Metacholine Lofarma

Package leaflet: Information for the user

METACOLINA LOFARMA 10 mg/ml powder and solvent for solution for nebuliser, 64 mg/ml powder for solution for nebuliser

Methacholine chloride
Please read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor.
• If you get any side effects, talk to your doctor. This includes any side effects not listed in this leaflet. See section 4.

Contents of this leaflet:

1. What METACOLINA LOFARMA is and what it is used for
2. What you need to know before you use METACOLINA LOFARMA
3. How to use METACOLINA LOFARMA
4. Possible side effects
5. How to store METACOLINA LOFARMA
6. Contents of the pack and other information

1. What METACOLINA LOFARMA is and what it is used for

METACOLINA LOFARMA contains the active substance methacholine chloride, a substance that causes bronchoconstriction (a bronchoconstrictor agent), used exclusively for diagnostic purposes in performing a non-specific bronchial provocation test.
This test is used for the diagnosis of:

• bronchial hyperreactivity (excessive reactivity of the bronchi causing airway closure in response to a stimulus);
• asthma in patients who do not present signs or symptoms (clinical manifestations) of asthma.

2. What you need to know before using METACOLINE LOFARMA

Do not use METACOLINE LOFARMA

• if you are allergic to methacholine chloride or to any of the other ingredients of this medicine (listed in section 6) or to similar substances;
• if you have signs and symptoms of asthma (clinically evident asthma);
• if you have difficulty breathing (dyspnea);
• if your lungs are not functioning properly (very low baseline pulmonary function tests with FEV1, forced expiratory volume in one second, < 80% of predicted);
• if you are taking beta-blockers, medicines used to treat various heart conditions and high blood pressure, as they may increase and prolong the response to methacholine (see section “Other medicines and METACOLINE LOFARMA”);
• if you have previously experienced severe allergic reactions (anaphylactic manifestations);
• if you have previously suffered from asthma or allergic rhinitis (hay fever): in this case, you must not handle methacholine powder;
• if you are pregnant or breastfeeding (see section “Pregnancy and breastfeeding”);
• if the person undergoing the test is a child under 5 years of age.

Warnings and precautions
Talk to your doctor before using METACOLINE LOFARMA.
When using METACOLINE LOFARMA, appropriate emergency equipment and medicines must be immediately available to treat severe bronchoconstriction (bronchoconstriction).
Do not take products containing vitamin C before undergoing the test (see section “Other medicines and METACOLINE LOFARMA”).
METACOLINE LOFARMA will be administered to you under strict medical supervision if any of the following conditions apply to you:

• if you have heart or circulatory problems (cardiovascular diseases) and a very slow heart rate (bradycardia);
• if you suffer from epilepsy;
• if you have stomach or intestinal ulcers (gastroduodenal ulcer);
• if you have thyroid problems (thyroid diseases);
• if you have undergone stomach surgery (vagotomy);
• if you have urinary tract problems (urinary tract obstructions).

Your doctor will inform you about the symptoms that may occur during the test and the measures that will be taken to manage them.
Children
Children under 5 years of age should not undergo non-specific bronchial provocation testing with methacholine.
Other medicines and METACOLINE LOFARMA
Inform your doctor if you are taking, have recently taken, or might take any other medicines.
Do not use METACOLINE LOFARMA if you are taking beta-blockers, medicines used to treat various heart conditions and high blood pressure, as they may increase and prolong the response to methacholine (see section “Do not use METACOLINE LOFARMA”).
Before undergoing the methacholine test, inform your doctor if you are taking:

• medicines or products containing ascorbic acid (vitamin C), as they may reduce the response to methacholine (see section “Warnings and precautions”);
• atropine, used to treat heart rhythm disorders (sinus bradycardia), before anesthesia, for certain eye examinations, or as an antidote in insecticide poisoning, as it prevents the response to methacholine testing;
• fenoterol, ipratropium bromide, prednisone, terfenadine, theophylline, sodium cromoglycate, and other medicines used to treat chronic respiratory diseases or breathing disorders, as they may interfere with test results.

Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, are planning a pregnancy, or are breastfeeding, consult your doctor before using this medicine.
Pregnancy
You must not use METACOLINE LOFARMA during pregnancy (see section “Do not use METACOLINE LOFARMA”). Therefore, undergo the methacholine test within 10 days after the start of your last menstrual period and no later than 2 weeks after a negative pregnancy test result.
Breastfeeding
You must not use METACOLINE LOFARMA if you are breastfeeding.
Driving and using machines
The effect of this medicine on the ability to drive or operate machinery is unknown.

3. How to use METACOLINE LOFARMA

Use this medicine exactly as directed by your doctor. If you have any doubts, consult your
physician.
This medicine will be administered to you in a hospital setting by a doctor.
METACOLINE LOFARMA will be administered by inhalation through the bronchi (intrabronchial inhalation) using a suitable nebulizer.

You may undergo the test only if your lungs are functioning adequately. (See section "Do not use METACOLINE LOFARMA".)
The test will be performed according to the following recommended procedure:

1. At the beginning of the test, your doctor will have you inhale the buffer/control/sodium chloride (NaCl) 0.9% solution 3-5 times to establish a baseline assessment of respiratory function (baseline spirometry).
2. Subsequently, every 2 minutes, your doctor will have you inhale increasing doses of methacholine (30 - 60 - 120 - 240 - 390 - 690 - 1,290 - 2,490 micrograms).
3. After each methacholine inhalation, your doctor will repeat the assessment of respiratory function. If airflow decreases by 20% or more compared to the baseline value, the test will be stopped. The test will also be stopped once the maximum dose has been reached. It is preferable to complete the test within 20 minutes, which corresponds to the duration of action of methacholine. At the end of the test, your doctor will administer inhaled medications to counteract bronchoconstriction caused by methacholine (beta-mimetics).
4. Using an appropriate calculation method, the doctor will determine the dose of methacholine (in micrograms) that causes a 20% reduction in respiratory function compared to the baseline value, thereby indicating the degree of bronchial reactivity:

• mild, if the methacholine dose is between 1,600 and 800 micrograms;
• moderate, if the methacholine dose is between 800 and 400 micrograms;
• high, if the methacholine dose is between 400 and 100 micrograms.

Preparation of the nebulizer solution
METACOLINE LOFARMA 10 mg/ml
Before performing the test, the methacholine powder and the buffer/control powder must be dissolved with 3 ml of water for injections. Once reconstituted, the buffer solution will serve both as a control and to dilute the 10 mg/ml methacholine solution to the required concentrations for the test.

METACOLINE LOFARMA 64 mg/ml
Before performing the test, the methacholine powder must be dissolved with 3 ml of water for injections. A sodium chloride (NaCl) 0.9% solution may be used both as a control and to dilute the reconstituted 64 mg/ml methacholine solution.

Use in children
Children under 5 years of age should not undergo non-specific bronchial provocation testing with methacholine.

If you use more METACOLINE LOFARMA than you should
This medicine will be administered by trained medical personnel, so overdose is unlikely.
However, following administration of excessive doses of METACOLINE LOFARMA, a transient loss of consciousness (syncopal reaction) may occur, accompanied by cardiac arrest and fainting, particularly if methacholine is administered orally (oral route) or by injection (injection route).
If you have any doubts about the use of this medicine, consult your doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The following side effects may occur:

• headache, feeling of emptiness in the head, increased excitability (state of hyperexcitability);
• throat irritation;
• feeling of tightness in the chest (thoracic oppression), difficulty in breathing (dyspnea), cough, increased bronchial secretions, worsening (exacerbation) of asthma symptoms;
• increased urinary tract motility (ureteric peristalsis);
• itching.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, please inform your doctor. You can also report side effects directly via the website:
https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse . By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store METACOLINE LOFARMA

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the packaging after "Exp.".
The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
Storage of the solution after preparation: store in a refrigerator (2°C – 8°C) and use within 24 hours.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What METACOLINA LOFARMA contains
METACOLINA LOFARMA 10 mg/ml powder and powder for solution for nebulizer
Powder vial

• The active substance is methacholine chloride. Each vial contains 30 mg of methacholine chloride.
• The other components are: disodium phosphate dibasic dihydrate, sodium phosphate monobasic monohydrate.
  Buffer powder vial
• Each vial contains 60.93 mg of disodium phosphate dibasic dihydrate and 14.85 mg of sodium phosphate monobasic monohydrate.

METACOLINA LOFARMA 64 mg/ml powder for solution for nebulizer
Powder vial

• The active substance is methacholine chloride. Each vial contains 192 mg of methacholine chloride.
• The other component is disodium phosphate dibasic dihydrate.

Description of the appearance of METACOLINA LOFARMA and contents of the pack
METACOLINA LOFARMA 10 mg/ml powder and powder for solution for nebulizer
5 or 10 powder vials with a capacity of 9 ml in glass + 5 buffer powder vials with a capacity of 9 ml in glass.
METACOLINA LOFARMA 64 mg/ml powder for solution for nebulizer
2 powder vials with a capacity of 9 ml in glass.
Marketing Authorization Holder and Manufacturer
Lofarma S.p.A., Viale Cassala, 40, 20143 Milano – Italy

The following information is intended exclusively for physicians or healthcare professionals:
METACOLINA LOFARMA 10 mg/ml powder and powder for solution for nebulizer
METACOLINA LOFARMA 64 mg/ml powder for solution for nebulizer
Methacholine chloride
CLINICAL INFORMATION
Dosage and method of administration
The methacholine vials (10 mg/ml and 64 mg/ml) and the buffer/control vials for methacholine 10 mg/ml must be reconstituted at the time of use with 3 ml of water for injections.
A sodium chloride (NaCl) 0.9% solution must be used both as a control and for subsequent dilutions of the reconstituted methacholine 64 mg/ml.
The buffer/control solution must be used both as a control and for subsequent dilutions of the reconstituted methacholine to maintain isotonicity of the solution.
The solutions are administered by inhalation via the intrabronchial route; therefore, the use of a nebulizer connected to a dosimeter powered by compressed air is recommended. Since the delivered drug dose depends on both the solution concentration and the drug consumption rate per unit of time, careful calibration of the nebulizer chamber—typically with a capacity of 2 ml—is recommended. Nebulizer consumption varies depending on the type, from 10 to 20 microliters per second.
For performing the bronchoconstriction test, which is generally carried out on subjects with good baseline ventilatory function (FEV not less than 80% of predicted), the recommended procedure is as follows:

1. Baseline FEV determination using a spirometer: the buffer/control/sodium chloride (NaCl) 0.9% solution is inhaled 3–5 times. After each inhalation, FEV is measured, and at the end of the cycle, the best observed value is selected.
2. Administration every 2 minutes, using a cumulative procedure, of the following methacholine doses: 30 – 60 – 120 – 240 – 390 – 690 – 1,290 – 2,490 micrograms (mcg).
   To calculate dosages, the consumption rate of the nebulizer chamber and the delivery time must naturally be taken into account.
   Table 1 shows an example of a dosing schedule using methacholine 10 mg/ml solutions.
   Table 1 - Example of concentrations obtainable with methacholine 10 mg/ml.
   In this example, a nebulizer delivering 15 µl/second is used.

If higher concentrations of methacholine than those obtainable with the 10 mg/ml (10,000 mcg/ml) preparation are required, the 64 mg/ml preparation should be used, performing dilutions by doubling (1:2, 1:4, 1:8, etc.), using procedures that ensure maintenance of solution sterility. Dilutions must be prepared with 0.9% sodium chloride (NaCl) solution at the time of use.
Table 2 shows an example of a dosing schedule with dilutions achievable using methacholine 64 mg/ml.
Table 2 - Example of concentrations obtainable with methacholine 64 mg/ml
In the example, 45 µl are administered at a time (e.g., 3 x 15 µl)

*The 64 mg/ml (64,000 mcg/ml) preparation must not be used as such for the provocation test,
but serves as a stock solution for preparing the various dilutions, made using a 0.9% sodium chloride (NaCl) solution.
3) Spirometric measurements of FEV must be performed immediately after inhalation of each dose of methacholine, and in any case within 1 minute. The test is stopped as soon as a 20% or greater decrease in FEV compared to baseline is observed, and in any case when the maximum dose has been reached (2,490 mcg cumulative dose in the example in Table 1 and 2,878 mcg in the example in Table 2).
However, it is advisable that methacholine administrations be completed within 20 minutes, which corresponds to the duration of action of methacholine.
Methacholine-induced bronchoconstriction is rapidly reversible by inhalation of beta-mimetics.
The result of the nonspecific methacholine provocation test is usually expressed as PD FEV, which is the dose of methacholine, expressed in micrograms, causing a 20% fall in FEV from the baseline value. Since it is rare to observe experimentally an exactly 20% decrease in FEV, this value usually needs to be extrapolated. A widely used method is graphical interpolation. A dose-response curve is plotted on a semilogarithmic scale, with the percentage change in FEV on the ordinate and the logarithm of the dose (expressed in mcg) on the abscissa. The points immediately above and below the selected value (20%) are connected, and the methacholine dose (mcg) corresponding to a 20% decrease from baseline is extrapolated.
Alternatively to the graphical interpolation method, computer software programs are now readily available that allow automatic and instantaneous extrapolation of the PD.
Regarding interpretation of results, the test is generally considered positive if the patient responds with a PD of less than 1,600 mcg cumulative dose; hyperreactivity is considered mild when PD is between 1,600 and 800 mcg, moderate between 800 and 400 mcg, and severe between 400 and 100 mcg.
For further information, consult the Summary of Product Characteristics.