Version May 2024
Severe bronchoconstriction can result from methacholine administration (including the lowest dose). The use of methacholine is contraindicated in pediatric and adult patients with baseline FEV1 <60% predicted or adults with FEV1 <1.5 L. Because of the potential for severe bronchoconstriction, the use of methacholine in patients with clinically apparent asthma or wheezing is not recommended.
Emergency equipment and medication should be immediately available to treat acute respiratory distress. If severe bronchoconstriction occurs, reverse immediately with a rapid-acting inhaled bronchodilator agent (beta-agonist).
If baseline spirometry is not performed or measured inaccurately, the initial FEV1 may be underestimated. In this situation, decreases in FEV1 may not be detected after administration of escalating methacholine doses, which may result in administration of unnecessary higher doses and an increased risk for excessive bronchoconstriction.
Note: For inhalation only mixed in solution; do not inhale powder.
Diagnostic agent, bronchial airway hyperactivity: Inhalation:
Note: Before inhalation challenge, perform baseline pulmonary function tests; the patient must have an FEV1 of ≥60% of the predicted value. Only administer and perform testing in a pulmonary function laboratory or clinic, by adequately trained personnel. Before inhalation challenge, perform baseline pulmonary function tests with 0.9% saline diluent or 0.9% saline with 0.4% phenol diluent; use same diluent to reconstitute methacholine. After challenge completion, an inhaled beta-agonist may be administered to expedite FEV1 return within 90% of baseline and to relieve any discomfort.
1 to 3 mcg followed by a stepwise doubling or quadrupling of dose based on nebulizer device output per minute, particle size distribution (to assess lower airway delivery), time of tidal breathing, and ratio of inspiratory time to total breathing time. Tidal breathing technique is preferred over deep breathing techniques. Base results on effective delivered dose causing a 20% fall in FEV1 (ERS [Coates 2017]). Refer to institutional protocols.
Manufacturer labeling: May not reflect current practice; nebulizers that were necessary for described methodology in the prescribing information are considered obsolete and may be difficult to obtain (ie, two-minute tidal breathing protocol utilized the English-Wright nebulizer and the five-breath dosimeter method used the DeVilbiss 646 nebulizer) (ERS [Coates 2017]).
Two-minute tidal breathing method: Use doubling or quadrupling dose protocol beginning with a 0.0625 mg/mL (1.484 mcg) solution for the first dose progressing to a 16 mg/mL (380 mcg) solution, if necessary. Stop dosing if the FEV1 has fallen by ≥20% from the mean baseline, the FEV1 is ≤1.5 L, or the highest dose has been administered (whichever comes first). Refer to manufacturer's labeling for detailed dosing and administration information.
Five-breath dosimeter method: Use quadrupling dose protocol beginning with a 0.0625 mg/mL (1.484 mcg) solution (English-Wright nebulizer; dose delivered by other devices may vary) for the first dose progressing to a 16 mg/mL (380 mcg) solution, if necessary. Stop dosing if the FEV1 has fallen by ≥20% from the mean baseline, the FEV1 is ≤1.5 L, or the highest dose has been administered (whichever comes first). Refer to manufacturer's labeling for detailed dosing and administration information.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling.
There are no dosage adjustments provided in the manufacturer's labeling.
Refer to adult dosing.
(For additional information see "Methacholine: Pediatric drug information")
Diagnostic agent, bronchial airway hyperactivity: Note: Patient must have an FEV1 of ≥60% of the predicted value. Only administer and perform testing in a pulmonary function laboratory or clinic, by adequately trained personnel. Before inhalation challenge, perform baseline pulmonary function tests with 0.9% saline diluent or 0.9% saline with 0.4% phenol diluent; use same diluent to reconstitute methacholine. After challenge completion, an inhaled beta-agonist may be administered to expedite FEV1 return within 90% of baseline and to relieve any discomfort.
Children ≥5 years and Adolescents: Limited data available [ERS [Coates 2017]): Inhalation: 1 to 3 mcg followed by a stepwise doubling or quadrupling of dose based on nebulizer device output per minute, particle size distribution (to assess lower airway delivery), time of tidal breathing, and ratio of inspiratory time to total breathing time. Tidal breathing technique is preferred over deep breathing techniques. Base results on effective delivered dose causing a 20% fall in FEV1. Refer to institutional protocols.
Manufacturer labeling: May not reflect current practice; nebulizers that were necessary for described methodology in the prescribing information are considered obsolete and may be difficult to obtain (ie, two-minute tidal breathing protocol utilized the English-Wright nebulizer and five-breath dosimeter method was the DeVilbiss 646 nebulizer) (ERS [Coates 2017]).
Two-minute tidal breathing method: Use doubling or quadrupling dose protocol beginning with a 0.0625 mg/mL solution and 1.484 mcg dose (English-Wright nebulizer; dose delivered by other devices may vary) for the first dose progressing to a 16 mg/mL solution and 380 mcg dose, if necessary. Stop dosing if the FEV1 has fallen by ≥20% from the mean baseline or the highest dose has been administered (whichever comes first). Refer to manufacturer's labeling for detailed dosing and administration information.
Five-breath dosimeter method: Use quadrupling dose protocol beginning with a 0.0625 mg/mL solution for the first dose progressing to a 16 mg/mL solution, if necessary. Stop dosing if the FEV1 has fallen by ≥20% from the mean baseline or the 16 mg/mL dose has been administered (whichever comes first). Refer to manufacturer's labeling for detailed dosing and administration information.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling.
There are no dosage adjustments provided in the manufacturer's labeling.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Frequency not defined.
Dermatologic: Pruritus
Nervous system: Dizziness, headache
Respiratory: Bronchospasm, throat irritation
Hypersensitivity to methacholine, other parasympathomimetic agents, or any component of the formulation; baseline FEV1 <60% predicted (adults or pediatric patients) or <1.5 L (adults only).
Canadian labeling: Additional contraindications (not in the US labeling): Repeat challenge test on the same day; baseline FEV1 <70% predicted (adults or pediatric patients); concurrent use with beta-agonists, anticholinergics, or theophylline.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Concerns related to adverse effects:
• Bronchoconstriction: [US Boxed Warning]: Severe bronchoconstriction can result from methacholine administration (including the lowest dose). Because of the potential for severe bronchoconstriction, the use of methacholine in patients with clinically apparent asthma or wheezing is not recommended. Emergency equipment and medication should be immediately available to treat acute respiratory distress. If severe bronchoconstriction occurs, reverse immediately with a rapid-acting inhaled bronchodilator agent (beta-agonist). If baseline spirometry is not performed or measured inaccurately, the initial FEV1 may be underestimated. In this situation, decreases in FEV1 may not be detected after administration of escalating methacholine doses, which may result in administration of unnecessary higher doses and an increased risk for excessive bronchoconstriction.
Disease-related concerns:
• Risk to benefit: Evaluate risk to benefit in patients with peptic ulcer disease, seizures, thyroid disease, urinary tract obstruction, vagotonia, or other condition that could be adversely affected by a cholinergic agent. Use only if benefit outweighs risk in these patients.
• Cardiovascular disease: Guidelines contraindicate methacholine challenge testing in patients who have had a myocardial infarction (MI) or stroke within 3 months, uncontrolled hypertension (systolic >200 mm Hg or diastolic >100 mm Hg) or known aortic aneurysm (ATS [Crapo 2000]).
• Ocular disease: Guidelines contraindicate methacholine challenge testing in patients who have had recent eye surgery or any conditions where increased pressures (caused by forceful exhalations) would be harmful (ERS [Coates 2017]).
• Respiratory disease: [US Boxed Warning]: The use of methacholine in patients with clinically apparent asthma or wheezing is not recommended and is contraindicated in pediatric and adult patients with baseline FEV1 <60% predicted or adults with FEV1 <1.5 L. Product should not be handled by persons with asthma or hay fever.
Other warnings/precautions:
• Appropriate use: Test should be administered in a pulmonary function laboratory or clinic, by adequately trained personnel, and should be performed only under the responsibility of a health care practitioner trained in and thoroughly familiar with all aspects of the technique of methacholine challenge test and the management of respiratory distress. For inhalation use only mixed in solution; do not inhale powder.
• Inhalation study interpretation: Use caution when interpreting inhalation study results. Methacholine challenge may occasionally be positive after influenza, upper respiratory tract infections or immunizations, in very young or very old patients, in patients with chronic lung disease (eg, cystic fibrosis, sarcoidosis, tuberculosis, chronic obstructive pulmonary disease [COPD]), allergic rhinitis without asthma, smokers, after exposure to air pollutants, or in patients who had had or will in the future develop asthma. Challenge testing has a greater negative predictive value (excluding asthma as a diagnosis) than positive predictive value (establishing an asthma diagnosis) (ATS [Crapo 2000]; ERS [Coates 2017]).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Kit, Inhalation:
Provocholine:
Solution Reconstituted, Inhalation, as chloride:
Provocholine: 100 mg (1 ea)
No
Solution (reconstituted) (Provocholine Inhalation)
100 mg (per each): $99.60
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Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Inhalation:
Provocholine: 160 mg (20 mL); 320 mg (20 mL) [contains benzyl alcohol]
Provocholine: 1280 mg (10 mL); 1600 mg (1 ea)
Generic: 1600 mg (1 ea)
Solution Reconstituted, Inhalation, as chloride:
Provocholine: 100 mg (1 ea) [contains benzyl alcohol]
Generic: 100 mg (1 ea)
Oral inhalation: Must be diluted prior to administration; do not inhale powder. Remove any previously reconstituted or diluted solutions from refrigerator and allow to equilibrate to room temperature (~30 minutes) before use. Many nebulizers or dosimeters may be used; however, it is important to know the device output and particle size to calculate concentration-dose steps (ERS [Coates 2017]). Refer to institutional protocol.
Manufacturer's labeling: Methodology may not be applicable to all devices and protocols. Administer via inhalation only using a nebulizer with dosimeter. When transferring solution from each vial to nebulizer, use a sterile 0.22-micron filter. Give ascending serial concentrations (designated vials E through A) of methacholine starting with vial E and ending with vial A. At each of 5 inhalations of a serial concentration, the patient begins at functional residual capacity and slowly and completely inhales the dose delivered. Within 5 minutes, FEV1 values are determined. Refer to manufacturer's labeling for further detailed administration instructions.
Inhalation: Must be diluted prior to administration, do not inhale powder. Remove any previously reconstituted or diluted solutions from refrigerator and allow to equilibrate to room temperature (~30 minutes) before use. Many nebulizers or dosimeter may be used; however, it is important to know the device output and particle size to calculate concentration-dose steps (ERS [Coates 2017]). Refer to institutional protocol.
Manufacturer's labeling: Methodology may not be applicable to all devices and protocols. Administer via inhalation only using a using a nebulizer with dosimeter. When transferring solution from each vial to nebulizer, use a sterile 0.22 micron filter. Give ascending serial concentrations (designated Vials E through A) of methacholine starting with Vial E and ending with Vial A. At each of 5 inhalations of a serial concentration, the patient begins at functional residual capacity and slowly and completely inhales the dose delivered. Within 5 minutes, FEV1 values are determined. Further detailed instructions are available in the manufacturer's labeling.
Diagnostic agent, bronchial airway hyperactivity: Diagnosis of bronchial airway hyperactivity in adults and pediatric patients ≥5 years of age who do not have clinically apparent asthma.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Acetylcholinesterase Inhibitors: May enhance the adverse/toxic effect of Cholinergic Agonists. Specifically, cholinergic effects may be enhanced or increased. Risk C: Monitor therapy
Beta2-Agonists (Long-Acting): May diminish the therapeutic effect of Methacholine. Management: Hold long-acting beta2 agonists for 36 hours before methacholine use. Risk D: Consider therapy modification
Beta2-Agonists (Short-Acting): May diminish the therapeutic effect of Methacholine. Management: Hold short-acting beta2 agonists for 6 hours before methacholine use. Risk D: Consider therapy modification
Beta-Blockers: May enhance the adverse/toxic effect of Methacholine. Risk C: Monitor therapy
Cimetropium: Cholinergic Agonists may diminish the anticholinergic effect of Cimetropium. Risk C: Monitor therapy
Ipratropium (Oral Inhalation): May diminish the therapeutic effect of Methacholine. Management: Hold ipratropium for 12 hours before methacholine use. Risk D: Consider therapy modification
Long-acting muscarinic antagonists (LAMAs): May diminish the therapeutic effect of Methacholine. Management: Hold long-acting muscarinic antagonists (LAMAs) for at least 7 days before methacholine use. Risk D: Consider therapy modification
Rivastigmine: Cholinergic Agonists may enhance the adverse/toxic effect of Rivastigmine. Specifically, cholinergic effects may be enhanced or increased. Rivastigmine may enhance the adverse/toxic effect of Cholinergic Agonists. Management: Use of rivastigmine with a cholinergic agonist is not recommended unless clinically necessary. If the combination is necessary, monitor for increased cholinergic effects. Risk D: Consider therapy modification
Sincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Risk D: Consider therapy modification
Theophylline: May diminish the therapeutic effect of Methacholine. Management: Hold theophylline for 12 to 48 hours before methacholine use. Risk D: Consider therapy modification
Diagnosis of bronchial airway hyperactivity during pregnancy is not recommended.
It is not known if methacholine is present in breast milk.
According to the manufacturer, the decision to breastfeed should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.
FEV1 at baseline.
Methacholine, a cholinergic (parasympathomimetic) synthetic analogue of acetylcholine, stimulates muscarinic, postganglionic parasympathetic receptors, which results in smooth muscle contraction of the airways and increased tracheobronchial secretions.
Duration: 30 to 45 minutes; 5 minutes if methacholine challenge is followed with a beta-agonist agent
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