Provocholine (Page 2 of 4)

2.5 Reconstitution and Dilution Prior to Administration and Storage of Solutions

Provocholine requires reconsitution before use (see Tables 3 and 4):

  • 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

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 3) or quadrupling the concentration (see Table 4)
  • After adding the diluent, shake each vial to obtain a clear solution
  • Use the same diluent to prepare all concentrations

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

Refrigerate the reconstituted and diluted solutions at 36o to 46o F (2o 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 3: Reconstitution and Dilution of Supplied Provocholine Powder: 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 4: Reconstitution and Dilution of Supplied Provocholine Powder: 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)

2.6 Calculation and Interpretation of Methacholine Challenge Test Results

A positive methacholine challenge test is a ≥ 20% reduction in the FEV1 (after Provocholine oral inhalation) compared with the mean post-diluent FEV1 . Calculate and record post-diluent FEV1 value before the methacholine challenge test is started. Express airway hyperreactivity as the provocative Provocholine concentration (mg/mL) providing a fall in FEV1 of ≥ 20% (PC20 ) when the methacholine challenge test is dosed using either the 5-breath dosimeter method or the 2-minute tidal breathing method, or as the provocative Provocholine dose (mcg) providing a fall in FEV1 of ≥ 20% (PD20 ) when using the 2-minute tidal breathing method.

Calculation of PC20


Calculate PC20 using one of the following methods. Determine the percent decrease in FEV1 using the mean post-diluent FEV1 and the lowest FEV1 post-dose, as shown below:


% fall in FEV1 = mean post-diluent FEV1 — lowest FEV1 post-Provocholine x 100
mean post-diluent FEV1

Method #1

Plot the percent decrease in FEV1 against the increasing methacholine concentration using a log scale and obtain the PC20 by linear interpolation between the last two points, as shown in Figure 1.

figure1
(click image for full-size original)

Method #2


Alternatively, calculate the PC20 as follows:


PC20 = antilog [log C1+ (log C2 -- log C1)(20 -- R1)]
(R2- R1)

Where:
• C1 = second last methacholine concentration (< 20% FEV1 decrease)
• C2 = last methacholine concentration (≥ 20% FEV1 decrease)
• R1 = % fall FEV1 after C1
• R2 = % fall FEV1 after C2

Calculation of PD20 (2-minute tidal breathing method only)


Calculate the PD20 as follows:


PD20 = antilog [log D1+ (log D2 -- log D1)(20 -- R1)]
(R2- R1)

Where:
• D1 = second last Provocholine dose (< 20% FEV1 decrease)
• D2 = last Provocholine dose (≥ 20% FEV1 decrease)
• R1 = % FEV1 decrease after D1
• R2 = % FEV1 decrease after D2

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 FEV1 reduction 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.

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