Provocholine® (methacholine chloride) – UK

Prescribing Information

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Provocholine (methacholine chloride) 100 mg powder for nebuliser solution. Please refer to the Summary of Product Characteristics (SmPC) before prescribing.
Abbreviated Prescribing Information.
Presentation: Each 20 mL vial contains 100 mg methacholine chloride, a white or off-white deliquescent crystalline powder for nebuliser solution, for inhalation, non-sterile.
Indications: This medicinal product is for diagnostic use only. Provocholine is indicated in adults (aged 17 and over) to detect bronchial airway hyperreactivity, to assist in the diagnosis of asthma when the clinical history is suggestive of the condition but there is normal spirometry and the diagnosis remains uncertain after additional evaluation.
Dosage and administration: Methacholine challenge, may occasionally induce severe bronchospasm and should therefore only be conducted in specialist respiratory centres with appropriate resuscitation facilities. Adults (aged 17 and over): Provocholine is intended for single use only. Once reconstituted, the prepared solutions should be used immediately and administered only in solution for inhalation. Before starting a Provocholine challenge test, pulmonary function must be tested and confirmed to be within the normal range. The patient’s baseline FEV1 (Forced Expiratory Volume in 1 second)/ FVC (forced vital capacity) ratio (FEV1/FVC ratio), without exposure to nebulised diluent or Provocholine, must be greater than 70%, considered normal baseline spirometry, for the challenge test to proceed. At commencement of the test, baseline FEV1 should be measured following exposure to nebulised diluent, without Provocholine. Baseline FEV1 following exposure to nebulised diluent should be used to calculate any subsequent decline in FEV1 following exposure to increasing concentrations of Provocholine. The test should be terminated if there is a 20%, or greater, decline in FEV1 from baseline. All dilutions must be made with sterile 0.9% sodium chloride solution for injection, using empty, sterile borosilicate Type I glass vials. For preparation and administration instructions, please refer to the SmPC and the training material included on the product website prior to preparation of solutions and administration. 
Contraindications: Hypersensitivity to the active substance or other parasympathomimetic agents. Clinically apparent asthma, wheezing or with abnormal baseline spirometry (FEV1/FVC ratio less than 70%). Patients treated with beta blockers. Repeated administration of Provocholine through inhalation of doses higher than the dose administered on the day of the diagnostic test. Bradycardia. Known aortic aneurysm. Heart attack or stroke in the last 3 months. Uncontrolled hypertension. Patients with myasthenia gravis undergoing treatment with cholinesterase inhibitors. Recent eye surgery. Risk from elevated intracranial pressure (e.g. cerebral aneurysm).
Warnings and Precautions: Provocholine is a bronchoconstrictor agent for diagnostic purposes only and should not be used as a therapeutic agent. Provocholine is to be administered only by inhalation. When administered orally or by injection, methacholine chloride is associated with nausea and vomiting, substernal pain or pressure, hypertension, fainting and transient complete heart block. The test should be performed in accordance to current clinical practice guidelines. Take a full clinical respiratory history, before embarking on a methacholine challenge, given the occurrence of false positive test results with methacholine in other respiratory conditions, such as after influenza, upper respiratory tract infections or immunisations, in very old patients or in patients with chronic pulmonary diseases. Challenge testing can be positive in patients with allergic rhinitis without asthma, in smokers, or in patients exposed to aerial contaminants. The challenge testing for Provocholine must only be carried out under specialist medical supervision by a doctor familiar with all aspects of the methacholine inhalation challenge testing technique, all contraindications, warnings and precautions, and the management of respiratory failure. The doctor responsible for the testing must be contactable while it is being carried out and available immediately if needed. If the doctor is carrying out the testing himself, another person must be available to assist him if needed. The patient must never be left unattended during the testing. Emergency equipment and medication must be available immediately to treat acute respiratory failure. 
Administration of Provocholine to patients with epilepsy, cardiovascular disease accompanied by bradycardia, vagotonia, peptic ulcer, thyroid disease, urinary tract obstruction or other conditions that could be adversely affected by a cholinergic agent should only be carried out if the doctor deems that the risk/benefit ratio to be positive for the patient. It is essential that the baseline spirometry is accurate. If the baseline spirometry is not performed or measured accurately, and the initial FEV1 is underestimated, subsequent falls after inhaling Provocholine solutions may not be detected, resulting in too high a dose and excessive bronchoconstriction. As a result of the administration of Provocholine, severe bronchoconstriction and a reduction in respiratory function may occur. Patients with airway hyperreactivity can experience bronchoconstriction with doses as low as 0.03125 mg/ml. If severe bronchoconstriction occurs, this must be immediately reversed by administration of a rapid-acting inhaled bronchodilator agent (beta-agonist), precautions for which must be taken when the inhalation challenge testing is performed in patients receiving beta blockers, since it is possible that bronchoconstriction may not be reversed easily. Subjects who suffer from asthma are noticeably more sensitive to bronchoconstriction induced by methacholine than healthy subjects. To ensure the safe and effective use of challenge testing with Provocholine, patients should be informed about the symptoms that may occur as a result of the testing and how to manage them. Laboratory staff with asthma or allergies should be particularly careful and take necessary measures when handling the material or if they are performing testing on patients.
Interactions: The concomitant treatment of Provocholine and beta blockers is contraindicated. The following medications for the treatment of asthma inhibit the airways’ response to Provocholine, whereby their treatment must be interrupted before the testing, due to the duration of their effect: beta agonists, anti-muscarinics and theophylline.
Fertility, pregnancy and lactation: There have been no animal reproduction studies with methacholine chloride. It is not known whether methacholine chloride can cause harm to the foetus when administered to pregnant patients or whether methacholine chloride is excreted in human milk.  Provocholine should not be used during pregnancy or breastfeeding, unless the benefits clearly outweigh the risks. It is not known whether methacholine chloride affects fertility.   
Effects on ability to drive and use machines: Provocholine has no influence on the ability to drive and on the use of machines.
Undesirable effects: Adverse reactions associated with inhaled methacholine challenge tests are rare, and include incidences of headache, throat irritation, light-headedness/dizziness and itching.  A positive reaction to methacholine challenge may produce symptoms of bronchospasm, such as chest tightness, cough or wheezing (the frequency of which is not known) that may require reliever bronchodilators.
Overdose: Refer to SmPC.
Handling and Disposal: Do not inhale the powder. Do not handle this product if you suffer from asthma or allergies. A low resistance filter should be applied to an expiratory port of any dosing apparatus, as necessary, to prevent Provocholine aerosol from being released into the air. When using Provocholine, any unused solution should be discarded from the nebuliser after each concentration. Please consult the SmPC for further instructions.
Legal Category: POM.
NHS Price: £420.00 per carton containing 6 vials.
Marketing Authorisation Holder: ACIC EUROPE LIMITED, Leontiou, 163, CLERIMOS BUILDING, 2nd floor 3022 Limassol, Cyprus.
MA Number: PL 41697/0006
Full prescribing information available from: Galen Limited, Seagoe Industrial Estate, Craigavon, BT63 5UA, United Kingdom.
Date of Preparation: May 2022.

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