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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.
2Recommended Dosage
The recommended dosage of Provocholine powder for inhalation solution (require reconstitution and dilution) or inhalation solution (in a ready-to-use kit) used in the methacholine challenge test administered via nebulization in adult and pediatric patients (5 years or older) is increasing concentrations of methacholine chloride solutions using either doubling or quadrupling dosing concentrations. Please refer to Table 3 for the doubling or quadrupling dosing concentrations.
3Reconstitution and Dilution Prior to Administration (Required for Provocholine Powder for Inhalation Solution or for Provocholine Inhalation Solution 16 mg/mL only)
A. When using Provocholine Powder for Inhalation Solution:
1. Provocholine Powder for Inhalation Solution requires reconstitution before use (
Add 6.25 mL of sterile 0.9% Sodium Chloride Injection (0.9% saline) to the supplied vials containing 100 mg of Provocholine powder. Shake the vial to obtain a clear solution.
2. Dilute the reconstituted Provocholine solution:
Using sterile, empty USP Type 1 borosilicate glass vials, dilute the reconstituted Provocholine solution with 0.9% saline or 0.9% saline with 0.4% phenol either by doubling the concentration
3. Refrigerate the reconstituted and diluted solutions at 36
B. When using Provocholine Inhalation Solution 16 mg/mL:
1. Transfer the contents of two 3 mL vials of Provocholine Inhalation Solution 16 mg/mL into a sterile, empty USP Type 1 borosilicate glass vial. Swirl the glass vial gently to mix. Dilute with sterile 0.9% saline for doubling concentrations (see Table 1) or for quadrupling concentrations (see Table 2). After adding the diluent, shake each vial to obtain a clear solution. Use the same diluent to prepare all concentrations.
2. Refrigerate the reconstituted and diluted solutions at 36oF to 46oF (2oC to 8oC) for up to 2 weeks. Since the temperature of the solution affects nebulizer output, solutions should be taken out of the refrigerator and allowed to equilibrate to room temperature (approximately 30 minutes).
Table 1: Preparation of Doubling Concentrations of Provocholine
Table 2: Preparation of Quadrupling Concentrations of Provocholine
4Administration with the Five (5)-Breath Dosimeter Dosing Method in Patients 5 Years of Age and Older
Prior to administering the Provocholine dose(s), determine the post-diluent FEV
Administration of the Diluent or Base to Obtain Post-Diluent FEV1Value
1.
Using a 3 mL syringe and needle, draw up 2 to 3 mL of the same diluent used to reconstitute the Provocholine Powder (sterile 0.9% saline). Transfer the diluent into the nebulizer using a sterile bacterial-retentive filter (porosity 0.22 µm).
b) When using solutions for Provocholine inhalation solution kit:
Dispense the contents of a vial containing 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.
4. Repeat Step 3 for a total of five inspiratory capacity inhalations. Take no more than 2 minutes to perform these 5 inhalations.
Administration of Provocholine in a Methacholine Challenge Test
6. a) When using the solutions prepared from Provocholine powder for inhalation or Provocholine Inhalation Solution 16 mg/mL:
Using a 3 mL syringe and needle, draw up the recommended Provocholine solution
Table 3: Recommended Provocholine Dose(s) By Nebulization [Doubling Dose(s) or Quadrupling Dose(s)]
*Table 1 preparation **Table 2 preparations
***Dose delivered based on on English Wright Nebulizer drug output after 2 minutes inhalation.
b) When using the solutions from the Provocholine inhalation solution kit:
For the Provocholine inhalation solution:
Dispense the contents of a vial of the appropriate Provocholine concentration, starting with the lowest dose, into the nebulizer. The Provocholine solution concentrations, 0.0625 mg/mL, 0.25 mg/mL, 1 mg/mL, 4 mg/mL, and 16 mg/mL, provided in the kit are ready-to-use. No further dilution is required.
7. Repeat steps 2 through 5 for each Provocholine concentration, emptying the nebulizer between each concentration. To keep the cumulative effect of Provocholine relatively constant, the time interval between the commencement of two subsequent concentrations should be kept to 5 minutes.
8. Stop dosing if the FEV1 has fallen by ≥ 20% from the post-diluent FEV1, or the highest Provocholine concentration (16 mg/mL) has been administered (whichever comes first). Do not administer additional Provocholine concentrations if severe bronchoconstriction occurs [see Warnings and Precautions (5.1)].
9. After the 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 5 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. Patients should not be allowed to leave the laboratory until their FEV1 has returned to within 90% of baseline.
10. After the test, wash and clean reusable nebulizers thoroughly according to manufacturer’s recommendations.
5Administration with the Two (2)-Minute Tidal Breathing Dosing Method in Patients 5 Years of Age and Older
Administer the diluent and the Provocholine dose(s) using the English Wright nebulizer or other suitable nebulizer as long as the device output and particle size are characterized.
Administration of the Diluent or Base Solution to Obtain Post-Diluent FEV1 Value
1. a) When using the solutions prepared from Provocholine powder for inhalation solution or Powder Inhalation Solution 16 mg/mL:
Using a 3 mL syringe and needle, draw up 2 to 3 mL of the same diluent used to reconstitute the Provocholine powder (sterile 0.9% saline). Transfer the diluent into the nebulizer using a sterile bacterial-retentive filter (porosity 0.22 µm).
b) When using the solutions from the Provocholine inhalation solution kit:
Dispense the contents of a vial containing the base solution (contains no methacholine chloride) into the nebulizer.
2. Instruct the patient to relax and breathe the aerosol quietly (tidal breathing) for 2 minutes of inhalation time.
3. Place the face mask loosely over the nose and mouth or the mouthpiece in the mouth (with a nose clip) of the patient. The patient should hold the nebulizer to avoid warming the solution. Nebulizer should be kept upright and vertical.
4. Start the nebulizer by adjusting the flow meter so that the nebulizer is operating at the calibrated output (0.13 mL/minute for the English Wright nebulizer). Start the stopwatch immediately.
5. After exactly 2 minutes, turn off the flow meter, remove the face mask (or the mouthpiece from the mouth), and discard any remaining solution.
6. Perform spirometry and measure the FEV1 30 and 90 seconds after the 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 Step 9. If the post-diluent FEV1 falls by < 20% from baseline FEV1, continue to Step 7.
Administration of Provocholine in a Methacholine Challenge Test
7. a) When using the solutions prepared from Provocholine powder for inhalation solution or Provocholine Inhalation Solution 16 mg/mL:
Using a 3 mL syringe and needle, draw up the recommended Provocholine solution concentration (see Table 3) using either the doubling or quadrupling dose method. Transfer the Provocholine solution into the nebulizer using a sterile bacterial-retentive filter (porosity 0.22 µm).
b) When using the solutions from the Provocholine inhalation solution kit:
Dispense the contents of a vial of the appropriate Provocholine solution, starting with the lowest dose, into the nebulizer. The Provocholine solution concentrations, 0.0625 mg/mL, 0.25 mg/mL, 1 mg/mL, 4 mg/mL, and 16 mg /mL, provided in the kit are ready-to-use. No further dilution is required.
8. Repeat steps 2 through 6 for each Provocholine dose, emptying the nebulizer between each dose. However, stop dosing if the FEV1 has fallen by ≥ 20% from the post-diluent FEV1 or the highest Provocholine concentration (16 mg/mL) has been administered (whichever comes first). Do not administer additional Provocholine doses if severe bronchoconstriction occurs [
9. After the 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 5 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. Patients should not be allowed to leave the laboratory until their FEV1 has returned to within 90% of baseline.
10. After the test, wash and clean reusable nebulizers thoroughly according to manufacturer’s recommendations and discard disposable nebulizers appropriately.
6Calculation and Interpretation of Methacholine Challenge Test Results
A positive methacholine challenge test is a ≥ 20% reduction in the FEV
Calculation of PC
Calculate PC 20using one of the following methods. Determine the percent decrease in FEV 1using the mean post-diluent FEV 1and the lowest FEV 1post-dose, as shown below:
% fall in FEV 1= mean post-diluent FEV
mean post-diluent FEV 1
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
Alternatively, calculate the PC 20as follows:
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:
When using the English Wright nebulizer, refer to Table 2 for D1 and D2.
Interpretation of Results
A negative (normal) methacholine challenge result is defined as FEV 1reduction of < 20% after all the doses (doubling or quadrupling dose increments) in Table 1 (for 5-breath dosimeter method) or Table 2 (for the 2-minute tidal breathing method) have been administered.
If asthma drugs are discontinued prior to the methacholine challenge test, consider the possibility of rebound airway hyperreactivity in the interpretation of the test results. The methacholine challenge test may occasionally be falsely positive after an influenza infection or upper respiratory infection, immunizations, in very young or very old patients, in patients with chronic lung disease (e.g., cystic fibrosis, sarcoidosis, tuberculosis, chronic obstructive pulmonary disease), in patients with allergic rhinitis without asthma symptoms, in smokers, or in patients after exposure to air pollutants.
7DOSAGE FORMS AND STRENGTHS
• For inhalation solution: 100 mg of white to off-white crystalline powder in amber glass vials (powder is reconstituted and then diluted prior to administration)
• Inhalation solution:
8CONTRAINDICATIONS
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 FEV
9ADVERSE 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.
10DRUG 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.
11DESCRIPTION
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):
Each kit is packaged in a carton with six plastic vials with twist-off cap each containing 3 mL of the following concentrations of methacholine chloride solution. Each solution also contains: Sodium Acetate Trihydrate, Sodium Chloride, glacial acetic acid as pH adjuster.
Each kit is packaged in a carton with six plastic vials with twist-off cap each containing 3 mL of the following concentrations of methacholine chloride solution. Each solution also contains: Sodium Acetate Trihydrate, Sodium Chloride, glacial acetic acid as pH adjuster.
a) base solution (contains no methacholine chloride)
12HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
- Provocholine (methacholine chloride) Powder for Inhalation Solution: in amber glass vials that contain 100 mg of methacholine chloride powder, white to off-white in color. Cartons have 6 vials (NDC 64281-100-06).
- Provocholine (methacholine chloride) Inhalation Solution Kit (Sterile):
Each kit (NDC: 64281-110-05) contains six (6) plastic vials with twist-off cap each containing 3 mL of different concentrations of methacholine chloride as shown below. Cartons have six (6) kits (NDC 64281-110-06).
a) base solution (contains no methacholine chloride) (NDC: 64281-111-00)
• Provocholine (methacholine chloride) Inhalation Solution 16 mg/mL (Sterile): in 3 mL plastic vial with twist-off cap. The solutions are packaged in inner cartons containing six (6) vials (NDC 64281-116-06). Two inner cartons are packaged in an outer carton (2x 6s cartons) (NDC 64281-110-12)
Storage and Handling
- Powder for inhalation solution: Store the supplied powder at 59
- Provocholine inhalation solution kit: Store between 59
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)].
Cough, Chest Tightness, or Shortness of Breath
Inform the patient or caregiver that Provocholine may produce mild cough, chest tightness or shortness of breath.
Inform the patient or caregiver that Provocholine may produce mild cough, chest tightness or shortness of breath.
Manufactured for:
Boca raton, FL,
USA 33065
For more information visit www.methapharmrespiratory.com,
®Provocholine is a registered trademark of Methapharm Inc.
Revision: September 2024