Provocholine

PROVOCHOLINE- methacholine chloride powder, for solution
PROVOCHOLINE INHALATION SOLUTION- methacholine chloride inhalation solution
Methapharm Inc.

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 [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, 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.

2 DOSAGE AND ADMINISTRATION

2.1 Methacholine Challenge Test Overview

  • 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.
  • 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 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).
  • Do not use Provocholine 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) ].
  • At commencement of the methacholine challenge test and prior to nebulization with Provocholine dose(s), FEV1 must be measured following exposure to nebulized diluent or base solution (contains no methacholine chloride) to obtain the post-diluent FEV1 [see Dosage and Administration (2.4, 2.5) ].
  • Provocholine powder for inhalation solution requires reconstitution and dilution before use (see Reconstitution and Dilution Prior to Administration (2.3)).
  • Provocholine inhalation solution (in a ready-to-use kit) does not require reconstitution and/or dilution.
  • 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 (2.4, 2.5) ].
  • Discard any unused solution from the nebulizer after each administration.
  • May use Provocholine with or without meals.
  • 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 (see Calculation and Interpretation of Methacholine Challenge Test Results (2.6)).
  • An inhaled β agonist must be administered after a methacholine challenge test with Provocholine 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 β agonist.

2.2 Recommended 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.

2.3 Reconstitution and Dilution Prior to Administration

1. Provocholine Powder for Inhalation Solution requires reconstitution before use (see Tables 1 and 2):

Add 6.25 mL of 0.9% Sodium Chloride Injection (0.9% saline) or 0.9% Sodium Chloride Injection with 0.4% phenol (0.9% saline with 0.4% phenol) 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 (see Table 1) or quadrupling the concentration (see Table 2). After adding the diluent, shake each vial to obtain a clear solution. Use the same diluent to prepare all concentrations

3. Use a sterile bacterial-retentive filter (porosity 0.22 µ m) when transferring the reconstituted or diluted solution from each vial (at least 2 mL) to a nebulizer.

4. Refrigerate the reconstituted and diluted solutions at 36o F to 46o F (2o C to 8o C) 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) before use.

Table 1: Reconstitution and Dilution of Supplied Provocholine powder for inhalation solution: Doubling Concentrations

TAKE

ADD 0.9% Saline or 0.9% Saline with 0.4% Phenol

Concentration (Total Volume) after reconstitution or dilution

100 mg of Provocholine Powder in one supplied vial

6.25 mL

16 mg/mL (6.25 mL) (Solution A)

3 mL of Solution A

3 mL

8 mg/mL (6 mL) (Solution B)

3 mL of Solution B

3 mL

4 mg/mL (6 mL) (Solution C)

3 mL of Solution C

3 mL

2 mg/mL (6 mL) (Solution D)

3 mL of Solution D

3 mL

1 mg/mL (6 mL) (Solution E)

3 mL of Solution E

3 mL

0.5 mg/mL (6 mL) (Solution F)

3 mL of Solution F

3 mL

0.25 mg/mL (6 mL) (Solution G)

3 mL of Solution G

3 mL

0.125 mg/mL (6 mL) (Solution H)

3 mL of Solution H

3 mL

0.0625 mg/mL (6 mL) (Solution I)

Table 2: Reconstitution and Dilution of Supplied Provocholine powder for inhalation solution: Quadrupling Concentrations

TAKE

ADD 0.9% Saline or 0.9% Saline with 0.4% Phenol

Concentration (Total Volume) after reconstitution or dilution

100 mg of Provocholine Powder in one supplied vial

6.25 mL

16 mg/mL (6.25 mL) (Solution 1)

3 mL of Solution 1

9 mL

4 mg/mL (12 mL) (Solution 2)

3 mL of Solution 2

9 mL

1 mg/mL (12 mL) (Solution 3)

3 mL of Solution 3

9 mL

0.25 mg/mL (12 mL) (Solution 4)

3 mL of Solution 4

9 mL

0.0625 mg/mL (12 mL) (Solution 5)

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