PROVOCHOLINE 100 mg POWDER FOR SOLUTION FOR INHALATION BY NEBULIZER

2. What you need to know before you use PROVOCHOLINE 100 mg Powder for Solution for Inhalation by Nebulizer

Do not use PROVOCHOLINE

• If you are allergic to the active substance or other parasympathomimetic agents (acetylcholine, carbachol, arecoline, pilocarpine...) or to any of the other components of this medicinal product (listed in section 6).

• If you have asthma, wheezing or the results of baseline tests (at rest) of respiratory function (FEV1) are equal to or less than 1-1.5 liters or 70% of the predicted value.

• If you are taking beta-adrenergic blockers (medicines for tension, circulation, or heart), see “Other medicines and PROVOCHOLINE”.

• If you have undergone a PROVOCHOLINE test, a second test with PROVOCHOLINE is contraindicated.

• If you have uncontrolled hypertension (high blood pressure) or have suffered a myocardial infarction (heart attack) in the last 3 months.

• If you have a disease called myasthenia gravis (muscle weakness and fatigue) and are being treated with cholinesterase inhibitor medications.

Warnings and precautions

Consult your doctor or pharmacist before undergoing the PROVOCHOLINE inhalation challenge test:

• If you have ever had an epileptic seizure, if you suffer from any cardiovascular disease (heart and blood vessel disease), peptic ulcer, urinary tract obstruction.

• If you have recently had or have the flu, any upper respiratory tract infection, chronic lung diseases (cystic fibrosis, sarcoidosis, tuberculosis, chronic obstructive pulmonary disease).

• If you have allergic rhinitis (inflammation of the nasal mucosa, with continuous dripping and nasal congestion) without asthma, are a smoker, or are exposed to air pollutants.

• If you are being treated with medications for asthma or allergies (see “Other medicines and PROVOCHOLINE”).

• If you are a woman, you should inform your doctor if you are pregnant, or of the date of your last menstruation, or of the date and result of your last pregnancy test. In women of childbearing age, before performing the PROVOCHOLINE test, the possibility of pregnancy should be ruled out.

• It is not recommended for use in children under 5 years of age due to the lack of data on its safety.

• As a result of the administration of PROVOCHOLINE, severe bronchoconstriction and a reduction in respiratory function may occur. Patients with hyperreactivity (exaggerated reaction) of the airways may experience bronchoconstriction (contraction of the bronchi that makes breathing difficult) with doses as low as 0.025 mg/ml. If severe bronchoconstriction occurs, your doctor will administer a medication containing a rapid-acting bronchodilator (beta-agonist) by inhalation to counteract it.

• The PROVOCHOLINE inhalation challenge test should only be performed under the direct supervision of a specialized doctor and in facilities with the appropriate equipment.

Other medicines and PROVOCHOLINE

Tell your doctor or pharmacist if you are using, have recently used, or may need to use any other medication.

If you are taking beta-adrenergic blockers (medicines for tension, circulation, or heart), you should not undergo the PROVOCHOLINE inhalation challenge test, as the response to metacholine hydrochloride may be exaggerated or prolonged, and you may not respond easily to the treatment used to return breathing to normal and for relief of discomfort.

The administration of medications for asthma and allergies (beta-agonists, anticholinergics, and theophylline) should be suspended before performing the PROVOCHOLINE test.

The use of other medications for asthma and allergies, such as corticosteroids, cromoglycate, and nedocromil, may alter the response capacity of PROVOCHOLINE; however, it is not necessary to interrupt treatment with them.

The effects of other more recent medications have not been investigated.

Using PROVOCHOLINE with food and drinks

Avoid consuming coffee, tea, cola drinks, and chocolate on the day of the PROVOCHOLINE test.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor or pharmacist before using this medicinal product.

PROVOCHOLINE should not be used in pregnant women.

Breastfeeding should be suspended if the PROVOCHOLINE test is necessary, as it is unknown whether it passes into breast milk.

Driving and using machines

No effects on driving or using machines have been described.

3. How to use PROVOCHOLINE 100 mg Powder for Solution for Inhalation by Nebulizer

Follow exactly the administration instructions of this medicinal product indicated by your doctor or pharmacist. In case of doubt, consult your doctor or pharmacist again.

This medicinal product should only be inhaled with a special breathing device (nebulizer) under the direct supervision of a specialized doctor. PROVOCHOLINE cannot be used orally or by injection. It must be diluted before inhalation. Your doctor will administer different concentrations of the diluted medicinal product by inhalation, as necessary, based on the results obtained. Inform your doctor if you experience any difficulty breathing at any time during the test.

Adults and children from 5 years of age

Before starting the PROVOCHOLINE test, your doctor will perform baseline tests (at rest) of lung function. You can only undergo the PROVOCHOLINE inhalation challenge test if you have an FEV1 (volume expelled in the first second of a forced exhalation) of at least 70% of the predicted value.

The test is positive if the reduction in FEV1 with PROVOCHOLINE is 20% compared to the value obtained in the lung function test without the medicinal product.

Standard inhalation procedure:The patient will receive a series of concentrations (from lower to higher) of PROVOCHOLINE. For each concentration, 5 inhalations will be administered in a nebulizer that allows intermittent release every 0.6 seconds using a dosimeter.

After the PROVOCHOLINE test, the doctor may administer a medication (bronchodilator) to accelerate the return to normal of the FEV1 value and relieve discomfort. Most patients return to normal lung function after 5 minutes of administration of a bronchodilator or 30-45 minutes without a bronchodilator.

Children under 5 years of age

It is not recommended for use in children under 5 years of age due to the lack of data on its safety.

If you use more PROVOCHOLINE than you should

PROVOCHOLINE is administered in solution and only by inhalation. If administered orally or by injection, an overdose of metacholine hydrochloride can cause syncope (fainting), cardiac arrest, and loss of consciousness.

Severe toxic reactions should be treated with 0.5-1 mg of atropine sulfate, administered intramuscularly or intravenously.

In case of overdose or accidental ingestion, consult your doctor or pharmacist immediately or call the Toxicology Information Service, telephone 91 562 04 20.

4. Possible side effects

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

Adverse reactions associated with PROVOCHOLINE inhalation challenge tests include the following side effects: headache, throat irritation, dizziness, and itching.

Reporting of side effects

If you experience any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly through the Spanish Medicines Monitoring System for Human Use http://www.notificaram.es. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of PROVOCHOLINE 100 mg Powder for Solution for Inhalation by Nebulizer

Keep this medicinal product out of the sight and reach of children.

• Unreconstituted vials (powder): No special storage conditions are required.

• Reconstituted vials (dilutions A, B, C, and D): Store in a refrigerator (between 2°C and 8°C) for a maximum of 2 weeks. The stability of solutions A, B, C, and D is not affected by freezing.

• Reconstituted vial E: Prepare on the same day as the challenge test.

Do not use this medicinal product after the expiry date stated on the packaging after EXP. The expiry date is the last day of the month indicated.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Contents of the pack and other information

Composition of PROVOCHOLINE

• The active substance is metacholine hydrochloride. Each 20 ml vial contains 100 mg of metacholine hydrochloride in powder form.
• The excipient is nitrogen.

Appearance of the product and contents of the pack

PROVOCHOLINE is presented in 20 ml amber-colored vials containing 100 mg of metacholine hydrochloride in powder form, which are reconstituted with an injection of 0.9% sodium chloride, containing 0.4% phenol (pH = 7.0). Each pack contains 6 vials.

Marketing Authorization Holder and Manufacturer

DIATER LABORATORIO DE DIAGNÓSTICO Y APLICACIONES TERAPÉUTICAS, S.A.

Avda. Gregorio Peces Barba 2,

28919 Leganés, Madrid

SPAIN

This information is intended only for healthcare professionals:

Standard inhalation procedure:The patient will receive a series of concentrations (from lower to higher) of PROVOCHOLINE. For each concentration, 5 inhalations will be administered in a nebulizer that allows intermittent release every 0.6 seconds using a dosimeter.

In each of the 5 inhalations of the series of concentrations, the patient will start with a functional residual capacity (FRC) and will inhale slowly and completely the released dose. At 5 minutes, the FEV1 values will be determined. The procedure will end when the FEV1 is reduced by 20% or more compared to the baseline value obtained with the sodium chloride solution (e.g., a positive response) or if a total of 188.88 accumulated units have been administered (see the table below) and the FEV1 has been reduced by 14% or less (e.g., a negative response). If a reduction in FEV1 of 15% to 19% is produced compared to the baseline value, the test can be repeated at the same concentration or a higher concentration can be given, provided that the administration of 188.88 accumulated units is not exceeded.

Before performing the PROVOCHOLINE inhalation challenge test, the doctor should prepare the corresponding dilutions of PROVOCHOLINE. To do this, the following instructions should be followed:

Dilutions:(Note: Do not inhale the powder. Do not handle this product if you have asthma or allergies). All dilutions must be made with 0.9% injectable sodium chloride, containing 0.4% phenol (pH = 7.0), using empty and sterile glass vials of borosilicate type I. After adding the sodium chloride solution, shake each vial until a clear solution is obtained.

Dilution sequence - test for multiple patients (2-5 patients)

2 vials of PROVOCHOLINE are required

Dilution sequence - test for a single patient

Use a sterile filter capable of retaining bacteria (0.22 μm) to transfer the solution from each vial (at least 2 ml) to the nebulizer.

Date of last revision of this leaflet:June 2020

Detailed information on this medicinal product is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) (http://www.aemps.gob.es/)