Prescription Drug Information: Provocholine (Page 2 of 3)

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.

3 DOSAGE FORMS AND STRENGTHS

Powder for Solution: 100 mg of white to off-white crystalline powder in amber glass vials (powder is reconstituted and then diluted prior to administration)

4 CONTRAINDICATIONS

Provocholine is contraindicated in the following situations:

  • Hypersensitivity to methacholine or other parasympathomimetic agents. Reactions have included rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.
  • Baseline FEV1 < 60% predicted (adults or pediatric patients) or <1.5 L (adults)

5 WARNINGS AND PRECAUTIONS

5.1 Risk of 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. Emergency equipment and medication should be immediately available to treat acute respiratory distress. Because of the potential for severe bronchoconstriction, the use of Provocholine in patients with clinically apparent asthma or wheezing is not recommended. If severe bronchoconstriction occurs, reverse immediately by the administration of a rapid-acting inhaled β-agonist.

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 escalating Provocholine doses, which may result in administration of unnecessary higher doses and an increase in the risk for excessive bronchoconstriction.

5.2 Risks to Healthcare Providers Administering Provocholine

The supplied Provocholine powder or the Provocholine nebulized aerosol (after reconstitution and/or dilution) may cause bronchoconstriction in healthcare providers administering Provocholine in a methacholine challenge test. Healthcare providers and any other personnel involved in the administration of Provocholine should take the following precautionary steps:

  • Do not inhale the supplied Provocholine powder
  • Do not handle the Provocholine powder if you have asthma or hay fever.
  • Apply a low resistance filter to expiratory ports of dosing apparatus, as necessary, to prevent Provocholine release in the room air

5.3 Coexisting Diseases and Conditions

Provocholine is not recommended for patients with uncontrolled hypertension, aortic aneurysm, or history of myocardial infarction or stroke diseases. Patients with epilepsy, vagotonia, peptic ulcer disease, thyroid disease, urinary tract obstruction or other condition that could be adversely affected by a cholinergic agent should undergo methacholine challenge only if the healthcare practitioner feels the benefit to the individual outweighs the potential risks.

6 ADVERSE REACTIONS

The following adverse reactions associated with the use of Provocholine were identified in clinical studies or post marketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Bronchospasm (includes symptoms such as chest tightness, cough or wheezing).

Adverse reactions less commonly associated with Provocholine include headache, throat irritation, light-headedness and itching.

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