ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions associated with the use of Provocholine were identified in clinical studies or post marketing reports. Because some of these reactions were reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Respiratory System: Bronchospasm (includes symptoms such as chest tightness, cough or wheezing).Less Common Adverse Reactions: Headache, throat irritation, light-headedness and itching.. Adverse reactions associated with Provocholine include headache, throat irritation, light-headedness and itching (6)To report SUSPECTED ADVERSE REACTIONS, contact Methapharm at 1-866-701-4636 or call FDA at 1-800-FDA-1088 or visit www.fda.gov/medwatch.

BOXED WARNING SECTION.

WARNING: SEVERE BRONCHOCONSTRICTION. WARNING: SEVERE BRONCHOCONSTRICTIONSevere bronchoconstriction can result from Provocholine administration (including the lowest dose). The use of Provocholine 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 Provocholine in patients with clinically apparent asthma or wheezing is not recommended see Warnings and Precautions (5.1)]. Emergency equipment and medication should be immediately available to treat acute respiratory distress. If severe bronchoconstriction occurs, reverse immediately with rapid-acting inhaled bronchodilator agent (-agonist) see Warnings and Precautions (5.1)]. If baseline spirometry is not performed or is measured inaccurately, the initial FEV1 may be underestimated. In this situation, decreases in FEV1 may not be detected after administration of escalating Provocholine doses, which may result in administration of unnecessary higher doses and an increased risk for excessive bronchoconstriction see Warnings and Precautions (5.1)]. WARNING: SEVERE BRONCHOCONSTRICTIONSee full prescribing information for complete boxed warning.Severe bronchoconstriction can result from Provocholine administration (including the lowest dose) (5.1)Use of Provocholine is contraindicated in pediatric and adult patients with baseline FEV1 60% predicted or adultswith FEV1 1.5 (5.1)Use of Provocholine is not recommended in patients with clinically apparent asthma or wheezing (5.1)If severe bronchoconstriction occurs, reverse immediately with rapid-acting inhaled bronchodilator agent (-Agonist) (5.1). Severe bronchoconstriction can result from Provocholine administration (including the lowest dose) (5.1). Use of Provocholine is contraindicated in pediatric and adult patients with baseline FEV1 60% predicted or adults. with FEV1 1.5 (5.1). Use of Provocholine is not recommended in patients with clinically apparent asthma or wheezing (5.1). If severe bronchoconstriction occurs, reverse immediately with rapid-acting inhaled bronchodilator agent (-Agonist) (5.1).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. There have been no studies with methacholine chloride that would permit an evaluation of its carcinogenic or mutagenic potential or of its effect on fertility.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. .. 12.1 Mechanism of Action. Methacholine chloride is cholinergic agonist. Bronchial smooth muscle contains significant parasympathetic (cholinergic) innervation. Methacholine chloride agonizes the muscarinic receptors which eventually induce bronchoconstriction.. 12.2 Pharmacodynamics. After oral inhalation of Provocholine, patients with asthma are more sensitive to Provocholine-induced bronchoconstriction than are healthy subjects. This difference in response is the pharmacological basis for Provocholine in the methacholine challenge test.. 12.3 Pharmacokinetics. There are no metabolic and pharmacokinetic data available on methacholine chloride.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Provocholine is contraindicated in patients with:Hypersensitivity to methacholine or other parasympathomimetic agents. Reactions have included rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.Baseline FEV 1< 60% predicted (adults or pediatric patients) or <1.5 (adults) Hypersensitivity to methacholine or other parasympathomimetic agents. Reactions have included rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.. Baseline FEV 1< 60% predicted (adults or pediatric patients) or <1.5 (adults) Known hypersensitivity to methacholine chloride or other parasympathomimetic agents (4)Baseline FEV 1<60% predicted (adults or children) or <1.5 (adults) (4) Known hypersensitivity to methacholine chloride or other parasympathomimetic agents (4). Baseline FEV 1<60% predicted (adults or children) or <1.5 (adults) (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Methacholine chloride, the active ingredient of Provocholine, is parasympathomimetic (cholinergic) bronchoconstrictor agent. Provocholine (methacholine chloride) powder for solution is administered by oral inhalation.Chemically, methacholine chloride (the active ingredient) is 1-propanaminium, 2-(acetyloxy)-N,N,N,-trimethyl-, chloride. It is white to practically white deliquescent compound, soluble in water, alcohol and chloroform and insoluble in ether. Aqueous solutions are neutral to litmus.Methacholine chloride has an empirical formula of 8H 18ClNO 2, molecular weight of 195.69, and the following structural formula: Provocholine Powder for Solution:Each vial of Provocholine contains 100 mg of methacholine chloride powder. Provocholine Solution for Inhalation Kit (Sterile):Ready-to-use kit (sterile): Plastic vials with twist-off cap containing mL of the following strengths of methacholine chloride solution. Each solution also contains the following inactive ingredients: sodium acetate trihydrate, sodium chloride, water for injection. Glacial acetic acid is added to adjust pH.a) base solution (contains no methacholine chloride) b) 0.0625 mg/mL (0.1875 mg/3 mL) c) 0.25 mg/mL (0.75 mg/3 mL) d) mg/mL (3 mg/3 mL) e) mg/mL (12 mg/3 mL) f) 16 mg/mL (48 mg/3 mL) Single-dose plastic vial with twist-off cap containing 16 mg/mL (48 mg/3 mL) of methacholine chloride solution. Solution also contains the following inactive ingredients: sodium acetate trihydrate, sodium chloride, and water for injection. Glacial acetic acid is added to adjust pH.. Ready-to-use kit (sterile): Plastic vials with twist-off cap containing mL of the following strengths of methacholine chloride solution. Each solution also contains the following inactive ingredients: sodium acetate trihydrate, sodium chloride, water for injection. Glacial acetic acid is added to adjust pH.. Single-dose plastic vial with twist-off cap containing 16 mg/mL (48 mg/3 mL) of methacholine chloride solution. Solution also contains the following inactive ingredients: sodium acetate trihydrate, sodium chloride, and water for injection. Glacial acetic acid is added to adjust pH.. structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. .. The methacholine challenge test should be conducted in pulmonary function laboratory or clinic, by adequately trained personnel, for safety and accuracy (2.1)Determine baseline FEV1 values to assess whether patient is able to undergo the methacholine challenge test (2.1)Recommended dosage(s) of Provocholine in the Methacholine Challenge Test is administration of increasing concentrations of Provocholine solution via nebulization (2.2)Administer using either the 5-Breath Dosimeter Dosing Method or the 2-Minute Tidal Breathing Dosing Method with the doubling or quadrupling stepwise protocols (2.4, 2.5)See the Full Prescribing Information for the required reconstitution and dilution procedures prior to use (2.3)See the Full Prescribing Information for the calculation and interpretation of the results (2.6). The methacholine challenge test should be conducted in pulmonary function laboratory or clinic, by adequately trained personnel, for safety and accuracy (2.1). Determine baseline FEV1 values to assess whether patient is able to undergo the methacholine challenge test (2.1). Recommended dosage(s) of Provocholine in the Methacholine Challenge Test is administration of increasing concentrations of Provocholine solution via nebulization (2.2). Administer using either the 5-Breath Dosimeter Dosing Method or the 2-Minute Tidal Breathing Dosing Method with the doubling or quadrupling stepwise protocols (2.4, 2.5). See the Full Prescribing Information for the required reconstitution and dilution procedures prior to use (2.3). See the Full Prescribing Information for the calculation and interpretation of the results (2.6). 2.1 Preparation and Administration Overview. Provocholine powder for inhalation solution requires reconstitution and dilution prior to use [see Dosage and Administration (2.2)]. Provocholine inhalation solution in ready-to-use kit does not require reconstitution and/ or silution prior to use.Provocholine inhalation solution 16 mg/mL in single-dose vial requires dilution prior to use [see Dosage and Administration (2.2)]. For safety and accuracy, administer Provocholine during methacholine challenge test in pulmonary function laboratory or clinic, by adequately trained personnel, for safety and accuracy, and should be performed only under the responsibility of healthcare practitioner trained in and thoroughly familiar with all aspects of the technique of the test and the management of respiratory distress. Emergency medication and equipment should be immediately available to treat acute respiratory distress.Consider Provocholine use in patients on chronic asthma drugs if the accuracy of the asthma diagnosis is in doubt. In these patients, only administer Provocholine if spirometry is normal after supervised withdrawal of the asthma drugs.Provocholine is not recommended for use in patients with clinically apparent asthma or wheezing.Before starting methacholine challenge test, baseline spirometry must be performed. For patient to be able to undergo the test, he or she must present with baseline FEV (Forced Expiratory Volume in second) greater than or equal to 60% of the predicted value (in adults and children) and greater than or equal to 1.5 (in adults). Provocholine is contraindicated in adult and pediatric patients with baseline FEV1 60% predicted or in adults with FEV < 1.5 [see Contraindications (4) and Warnings and Precautions (5.1)]. At commencement of the methacholine challenge test and prior to administration of Provocholine, post-diluent FEV must be measured following nebulization of the diluent or base solution (contains no methacholine chloride) see Dosage and Administration (2.4, 2.5)]. Administer Provocholine by oral inhalation, with or without food, using either the 5-Breath Dosimeter Dosing Method or the 1-Minute Tidal Breathing Dosing Method with the dose doubling or quadrupling protocols [see Dosage and Administration (2.3, 2.4, 2.5)]. Discard any unused solution from the nebulizer after each administration.The methacholine challenge test is considered positive if there is reduction of FEV of 20% or more from the post-diluent FEV 1. The test should be stopped at this point. Calculate and record the FEV reduction value before starting the test [see Dosage and Administration (2.3, 2.4, 2.5)]. After the methacholine challenge test with Provocholine, administer an inhaled -agonist to expedite the return of the FEV to baseline and to relieve any discomfort the patient may experience. Most patients revert to normal pulmonary function within 10 to 20 minutes following administration of an inhaled -agonist [see Dosage and Administration (2.6)]. Provocholine powder for inhalation solution requires reconstitution and dilution prior to use [see Dosage and Administration (2.2)]. Provocholine inhalation solution in ready-to-use kit does not require reconstitution and/ or silution prior to use.. Provocholine inhalation solution 16 mg/mL in single-dose vial requires dilution prior to use [see Dosage and Administration (2.2)]. For safety and accuracy, administer Provocholine during methacholine challenge test in pulmonary function laboratory or clinic, by adequately trained personnel, for safety and accuracy, and should be performed only under the responsibility of healthcare practitioner trained in and thoroughly familiar with all aspects of the technique of the test and the management of respiratory distress. Emergency medication and equipment should be immediately available to treat acute respiratory distress.. Consider Provocholine use in patients on chronic asthma drugs if the accuracy of the asthma diagnosis is in doubt. In these patients, only administer Provocholine if spirometry is normal after supervised withdrawal of the asthma drugs.. Provocholine is not recommended for use in patients with clinically apparent asthma or wheezing.. Before starting methacholine challenge test, baseline spirometry must be performed. For patient to be able to undergo the test, he or she must present with baseline FEV (Forced Expiratory Volume in second) greater than or equal to 60% of the predicted value (in adults and children) and greater than or equal to 1.5 (in adults). Provocholine is contraindicated in adult and pediatric patients with baseline FEV1 60% predicted or in adults with FEV < 1.5 [see Contraindications (4) and Warnings and Precautions (5.1)]. At commencement of the methacholine challenge test and prior to administration of Provocholine, post-diluent FEV must be measured following nebulization of the diluent or base solution (contains no methacholine chloride) see Dosage and Administration (2.4, 2.5)]. Administer Provocholine by oral inhalation, with or without food, using either the 5-Breath Dosimeter Dosing Method or the 1-Minute Tidal Breathing Dosing Method with the dose doubling or quadrupling protocols [see Dosage and Administration (2.3, 2.4, 2.5)]. Discard any unused solution from the nebulizer after each administration.. The methacholine challenge test is considered positive if there is reduction of FEV of 20% or more from the post-diluent FEV 1. The test should be stopped at this point. Calculate and record the FEV reduction value before starting the test [see Dosage and Administration (2.3, 2.4, 2.5)]. After the methacholine challenge test with Provocholine, administer an inhaled -agonist to expedite the return of the FEV to baseline and to relieve any discomfort the patient may experience. Most patients revert to normal pulmonary function within 10 to 20 minutes following administration of an inhaled -agonist [see Dosage and Administration (2.6)]. 2.2 Reconstitution and/or Dilution Instructions for Provocholine Powder for Inhalation Solution and Provocholine Inhalation Solution 16 mg/mL (in Single-Dose Vial). Reconstitution and Dilution of Provocholine Powder for Inhalation SolutionReconstitute Provocholine Powder for Inhalation Solution by adding 6.25 mL of 0.9% Sodium Chloride Injection to the supplied vial(s) containing 100 mg of Provocholine powder. Shake the vial to obtain clear solution.Dilute the reconstituted Provocholine solution, using sterile, empty USP Type borosilicate glass vials. Dilute the reconstituted Provocholine solution with 0.9% Sodium Chloride Injection based on Table to obtain doubling strengths or Table to obtain quadrupling strengths. After adding the 0.9% Sodium Chloride Injection, shake each vial to obtain clear solution.If not used immediately, refrigerate the reconstituted and diluted solutions at 36F to 46F (2C to 8C) for up to weeks. Since the temperature of the solution affects nebulizer output, take the diluted solutions out of the refrigerator and allow them to equilibrate to room temperature (approximately 30 minutes) before use.Table 1: Reconstitution and Dilution Instructions for Provocholine Powder for Inhalation Solution to Obtain Doubling StrengthsTAKEAdd 0.9% Sodium Chloride InjectionProvocholine Solution Strength after reconstitution or dilution100 mg of Provocholine Powder in one single-dose vial6.25 mL16 mg/mL3 mL of 16 mg/mL Provocholine Solution3 mL8 mg/mL3 mL of mg/mL Provocholine Solution3 mL4 mg/mL3 mL of mg/mL Provocholine Solution3 mL2 mg/mL3 mL of mg/mL Provocholine Solution3 mL1 mg/mL3 mL of mg/mL Provocholine Solution3 mL0.5 mg/mL3 mL of 0.5 mg/mL Provocholine Solution3 mL0.25 mg/mL3 mL of 0.25 mg/mL Provocholine Solution3 mL0.125 mg/mL3 mL of 0.125 mg/mL Provocholine Solution3 mL0.0625 mg/mLTable 2: Reconstitution and Dilution Instructions for Provocholine Powder for Inhalation Solution to Obtain Quadrupling StrengthsTAKEAdd 0.9% Sodium Chloride InjectionProvocholine Solution Strength after reconstitution or dilution100 mg of Provocholine Powder in one single-dose vial6.25 mL16 mg/mL3 mL of 16 mg/mL Provocholine Solution9 mL4 mg/mL3 mL of mg/mL Provocholine Solution9 mL1 mg/mL3 mL of mg/mL Provocholine Solution9 mL0.25 mg/mL3 mL of 0.25 mg/mL Provocholine Solution9 mL0.0625 mg/mLDilution of Provocholine Inhalation Solution 16 mg/mL (in Single-Dose Vial)Transfer the contents of the specified number of mL vials (as per Tables or 4) of Provocholine inhalation solution 16 mg/mL (in Single-Dose Vial) into sterile, empty USP Type borosilicate glass vial. Swirl the glass vial gently to mix.Dilute the solution with 0.9% Sodium Chloride Injection based on Table (to obtain doubling strengths) or Table (to obtain quadrupling strengths). After adding 0.9% Sodium Chloride Injection, shake each vial to obtain clear solution.If not used immediately, refrigerate the diluted solutions at 36oF to 46oF (2oC to 8oC) for up to weeks. Since the temperature of the solution affects nebulizer output, take the diluted solutions out of the refrigerator and allow them to equilibrate to room temperature (approximately 30 minutes) before use.Table 3: Dilution Instructions for Provocholine Inhalation Solution 16 mg/mL (in Single-Dose Vial) to Obtain Doubling StrengthsTAKEAdd 0.9% Sodium Chloride InjectionProvocholine Solution Strength after dilutionProvocholine Inhalation Solution 16 mg/mL (2 3 mL vial)None16 mg/mL3 mL of 16 mg/mL Provocholine Solution3 mL8 mg/mL3 mL of mg/mL Provocholine Solution3 mL4 mg/mL3 mL of mg/mL Provocholine Solution3 mL2 mg/mL3 mL of mg/mL Provocholine Solution3 mL1 mg/mL3 mL of mg/mL Provocholine Solution3 mL0.5 mg/mL3 mL of 0.5 mg/mL Provocholine Solution3 mL0.25 mg/mL3 mL of 0.25 mg/mL Provocholine Solution3 mL0.125 mg/mL3 mL of 0.125 mg/mL Provocholine Solution3 mL0.0625 mg/mLTable 4: Dilution Instructions for Provocholine Inhalation Solution 16 mg/mL (in Single-Dose Vial) to Obtain Quadrupling StrengthsTAKEAdd 0.9% Sodium Chloride InjectionProvocholine Solution Strength after dilutionProvocholine Inhalation Solution 16 mg/Ml (1 3 mL vial)None16 mg/mL1 mL of 16 mg/mL Provocholine Solution3 mL4 mg/mL1 mL of mg/mL Provocholine Solution3 mL1 mg/mL1 mL of mg/mL Provocholine Solution3 mL0.25 mg/mL1 mL of 0.25 mg/mL Provocholine Solution3 mL0.0625 mg/mL. Reconstitute Provocholine Powder for Inhalation Solution by adding 6.25 mL of 0.9% Sodium Chloride Injection to the supplied vial(s) containing 100 mg of Provocholine powder. Shake the vial to obtain clear solution.. Dilute the reconstituted Provocholine solution, using sterile, empty USP Type borosilicate glass vials. Dilute the reconstituted Provocholine solution with 0.9% Sodium Chloride Injection based on Table to obtain doubling strengths or Table to obtain quadrupling strengths. After adding the 0.9% Sodium Chloride Injection, shake each vial to obtain clear solution.. If not used immediately, refrigerate the reconstituted and diluted solutions at 36F to 46F (2C to 8C) for up to weeks. Since the temperature of the solution affects nebulizer output, take the diluted solutions out of the refrigerator and allow them to equilibrate to room temperature (approximately 30 minutes) before use.. Transfer the contents of the specified number of mL vials (as per Tables or 4) of Provocholine inhalation solution 16 mg/mL (in Single-Dose Vial) into sterile, empty USP Type borosilicate glass vial. Swirl the glass vial gently to mix.. Dilute the solution with 0.9% Sodium Chloride Injection based on Table (to obtain doubling strengths) or Table (to obtain quadrupling strengths). After adding 0.9% Sodium Chloride Injection, shake each vial to obtain clear solution.. If not used immediately, refrigerate the diluted solutions at 36oF to 46oF (2oC to 8oC) for up to weeks. Since the temperature of the solution affects nebulizer output, take the diluted solutions out of the refrigerator and allow them to equilibrate to room temperature (approximately 30 minutes) before use.. 2.3 Recommended Provocholine Doses for Methacholine Challenge Test. The recommended doses of Provocholine for oral inhalation for the diagnosis of bronchial airway hyperreactivity in adults and pediatric patients five years of age and older during methacholine challenge test, based on the dose doubling or quadrupling protocol, are provided in Table 5. Table 5: Recommended Provocholine Doses for Methacholine Challenge Test Based on Dose Doubling or Quadrupling DilutionDoubling ProtocolProvocholine strengthRecommended VolumeProvocholine Dose0.0625 mg/mLAt least mL1.484 mcg0.125 mg/mL2.969 mcg0.25 mg/mL5.938 mcg0.5 mg/mL11.875 mcg1 mg/mL23.75 mcg2 mg/mL47.5 mcg4 mg/mL95 mcg8 mg/mL190 mcg16 mg/mL380 mcgQuadrupling Protocol or Ready-to-Use KitProvocholine strengthRecommended VolumeProvocholine Dose0.0625 mg/mLAt least mL1.484 mcg0.25 mg/mL5.938 mcg1 mg/mL23.75 mcg4 mg/mL95 mcg16 mg/mL380 mcgProvocholine dose was based on the Hudson RCI(R) MicroMist(R) Small Volume Nebulizer using dry compressed air to power the nebulizer with pressure regulator set to 50 lb/in (psi) and flow controller set to flow rate of 4.5 LPM (liters per minute) with nebulization time of one (1) minute. Under these conditions, the device output was within 10% of 0.13 mL/min (or g/min) (measured gravimetrically), the measured MMD was found to be 3.4 um, i.e. within the acceptable range of MMD of 1.0 3.6 um. The delivered dose of the respirable fraction for the Provocholine 16 mg/mL inhalation solution was about 380 mcg. 2.4 Determination of Post-Diluent FEV1 and Administration of Provocholine Using the 5-Breath Dosimeter Dosing Method. Determination of Post-Diluent FEV Prior to Administration of Provocholine Prior to administration of Provocholine, determine thepost-diluent FEV value required for the methacholine challenge test. Instill diluent (sterile 0.9% Sodium Chloride Injection) or base solution into the nebulizer.If using Provocholine powder for inhalation solution or Provocholine inhalation solution 16 mg/mL (in single-dose vial), using 3 mL syringe and needle, draw up to mL of diluent (sterile 0.9% Sodium Chloride Injection), and instill the 0.9% Sodium Chloride Injection into the nebulizer using sterile bacterial-retentive filter (porosity 0.22 um).If using the Provocholine inhalation solution ready-to-use kit, instill the contents of the base solution (contains no methacholine chloride) into the nebulizer.2. Instruct the patient to hold the nebulizer upright with the mouthpiece in his/her mouth. The patient should wear nose clip while inhaling from the nebulizer.3. At the end of exhalation during tidal breathing (functional residual capacity), instruct the patient to inhale slowly and deeply through the mouthpiece. Trigger the dosimeter soon after oral inhalation begins. Encourage the patient to continue inhaling slowly (about seconds to complete the inhalation) and to hold the breath at total lung capacity (TLC) for another seconds.4. Repeat Step for total of five inspiratory capacity inhalations. Take no more than minutes to perform these inhalations. 5. Perform spirometry and measure the FEV 30 and 90 seconds after the fifth inhalation from the nebulizer to obtain the post-diluent FEV value. These values may be left at ambient (spirometer) temperature pressure saturated (ATPS). If the FEV value is not of acceptable quality, repeat the procedure. If the post-diluent FEV falls by >= 20% from baseline FEV 1, do not proceed with administration with Provocholine and administer an inhaled -agonist [see Dosage and Administration (2.6)]. If the post-diluent FEV falls by< 20% from baseline FEV1, proceed to Step 6. Administer of Provocholine Using the 5-Breath Dosimeter Dosing Method6. Instill Provocholine solution into the nebulizerIf using Provocholine powder for inhalation solution or Provocholine inhalation solution 16 mg/mL (in single-dose vial), using 3 mL syringe and needle, draw up at least mL of the recommended Provocholine strength based on the dose doubling or quadrupling protocol in Table [see Dosage and Administration (2.3)] and instill into the nebulizer using sterile bacterial-retentive filter (porosity 0.22 um). Refer to Tables 1, 2, or for preparation of the doubling or quadrupling strengths of Provocholine [see Dosage and Administration (2.2)]. If using the Provocholine inhalation solution ready-to-use kit, instill at least mL of the recommended Provocholine strength based on the dose quadrupling protocol in Table [see Dosage and Administration (2.3)] into the nebulizer. 7. Repeat Steps through for each Provocholine strength, emptying the nebulizer between each strength. To keep the cumulative effect of Provocholine relatively constant, the time interval between the end of one strength and beginning of the subsequent strength should not be more than minutes.8. Stop dosing if the FEV has fallen >= 20% from the post-diluent FEV 1, or the highest Provocholine strength (16 mg/mL) has been administered (whichever comes first). Do not administer additional Provocholine doses if severe bronchoconstriction occurs [see Warnings and Precautions (5.1)]. After the test is completed, administer an inhaled -agonist to the patient [see Dosage and Administration (2.6)]. 9. Wash and clean reusable nebulizers thoroughly according to manufacturers recommendations.. Instill diluent (sterile 0.9% Sodium Chloride Injection) or base solution into the nebulizer.. If using Provocholine powder for inhalation solution or Provocholine inhalation solution 16 mg/mL (in single-dose vial), using 3 mL syringe and needle, draw up to mL of diluent (sterile 0.9% Sodium Chloride Injection), and instill the 0.9% Sodium Chloride Injection into the nebulizer using sterile bacterial-retentive filter (porosity 0.22 um).. If using the Provocholine inhalation solution ready-to-use kit, instill the contents of the base solution (contains no methacholine chloride) into the nebulizer.. If the FEV value is not of acceptable quality, repeat the procedure. If the post-diluent FEV falls by >= 20% from baseline FEV 1, do not proceed with administration with Provocholine and administer an inhaled -agonist [see Dosage and Administration (2.6)]. If the post-diluent FEV falls by< 20% from baseline FEV1, proceed to Step 6. If using Provocholine powder for inhalation solution or Provocholine inhalation solution 16 mg/mL (in single-dose vial), using 3 mL syringe and needle, draw up at least mL of the recommended Provocholine strength based on the dose doubling or quadrupling protocol in Table [see Dosage and Administration (2.3)] and instill into the nebulizer using sterile bacterial-retentive filter (porosity 0.22 um). Refer to Tables 1, 2, or for preparation of the doubling or quadrupling strengths of Provocholine [see Dosage and Administration (2.2)]. If using the Provocholine inhalation solution ready-to-use kit, instill at least mL of the recommended Provocholine strength based on the dose quadrupling protocol in Table [see Dosage and Administration (2.3)] into the nebulizer. 2.5 Determination of Post-Diluent FEV and Administration of Provocholine Using the 1-Minute Tidal Breathing Dosing Method Determination of Post-Diluent FEV Prior to Administration of Provocholine Prior to administration of Provocholine, determine the post-diluent FEV required for the methacholine challenge test. Instill diluent (sterile 0.9% Sodium Chloride Injection) or base solution into the nebulizer.If using Provocholine powder for inhalation solution or Provocholine inhalation solution 16 mg/mL (in single-dose vial), using 3 mL syringe and needle, draw up to mL of diluent (sterile 0.9% Sodium Chloride Injection). Instill the 0.9% Sodium Chloride Injection into the nebulizer using sterile bacterial-retentive filter (porosity 0.22 um). Attach the nebulizer and necessary tubing to the dry compressed air source.If using the Provocholine inhalation solution ready-to-use kit, instill the contents of the base solution (contains no methacholine chloride) into the nebulizer.2. Place the face mask loosely over the nose and mouth or the mouthpiece in the mouth (with nose clip) of the patient. Instruct the patient to hold the nebulizer to avoid warming the solution. Keep the nebulizer upright and vertical. 3. Set the pressure regulator to 50 lb/in (psi) and start the nebulizer by setting the flow controller to flow rate of 4.5 LPM. Start the stopwatch immediately. 4. Instruct the patient to relax and breath the aerosol quietly (tidal breathing) for minute of inhalation time. 5. After exactly minute of tidal breathing, turn off the nebulizer and flow meter, remove the face mask (or the mouthpiece from the mouth), and discard any remaining solution. 6. Perform spirometry and measure the FEV 30 and 90 seconds after the end of 1-minute tidal breathing to obtain the post-diluent FEV 1. These values may be left at ambient (spirometer) temperature pressure saturated (ATPS). If the FEV value is not of acceptable quality, repeat the procedure. If the post-diluent FEV falls by >= 20% from baseline FEV1, do not proceed with administration of Provocholine and administer an inhaled -agonist to the patient [see Dosage and Administration (2.6)]. If the post-diluent FEV falls by 20% from baseline FEV 1, proceed to Step 7. Administration of Provocholine Using the 1-Minute Tidal Breathing Dosing Method7. Instill Provocholine solution into the nebulizer. If using Provocholine powder for inhalation solution or Provocholine inhalation solution 16 mg/mL (in single-dose vial), using 3 mL syringe and needle, draw up at least mL of the recommended Provocholine strength based on the dose doubling or quadrupling protocol in Table [see Dosage and Administration (2.3)] and instill into the nebulizer using sterile bacterial-retentive filter (porosity 0.22 um). Refer to Tables 1, 2, and for preparation of the doubling and quadrupling strengths of Provocholine [see Dosage and Administration (2.2)]. If using the Provocholine inhalation solution ready-to-use kit, instill at least mL of the recommended Provocholine strength, based on the dose quadrupling protocol in Table [see Dosage and Administration (2.3)] into the nebulizer. 8. Repeat steps through for each Provocholine strength, emptying the nebulizer between each strength or dose. However, stop dosing if the FEV has fallen by >= 20% from the post-diluent FEV or the highest Provocholine strength (16 mg/mL) has been administered (whichever comes first). Do not administer additional Provocholine doses if severe bronchoconstriction occurs [see Warnings and Precautions (5.1)]. 9. After the test is completed, administer an inhaled -agonist to the patient [see Dosage and Administration (2.6)]. 10.Wash and clean reusable nebulizers thoroughly according to manufacturers recommendations and discard disposable nebulizers appropriately. Instill diluent (sterile 0.9% Sodium Chloride Injection) or base solution into the nebulizer.. If using Provocholine powder for inhalation solution or Provocholine inhalation solution 16 mg/mL (in single-dose vial), using 3 mL syringe and needle, draw up to mL of diluent (sterile 0.9% Sodium Chloride Injection). Instill the 0.9% Sodium Chloride Injection into the nebulizer using sterile bacterial-retentive filter (porosity 0.22 um). Attach the nebulizer and necessary tubing to the dry compressed air source.. If using the Provocholine inhalation solution ready-to-use kit, instill the contents of the base solution (contains no methacholine chloride) into the nebulizer.. If the FEV value is not of acceptable quality, repeat the procedure. If the post-diluent FEV falls by >= 20% from baseline FEV1, do not proceed with administration of Provocholine and administer an inhaled -agonist to the patient [see Dosage and Administration (2.6)]. If the post-diluent FEV falls by 20% from baseline FEV 1, proceed to Step 7. If using Provocholine powder for inhalation solution or Provocholine inhalation solution 16 mg/mL (in single-dose vial), using 3 mL syringe and needle, draw up at least mL of the recommended Provocholine strength based on the dose doubling or quadrupling protocol in Table [see Dosage and Administration (2.3)] and instill into the nebulizer using sterile bacterial-retentive filter (porosity 0.22 um). Refer to Tables 1, 2, and for preparation of the doubling and quadrupling strengths of Provocholine [see Dosage and Administration (2.2)]. If using the Provocholine inhalation solution ready-to-use kit, instill at least mL of the recommended Provocholine strength, based on the dose quadrupling protocol in Table [see Dosage and Administration (2.3)] into the nebulizer. 2.6 Recommended Administration of Inhaled -agonist after Methacholine Challenge Test. After the methacholine challenge test is completed, administer an inhaled -agonist to the patient to expedite the return of the FEV1 to within 90% of baseline and to relieve any discomfort (the majority of patients revert to normal pulmonary function within 10 to 20 minutes after -agonist administration; in contrast the majority of patients revert to normal pulmonary function within 30-45 minutes without -agonist administration). Wait 10 minutes and measure the FEV1 and Vital Capacity. Do not allow patients to leave the laboratory or clinic until their FEV1 has returned to within 90% of baseline.. 2.7 Calculation and Interpretation of Methacholine Challenge Test Results. Positive Methacholine Challenge TestA positive methacholine challenge test is >= 20% reduction in the FEV 1(after Provocholine oral inhalation) compared with the mean post-diluent FEV 1. Calculate and record post-diluent FEV 1value before the methacholine challenge test is started. Express airway hyperreactivity as the provocative Provocholine concentration (mg/mL) providing fall in FEV 1of >= 20% (PC 20) when the methacholine challenge test is dosed using either the 5-breath dosimeter method or the 2-minute tidal breathing method, or as the provocative Provocholine dose (mcg) providing fall in FEV 1of >= 20% (PD 20) when using the 2-minute tidal breathing method. Calculation of PC 20 (5-breath dosimeter dosing method) 1. Determine the percent decrease [was fall] in FEV1 using the mean post-diluent FEV and the lowest FEV post-Provocholine (post-dose), as shown below: % fall in FEV 1= mean post-diluent FEV - lowest FEV 1post-Provocholine 100 mean post-diluent FEV 2. Calculate PC 20 using one of the following methods: Method 1: Plot the percent decrease in FEV 1against the increasing methacholine concentration using log scale and obtain the PC 20by linear interpolation between the last two points, as shown in Figure 1. Method 2: Calculate the PC 20 using the following equation: PC 20= antilog [log C1+ (log C2 log C1)(20 R1)] (R2- R1) Where: C1 second last methacholine concentration (< 20% FEV 1decrease) C2 last methacholine concentration (>= 20% FEV 1decrease) R1 % fall FEV 1after C1 R2 % fall FEV 1after C2 Calculation of PD 20(1-minute tidal breathing dosing method) Calculate the PD 20as follows: PD 20= antilog [log D1+ (log D2 log D1)(20 R1)] (R2- R1) Where: D1 second last Provocholine dose (< 20% FEV 1decrease) D2 last Provocholine dose (>= 20% FEV 1decrease) R1 % FEV 1decrease after D1 R2 % FEV 1decrease after D2 Negative Methacholine Challenge TestA negative (normal) methacholine challenge result is defined as FEV 1reduction of 20% after all the doses, as part of the dose doubling or quadrupling protocol in Table 5, have been administered See Dosage and Administration (2.3)] Graph.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS o For inhalation solution: 100 mg of methacholine chloride crystalline powder, white to off-white in color in amber glass vials (powder is reconstituted and then diluted prior to administration)o Inhalation solution ready-to-use (sterile): Contain the following strengths of methacholine chloride in clear, colorless solution. i. mL base solution (contains no methacholine chloride) ii. 0.0625 mg/mL (0.1875 mg/ mL) of methacholine chlorideiii. 0.25 mg/mL (0.75 mg/ mL) of methacholine chlorideiv. mg/mL (3 mg/ mL) of methacholine chloridev. mg/mL (12 mg/ mL) of methacholine chloridevi. 16 mg/mL (48 mg/ mL) of methacholine chlorideo Inhalation solution (in single-dose vial): 16 mg/mL (48 mg/ mL) of methacholine chloride in clear, colorless solution in 3 mL plastic single-dose vial with twist-off cap.. For inhalation solution: 100 mg methacholine chloride powder in amber glass vials (3) Inhalation solution: base solution (contains no methacholine chloride), 0.0625 mg/mL, 0.25 mg/mL, mg/mL, mg/mL, and 16 mg/mL, each containing mL of the concentrations of methacholine chloride per vial in kit (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Beta-Adrenergic BlockersThe use of beta-adrenergic blockers may impair reversal of Provocholine-caused bronchoconstriction.Beta-Agonists, Anticholinergics, and TheophyllineBeta-agonists, anticholinergics, and theophylline inhibit the response of airways to Provocholine; therefore, hold these drugs before Provocholine use for the following duration: Short-acting -agonists (e.g., albuterol): hours Long-acting -agonists (e.g., salmeterol): 36 hours Short-acting anti-cholinergics (e.g., ipratropium): 12 hours Long-acting anti-cholinergics (e.g., tiotropium): >=168 hours Oral theophylline: 12-48 hours Oral or Inhaled Corticosteroids, and Inhaled CromoglycateRegular use of oral or inhaled corticosteroids and inhaled cromoglycate may acutely decrease bronchial responsiveness to Provocholine. However, these drugs may be continued with Provocholine use.. Beta-Adrenergic Blockers: May impair reversal of Provocholine-caused bronchoconstriction (7) Beta-Agonists, Anticholinergics, and Theophylline: Inhibit response to Provocholine; therefore, hold these drugs prior to Provocholine use (7) Oral or Inhaled Corticosteroids, and Inhaled Cromyoglycate: May decrease response to Provocholine (7) Beta-Adrenergic Blockers: May impair reversal of Provocholine-caused bronchoconstriction (7) Beta-Agonists, Anticholinergics, and Theophylline: Inhibit response to Provocholine; therefore, hold these drugs prior to Provocholine use (7) Oral or Inhaled Corticosteroids, and Inhaled Cromyoglycate: May decrease response to Provocholine (7).

GERIATRIC USE SECTION.

8.5 Geriatric Use. The diagnosis of bronchial airway hyperreactivity is largely performed in pediatric and younger adult patients. Clinical studies of Provocholine did not include patients 65 years of age or older.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Provocholine (methacholine chloride) for Inhalation Solution:Powder: 100 mg of methacholine chloride as white to off-white powder in amber glass vials. Each carton contains six vials (NDC 64281-100-06).Store the supplied powder at 59F to 86F (15C to 30C).Provocholine (methacholine chloride) Inhalation Solution:Ready-to-use kit: Each carton contains six sterile ready-to-use (NDC: 64281-110-06). Each sterile ready-to-use kit (NDC: 64281-110-05) contains six plastic vials with twist-off cap. Each vial contains mL of different strengths of methacholine chloride in clear, colorless solution as follows:a) base solution (contains no methacholine chloride) (NDC: 64281-111-00) b) 0.0625 mg/mL (0.1875 mg/3 mL) (NDC:64281-112-00) c) 0.25 mg/mL (0.75 mg/3 mL) (NDC:64281-113-00) d) mg/mL (3 mg/3 mL) (NDC:64281-114-00) e) mg/mL (12 mg/3 mL) (NDC:64281-115-00) f) 16 mg/mL (48 mg/3 mL) (NDC:64281-116-00) Single-dose vial: 16 mg/mL of methacholine chloride in clear, colorless solution in 3 mL plastic single-dose vial with twist-off cap. Each carton contains two inner cartons (NDC: 64281-116-112). Each inner carton contains six vials of 16 mg/mL solution (NDC: 64281-116-06).Store kits and single-dose vials between 15C to 30C (59F to 86F). Use immediately upon opening the vial.. Powder: 100 mg of methacholine chloride as white to off-white powder in amber glass vials. Each carton contains six vials (NDC 64281-100-06).. Ready-to-use kit: Each carton contains six sterile ready-to-use (NDC: 64281-110-06). Each sterile ready-to-use kit (NDC: 64281-110-05) contains six plastic vials with twist-off cap. Each vial contains mL of different strengths of methacholine chloride in clear, colorless solution as follows:.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Provocholine, used in methacholine challenge test, is indicated for the diagnosis of bronchial airway hyperreactivity in adults and pediatric patients five years of age and older who do not have clinically apparent asthma.. Provocholine, cholinergic agonist used in methacholine challenge test, is indicated for the diagnosis of bronchial airway hyperreactivity in adults and pediatric patients five years of age and older who do not have clinically apparent asthma (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Risk of Severe BronchoconstrictionInform the patient or caregiver that severe bronchoconstriction can result from Provocholine administration [see Warnings and Precautions (5.1)]. Manufactured for:Methapharm, Inc.8230 210th Street 109Boca Raton, FL,USA 33433For more information visit www.methapharmrespiratory.com, email ussalesmethapharm.com or call 1-833-887-7686. (R)Provocholine is registered trademark of Methapharm Inc. Revision: June 2026. methapharm.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere are no available data on the presence of methacholine chloride in human milk, the effect on the breastfed infant, or the effect on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Provocholine and any potential adverse effects on the breastfed infant from Provocholine or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Methacholine chloride is cholinergic agonist. Bronchial smooth muscle contains significant parasympathetic (cholinergic) innervation. Methacholine chloride agonizes the muscarinic receptors which eventually induce bronchoconstriction.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. .. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. There have been no studies with methacholine chloride that would permit an evaluation of its carcinogenic or mutagenic potential or of its effect on fertility.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

outer-carton-100mg. inner-carton-100mg. outer-carton-solution. inner-carton-solution. vial-label-base-0mgmL. vial-label-0.0625mgmL. vial-label-0.25mgmL. vial-label-1mgmL. vial-label-4mgmL. vial-label-16mgmL. foil pouches. cartons. carton 16mg-ml.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of Provocholine used in methacholine challenge test, has been established for the diagnosis of bronchial airway hyperreactivity in pediatric patients years of age and older who do not have clinically apparent asthma.The safety and effectiveness of Provocholine have not been established in pediatric patients younger than years of age.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. After oral inhalation of Provocholine, patients with asthma are more sensitive to Provocholine-induced bronchoconstriction than are healthy subjects. This difference in response is the pharmacological basis for Provocholine in the methacholine challenge test.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. There are no metabolic and pharmacokinetic data available on methacholine chloride.

PREGNANCY SECTION.

8.1 Pregnancy. RiskSummaryThe available data from published literature on Provocholine use in pregnant women are insufficient to evaluate for drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal reproduction studies evaluating effects of methacholine chloride on embryofetal development have not been conducted. Diagnosis of bronchial airway hyperreactivity with bronchoprovocation challenge is not recommended for pregnant women because of the potential for hypoxia in the fetus. If bronchial airway hyperreactivity is suspected, consider trial of empiric treatment. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the United States general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.

SPL UNCLASSIFIED SECTION.

2.1 Preparation and Administration Overview. Provocholine powder for inhalation solution requires reconstitution and dilution prior to use [see Dosage and Administration (2.2)]. Provocholine inhalation solution in ready-to-use kit does not require reconstitution and/ or silution prior to use.Provocholine inhalation solution 16 mg/mL in single-dose vial requires dilution prior to use [see Dosage and Administration (2.2)]. For safety and accuracy, administer Provocholine during methacholine challenge test in pulmonary function laboratory or clinic, by adequately trained personnel, for safety and accuracy, and should be performed only under the responsibility of healthcare practitioner trained in and thoroughly familiar with all aspects of the technique of the test and the management of respiratory distress. Emergency medication and equipment should be immediately available to treat acute respiratory distress.Consider Provocholine use in patients on chronic asthma drugs if the accuracy of the asthma diagnosis is in doubt. In these patients, only administer Provocholine if spirometry is normal after supervised withdrawal of the asthma drugs.Provocholine is not recommended for use in patients with clinically apparent asthma or wheezing.Before starting methacholine challenge test, baseline spirometry must be performed. For patient to be able to undergo the test, he or she must present with baseline FEV (Forced Expiratory Volume in second) greater than or equal to 60% of the predicted value (in adults and children) and greater than or equal to 1.5 (in adults). Provocholine is contraindicated in adult and pediatric patients with baseline FEV1 60% predicted or in adults with FEV < 1.5 [see Contraindications (4) and Warnings and Precautions (5.1)]. At commencement of the methacholine challenge test and prior to administration of Provocholine, post-diluent FEV must be measured following nebulization of the diluent or base solution (contains no methacholine chloride) see Dosage and Administration (2.4, 2.5)]. Administer Provocholine by oral inhalation, with or without food, using either the 5-Breath Dosimeter Dosing Method or the 1-Minute Tidal Breathing Dosing Method with the dose doubling or quadrupling protocols [see Dosage and Administration (2.3, 2.4, 2.5)]. Discard any unused solution from the nebulizer after each administration.The methacholine challenge test is considered positive if there is reduction of FEV of 20% or more from the post-diluent FEV 1. The test should be stopped at this point. Calculate and record the FEV reduction value before starting the test [see Dosage and Administration (2.3, 2.4, 2.5)]. After the methacholine challenge test with Provocholine, administer an inhaled -agonist to expedite the return of the FEV to baseline and to relieve any discomfort the patient may experience. Most patients revert to normal pulmonary function within 10 to 20 minutes following administration of an inhaled -agonist [see Dosage and Administration (2.6)]. Provocholine powder for inhalation solution requires reconstitution and dilution prior to use [see Dosage and Administration (2.2)]. Provocholine inhalation solution in ready-to-use kit does not require reconstitution and/ or silution prior to use.. Provocholine inhalation solution 16 mg/mL in single-dose vial requires dilution prior to use [see Dosage and Administration (2.2)]. For safety and accuracy, administer Provocholine during methacholine challenge test in pulmonary function laboratory or clinic, by adequately trained personnel, for safety and accuracy, and should be performed only under the responsibility of healthcare practitioner trained in and thoroughly familiar with all aspects of the technique of the test and the management of respiratory distress. Emergency medication and equipment should be immediately available to treat acute respiratory distress.. Consider Provocholine use in patients on chronic asthma drugs if the accuracy of the asthma diagnosis is in doubt. In these patients, only administer Provocholine if spirometry is normal after supervised withdrawal of the asthma drugs.. Provocholine is not recommended for use in patients with clinically apparent asthma or wheezing.. Before starting methacholine challenge test, baseline spirometry must be performed. For patient to be able to undergo the test, he or she must present with baseline FEV (Forced Expiratory Volume in second) greater than or equal to 60% of the predicted value (in adults and children) and greater than or equal to 1.5 (in adults). Provocholine is contraindicated in adult and pediatric patients with baseline FEV1 60% predicted or in adults with FEV < 1.5 [see Contraindications (4) and Warnings and Precautions (5.1)]. At commencement of the methacholine challenge test and prior to administration of Provocholine, post-diluent FEV must be measured following nebulization of the diluent or base solution (contains no methacholine chloride) see Dosage and Administration (2.4, 2.5)]. Administer Provocholine by oral inhalation, with or without food, using either the 5-Breath Dosimeter Dosing Method or the 1-Minute Tidal Breathing Dosing Method with the dose doubling or quadrupling protocols [see Dosage and Administration (2.3, 2.4, 2.5)]. Discard any unused solution from the nebulizer after each administration.. The methacholine challenge test is considered positive if there is reduction of FEV of 20% or more from the post-diluent FEV 1. The test should be stopped at this point. Calculate and record the FEV reduction value before starting the test [see Dosage and Administration (2.3, 2.4, 2.5)]. After the methacholine challenge test with Provocholine, administer an inhaled -agonist to expedite the return of the FEV to baseline and to relieve any discomfort the patient may experience. Most patients revert to normal pulmonary function within 10 to 20 minutes following administration of an inhaled -agonist [see Dosage and Administration (2.6)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. .. Pregnancy: Provocholine is not recommended (8.1) 8.1 Pregnancy. RiskSummaryThe available data from published literature on Provocholine use in pregnant women are insufficient to evaluate for drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal reproduction studies evaluating effects of methacholine chloride on embryofetal development have not been conducted. Diagnosis of bronchial airway hyperreactivity with bronchoprovocation challenge is not recommended for pregnant women because of the potential for hypoxia in the fetus. If bronchial airway hyperreactivity is suspected, consider trial of empiric treatment. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the United States general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. 8.2 Lactation. Risk SummaryThere are no available data on the presence of methacholine chloride in human milk, the effect on the breastfed infant, or the effect on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Provocholine and any potential adverse effects on the breastfed infant from Provocholine or from the underlying maternal condition. 8.4 Pediatric Use. The safety and effectiveness of Provocholine used in methacholine challenge test, has been established for the diagnosis of bronchial airway hyperreactivity in pediatric patients years of age and older who do not have clinically apparent asthma.The safety and effectiveness of Provocholine have not been established in pediatric patients younger than years of age.. 8.5 Geriatric Use. The diagnosis of bronchial airway hyperreactivity is largely performed in pediatric and younger adult patients. Clinical studies of Provocholine did not include patients 65 years of age or older.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. .. Healthcare provider and any other personnel involved in the administration of the methacholine challenge test should take precautions to minimize inhalation of Provocholine powder and nebulized aerosol (5.2). 5.1 Risk of Severe Bronchoconstriction. Severe bronchoconstriction can result from Provocholine administration (including the lowest dose). The use of Provocholine is contraindicated in pediatric and adult patients with baseline FEV 1< 60% predicted or adults with FEV 1< 1.5 L. Emergency equipment and medication should be immediately available to treat acute respiratory distress. Because of the potential for severe bronchoconstriction, the use of Provocholine in patients with clinically apparent asthma or wheezing is not recommended. If severe bronchoconstriction occurs, reverse immediately by the administration of rapid-acting inhaled -agonist. If baseline spirometry is not performed or is measured inaccurately, the initial FEV 1may be underestimated. In this situation, decreases in FEV 1may not be detected after escalating Provocholine doses, which may result in administration of unnecessary higher doses and an increase in the risk for excessive bronchoconstriction. 5.2 Risks to Healthcare Providers Administering Provocholine. The supplied Provocholine powder or the Provocholine nebulized aerosol may cause bronchoconstriction in healthcare providers administering Provocholine in methacholine challenge test. Healthcare providers and any other personnel involved in the administration of Provocholine should take the following precautionary steps:Do not inhale the supplied Provocholine powderDo not handle the Provocholine powder if you have asthma or hay fever.Apply low resistance filter to expiratory ports of dosing apparatus, as necessary, to prevent Provocholine release in the room air. Do not inhale the supplied Provocholine powder. Do not handle the Provocholine powder if you have asthma or hay fever.. Apply low resistance filter to expiratory ports of dosing apparatus, as necessary, to prevent Provocholine release in the room air. 5.3 Coexisting Diseases and Conditions. Provocholine is not recommended for patients with uncontrolled hypertension, aortic aneurysm, or history of myocardial infarction or stroke diseases. Patients with epilepsy, vagotonia, peptic ulcer disease, thyroid disease, urinary tract obstruction or other condition that could be adversely affected by cholinergic agent should undergo methacholine challenge only if the healthcare practitioner considers the benefit to the individual outweighs the potential risks.