Provocholine

Diagnostic Agents, Other

For safety and accuracy, limit methacholine use to a pulmonary function laboratory or clinic, by adequately trained personnel and only under the responsibility of a healthcare professional trained in and thoroughly familiar with the aspects of the technique of the methacholine challenge test and the management of respiratory distress.
Methacholine may cause bronchoconstriction in the healthcare providers administering methacholine. To avoid accidental exposure, precautionary steps are necessary for healthcare providers and any other personnel involved in methacholine administration.
Do not handle methacholine powder if have hay fever or asthma.
Do not inhale the methacholine powder.
Apply a low resistance filter to expiratory ports of the dosing apparatus, as necessary, to prevent methacholine release in the room air.
Ensure emergency equipment and medication are immediately available to treat acute respiratory distress. If severe bronchoconstriction occurs, reverse immediately by administration of a rapid-acting inhaled beta-agonist.

May use methacholine with or without meals.
Remove any previously reconstituted or diluted solutions from refrigerator and allow to equilibrate to room temperature (approximately 30 minutes) before use.
Before using methacholine, perform baseline pulmonary function tests (PFTs) with the 0.9% Sodium Chloride Injection diluent or the 0.9% Sodium Chloride Injection with 0.4% phenol diluent. Use the same diluent to reconstitute the methacholine powder. If the baseline FEV1 value is not of acceptable quality, repeat the procedure. The patient must have a baseline FEV1 of 60% or more of the predicted value.
Stop methacholine dosing if the FEV1 falls by 20% or more from mean baseline, the FEV1 is 1.5 L or less (adults only), or the highest dose (380 mcg, 16 mg/mL) has been administered, whichever comes first. Do not administer additional methacholine doses.
After the test is completed, administer an inhaled beta-agonist to the patient to expedite the return of the FEV1 to within 90% of baseline and to relieve any discomfort. Wait 10 minutes and measure the FEV1 and vital capacity. Monitor patients in the pulmonary function laboratory until FEV1 has returned to within 90% of baseline.
 
Reconstitution:
Add 6.25 mL of the 0.9% Sodium Chloride Injection or the 0.9% Sodium Chloride Injection with 0.4% phenol diluent to the vial containing methacholine 100 mg powder.
Shake the vial until a clear solution is obtained.
Storage: Refrigerate the reconstituted solution at 2 to 8 degrees C (36 to 46 degrees F) for up to 2 weeks.
 
Dilution:
Using sterile, empty USP Type I borosilicate glass vials for the dilution procedure, dilute the reconstituted methacholine solution with the 0.9% Sodium Chloride Injection or the 0.9% Sodium Chloride Injection with 0.4% phenol diluent either by doubling or quadrupling the concentrations as shown below. Use the same diluent used to prepare all concentrations.
After adding the diluent, shake each vial to obtain a clear solution.
Storage: Refrigerate the diluted solutions at 2 to 8 degrees C (36 to 46 degrees F) for up to 2 weeks.
Doubling concentrations:
Solution A. Add 6.25 mL of diluent to the vial containing methacholine 100 mg powder. Resulting concentration is 16 mg/mL.
Solution B. Transfer 3 mL of Solution A to a sterile, empty glass vial; add 3 mL of diluent. Resulting concentration is 8 mg/mL.
Solution C. Transfer 3 mL of Solution B to a sterile, empty glass vial; add 3 mL of diluent. Resulting concentration is 4 mg/mL.
Solution D. Transfer 3 mL of Solution C to a sterile, empty glass vial; add 3 mL of diluent. Resulting concentration is 2 mg/mL.
Solution E. Transfer 3 mL of Solution D to a sterile, empty glass vial; add 3 mL of diluent. Resulting concentration is 1 mg/mL.
Solution F. Transfer 3 mL of Solution E to a sterile, empty glass vial; add 3 mL of diluent. Resulting concentration is 0.5 mg/mL.
Solution G. Transfer 3 mL of Solution F to a sterile, empty glass vial; add 3 mL of diluent. Resulting concentration is 0.25 mg/mL.
Solution H. Transfer 3 mL of Solution G to a sterile, empty glass vial; add 3 mL of diluent. Resulting concentration is 0.125 mg/mL.
Solution I. Transfer 3 mL of Solution H to a sterile, empty glass vial; add 3 mL of diluent. Resulting concentration is 0.0625 mg/mL.
Quadrupling concentrations:
Solution 1. Add 6.25 mL of diluent to the vial containing methacholine 100 mg powder. Resulting concentration is 16 mg/mL.
Solution 2. Transfer 3 mL of Solution 1 to a sterile, empty glass vial; add 9 mL of diluent. Resulting concentration is 4 mg/mL.
Solution 3. Transfer 3 mL of Solution 2 to a sterile, empty glass vial; add 9 mL of diluent. Resulting concentration is 1 mg/mL.
Solution 4. Transfer 3 mL of Solution 3 to a sterile, empty glass vial; add 9 mL of diluent. Resulting concentration is 0.25 mg/mL.
Solution 5. Transfer 3 mL of Solution 4 to a sterile, empty glass vial; add 9 mL of diluent. Resulting concentration is 0.0625 mg/mL.
 
2-minute tidal breathing dosing method:
Using a 3 mL syringe and needle, draw up 2 to 3 mL of diluent (0.9% Sodium Chloride Injection or 0.9% Sodium Chloride Injection with 0.4% phenol) or the recommended methacholine dose using the doubling or quadrupling concentrations.
Dispense into the nebulizer using a sterile bacterial-retentive filter (0.22 millimicrons).
Instruct the patient to relax and breathe the aerosol quietly (tidal breathing) for 2 minutes of inhalation time.
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. Nebulizer should be kept upright and vertical.
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.
After exactly 2 minutes, turn off the flow meter, remove the face mask (or the mouthpiece from the mouth), and discard any remaining solution.
Perform spirometry and measure FEV1 at 30 and 90 seconds after the end of the inhalation.
Repeat the procedure for each methacholine dose, emptying the nebulizer between each dose. Stop dosing if the FEV1 falls by 20% or more from the post-diluent FEV1, or the highest methacholine dose (380 mcg) has been administered (whichever comes first). Do not administer additional methacholine concentrations if severe bronchoconstriction occurs.

 
5-breath dosimeter dosing method:
Using a 3 mL syringe and needle, draw up 2 mL of diluent (0.9% Sodium Chloride Injection or 0.9% Sodium Chloride Injection with 0.4% phenol) or the recommended methacholine dose using the quadrupling concentrations.
Dispense into the nebulizer using a sterile bacterial-retentive filter (0.22 millimicrons).
Instruct the patient to hold the nebulizer upright with the mouthpiece in mouth. The patient should wear a nose clip.
At end exhalation during tidal breathing (functional residual capacity), instruct the patient to slowly and deeply inhale through the mouthpiece for about 5 seconds and to hold the breath at total lung capacity for another 5 seconds. Trigger the dosimeter soon after oral inhalation begins.
Repeat these steps to perform 5 inhalations. Take no more than 2 minutes to perform these 5 inhalations.
Perform spirometry and measure the FEV1 at 30 and 90 seconds after the fifth inhalation.
Repeat the procedure for each methacholine dose, emptying the nebulizer between each dose. To keep the cumulative effect of methacholine relatively constant, keep the time interval between doses at 5 minutes. Stop dosing if the FEV1 falls by 20% or more from the post-diluent FEV1, or the highest methacholine concentration (16 mg/mL) has been administered (whichever comes first). Do not administer additional methacholine concentrations if severe bronchoconstriction occurs.
After the test, wash and clean reusable nebulizers thoroughly according to manufacturer's recommendations.

bronchospasm / Rapid / Incidence not known

wheezing / Rapid / Incidence not known

throat irritation / Early / Incidence not known
headache / Early / Incidence not known
pruritus / Rapid / Incidence not known
cough / Delayed / Incidence not known

Before starting a methacholine challenge test, baseline spirometry must be performed. Methacholine is contraindicated for use in pediatric and adult patients with a baseline FEV1 less than 60% predicted or adults with FEV1 less than 1.5 L. Severe acute bronchospasm can result from methacholine administration, including at the lowest dose. Because of the potential for severe bronchoconstriction, methacholine use is not recommended in patients with clinically apparent asthma or wheezing. Only consider methacholine use in patients on chronic asthma drugs if the accuracy of the asthma diagnosis is in doubt. In these patients, only administer methacholine if spirometry is normal after withdrawal of the asthma drugs under supervision. Ensure emergency equipment and medication are readily available to treat acute respiratory distress. If severe bronchoconstriction occurs, reverse immediately by the administration of a rapid-acting inhaled beta-agonist. If the baseline spirometry is not performed or measured accurately, the initial FEV1 may be underestimated. In this situation, decreases in FEV1 may not be detected after escalating methacholine doses, which may result in administration of unnecessary higher doses and an increase in the risk for excessive bronchoconstriction.

Provocholine

Rx

Orally inhaled cholinergic agonist
Used for diagnosis of bronchial airway hyperreactivity (methacholine challenge test) in patients 5 years of age and older who do not have clinically apparent asthma
May occasionally be false-positive after influenza or other upper respiratory infection; after vaccination; in very young or geriatric patients; in patients with chronic lung disease (CLD); in patients with allergic rhinitis with or without asthma symptoms; in tobacco smoking patients; or in patients after exposure to air pollutants

1.484 mcg (0.0625 mg/mL) via nebulizer followed by quadrupling doses of 5.938 mcg (0.25 mg/mL), 23.75 mcg (1 mg/mL), 95 mcg (4 mg/mL), and 380 mcg (16 mg/mL). Deliver each dose over 2 minutes of inhalation time. Keep time interval between doses at 5 minutes. Stop dosing if the FEV1 falls by 20% or more from mean baseline, the FEV1 is 1.5 L or less, or the highest dose has been administered, whichever comes first.[43792]

1.484 mcg (0.0625 mg/mL) via nebulizer followed by quadrupling doses of 5.938 mcg (0.25 mg/mL), 23.75 mcg (1 mg/mL), 95 mcg (4 mg/mL), and 380 mcg (16 mg/mL). Deliver each dose over 2 minutes of inhalation time. Keep time interval between doses at 5 minutes. Stop dosing if the FEV1 falls by 20% or more from mean baseline or the highest dose has been administered, whichever comes first.[43792]

1.484 mcg (0.0625 mg/mL) via nebulizer followed by doubling doses of 2.969 mcg (0.125 mg/mL), 5.938 mcg (0.25 mg/mL), 11.875 mcg (0.5 mg/mL), 23.75 mcg (1 mg/mL), 47.5 mcg (2 mg/mL), 95 mcg (4 mg/mL), 190 mcg (8 mg/mL), and 380 mcg (16 mg/mL). Deliver each dose over 2 minutes of inhalation time. Stop dosing if the FEV1 falls by 20% or more from mean baseline, the FEV1 is 1.5 L or less, or the highest dose has been administered, whichever comes first.[43792]

1.484 mcg (0.0625 mg/mL) via nebulizer followed by doubling doses of 2.969 mcg (0.125 mg/mL), 5.938 mcg (0.25 mg/mL), 11.875 mcg (0.5 mg/mL), 23.75 mcg (1 mg/mL), 47.5 mcg (2 mg/mL), 95 mcg (4 mg/mL), 190 mcg (8 mg/mL), and 380 mcg (16 mg/mL). Deliver each dose over 2 minutes of inhalation time. Stop dosing if the FEV1 falls by 20% or more from mean baseline or the highest dose has been administered, whichever comes first.[43792]

1.484 mcg (0.0625 mg/mL) via nebulizer followed by quadrupling doses of 5.938 mcg (0.25 mg/mL), 23.75 mcg (1 mg/mL), 95 mcg (4 mg/mL), and 380 mcg (16 mg/mL). Deliver each dose over 2 minutes of inhalation time. Stop dosing if the FEV1 falls by 20% or more from mean baseline, the FEV1 is 1.5 L or less, or the highest dose has been administered, whichever comes first.[43792]

1.484 mcg (0.0625 mg/mL) via nebulizer followed by quadrupling doses of 5.938 mcg (0.25 mg/mL), 23.75 mcg (1 mg/mL), 95 mcg (4 mg/mL), and 380 mcg (16 mg/mL). Deliver each dose over 2 minutes of inhalation time. Keep time interval between doses at 5 minutes. Stop dosing if the FEV1 falls by 20% or more from mean baseline or the highest dose has been administered, whichever comes first.[43792]

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

Acebutolol: (Moderate) Beta-blockers may impair reversal of methacholine-induced bronchoconstriction with an inhaled rapid-acting beta-agonist.
Aclidinium: (Major) Discontinue use of aclidinium 168 hours or more before a methacholine challenge test. Aclidinium inhibits the airway response to methacholine.
Aclidinium; Formoterol: (Major) Discontinue use of aclidinium 168 hours or more before a methacholine challenge test. Aclidinium inhibits the airway response to methacholine. (Major) Discontinue use of formoterol 36 hours before a methacholine challenge test. Beta-agonists inhibit the airway response to methacholine.
Albuterol: (Major) Discontinue use of short-acting beta-agonists 6 hours before a methacholine challenge test. Beta-agonists inhibit the airway response to methacholine.
Albuterol; Budesonide: (Major) Discontinue use of short-acting beta-agonists 6 hours before a methacholine challenge test. Beta-agonists inhibit the airway response to methacholine.
Arformoterol: (Major) Discontinue use of arformoterol 36 hours before a methacholine challenge test. Beta-agonists inhibit the airway response to methacholine.
Atenolol: (Moderate) Beta-blockers may impair reversal of methacholine-induced bronchoconstriction with an inhaled rapid-acting beta-agonist.
Atenolol; Chlorthalidone: (Moderate) Beta-blockers may impair reversal of methacholine-induced bronchoconstriction with an inhaled rapid-acting beta-agonist.
Beta-blockers: (Moderate) Beta-blockers may impair reversal of methacholine-induced bronchoconstriction with an inhaled rapid-acting beta-agonist.
Betaxolol: (Moderate) Beta-blockers may impair reversal of methacholine-induced bronchoconstriction with an inhaled rapid-acting beta-agonist.
Bisoprolol: (Moderate) Beta-blockers may impair reversal of methacholine-induced bronchoconstriction with an inhaled rapid-acting beta-agonist.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Beta-blockers may impair reversal of methacholine-induced bronchoconstriction with an inhaled rapid-acting beta-agonist.
Brimonidine; Timolol: (Moderate) Beta-blockers may impair reversal of methacholine-induced bronchoconstriction with an inhaled rapid-acting beta-agonist.
Budesonide; Formoterol: (Major) Discontinue use of formoterol 36 hours before a methacholine challenge test. Beta-agonists inhibit the airway response to methacholine.
Budesonide; Glycopyrrolate; Formoterol: (Major) Discontinue use of formoterol 36 hours before a methacholine challenge test. Beta-agonists inhibit the airway response to methacholine.
Carteolol: (Moderate) Beta-blockers may impair reversal of methacholine-induced bronchoconstriction with an inhaled rapid-acting beta-agonist.
Carvedilol: (Moderate) Beta-blockers may impair reversal of methacholine-induced bronchoconstriction with an inhaled rapid-acting beta-agonist.
Dorzolamide; Timolol: (Moderate) Beta-blockers may impair reversal of methacholine-induced bronchoconstriction with an inhaled rapid-acting beta-agonist.
Esmolol: (Moderate) Beta-blockers may impair reversal of methacholine-induced bronchoconstriction with an inhaled rapid-acting beta-agonist.
Fluticasone; Salmeterol: (Major) Discontinue use of salmeterol 36 hours before a methacholine challenge test. Beta-agonists inhibit the airway response to methacholine.
Fluticasone; Umeclidinium; Vilanterol: (Major) Discontinue use of umeclidinium 168 hours or more before a methacholine challenge test. Umeclidinium inhibits the airway response to methacholine. (Major) Discontinue use of vilanterol 48 hours before a methacholine challenge test. Beta-agonists inhibit the airway response to methacholine.
Fluticasone; Vilanterol: (Major) Discontinue use of vilanterol 48 hours before a methacholine challenge test. Beta-agonists inhibit the airway response to methacholine.
Formoterol: (Major) Discontinue use of formoterol 36 hours before a methacholine challenge test. Beta-agonists inhibit the airway response to methacholine.
Formoterol; Mometasone: (Major) Discontinue use of formoterol 36 hours before a methacholine challenge test. Beta-agonists inhibit the airway response to methacholine.
Glycopyrrolate; Formoterol: (Major) Discontinue use of formoterol 36 hours before a methacholine challenge test. Beta-agonists inhibit the airway response to methacholine.
Indacaterol: (Major) Discontinue use of indacaterol 48 hours before a methacholine challenge test. Beta-agonists inhibit the airway response to methacholine.
Indacaterol; Glycopyrrolate: (Major) Discontinue use of indacaterol 48 hours before a methacholine challenge test. Beta-agonists inhibit the airway response to methacholine.
Ipratropium: (Major) Discontinue use of ipratropium 12 hours before a methacholine challenge test. Ipratropium inhibits the airway response to methacholine.
Ipratropium; Albuterol: (Major) Discontinue use of ipratropium 12 hours before a methacholine challenge test. Ipratropium inhibits the airway response to methacholine. (Major) Discontinue use of short-acting beta-agonists 6 hours before a methacholine challenge test. Beta-agonists inhibit the airway response to methacholine.
Labetalol: (Moderate) Beta-blockers may impair reversal of methacholine-induced bronchoconstriction with an inhaled rapid-acting beta-agonist.
Levalbuterol: (Major) Discontinue use of short-acting beta-agonists 6 hours before a methacholine challenge test. Beta-agonists inhibit the airway response to methacholine.
Levobunolol: (Moderate) Beta-blockers may impair reversal of methacholine-induced bronchoconstriction with an inhaled rapid-acting beta-agonist.
Metaproterenol: (Major) Discontinue use of short-acting beta-agonists 6 hours before a methacholine challenge test. Beta-agonists inhibit the airway response to methacholine.
Metoprolol: (Moderate) Beta-blockers may impair reversal of methacholine-induced bronchoconstriction with an inhaled rapid-acting beta-agonist.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Beta-blockers may impair reversal of methacholine-induced bronchoconstriction with an inhaled rapid-acting beta-agonist.
Nadolol: (Moderate) Beta-blockers may impair reversal of methacholine-induced bronchoconstriction with an inhaled rapid-acting beta-agonist.
Nebivolol: (Moderate) Beta-blockers may impair reversal of methacholine-induced bronchoconstriction with an inhaled rapid-acting beta-agonist.
Nebivolol; Valsartan: (Moderate) Beta-blockers may impair reversal of methacholine-induced bronchoconstriction with an inhaled rapid-acting beta-agonist.
Olodaterol: (Major) Discontinue use of olodaterol 48 hours before a methacholine challenge test. Beta-agonists inhibit the airway response to methacholine.
Pindolol: (Moderate) Beta-blockers may impair reversal of methacholine-induced bronchoconstriction with an inhaled rapid-acting beta-agonist.
Propranolol: (Moderate) Beta-blockers may impair reversal of methacholine-induced bronchoconstriction with an inhaled rapid-acting beta-agonist.
Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Beta-blockers may impair reversal of methacholine-induced bronchoconstriction with an inhaled rapid-acting beta-agonist.
Salmeterol: (Major) Discontinue use of salmeterol 36 hours before a methacholine challenge test. Beta-agonists inhibit the airway response to methacholine.
Short-acting beta-agonists: (Major) Discontinue use of short-acting beta-agonists 6 hours before a methacholine challenge test. Beta-agonists inhibit the airway response to methacholine.
Sotalol: (Moderate) Beta-blockers may impair reversal of methacholine-induced bronchoconstriction with an inhaled rapid-acting beta-agonist.
Terbutaline: (Major) Discontinue use of short-acting beta-agonists 6 hours before a methacholine challenge test. Beta-agonists inhibit the airway response to methacholine.
Theophylline, Aminophylline: (Major) Discontinue use of oral theophylline 12 to 48 hours before a methacholine challenge test. Theophylline inhibits the airway response to methacholine.
Timolol: (Moderate) Beta-blockers may impair reversal of methacholine-induced bronchoconstriction with an inhaled rapid-acting beta-agonist.
Tiotropium: (Major) Discontinue use of tiotropium 168 hours or more before a methacholine challenge test. Tiotropium inhibits the airway response to methacholine.
Tiotropium; Olodaterol: (Major) Discontinue use of olodaterol 48 hours before a methacholine challenge test. Beta-agonists inhibit the airway response to methacholine. (Major) Discontinue use of tiotropium 168 hours or more before a methacholine challenge test. Tiotropium inhibits the airway response to methacholine.
Umeclidinium: (Major) Discontinue use of umeclidinium 168 hours or more before a methacholine challenge test. Umeclidinium inhibits the airway response to methacholine.
Umeclidinium; Vilanterol: (Major) Discontinue use of umeclidinium 168 hours or more before a methacholine challenge test. Umeclidinium inhibits the airway response to methacholine. (Major) Discontinue use of vilanterol 48 hours before a methacholine challenge test. Beta-agonists inhibit the airway response to methacholine.

Provocholine Respiratory (Inhalation) Pwd: 100mg

 380 mcg oral inhalation as single dose and 758.516 mcg oral inhalation as cumulative dose per methacholine challenge test.

 380 mcg oral inhalation as single dose and 758.516 mcg oral inhalation as cumulative dose per methacholine challenge test.

 380 mcg oral inhalation as single dose and 758.516 mcg oral inhalation as cumulative dose per methacholine challenge test.

Children 5 to 12 years:  380 mcg oral inhalation as single dose and 758.516 mcg oral inhalation as cumulative dose per methacholine challenge test.
Children 1 to 4 years: Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Methacholine is a cholinergic agonist which stimulates the muscarinic receptors of bronchial smooth muscles to induce bronchoconstriction. After oral inhalation, patients with asthma are more sensitive to methacholine-induced bronchoconstriction than are healthy subjects; this difference in response is the pharmacologic basis for a methacholine challenge test. Methacholine is a structural analog of acetylcholine. The addition of a methyl group at the beta-carbon atom of choline produces a longer duration of action and increased selectivity of action compared to acetylcholine. Unlike acetylcholine, methacholine is hydrolyzed only by acetylcholinesterase and at a much slower rate. Also, methacholine binds directly to muscarinic receptors of smooth muscles, glands, and the heart and possess weak activity on nicotinic receptors of skeletal muscles.

Methacholine is administered by oral inhalation. There are no metabolic and pharmacokinetic data available on methacholine.
 
Affected cytochrome P450 isoenzymes and drug transporters: none

Diagnosis of bronchial airway hyperreactivity with bronchoprovocation challenge is not recommended during pregnancy because of the potential for hypoxia in the fetus. If bronchial airway hyperactivity is suspected, consider a trial of empiric treatment. Available data on methacholine use in pregnant women are insufficient to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal reproduction studies evaluating the effects of methacholine on embryofetal development have not been conducted.

There are no available data on the presence of methacholine in human milk, the effect on the breast-fed infant, or the effect on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for methacholine and any potential adverse effects on the breast-fed infant from methacholine or from the underlying maternal condition.