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Brand Name
Provocholine
Generic Name
Methacholine
View Brand Information FDA approval date: March 27, 2013
Classification: Cholinergic Receptor Agonist
Form: Kit, Powder
What is Provocholine (Methacholine)?
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.
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Related Clinical Trials
Body Composition Related Evaluation of Airway Tone and Hyper-rEactivity Using Oscillometry
Summary: This study will determine if airway resistance to airflow and pressure, measured by Oscillometry, is associated with abnormal findings on methacholine challenge testing and whether these findings are associated with body habitus,
A Multi-center Study Examining Bronchial Hyperresponsiveness in Primary Ciliary Dyskinesia
Summary: The purpose of this study is to look at children with PCD and see if they have another condition called bronchial hyperresponsiveness.
A Phase 1, Randomized, 2-part, 7-way Cross-over (Part 1) and 7-way Cross-over (Part 2), Blinded, Single Dose Study in Mild Asthmatics Aged 18-65 to Assess the Relative Potency of Salbutamol Administered Via Metered Dose Inhalers Containing Propellants HFA-152a (Test) and HFA-134a (Reference) Via Methacholine Bronchoprovocation and Systemic Pharmacodynamic Effects
Summary: The primary objectives of the study are: Part 1: to characterize the potency and variability of dose response on efficacy (Provocative concentration of methacholine causing at least a 20% fall in forced expiratory volume (FEV1) \[PC20\]) of salbutamol administered via MDI with salbutamol HFA-134a or salbutamol HFA-152a in participants with mild asthma. Part 2: to compare the comparative dose respo...
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Brand Information
Provocholine (methacholine chloride)
WARNING: SEVERE BRONCHOCONSTRICTION
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 [
Emergency equipment and medication should be immediately available to treat acute respiratory distress. If severe bronchoconstriction occurs, reverse immediately with a rapid-acting inhaled bronchodilator agent (β-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 administration of escalating Provocholine doses, which may result in administration of unnecessary higher doses and an increased risk for excessive bronchoconstriction [
1INDICATIONS 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.
2DOSAGE AND ADMINISTRATION
.
2.1Preparation and Administration Overview
- Provocholine powder for inhalation solution requires reconstitution and dilution prior to use
- 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
- 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
- Provocholine is contraindicated in adult and pediatric patients with baseline FEV1 < 60% predicted or in adults with FEV
- At commencement of the methacholine challenge test and prior to administration of Provocholine, a post-diluent FEV
- 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
- Discard any unused solution from the nebulizer after each administration.
- The methacholine challenge test is considered positive if there is a reduction of FEV
- After the methacholine challenge test with Provocholine, administer an inhaled β-agonist to expedite the return of the FEV
2.2Reconstitution and/or Dilution Instructions for Provocholine Powder for Inhalation Solution and Provocholine Inhalation Solution 16 mg/mL (in Single-Dose Vial)
Reconstitution and Dilution of Provocholine Powder for Inhalation Solution
- Reconstitute Provocholine Powder for Inhalation Solution by adding 6.25 mL of 0.9% Sodium Chloride Injection to the supplied vial(s) containing 100 mg of Provocholine powder. Shake the vial to obtain a clear solution.
- Dilute the reconstituted Provocholine solution, using sterile, empty USP Type 1 borosilicate glass vials. Dilute the reconstituted Provocholine solution with 0.9% Sodium Chloride Injection based on Table 1 to obtain doubling strengths or Table 2 to obtain quadrupling strengths. After adding the 0.9% Sodium Chloride Injection, shake each vial to obtain a clear solution.
- If not used immediately, refrigerate the reconstituted and diluted solutions at 36°F to 46°F (2°C to 8°C) for up to 2 weeks. Since the temperature of the solution affects nebulizer output, take the diluted solutions out of the refrigerator and allow them to equilibrate to room temperature (approximately 30 minutes) before use.
Dilution of Provocholine Inhalation Solution 16 mg/mL (in a Single-Dose Vial)
- Transfer the contents of the specified number of 3 mL vials (as per Tables 3 or 4) of Provocholine inhalation solution 16 mg/mL (in Single-Dose Vial) into a sterile, empty USP Type 1 borosilicate glass vial. Swirl the glass vial gently to mix.
- Dilute the solution with 0.9% Sodium Chloride Injection based on Table 3 (to obtain doubling strengths) or Table 4 (to obtain quadrupling strengths). After adding 0.9% Sodium Chloride Injection, shake each vial to obtain a clear solution.
- If not used immediately, refrigerate the diluted solutions at 36oF to 46oF (2oC to 8oC) for up to 2 weeks. Since the temperature of the solution affects nebulizer output, take the diluted solutions out of the refrigerator and allow them to equilibrate to room temperature (approximately 30 minutes) before use.
2.3Recommended Provocholine Doses for Methacholine Challenge Test
The recommended doses of Provocholine for oral inhalation for the diagnosis of bronchial airway hyperreactivity in adults and pediatric patients five years of age and older during a methacholine challenge test, based on the dose doubling or quadrupling protocol, are provided in Table 5.
*Provocholine dose was based on the Hudson RCI® MicroMist® Small Volume Nebulizer using dry compressed air to power the nebulizer with a pressure regulator set to 50 lb/in
2.4Determination of Post-Diluent FEV1 and Administration of Provocholine Using the 5-Breath Dosimeter Dosing Method
Determination of Post-Diluent FEV
Prior to administration of Provocholine, determine thepost-diluent FEV
- Instill diluent (sterile 0.9% Sodium Chloride Injection) or base solution into the nebulizer.
- If using Provocholine powder for inhalation solution or Provocholine inhalation solution 16 mg/mL (in single-dose vial), using a 3 mL syringe and needle, draw up 2 to 3 mL of diluent (sterile 0.9% Sodium Chloride Injection), and instill the 0.9% Sodium Chloride Injection into the nebulizer using a sterile bacterial-retentive filter (porosity 0.22 μm).
- If using the Provocholine inhalation solution ready-to-use kit, instill the contents of the base solution (contains no methacholine chloride) into the nebulizer.
2. Instruct the patient to hold the nebulizer upright with the mouthpiece in his/her mouth. The patient should wear a nose clip while inhaling from the nebulizer.
3. At the end of exhalation during tidal breathing (functional residual capacity), instruct the patient to inhale slowly and deeply through the mouthpiece. Trigger the dosimeter soon after oral inhalation begins. Encourage the patient to continue inhaling slowly (about 5 seconds to complete the inhalation) and to hold the breath at total lung capacity (TLC) for another 5 seconds.
4. Repeat Step 3 for a total of five inspiratory capacity inhalations. Take no more than 2 minutes to perform these 5 inhalations.
- If the FEV
- If the post-diluent FEV
- If the post-diluent FEV
Administer of Provocholine Using the 5-Breath Dosimeter Dosing Method
6. Instill Provocholine solution into the nebulizer
- If using Provocholine powder for inhalation solution or Provocholine inhalation solution 16 mg/mL (in single-dose vial), using a 3 mL syringe and needle, draw up at least 2 mL of the recommended Provocholine strength based on the dose doubling or quadrupling protocol in Table 5
- If using the Provocholine inhalation solution ready-to-use kit, instill at least 2 mL of the recommended Provocholine strength based on the dose quadrupling protocol in Table 5
7. Repeat Steps 2 through 5 for each Provocholine strength, emptying the nebulizer between each strength. To keep the cumulative effect of Provocholine relatively constant, the time interval between the end of one strength and beginning of the subsequent strength should not be more than 5 minutes.
8. Stop dosing if the FEV
9. Wash and clean reusable nebulizers thoroughly according to manufacturer's recommendations.
2.5Determination of Post-Diluent FEV and Administration of Provocholine Using the 1-Minute Tidal Breathing Dosing Method
Determination of Post-Diluent FEV
Prior to administration of Provocholine, determine the post-diluent FEV
- Instill diluent (sterile 0.9% Sodium Chloride Injection) or base solution into the nebulizer.
- If using Provocholine powder for inhalation solution or Provocholine inhalation solution 16 mg/mL (in single-dose vial), using a 3 mL syringe and needle, draw up 2 to 3 mL of diluent (sterile 0.9% Sodium Chloride Injection). Instill the 0.9% Sodium Chloride Injection into the nebulizer using a sterile bacterial-retentive filter (porosity 0.22 μm). Attach the nebulizer and necessary tubing to the dry compressed air source.
- If using the Provocholine inhalation solution ready-to-use kit, instill the contents of the base solution (contains no methacholine chloride) into the nebulizer.
2. Place the face mask loosely over the nose and mouth or the mouthpiece in the mouth (with a nose clip) of the patient. Instruct the patient to hold the nebulizer to avoid warming the solution. Keep the nebulizer upright and vertical.
- If the FEV
- If the post-diluent FEV
- If the post-diluent FEV
Administration of Provocholine Using the 1-Minute Tidal Breathing Dosing Method
7. Instill Provocholine solution into the nebulizer.
7. Instill Provocholine solution into the nebulizer.
- If using Provocholine powder for inhalation solution or Provocholine inhalation solution 16 mg/mL (in single-dose vial), using a 3 mL syringe and needle, draw up at least 2 mL of the recommended Provocholine strength based on the dose doubling or quadrupling protocol in Table 5
- If using the Provocholine inhalation solution ready-to-use kit, instill at least 2 mL of the recommended Provocholine strength, based on the dose quadrupling protocol in Table 5
8. Repeat steps 2 through 6 for each Provocholine strength, emptying the nebulizer between each strength or dose.
2.6Recommended Administration of Inhaled β-agonist after Methacholine Challenge Test
After the methacholine challenge test is completed, administer an inhaled β-agonist to the patient to expedite the return of the FEV1 to within 90% of baseline and to relieve any discomfort (the majority of patients revert to normal pulmonary function within 10 to 20 minutes after β-agonist administration; in contrast the majority of patients revert to normal pulmonary function within 30-45 minutes without β-agonist administration). Wait 10 minutes and measure the FEV1 and Vital Capacity. Do not allow patients to leave the laboratory or clinic until their FEV1 has returned to within 90% of baseline.
2.7Calculation and Interpretation of Methacholine Challenge Test Results
Positive Methacholine Challenge Test
A positive methacholine challenge test is a ≥ 20% reduction in the FEV
Calculation of PC
1. Determine the percent decrease [was fall] in FEV1 using the mean post-diluent FEV 1 and the lowest FEV 1 post-Provocholine (post-dose), as shown below: :
% fall in FEV 1= mean post-diluent FEV x 100
mean post-diluent FEV 1
2. Calculate PC
Method #1: Plot the percent decrease in FEV 1against the increasing methacholine concentration using a log scale and obtain the PC 20by linear interpolation between the last two points, as shown in Figure 1.
Method #2: Calculate the PC
PC 20= antilog [log C1+ (log C2 - log C1)(20 - R1)]
(R2- R1)
Where:
Calculation of PD
Calculate the PD 20as follows:
PD 20= antilog [log D1+ (log D2 - log D1)(20 - R1)]
(R2- R1)
Where:
Negative Methacholine Challenge Test
A negative (normal) methacholine challenge result is defined as FEV 1reduction of < 20% after all the doses, as part of the dose doubling or quadrupling protocol in Table 5, have been administered [ See Dosage and Administration (2.3)]
3DOSAGE FORMS AND STRENGTHS
• For inhalation solution: 100 mg of methacholine chloride crystalline powder, white to off-white in color in amber glass vials (powder is reconstituted and then diluted prior to administration)
• Inhalation solution ready-to-use (sterile): Contain the following strengths of methacholine chloride in a clear, colorless solution.
ii. 0.0625 mg/mL (0.1875 mg/ 3 mL) of methacholine chloride
iii. 0.25 mg/mL (0.75 mg/ 3 mL) of methacholine chloride
iv. 1 mg/mL (3 mg/ 3 mL) of methacholine chloride
v. 4 mg/mL (12 mg/ 3 mL) of methacholine chloride
vi. 16 mg/mL (48 mg/ 3 mL) of methacholine chloride
• Inhalation solution (in a single-dose vial): 16 mg/mL (48 mg/ 3 mL) of methacholine chloride in a clear, colorless solution in a 3 mL plastic single-dose vial with a twist-off cap.
4CONTRAINDICATIONS
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
5WARNINGS AND PRECAUTIONS
.
5.1Risk 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
If baseline spirometry is not performed or is measured inaccurately, the initial FEV
5.2Risks 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
5.3Coexisting 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.
6ADVERSE 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.
7DRUG 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:
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
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.
8USE IN SPECIFIC POPULATIONS
.
8.1Pregnancy
RiskSummary
The available data from published literature on Provocholine use in pregnant women are insufficient to evaluate for a 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 available data from published literature on Provocholine use in pregnant women are insufficient to evaluate for a 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 a 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 2 to 4% and 15 to 20%, respectively.
8.2Lactation
Risk Summary
There 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 mother’s clinical need for Provocholine and any potential adverse effects on the breastfed infant from Provocholine or from the underlying maternal condition.
There 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 mother’s clinical need for Provocholine and any potential adverse effects on the breastfed infant from Provocholine or from the underlying maternal condition.
8.3Pediatric Use
The safety and effectiveness of Provocholine used in a methacholine challenge test, has been established for the diagnosis of bronchial airway hyperreactivity in pediatric patients 5 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 younger than 5 years of age.
8.4Geriatric 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.
9DESCRIPTION
Methacholine chloride, the active ingredient of Provocholine, is a 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 a 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 C
Provocholine Powder for Solution:Each vial of Provocholine contains 100 mg of methacholine chloride powder.
Provocholine Solution for Inhalation Kit (Sterile):
- Ready-to-use kit (sterile): Plastic vials with twist-off cap containing 3 mL of the following strengths of methacholine chloride solution. Each solution also contains the following inactive ingredients: sodium acetate trihydrate, sodium chloride, water for injection. Glacial acetic acid is added to adjust pH.
a) base solution (contains no methacholine chloride)
- Single-dose plastic vial with twist-off cap containing 16 mg/mL (48 mg/3 mL) of methacholine chloride solution. Solution also contains the following inactive ingredients: sodium acetate trihydrate, sodium chloride, and water for injection. Glacial acetic acid is added to adjust pH.
10CLINICAL PHARMACOLOGY
.
10.1Mechanism 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.
10.2Pharmacodynamics
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.
10.3Pharmacokinetics
There are no metabolic and pharmacokinetic data available on methacholine chloride.
11NONCLINICAL TOXICOLOGY
.
11.1Carcinogenesis, Mutagenesis, Impairment of Fertility
There have been no studies with methacholine chloride that would permit an evaluation of its carcinogenic or mutagenic potential or of its effect on fertility.
12HOW SUPPLIED/STORAGE AND HANDLING
Provocholine (methacholine chloride) for Inhalation Solution:
- Powder: 100 mg of methacholine chloride as a white to off-white powder in amber glass vials. Each carton contains six vials (NDC 64281-100-06).
Store the supplied powder at 59°F to 86°F (15°C to 30°C).
Provocholine (methacholine chloride) Inhalation Solution:
- Ready-to-use kit: Each carton contains six sterile ready-to-use (NDC: 64281-110-06). Each sterile ready-to-use kit (NDC: 64281-110-05) contains six plastic vials with twist-off cap. Each vial contains 3 mL of different strengths of methacholine chloride in a clear, colorless solution as follows:
a) base solution (contains no methacholine chloride) (NDC: 64281-111-00)
• Single-dose vial: 16 mg/mL of methacholine chloride in a clear, colorless solution in a 3 mL plastic single-dose vial with twist-off cap. Each carton contains two inner cartons (NDC: 64281-116-112). Each inner carton contains six vials of 16 mg/mL solution (NDC: 64281-116-06).
Store kits and single-dose vials between 15°C to 30°C (59°F to 86°F). Use immediately upon opening the vial.
13PATIENT COUNSELING INFORMATION
Risk of Severe Bronchoconstriction
Inform the patient or caregiver that severe bronchoconstriction can result from Provocholine administration [see Warnings and Precautions (5.1)].
Inform the patient or caregiver that severe bronchoconstriction can result from Provocholine administration [see Warnings and Precautions (5.1)].
Manufactured for:
Methapharm, Inc.
8230 210th Street #109
Boca Raton, FL,
USA 33433
For more information visit www.methapharmrespiratory.com,
®Provocholine is a registered trademark of Methapharm Inc.
Revision: June 2026