Prescribing Information

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PrPROVOCHOLINE (methacholine chloride USP)

Therapeutic Classification
Cholinergic / Diagnostic Aid (Bronchial Asthma)

SUMMARY PRODUCT INFORMATION

Summary of Product Information

Indications and Clinical Use

Provocholine is indicated for:

Provocholine (methacholine chloride USP) is indicated for the diagnosis of bronchial airway hyperresponsiveness in subjects suspected of having asthma. The methacholine challenge test with Provocholine (methacholine chloride USP) provides a measure of the severity of asthma. The methacholine challenge test with Provocholine may be used to confirm occupational asthma.

The product should be administered under the supervision of a qualified health professional who is experienced in the use of inhalation agents and in the management of patients experiencing severe bronchoconstriction. Appropriate management of therapy and complications is only possible when adequate diagnostic and treatment facilities are readily available.

Geriatrics: No data is available.

Pediatrics (<5 years of age): The safety and efficacy of methacholine challenge tests with Provocholine (methacholine chloride USP) have not been established in children below the age of 5 years. Back To Top

Contraindications

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Warnings and Precautions

Serious Warnings and Precautions

General

Provocholine (methacholine chloride USP) is to be administered only by inhalation. Provocholine (methacholine chloride USP) is a bronchoconstrictor agent for diagnostic purposes only, and should not be used as a therapeutic agent.

Administration of Provocholine (methacholine chloride USP) to patients with epilepsy, cardiovascular disease accompanied by bradycardia, vagotonia, peptic ulcer disease, thyroid disease, urinary tract obstruction or other condition that could be adversely affected by a cholinergic agent should be undertaken only if the physician feels the benefit to the individual outweighs the potential risks.

It is essential that the baseline spirometry is accurate. If the baseline spirometry is not performed or measured accurately, and the initial FEV1 is underestimated, subsequent falls after inhaling Provocholine (methacholine chloride USP) solutions may not be detected, resulting in too high a dose and excessive bronchoconstriction.

Methacholine challenge test with Provocholine (methacholine chloride USP) should be performed only under the supervision of a physician trained in and thoroughly familiar with all aspects of the technique of methacholine challenge, all contraindications, warnings and precautions, and the management of respiratory distress. A physician responsible for the tests must be present in the building when tests are carried out, and available to be contacted quickly if necessary. If the physician is performing the test, another person must be available in the building to give assistance if required. The patient must never be left unattended during the test.

Emergency medication and equipment should be immediately available to treat acute respiratory distress.

Carcinogenesis, Mutagenesis and 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.

Cardiovascular

Administration of Provocholine (methacholine chloride USP) to patients with cardiovascular disease accompanied by bradycardia, which could be adversely affected by a cholinergic agent, should be undertaken only if the physician feels benefit to the individual outweighs the potential risks.

Endocrine and Metabolism

Administration of Provocholine (methacholine chloride USP) to patients with thyroid disease, which could be adversely affected by a cholinergic agent, should be undertaken only if the physician feels benefit to the individual outweighs the potential risks.

Gastrointestinal

Administration of Provocholine (methacholine chloride USP) to patients with peptic ulcer disease, which could be adversely affected by a cholinergic agent, should be undertaken only if the physician feels benefit to the individual outweighs the potential risks.

Genitourinary

Administration of Provocholine (methacholine chloride USP) to patients with urinary tract obstruction, which could be adversely affected by a cholinergic agent, should be undertaken only if the physician feels benefit to the individual outweighs the potential risks.

Neurological

Administration of Provocholine (methacholine chloride USP) to patients with epilepsy, which could be adversely affected by a cholinergic agent, should be undertaken only if the physician feels benefit to the individual outweighs the potential risks.

Respiratory

Severe bronchoconstriction can result from the administration of Provocholine (methacholine chloride USP), if guidelines for careful administration are not followed. Patients with severe hyperresponsiveness of the airways can experience bronchoconstriction at the lowest dosages of Provocholine (methacholine chloride USP), or with the diluent alone. If severe bronchoconstriction occurs, it should be reversed immediately by the administration of a rapid-acting inhaled ß-agonist. Because of the potential for severe bronchoconstriction, Provocholine (methacholine chloride USP) challenge should not be performed in any patient with low baseline FEV1 of less than 1.5 litres or less than 70% of the predicted value. Please consult standard nomograms for predicted values.1

Special Populations

Pregnancy: Teratogenic Effects - Animal reproduction studies have not been conducted with methacholine chloride. It is not known whether methacholine chloride can cause fetal harm when administered to a pregnant patient or affect reproductive capacity. Provocholine (methacholine chloride USP) should be given to a pregnant woman only when the benefits clearly outweigh the risks.

Nursing Mothers: It is not known if methacholine chloride when inhaled is excreted in breast milk. Methacholine challenge test with Provocholine (methacholine chloride USP) should be administered to nursing mothers only when the benefits clearly outweigh the risks.

Pediatric Use: The safety and efficacy of methacholine challenge tests with Provocholine (methacholine chloride USP) have not been established in children below the age of 5 years.

Laboratory Personnel: Provocholine (methacholine chloride USP) aerosol may cause bronchoconstriction in laboratory personnel and others in the same room as the patient undergoing the test. Laboratory personnel with asthma or hay fever should take appropriate precautions when handling the material. (See SPECIAL HANDLING INSTRUCTIONS) Back To Top

Information to be Provided to the Patient

To assure the safe and effective use of the methacholine challenge test with Provocholine (methacholine chloride USP), the following instructions and information should be given to patients:

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Adverse Reactions

Adverse reactions associated with inhaled methacholine challenge tests are rare, and include incidences of headache, throat irritation, light-headedness and itching.

A positive reaction to methacholine challenge may produce symptoms of bronchospasm, such as chest tightness, cough or wheezing.

Incidences of severe bronchoconstriction can be avoided by limiting the challenge test to cases of potentially mild asthma, in those patients with normal or near normal FEV1, and by cautiously increasing the dosage.

Provocholine (methacholine chloride USP) is to be administered only by inhalation. When administered orally or by injection, Provocholine (methacholine chloride USP) is reported to be associated with nausea and vomiting, substernal pain or pressure, hypotension, fainting and transient complete heart block. (See OVERDOSAGE) Back To Top

Drug Interactions

Overview

Provocholine (methacholine chloride USP) is a parasympathomimetic (cholinergic) bronchoconstrictor agent to be administered in solution only, by inhalation. Methacholine chloride is the ß-methyl homolog of acetylcholine, is slowly hydrolysed by acetylcholinesterase and almost totally resistant to inactivation by non-specific cholinesterase or pseudocholinesterase.

Drug-Drug Interactions

Precaution should be taken when the inhalation challenge is performed in patients receiving any ß-adrenergic blocking agents, as it is possible that bronchoconstriction may not reverse as readily.

The following asthma and hay fever medications inhibit the response of airways to Provocholine (methacholine chloride USP), and should be withheld before the test, for their duration of action: ß-agonists, anticholinergics and theophylline. Corticosteroids, cromoglycate and nedocromil, after regular use, may alter Provocholine (methacholine chloride USP) responsiveness but they do not do this acutely; thus, they may be continued in their regular dose before any test. The effects of other newer medications have not been investigated.

Drug-Food Interactions

Methacholine chloride can be administered without regards to timing of meals.

Drug-Herb Interactions

The interactions of methacholine chloride with herbal medications or supplements have not been established.

Drug-Laboratory Test Interactions

The interactions of methacholine chloride with laboratory tests have not been established. Back To Top

Dosage and Administration

Recommended Dose and Dosage Adjustments

For Provocholine (methacholine chloride USP) Powder, adults and children (5 years or older) are exposed to the following increasing concentrations: 0.03, 0.0625, 0.125, 0.25, 0.5, 1, 2, 4, 8 and 16 mg/ mL. (See Tables 1A, 1B, 1C, 1D, and 1E).

Preparation of Dilutions:

Provocholine (methacholine chloride USP) Powder requires dilution before use. All dilutions using Provocholine (methacholine chloride USP) Powder should be made with 0.9% sodium chloride solution for injection (saline) or 0.9% sodium chloride solution with 0.4% phenol (saline with 0.4% phenol) or 0.9% sodium chloride solution for injection with 0.9% benzyl alcohol (saline with 0.9% benzyl), as suggested in Table 1A for Provocholine (methacholine chloride USP) 100 mg/vial, Table 1B for Provocholine (methacholine chloride USP) 160 mg/vial, Table 1C for Provocholine (methacholine chloride USP) 320 mg/vial, Table 1D for Provocholine (methacholine chloride USP) 1280 mg/vial and Table 1E for Provocholine (methacholine chloride USP) 1600 mg/vial in sterile USP Type I Glass vials. After adding the 0.9% saline or 0.9% saline with 0.4% phenol or 0.9% saline with 0.9% benzyl, shake each vial to obtain a clear solution. Check the date of preparation or expiry before using dilutions that are not freshly prepared. (Note: When preparing dilutions, use only the same kind of diluent to prepare all concentrations).

Provocholine (methacholine chloride USP) solutions prepared from powder and using aseptic technique may be stored in a refrigerator (2° to 8°C) for up to 2 weeks. After this time, discard the vials and prepare new dilutions. Freezing does not affect the stability of the dilutions. 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) before use.

Tables 1A, 1B, 1C, 1D and 1E describe methods of producing appropriate dilutions, using a single vial of Provocholine (methacholine chloride USP) Powder.

NOTE: The initial dilutions of the 320 mg, 1280 mg and 1600 mg vials to obtain solutions of 32 mg/mL (320 mg and 1600 mg) or 128 mg/mL (1280 mg) are NOT to be administered to the patient during the methacholine challenge test with Provocholine (methacholine chloride USP). They are only used in the preparation of the 16 mg/mL and 8 mg/mL dilutions.

When preparing dilutions using Provocholine (methacholine chloride USP), a sterile bacterial-retentive filter (porosity 0.22 μm) should be used when transferring a solution from each vial (at least 2 mL) to a nebulizer. Back To Top

Table 1A: Preparation of Serial Dilutions Using a Single 100 mg Vial of Provocholine Powder (methacholine chloride USP)

TAKE ADD 0.9% saline or 0.9% saline with 0.4% phenol or 0.9% saline with 0.9% benzyl OBTAIN DILUTION
100 mg Provocholine 6.25 mL 16 mg/mL (A)
3 mL of dilution A 3 mL 8 mg/mL (B)
3 mL of dilution B 3 mL 4 mg/mL (C)
3 mL of dilution C 3 mL 2 mg/mL (D)
3 mL of dilution D 3 mL 1 mg/mL (E)
3 mL of dilution E 3 mL 0.5 mg/mL (F)
3 mL of dilution F 3 mL 0.25 mg/mL (G)
3 mL of dilution G 3 mL 0.125 mg/mL (H)
3 mL of dilution H 3 mL 0.0625 mg/mL (I)
3 mL of dilution I 3 mL 0.03 mg/mL (J)

Table 1B: Preparation of Serial Dilutions Using a Single 160 mg Vial of Provocholine Powder (methacholine chloride USP)

TAKE ADD 0.9% saline or 0.9% saline with 0.4% phenol or 0.9% saline with 0.9% benzyl OBTAIN DILUTION
160 mg Provocholine 10 mL 16 mg/mL (A)
3 mL of dilution A 3 mL 8 mg/mL (B)
3 mL of dilution B 3 mL 4 mg/mL (C)
3 mL of dilution C 3 mL 2 mg/mL (D)
3 mL of dilution D 3 mL 1 mg/mL (E)
3 mL of dilution E 3 mL 0.5 mg/mL (F)
3 mL of dilution F 3 mL 0.25 mg/mL (G)
3 mL of dilution G 3 mL 0.125 mg/mL (H)
3 mL of dilution H 3 mL 0.0625 mg/mL (I)
3 mL of dilution I 3 mL 0.03 mg/mL (J)

Table 1C: Preparation of Serial Dilutions Using a Single 320 mg Vial of Provocholine Powder (methacholine chloride USP)

TAKE ADD 0.9% saline or 0.9% saline with 0.4% phenol or 0.9% saline with 0.9% benzyl OBTAIN DILUTION
160 mg Provocholine 10 mL 32 mg/mL (A)
3 mL of dilution A 3 mL 16 mg/mL (B)
3 mL of dilution B 3 mL 8 mg/mL (C)
3 mL of dilution C 3 mL 4 mg/mL(D)
3 mL of dilution D 3 mL 2 mg/mL (E)
3 mL of dilution E 3 mL 1 mg/mL (F)
3 mL of dilution F 3 mL 0.5 mg/mL(G)
3 mL of dilution G 3 mL 0.25 mg/mL (H)
3 mL of dilution H 3 mL 0.125 mg/mL (I)
3 mL of dilution I 3 mL 0.0625 mg/mL (J)
3 mL of dilution J 3 mL 0.03 mg/mL (K)

Table 1D: Preparation of Serial Dilutions Using a Single 1280 mg Vial of Provocholine Powder (methacholine chloride USP)

TAKE ADD 0.9% saline or 0.9% saline with 0.4% phenol or 0.9% saline with 0.9% benzyl OBTAIN DILUTION
1280 mg Provocholine 10 mL 128 mg/mL (A)
1 mL of dilution A 7 mL 16 mg/mL (B)
1 mL of dilution A 15 mL 8 mg/mL (C)
4 mL of dilution C 4 mL 4 mg/mL(D)
2 mL of dilution C 6 mL 2 mg/mL (E)
1 mL of dilution C 7 mL 1 mg/mL (F)
1 mL of dilution C 15 mL 0.5 mg/mL(G)
4 mL of dilution G 4 mL 0.25 mg/mL (H)
2 mL of dilution G 6 mL 0.125 mg/mL (I)
1 mL of dilution G 7 mL 0.0625 mg/mL (J)
1 mL of dilution G 15 mL 0.03 mg/mL (K)

Table 1E: Preparation of Serial Dilutions Using a Single 1600 mg Vial of Provocholine Powder (methacholine chloride USP)

TAKE ADD 0.9% saline or 0.9% saline with 0.4% phenol or 0.9% saline with 0.9% benzyl OBTAIN DILUTION
1600 mg Provocholine 50 mL 32 mg/mL (A)
3 mL of dilution A 3 mL 16 mg/mL (B)
3 mL of dilution B 3 mL 8 mg/mL (C)
3 mL of dilution C 3 mL 4 mg/mL(D)
3 mL of dilution D 3 mL 2 mg/mL (E)
3 mL of dilution E 3 mL 1 mg/mL (F)
3 mL of dilution F 3 mL 0.5 mg/mL(G)
3 mL of dilution G 3 mL 0.25 mg/mL (H)
3 mL of dilution H 3 mL 0.125 mg/mL (I)
3 mL of dilution I 3 mL 0.0625 mg/mL (J)
3 mL of dilution J 3 mL 0.03 mg/mL (K)

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Administration

General Procedures:

The challenge test must be conducted in a pulmonary function laboratory or clinic, by adequately trained personnel, for safety and accuracy.

The FEV1 value should be established before and after diluent inhalation. After determination of the post diluent baseline pulmonary function, the predicted value of a positive response is then calculated from the mean before diluent inhalation.

The methacholine challenge is performed by giving a subject increasing serial concentrations of Provocholine (methacholine chloride USP), after determining baseline FEV1. When using Provocholine (methacholine chloride USP), baseline FEV1 is determined with inhaled normal saline control or normal saline control containing 0.4% phenol or normal saline control containing 0.9% benzyl (Note: Use the same diluent that the Provocholine (methacholine chloride USP) Powder has been reconstituted with). A subject to be challenged must have an FEV1 of at least 70% of the predicted value. A common error giving inaccurate results is caused by not taking a full inspiratory breath prior to baseline FEV1 determination. Consult a physician if the FEV1 falls below 1.5 litres. Do not leave the patient unattended at any time.

An inhaled ß-agonist must be administered after a methacholine challenge test with Provocholine (methacholine chloride USP) to expedite the return of the FEV1 to baseline and to relieve any discomfort of the subject. Most patients revert to normal pulmonary function within 10 to 20 minutes following administration of a ß-agonist.

In order to produce interpretable results, it is important to calibrate nebulizers to produce a standard output, and validate the reproducibility of the delivery system. Suitable nebulizers and standard settings are discussed in published sources.

Two methods of administration of the methacholine challenge test with Provocholine (methacholine chloride USP) have been widely used in current clinical practice; the tidal breathing method and the dosimeter method. The tidal breathing technique requires the patient to breathe normally, over a two minute period, a constantly generated aerosol of Provocholine (methacholine chloride USP). By contrast, the dosimeter method requires the patient to take five full breaths of Provocholine (methacholine chloride USP) aerosol generated by an appropriate dosimeter to produce a specific dose per breath. Additional delivery devices and methods have been described in the literature. Approved manufacturer’s instructions should be followed when using these devices. With all techniques, the test is stopped if the FEV1 falls by 20% or more from the mean baseline FEV1. The dose concentration and the percent fall in FEV1 are then used to calculate either the provocative concentration to cause a fall in FEV1 of 20% (PC20), or the provocative dose (PD20). Back To Top

Tidal Breathing Method:

The following method is based on the use of the Wright nebulizer. If using other nebulizer models, consult published sources on methacholine challenge tests for the appropriate operation of alternate nebulizers.

  1. Using a 3 mL syringe and needle, draw up 2-3 mL of the diluent (0.9% saline or 0.9% saline with 0.4% phenol or 0.9% saline with 0.9% benzyl) and place it in the nebulizer vial. Attach the nebulizer and necessary tubing to an appropriate compressed gas source.
  2. At this time, the subject should be told that subsequent aerosols may produce mild cough, chest tightness or shortness of breath. Tell the subject that if these symptoms become uncomfortable, to remove the face mask or mouthpiece and to stop inhaling the aerosol immediately. Try to avoid suggesting that these symptoms will definitely develop, as suggestion alone can lower the FEV1. Remember that perception of airway narrowing can vary considerably between subjects, making it advisable to watch and listen for other signs such as wheeze and an altered pattern of breathing. Instructions to cease inhaling the aerosol if symptoms become troublesome should be repeated before every dose.
  3. Instruct the patient to relax and breathe the aerosol quietly (tidal breathing) for 2 minutes.
  4. Keeping the nebulizer well away from the patient, adjust the flow meter so that the nebulizer is operating at the calibrated output (0.13 mL/min for the Wright nebulizer).
  5. Apply a nose clip and place the face mask loosely over the nose and mouth (or the mouthpiece in the mouth). Start the stopwatch immediately. The nebulizer should be kept vertical. The patient should hold the nebulizer so as to avoid warming the solution, and subsequently altering the output.
  6. After exactly two minutes, remove the nebulizer from the patient’s mouth, turn off the flow meter, and discard the solution.
  7. Measure the FEV1 30 and 90 seconds after the end of the inhalation. These values may be left at ATPS. If the FEV1 at 90 seconds is the same or lower than that at 30 seconds, the measurement must be repeated at 3 minutes and, if needed, at 2 minute intervals until the FEV1 starts to rise. To avoid tiring the patient, the FEV1 should only be measured once on each occasion. If it is not technically satisfactory, it should be repeated after 10 seconds.
  8. If the FEV1 falls by 20% or more from the mean baseline FEV1 (ATPS) or to less than 1.0 litre, no further inhalations are given. (A physician should be consulted if the FEV1 falls below 1.5 litres.) If the FEV1 has fallen by 16% or more from baseline, it is unwise to give further doses. The PC20 may be extrapolated from the last two points of the dose response curve.
  9. For Provocholine (methacholine chloride USP) Powder, the concentration of the first aerosol of Provocholine (methacholine chloride USP) is 0.03 mg/mL. Subsequent doses are given at approximately 5-minute intervals in doubling concentrations. (0.0625, 0.125, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0 and 16.0 mg/mL).
  10. Repeat steps 1 through 8 with each increasing concentration of Provocholine (methacholine chloride USP) until the FEV1 has fallen by 20% or more from baseline, or the FEV1 is 1.5 litres or less, or the highest concentration has been given. Do not give any further aerosols of Provocholine (methacholine chloride USP).
  11. After the test is completed, give the patient 2 puffs of a ßagonist. Wait 10 minutes and measure the FEV1 and VC. Patients should not be allowed to leave the laboratory until their FEV1 has returned to within 90% of baseline.
  12. After the test, reusable nebulizers should be sterilized according to manufacturer’s recommendations. Disposable nebulizers should be discarded appropriately.

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Dosimeter Method:

The following method is based on the use of a DeVilbiss jet nebulizer attached to a Rosenthal French dosimeter operating at 20 psi and a period of 0.6 seconds per actuation. If using other nebulizers or dosimeters, consult manufacturer’s instructions and published sources on methacholine inhalation challenge for the appropriate operation of alternate nebulizers and dosimeters. The dosimeter should be calibrated to ensure accurate dose delivery and re-calibrated whenever the length of the tubing is changed.

All solutions are delivered from functional residual capacity (FRC) to total lung capacity (TLC). Factors that influence the response to inhalation challenge, and which should be consistent, are nebulizer output and inspiratory time.

The FEV1 value should be established before and after diluent inhalation. After determination of the post-diluent baseline pulmonary function, the predicted value of a positive response is then calculated from the mean before diluent inhalation.

  1. Solution is put in the nebulizer, and the necessary tubing attached to the dosimeter. The aerosol is generated by the compressed air delivered at 20 psi through the nebulizer. The output is controlled by a solenoid valve that is triggered by the inspiration and is kept open for 0.6 seconds. A nose clip is used. The subjects are instructed to inhale slowly from functional residual capacity (FRC) to total lung capacity (TLC). During the inhalation, the vent of the nebulizer should be kept open.
  2. Baseline pulmonary function is established with five inhalations of the diluent for Provocholine (methacholine chloride USP) Powder (0.9% saline or 0.9% saline with 0.4% phenol or 0.9% saline with 0.9% benzyl), and the baseline FEV1 noted. A subject to be challenged must have an FEV1 of at least 70% of the predicted value when tested with the diluent. Spirometry is measured within 5 minutes of the fifth inspiration of the diluent.
  3. At this time, the subject should be told that subsequent aerosols may produce mild cough, chest tightness or shortness of breath. Tell the subject that if these symptoms become uncomfortable, to remove the mouthpiece immediately. Try to avoid suggesting that these symptoms will definitely develop, as suggestion alone can lower the FEV1. Remember that perception of airway narrowing can vary considerably between subjects, making it advisable to watch and listen for other signs such as wheeze and an altered pattern of breathing. Instructions to cease inhaling the aerosol if symptoms become troublesome should be repeated before every step up in concentration.
  4. As with the tidal breathing technique, serial concentrations of Provocholine (methacholine chloride USP) are administered. Five inhalations of each concentration are taken, followed by measurement of FEV1 within 5 minutes of the last inhalation at each dosage. One inhalation unit is defined as one inhalation of a solution of Provocholine (methacholine chloride USP) containing 1 mg/mL. Because doses are taken in rapid succession, the units are expressed as cumulative units, as shown in Table 2 below.
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    Table 2: Cumulative Inhalation Units

    Serial Concentration Number of Breaths Cumulative Units per Concentration Total Cumulative Units
    0.03 mg/mL 5 0.15 0.15
    0.0625 mg/mL 5 0.3 0.45
    0.125 mg/mL 5 0.625 1.08
    0.25 mg/mL 5 1.25 2.33
    0.5 mg/mL 5 2.5 4.83
    1 mg/mL 5 5 9.83
    2 mg/mL 5 10 19.83
    4 mg/mL 5 PC20 39.83
    8 mg/mL 5 40 79.83
    16 mg/mL 5 80 159.83
  6. If the FEV1 falls by 20% or more from the mean baseline FEV1 (ATPS) or to less than 1.0 litre, no further inhalations are given. (A physician should be consulted if the FEV1 falls below 1.5 litres.) Partial doses (fewer than 5 inhalations) may be given if the FEV1 is between 15% and 20% less than baseline control, in order to protect against an excessive fall in pulmonary function.
  7. After the test is completed, give the patient 2 puffs of a ßagonist. Wait 10 minutes and measure the FEV1. Patients should not be allowed to leave the laboratory until their FEV1 has returned to within 90% of baseline.
  8. After the test, reusable nebulizers should be sterilized according to manufacturer’s recommendations. Disposable nebulizers should be discarded appropriately.

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Shortening the Test Procedure:

Technicians should be well versed on the longer procedure before attempting a shorter version. Shortening the test does run the risk of inadvertently giving the patient too high a dose; always err on the side of safety and give a lower dose when in doubt. If clinical history suggests that the patient may not have asthma or that their asthma is very mild, then the lowest concentration may be omitted, as described below:

1. Starting Concentrations in Adults

As a guide, the first concentration of Provocholine (methacholine chloride USP) can be based on the following criteria:

Starting Concentration

Starting concentration

2. Starting Concentrations in Children

Starting Concentrations

3. Omission of Concentrations

If, after the first concentration of Provocholine (methacholine chloride USP), there has been no evidence of any significant fall in the FEV1 (less than 5% from mean baseline) and there is NO clinical evidence of any bronchoconstriction (chest tightness, cough or wheezing), the next dose may be omitted. As soon as there is any evidence of symptoms or a fall greater than 5% from mean baseline FEV1, DO NOT omit any further concentrations. If a concentration is omitted, it is important to stress before every subsequent inhalation that the subject should remove the face mask/mouthpiece as soon as they experience any breathing or chest discomfort.

Calculation and Interpretation of Results:

Either the provocative concentration or the provocative dose causing a 20% fall in FEV1 (PC20 or PD20) may be calculated as described below:

1. Calculation of PC20

With either the tidal breathing method or the dosimeter method, airway responsiveness may be expressed as that concentration of Provocholine (methacholine chloride USP) provoking a fall in FEV1 of 20% (PC20). The percent fall in FEV1 can be calculated using the mean baseline FEV1, as shown below:

Fall in FEV1

The percent fall in is then plotted against the rising concentration of Provocholine (methacholine chloride USP) (log scale). The PC20 is obtained by linear interpolation between the last two points, as shown in Figure 1.

Concentration in methacholine

Figure 1: Calculation of PC20

Calculating PC20

Calculating of PD20

The FEV1 from the best spirogram at each dose is plotted on semilog paper (see example Figure 2, below) and a dose response curve constructed. The dose is expressed as cumulative units, either μmoles or breath units, where 1 mg/mL is equal to 0.5 μmoles or 10 breath units. The curve starts at 100%, and the last data point should be at 80% of saline control or lower. From this curve, the PD20, the provocation dose of agonist necessary for a 20% drop in FEV1, can be interpolated. The PD20 is the measure of the sensitivity to Provocholine (methacholine chloride USP). Patients who do not respond to five inhalations of Provocholine (methacholine chloride USP) at the 16 mg/ mL concentration can be said to have a negative challenge.

Cummulative Methacholine Units

Figure 2: Airway responsiveness to Provocholine (PD20), expressed as cumulative units (either μmoles or breath units)

3. Interpretation of Results

In clinical trials, most asthmatics had a positive response at the 10 mg/mL concentration or less. Results can be interpreted with respect to the presence or absence of asthma only if the initial FEV1/VC is > 70%. The cut off point between normal and increased responsiveness is a PC20 of 8 mg/mL, or a PD20 of 4 cumulative μmoles or 80 cumulative breath units. (Figure 3). Increased responsiveness is arbitrarily graded as borderline if between 4 and 8 mg/mL (2 and 4 μmoles or 40 and 80 breath units), as mild between 2 and < 4 mg/mL (1 and < 2 μmoles or 20 and 40 breath units), as moderate if between 0.25 and < 2 mg/mL (0.125 and < 1 μmoles or 5 and < 20 breath units), and as severe if < 0.25 mg/mL (< 0.125 μmoles or < 2.5 breath units). Patients with a PC20 >16 mg/ mL (or a PD20 8 μmoles or >160 cumulative breath units) are unlikely to have current symptoms due to asthma. When the PC20 is between 2 and 16 mg/mL, or the PD20 is between 1 and 8 μmoles or 20 and 160 cumulative breath units, current symptoms due to asthma are likely to be mild, infrequent or absent. Current symptoms of asthma are usual when the PC20 is < 2 mg/mL, or the PD20 is < 1 μmoles or < 20 cumulative breath units.

NOTE: When using a single dose automatic provocation device system to administer Provocholine (methacholine chloride USP), the equivalent of the above values will need to be calculated, as appropriate.

Figure 3

Figure 3: Comparison of Provocholine (methacholine chloride USP) airway responsiveness expressed as PC20 (mg/mL), using the tidal breathing method, and expressed as PD20 (cumulative µmoles and cumulative breath units) using the dosimeter method. Back To Top

Overdosage

Provocholine (methacholine chloride USP) is to be administered only by inhalation. When administered orally or by injection, overdosage with Provocholine (methacholine chlordie USP) can result in a syncopal reaction, with cardiac arrest and loss of consciousness. Serious toxic reactions should be treated with 0.5 mg to 1 mg of atropine sulfate, administered IM or IV. Back To Top

Action and Clinical Pharmacology

Mechanism of Action

Provocholine (methacholine chloride USP) is a parasympathomimetic (cholinergic) bronchoconstrictor agent to be administered in solution only, by inhalation, for diagnostic purposes.

Methacholine chloride is the ß-methyl homolog of acetylcholine and differs from the latter primarily in its greater duration and selectivity of action. Bronchial smooth muscle contains significant parasympathetic (cholinergic) innervation. Bronchoconstriction occurs when the vagus nerve is stimulated and acetylcholine is released from the nerve endings. Muscle constriction is essentially confined to the local site of release because acetylcholine is rapidly inactivated by acetylcholinesterase.

Compared with acetylcholine, methacholine chloride is more slowly hydrolysed by acetylcholinesterase and is almost totally resistant to inactivation by non-specific cholinesterase or pseudocholinesterase.

When a solution containing Provocholine (methacholine chlordie USP) is inhaled, subjects with current asthma are more sensitive to methacholine and bronchoconstrict at lower doses than healthy subjects. This difference in response is the pharmacologic basis for the Provocholine(methacholine chlordie USP) inhalation diagnostic challenge. The test is most useful diagnostically when there are current symptoms consistent with asthma and when the forced expiratory volume at one second (FEV1) is normal at > 70% predicted. A normal result excludes current asthma (variable airflow limitation), but does not exclude past asthma. Back To Top

Pharmacodynamics

When there is chronic airflow limitation with an FEV1/VC of < 70%, the test can be abnormal due to other pathophysiological causes such as smoker’s bronchitis, emphysema or cystic fibrosis. The challenge may also be positive in patients with allergic rhinitis without symptoms of asthma, or in patients who have had or will in the future develop asthma symptoms.

Certain drugs can affect the pharmacodynamic response to Provocholine (methacholine chloride USP) - See Drug-Drug Interactions.
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Storage and Stability

Temperature:

Reconstituted Solutions:

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Special Handling Instructions

Provocholine (methacholine chloride USP) is a potent bronchoconstrictor. Do not inhale the powder. Do not handle this material if you have asthma or hay fever. A low resistance filter should be applied to an expiratory port of any dosing apparatus, as necessary, to prevent Provocholine (methacholine chloride USP) aerosol from being released into the air of the room.

When using Provocholine (methacholine chloride USP) any unused solution should be discarded from the nebulizer after each concentration. Back To Top

DOSAGE FORMS, COMPOSITION AND PACKAGING

Provocholine (methacholine chloride USP) Powder:

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References

  1. Morris JF, Koski WA, Johnson LC. Spirometric standards for healthy non-smoking adults. Am Rev Resp Dis 1971;103:57-67.