Adverse reactions : תופעות לוואי

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 is to be administered only by inhalation. When administered orally or by injection, Provocholine is reported to be associated with nausea and vomiting, substernal pain or pressure, hypotension, fainting and transient complete heart block. (See OVERDOSAGE) 
Reporting of suspected adverse reactions:
Reporting suspected adverse reactions after authorisation of the medicinal product is important.
It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il Additionally, you should also report to Kamada Ltd. to email address: pharmacovigilance@kamada.com



DRUG INTERACTIONS
Overview

Provocholine 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, 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 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.

DOSAGE AND ADMINISTRATION

Two methods of administration of the Provocholine (methacholine chloride powder for inhalation) inhalation challenge test 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. By contrast, the dosimeter method requires the patient to take five full breaths of Provocholine aerosol generated to produce a specific dose per breath. With either technique, the test is stopped if the FEV1 falls by more than 20% from the mean baseline FEV1.
The concentration at dose 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 provocation dose (PD20).
DOSAGES
Adults and children (5 years or older) are exposed to the following increasing concentrations of Provocholine: 0.03, 0.06, 0.125, 0.25, 0.5, 1, 2, 4, 8 and 16 mg/mL. (See Table 1.) 
PREPARATION OF DILUTIONS
All dilutions should be made with 0.9% sodium chloride injection containing 0.9% benzyl alcohol, as suggested in Table 1, in sterile Type I Glass vials. After adding the 0.9% sodium chloride solution, shake each vial to obtain a clear solution. Check the date of preparation or expiry before using dilutions that are not freshly prepared.
Provocholine solutions prepared 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.
Discard used solution from the nebulizer after each concentration.
Table 1 describes a method of producing appropriate dilutions, using a single 20 mL vial containing 100 mg of methacholine chloride.

Table 1: Preparation of Serial Dilutions Using a Single 100 mg Vial

TAKE                    ADD               OBTAIN DILUTION
Provocholine (Methacholine    NaCl 0.9% with
Chloride Powder for             0.9% Benzyl inhalation)                        alcohol
100 mg                            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                0.06 mg/mL (I) 3 mL of dilution I                  3 mL                0.03 mg/mL (J) 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.

ADMINISTRATION
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 challenge is performed by giving a subject increasing serial concentrations of Provocholine, after determining baseline FEV1 with inhaled normal saline control containing 0.9% benzyl alcohol. 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.
Increasing concentrations of Provocholine are administered until there is a 20% fall in FEV1 or the highest concentration of 16 mg/mL is reached.

When using the dosimeter method, one inhalation unit is defined as one inhalation of a solution of Provocholine containing 1 mg/mL. Because doses are taken in rapid succession, the units are expressed as cumulative breath units, as shown in Table 2, below.

Table 2: Cumulative Inhalation Units
Serial             Number of      Cumulative Units          Total Cumulative Concentration          Breaths       per Concentration               Units 0.03          mg/mL           5                  0.15                     0.15 0.06          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                   20                     39.83
8             mg/mL           5                   40                     79.83 16            mg/mL           5                   80                    159.83 

An inhaled ß-agonist must be administered after Provocholine challenge 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. Patients should not be allowed to leave the laboratory until their FEV1 has returned to within 90% of baseline.
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.
Detailed instructions for carrying out the tidal breathing or the dosimeter methods are provided in the Product Monograph, as are alternative methods of calculating the PC20 (in mg/mL) or the PD20 (in cumulative μmoles or cumulative breath units).
Results can be interpreted with respect to the presence or absence of asthma only if the 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. 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.

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 can be based on the following criteria: a) If FEV1/VC >80% AND FEV1 >70% predicted AND FEV1 falls <10% after the diluent inhalation AND the patient's symptoms are well controlled on the following medications, use these starting concentrations:

Medication                                 Starting
Concentration
Inhaled or ingested corticosteroids                         0.125 mg/mL Daily bronchodilators                                        0.25 mg/mL Occasional bronchodilators (< once/day)                       1.0 mg/mL No medications                                                2.0 mg/mL  b) If FEV1/VC <80% OR FEV1 <70% predicted AND FEV1 falls <10% after the diluent inhalation AND the patient's symptoms are well controlled on the following medications, use these starting concentrations:

Medication                                          Starting
Concentration
Inhaled or ingested corticosteroids               0.03 mg/mL
Other or no medications                          0.125 mg/mL
 c) If a patient's FEV1 falls by 10% or more after the diluent inhalation, or if asthma symptoms do not appear to be well controlled, DO NOT omit any concentrations, and start all patients at 0.03 mg/mL.

2. Starting Concentrations in Children a) If FEV1/VC >80% AND the child’s symptoms are well controlled on the following medications, use these starting concentrations:

Medication                           Starting Concentration
Inhaled or ingested corticosteroids                        0.03 mg/mL Daily or occasional bronchodilators                        0.06 mg/mL No medications                                             0.25 mg/mL  b) If FEV1/VC <80% OR if asthma symptoms do not appear to be well controlled, DO NOT omit any concentrations, and start all patients at 0.03 mg/mL.

3. Omission of Concentrations
If, after the first concentration of Provocholine, 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 2-minute inhalation that the subject should remove the face mask/mouthpiece as soon as they experience any breathing or chest discomfort.