Schedule H

Inhalation (via nebuliser)

• Powder for reconstitution: 100 mg vial (used to prepare serial dilutions)

• Note: Not routinely commercially available; typically imported via special access or prepared extemporaneously from pharmaceutical-grade methacholine chloride powder in specialised pulmonary function laboratories

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India)

1. Diagnosis of Bronchial Hyperreactivity (Bronchial Provocation Test / Methacholine Challenge Test)

Indication criteria:

• Normal baseline spirometry but high clinical suspicion of asthma

• Evaluation of occupational asthma

• Assessment of exercise-induced bronchospasm

• Research protocols for airway hyperresponsiveness

Dosing Protocol (Standardised Five-Breath Dosimeter Method):

Step Concentration (mg/mL) Action

1 Diluent (normal saline) Control; perform baseline spirometry

2 0.0625 5 breaths via dosimeter; spirometry at 90 seconds

3 0.25 5 breaths via dosimeter; spirometry at 90 seconds

4 1.0 5 breaths via dosimeter; spirometry at 90 seconds

5 4.0 5 breaths via dosimeter; spirometry at 90 seconds

6 16.0 5 breaths via dosimeter; spirometry at 90 seconds

Parameter Details

Starting dose Diluent control, then 0.0625 mg/mL

Titration Quadrupling concentrations (0.0625 → 0.25 → 1.0 → 4.0 → 16.0 mg/mL)

Usual maintenance dose Not applicable (single diagnostic procedure)

Maximum dose 16 mg/mL concentration (cumulative dose approximately 2 mg)

Endpoint:

• Positive test: FEV₁ falls ≥20% from post-diluent baseline (PC₂₀ calculated)

• Negative test: FEV₁ does not fall ≥20% at maximum concentration (16 mg/mL)

Clinical Notes:

• Perform only in accredited pulmonary function laboratory with full resuscitation capability

• Baseline FEV₁ must be ≥70% predicted before initiating test

• Short-acting bronchodilator (salbutamol) must be immediately available for reversal

• Administer inhaled salbutamol after test completion regardless of result

• Withhold bronchodilators prior to test as per laboratory protocol

Secondary Indications — Adults (Off-label)

• No off-label therapeutic indications supported by Indian data

• Methacholine is exclusively a diagnostic agent

PAEDIATRIC DOSING (Specialist Only)

Primary Indications (Approved / Standard in India)

1. Diagnosis of Bronchial Hyperreactivity / Asthma

Age Group Dosing Protocol Maximum Concentration

<6 years NOT RECOMMENDED (inadequate spirometry cooperation) —

6–12 years Modified protocol with lower starting concentration (0.03 mg/mL); quadrupling increments 8 mg/mL

12 years Adult protocol may be applied 16 mg/mL

Parameter Details

Starting dose 0.03 mg/mL (paediatric protocol)

Titration Doubling or quadrupling concentrations based on response

Usual maintenance dose Not applicable

Maximum dose 8 mg/mL in children 6–12 years

Clinical Notes:

• Mandatory specialist paediatric pulmonologist supervision

• Child must be able to perform reproducible spirometry manoeuvres

• Continuous pulse oximetry during procedure

• Emergency reversal: inhaled salbutamol 200–400 mcg immediately available

• Systemic corticosteroids available for severe reactions

Safety Monitoring:

• Spirometry before and after each dose step

• Monitor for wheeze, cough, chest tightness, oxygen desaturation

• Stop test immediately if SpO₂ falls below 90% or severe symptoms develop

Secondary Indications — Paediatrics (Off-label)

• No established off-label paediatric indications in Indian practice

Age Restriction Statement:

• Not recommended in children below 6 years due to inability to perform reliable spirometry and safety concerns

• No dose adjustment required

• Minimal systemic absorption via inhalation route

• Rapidly hydrolysed by plasma cholinesterases

• Baseline FEV₁ <70% predicted or <1.5 L absolute

• Severe airflow obstruction

• Recent myocardial infarction or stroke (within 3 months)

• Known or suspected aortic aneurysm

• Uncontrolled hypertension (systolic >200 mmHg or diastolic >100 mmHg)

• Known hypersensitivity to methacholine or related compounds

• Recent eye surgery (risk of increased intraocular pressure)

• Current use of cholinesterase inhibitors

• Severe bullous lung disease

• Inability to perform acceptable spirometry

• Stable cardiovascular disease (risk of vagal-mediated effects during bronchospasm)

• Controlled epilepsy (cholinergic stimulation may lower seizure threshold)

• Narrow-angle glaucoma

• Urinary retention or prostatic hypertrophy

• Peptic ulcer disease

• Current respiratory tract infection (may cause false-positive result; defer testing 4–6 weeks)

• Pregnancy (relative contraindication; defer if possible)

• Testing must be performed in facility with immediate access to resuscitation equipment

Parameter Recommendation

Risk category Avoid unless essential for diagnosis; insufficient human data

Preferred alternatives Clinical assessment and therapeutic trial of bronchodilators preferred during pregnancy

When may be used Only if diagnosis significantly impacts pregnancy management; benefit must clearly outweigh risk

Monitoring If performed: fetal heart rate monitoring; maternal SpO₂; immediate bronchodilator availability

Parameter Recommendation

Compatibility Probably compatible; minimal systemic absorption

Drug levels in milk Expected to be very low to negligible

Preferred alternatives Defer testing if clinically feasible

Infant monitoring If breastfeeding continues: observe for respiratory irritation, feeding difficulty (unlikely)

Parameter Recommendation

Starting dose Begin with lowest concentration (0.03–0.0625 mg/mL)

Titration Slower increments; may use doubling rather than quadrupling concentrations

Special risks Increased cardiovascular risk during induced bronchospasm; higher likelihood of comorbid CAD, COPD, hypertension; increased sensitivity to cholinergic effects

Recommendation Consider alternative diagnostic approaches (clinical assessment, therapeutic trial) if cardiovascular risk is significant

Interacting Drug Effect Recommendation

Beta-blockers (systemic or ophthalmic) May potentiate and prolong bronchospasm; impair response to rescue bronchodilator Withhold for 24–48 hours before test if medically safe; avoid testing if cannot be withheld

Anticholinergic bronchodilators (ipratropium, tiotropium) Attenuate airway response; false-negative results Withhold short-acting 6–8 hours, long-acting 24–48 hours prior

Cholinesterase inhibitors (neostigmine, pyridostigmine) Potentiate methacholine effect; increased toxicity risk Contraindicated; do not perform test

Interacting Drug Effect Recommendation

Short-acting beta-2 agonists (salbutamol) Attenuate airway response; may cause false-negative Withhold 6–8 hours prior to testing

Long-acting beta-2 agonists (salmeterol, formoterol) May blunt response Withhold 24–48 hours prior

Inhaled corticosteroids May reduce airway hyperresponsiveness over time Note in interpretation; no acute withholding needed

Theophylline May reduce test sensitivity Withhold 12–24 hours prior (per lab protocol)

ACE inhibitors Cough may confound symptom assessment Document use; note during interpretation

Caffeine May have mild bronchodilator effect Withhold on day of testing

• Cough

• Throat irritation

• Mild dyspnoea

• Chest tightness

• Headache

• Flushing

• Dizziness

• Transient wheeze (expected positive response)

Adverse Effect Clinical Action

Severe bronchospasm Immediate inhaled salbutamol (400–800 mcg); oxygen supplementation; may require nebulised bronchodilator

Hypoxaemia (SpO₂ <90%) Stop test immediately; high-flow oxygen; bronchodilator; monitor until recovery

Chest pain Stop test; ECG if cardiac aetiology suspected; supportive care

Syncope / Presyncope Stop test; supine positioning; assess for vasovagal or hypoxic cause

Life-threatening asthma attack Emergency protocol: IV access, nebulised salbutamol, systemic corticosteroids, oxygen; hospitalisation if required

Cardiac arrhythmia Stop test; ECG; cardiology consultation if indicated

Phase Parameters

Baseline (Pre-test) FEV₁ (must be ≥70% predicted); blood pressure; heart rate; SpO₂; medication history (bronchodilator withholding confirmed)

During procedure Spirometry (FEV₁) after each dose step; continuous pulse oximetry; symptom assessment

Post-test Administer salbutamol; repeat spirometry until FEV₁ returns to within 90% of baseline; observe for 30–60 minutes for delayed bronchospasm

Brand Name Manufacturer Availability

Provocholine Methapharm (imported) Special import via authorised channels

Methacholine Chloride USP Pharmaceutical-grade powder Extemporaneous preparation in specialised PFT laboratories

• No fixed-dose combinations available

• Not routinely stocked in retail pharmacies

• Available only in tertiary care pulmonary function laboratories

• Not under NPPA price control

• Not included in NLEM

• Cost varies significantly based on import channel and laboratory

1. Diagnostic test only — Methacholine has no therapeutic role; it is solely for confirming bronchial hyperreactivity when clinical suspicion of asthma exists despite normal spirometry.

1. Medication withholding is critical — Ensure bronchodilators and anticholinergics are withheld as per protocol; document all medications taken prior to test for accurate interpretation.

1. Never perform without resuscitation capability — Severe bronchospasm can be life-threatening; salbutamol, oxygen, and emergency equipment must be immediately accessible.

1. Negative test does not exclude asthma — A negative methacholine challenge reduces probability but does not definitively rule out asthma; clinical correlation remains essential.

1. Interpret PC₂₀ in clinical context — PC₂₀ <4 mg/mL indicates moderate-to-severe hyperreactivity; 4–16 mg/mL suggests mild hyperreactivity; values may vary with concurrent medications and recent infections.

1. Avoid in acute illness — Respiratory tract infections can cause transient airway hyperreactivity; defer testing for 4–6 weeks after acute infection.

methacholine; bronchial provocation test; asthma diagnosis; bronchial hyperreactivity; muscarinic agonist; pulmonary function test; PC20; diagnostic agent; specialist use; pulmonology

RxIndia v1.0 — 01 Feb 2026

• CDSCO guidelines

• Indian Pharmacopoeia / NFI

• AIIMS Pulmonology Department protocols

• API Textbook of Medicine — Asthma and Pulmonary Function Testing

• ICMR guidance on asthma diagnosis

• Goodman & Gilman's The Pharmacological Basis of Therapeutics

• Indian Chest Society recommendations

• Global Initiative for Asthma (GINA) — supportive reference where aligned with Indian practice