in pediatric patients years of age and older who do not have clinically apparent asthma. The safety and effectiveness of Provocholine have not been established in pediatric patients below the age of years.. 8.5 Geriatric Use. The diagnosis of bronchial airway hyperreactivity is largely performed in pediatric and younger adult patients. Clinical studies of Provocholine did not include patients 65 years of age or older.

WARNINGS AND PRECAUTIONS SECTION.

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 FEV1 60% predicted or adults with FEV1 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 rapid-acting inhaled -agonist.If baseline spirometry is not performed or is measured inaccurately, the initial FEV1 may be underestimated. In this situation, decreases in FEV1 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 (after reconstitution and/or dilution) may cause bronchoconstriction in healthcare providers administering Provocholine in 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 powderDo not handle the Provocholine powder if you have asthma or hay fever.Apply low resistance filter to expiratory ports of dosing apparatus, as necessary, to prevent Provocholine release in the room air. Do not inhale the supplied Provocholine powder. Do not handle the Provocholine powder if you have asthma or hay fever.. Apply 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 cholinergic agent should undergo methacholine challenge only if the healthcare practitioner considers the benefit to the individual outweighs the potential risks.