Prescription Drug Information: Provocholine

PROVOCHOLINE- methacholine chloride powder, for solution
Methapharm Inc.

WARNING: SEVERE BRONCHOCONSTRICTION

Severe bronchoconstriction can result from Provocholine administration (including the lowest dose). The use of Provocholine is contraindicated in pediatric and adult patients with baseline FEV1 < 60% predicted or adults with FEV1 < 1.5 L. Because of the potential for severe bronchoconstriction, the use of Provocholine in patients with clinically apparent asthma or wheezing is not recommended [see Warnings and Precautions (5.1)].

Emergency equipment and medication should be immediately available to treat acute respiratory distress. If severe bronchoconstriction occurs, reverse immediately with a rapid-acting inhaled bronchodilator agent (β-agonist) [see Warnings and Precautions (5.1)].

If baseline spirometry is not performed or is measured inaccurately, the initial FEV1 may be underestimated. In this situation, decreases in FEV1 may not be detected after administration of escalating Provocholine doses, which may result in administration of unnecessary higher doses and an increased risk for excessive bronchoconstriction [see Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE

Provocholine is used in a methacholine challenge test 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.

2 DOSAGE AND ADMINISTRATION

2.1 Important Handling Instructions

Given that Provocholine is a potent bronchoconstrictor:

  • Provocholine is contraindicated in pediatric and adult patients with baseline FEV1 < 60% predicted or in adults with FEV1 < 1.5 L [see Contraindications (4) and Warnings and Precautions (5.1)]
  • Use of Provocholine is not recommended in patients with clinically apparent asthma or wheezing
  • Discard any unused solution from the nebulizer after each administration.

2.2 Important Administration Instructions

Provocholine should be administered in 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.


Only 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.


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 FEV1 (Forced Expiratory Volume in 1 second) greater than or
equal to 60% of the predicted value (in adults and children) and greater than or equal to 1.5 L (in adults).


At commencement of the methacholine challenge test and prior to nebulization with Provocholine, FEV1 must be
measured following exposure to nebulized diluent (post-diluent FEV1 ) [see Dosage and Administration (2.3, 2.4)]. The
methacholine challenge test is considered positive if there is a reduction in FEV1 of 20% or more from post-diluent FEV1 .
The test should be stopped at this point. The reduction value must be calculated and recorded before starting the test
with Provocholine.


May use Provocholine with or without meals.


Administer Provocholine by oral inhalation using either the 5-Breath Dosimeter Dosing Method or the 2-Minute Tidal
Breathing Dosing Method with the doubling or quadrupling stepwise protocols [see Dosage and Administration (2.3,
2.4)]. Prepare the Provocholine concentrations/doses by reconstituting Provocholine powder using either 0.9% saline
diluent or 0.9% saline with 0.4% phenol diluent [see 2.5 Reconstitution and Dilution Prior to Administration and Storage
of Solutions].

2.3 Five (5)-Breath Dosimeter Dosing Method in Patients 5 Years of Age and Older

Administer the diluent (the same diluent used to reconstitute the Provocholine powder) prior to administering the
Provocholine dose(s) to obtain post-diluent FEV1 values.


Administration of the Diluent to Obtain Post-Diluent FEV1 Value

1. Using a 3 mL syringe and needle, draw up 2 to 3 mL of the diluent (0.9% saline or 0.9% saline with 0.4% phenol)
and dispense into the nebulizer using a sterile bacterial-retentive filter (porosity 0.22 μm).

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.

5. Perform spirometry and measure the FEV1 30 and 90 seconds after the fifth inhalation from the nebulizer to obtain
the post-diluent FEV1 value. 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 8. If the post-diluent FEV1 falls by < 20%
from baseline FEV1 , continue to Step 6.

Administration of Provocholine in a Methacholine Challenge Test

6. Using a 3 mL syringe and needle, draw up the recommended Provocholine concentration (see Table 1) that was
prepared using the quadrupling dose method and dispense into the nebulizer using a sterile bacterial-retentive filter(porosity 0.22 μm). See Table 4 for preparation of the Provocholine solutions by the quadrupling dose method.

Table 1: Recommended Provocholine Oral Inhalation Concentrations(s) [Quadrupling Dose(s)]

Provocholine Concentration
0.0625 mg/mL (Solution 5)
0.25 mg/mL (Solution 4)
1 mg/mL (Solution 3)
4 mg/mL (Solution 2)
16 mg/mL (Solution 1)

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. Stop dosing if the FEV1 has fallen by ≥ 20% from the post diluent FEV1 is ≤ 1.5 liters in adults, or the highest Provocholine concentration (16 mg/mL) has been administered (whichever comes first). For severe bronchoconstriction, see Warnings and Precautions (5.1). Do not administer additional Provocholine concentrations.

8. 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.

9. After the test, wash and clean reusable nebulizers thoroughly according to manufacturers recommendations.

2.4 Two (2)-Minute Tidal Breathing Dosing Method in Patients 5 Years of Age and Older

Administer the diluent (the same diluent used to reconstitute the Provocholine powder) prior to administering the Provocholine dose(s) to obtain post-diluent FEV1 values. 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 to Obtain Post-Diluent FEV 1 Value

1. Using a 3 mL syringe and needle, draw up 2 to 3 mL of the diluent (0.9% saline or 0.9% saline with 0.4% phenol) and dispense into the nebulizer using a sterile bacterial-retentive filter (porosity 0.22 µm).

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. Using a 3 mL syringe and needle, draw up the recommended Provocholine oral inhalation dose (see Table 2) using either the doubling or quadrupling dose method and dispense into the nebulizer using a sterile bacterial-retentive filter (porosity 0.22 µm). See Tables 3 and 4 for preparation of the Provocholine solutions for the doubling and quadrupling dose methods, respectively.

Table 2: Recommended Provocholine Oral Inhalation Dose(s) By Nebulization [Doubling Dose(s) or Quadrupling Dose(s)]

Doubling Dose Increments
Provocholine Concentration Provocholine Dose*
0.0625 mg/mL (Solution I) 1.484 mcg
0.125 mg/mL (Solution H) 2.969 mcg
0.25 mg/mL (Solution G) 5.938 mcg
0.5 mg/mL (Solution F) 11.875 mcg
1 mg/mL (Solution E) 23.75 mcg
2 mg/mL (Solution D) 47.5 mcg
4 mg/mL (Solution C) 95 mcg
8 mg/mL (Solution B) 190 mcg
16 mg/mL (Solution A) 380 mcg
Quadrupling Dose Increments
Provocholine Concentration Provocholine Dose*
0.0625 mg/mL (Solution 5) 1.484 mcg
0.25 mg/mL (Solution 4) 5.938 mcg
1 mg/mL (Solution 3) 23.75 mcg
4 mg/mL (Solution 2) 95 mcg
16 mg/mL (Solution 1) 380 mcg

* Dose delivered based on the drug output of the English Wright Nebulizer and the duration of inhalation (2 minutes).

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 dose (380 mcg) has been administered (whichever comes first). For severe bronchoconstriction, see Warnings and Precautions (5.1). Do not administer additional Provocholine doses.

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.

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