PRODUCT MONOGRAPH

Pr

METHACHOLINE OMEGA

(Methacholine chloride powder for inhalation solution)

100 mg/vial

480 mg/vial

& 1600 mg/vial

Cholinergic / Diagnostic Aid (Bronchial Asthma)

Omega Laboratories, Ltd. Date of Preparation: 11 177, Hamon St. January 26, 2005 Montreal, Quebec H3M 3E4 Control Number: 084020

PRODUCT MONOGRAPH

Pr

METHACHOLINE OMEGA

(Methacholine chloride powder for inhalation solution)

100 mg/vial, 480 mg/vial & 1600 mg/vial

ACTIONS AND CLINICAL PHARMACOLOGY

METHACHOLINE OMEGA METHACHOLINE OMEGA

(Methacholine chloride powder for inhalation solution) is a parasympathomimetic (cholinergic) bronchoconstrictor agent to be administered in solution only, by inhalation, for diagnostic purposes. Each vial of

contains 100 mg, 480 mg or 1600 mg of Methacholine Chloride powder which is to be reconstituted with 0.9% sodium chloride aquous solution for injection containing 0.9% benzyl alcohol (pH 7.0). See DOSAGE AND ADMINISTRATION for dilution procedures, concentrations and schedule of administration.

Methacholine Chloride is the $-methyl homolog of acetylcholine and differs from the latter primarily in its greater duration and selectivity of action. Bronchial smooth muscle contains significant parasympathetic (cholinergic) innervation. Bronchoconstriction occurs when the vagus nerve is stimulated and acetylcholine is released from the nerve endings. Muscle constriction is essentially confined to the local site of release because acetylcholine is rapidly inactivated by acetylcholinesterase. Compared with acetylcholine, Methacholine Chloride is more slowly hydrolysed by acetylcholinesterase and is almost totally resistant to inactivation by nonspecific cholinesterase or pseudocholinesterase. When a sodium chloride solution containing METHACHOLINE OMEGA (Methacholine chloride powder for inhalation solution) is inhaled, subjects with current asthma are more sensitive to methacholine and bronchoconstrict to lower doses than healthy subjects. This difference in response is the pharmacologic basis for the METHACHOLINE OMEGA inhalation diagnostic challenge. The test is most useful diagnostically when there are current symptoms consistent with asthma and when the forced expiratory volume at one second (FEV1) is normal at > 70% predicted. A normal result excludes current asthma (variable airflow limitation), but does not exclude past asthma. When there is chronic airflow limitation with an FEV1/VC of < 70%, the test can be abnormal due to other pathophysiological causes such as smoker's bronchitis, emphysema or cystic fibrosis. The challenge may also be positive in patients with allergic rhinitis without symptoms of asthma, or in patients who have had or will in the future develop asthma symptoms. There are no metabolic and pharmacokinetic data available on methacholine chloride.

CONTRAINDICATIONS

METHACHOLINE OMEGA

(Methacholine chloride powder for inhalation solution) is contraindicated in patients with known hypersensitivity to this drug or to other parasympathomimetic agents.

A repeated challenge test on the same day is contraindicated.

WARNINGS

METHACHOLINE OMEGA (METHACHOLINE CHLORIDE POWDER FOR INHALATION SOLUTION) IS A BRONCHOCONSTRICTOR AGENT FOR DIAGNOSTIC PURPOSES ONLY, AND SHOULD NOT BE USED AS A THERAPEUTIC AGENT. METHACHOLINE OMEGA (METHACHOLINE CHLORIDE POWDER FOR INHALATION SOLUTION) INHALATION CHALLENGE SHOULD BE PERFORMED ONLY UNDER THE

SUPERVISION OF A PHYSICIAN TRAINED IN AND THOROUGHLY FAMILIAR WITH ALL ASPECTS OF THE TECHNIQUE OF METHACHOLINE CHALLENGE, ALL CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, AND THE MANAGEMENT OF RESPIRATORY DISTRESS. A PHYSICIAN RESPONSIBLE FOR THE TESTS MUST BE PRESENT IN THE BUILDING WHEN TESTS ARE CARRIED OUT, AND AVAILABLE TO BE CONTACTED QUICKLY IF NECESSARY. IF THE PHYSICIAN IS PERFORMING THE TEST, ANOTHER PERSON MUST BE AVAILABLE IN THE BUILDING TO GIVE ASSISTANCE IF REQUIRED. THE PATIENT MUST NEVER BE LEFT UNATTENDED DURING THE TEST.

EMERGENCY MEDICATION AND EQUIPMENT SHOULD BE IMMEDIATELY AVAILABLE TO TREAT ACUTE RESPIRATORY DISTRESS. METHACHOLINE OMEGA (Methacholine chloride powder for inhalation solution) should be administered only by inhalation. Severe bronchoconstriction can result from the administration of METHACHOLINE OMEGA, if guidelines for careful administration are not followed. Patients with severe hyperresponsiveness of the airways can experience bronchoconstriction at the lowest dosages of METHACHOLINE OMEGA , or with the saline diluent alone. If severe bronchoconstriction occurs, it should be reversed immediately by the administration of a rapid-acting inhaled $-agonist. Because of the potential for severe bronchoconstriction, METHACHOLINE OMEGA challenge should not be performed in any patient with low baseline FEV1 of less than 1.5 litres or less than 70% of the predicted value. Please consult standard nomograms for predicted values.1

1. Morris JF, Koski WA, Johnson LC. Spirometric standards for healthy non-smoking adults. Am Rev Resp Dis 1971; 103: 57-67.

PRECAUTIONS

General: METHACHOLINE OMEGA (Methacholine chloride powder for inhalation solution) is to be administered only by inhalation. Serial dilutions of METHACHOLINE OMEGA are to be administered in a dose-response way, discontinuing when there are signs of excessive bronchoconstriction or the FEV1 falls by more than 20%. Administration of METHACHOLINE OMEGA to patients with epilepsy, cardiovascular disease accompanied by bradycardia, vagotonia, peptic ulcer disease, thyroid disease, urinary tract obstruction or other conditions that could be adversely affected by a cholinergic agent should be undertaken only if the physician feels benefit to the individual outweighs the potential risks. 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 METHACHOLINE OMEGA (Methacholine Chloride Powder for inhalation solution) dilutions may not be detected, resulting in too high a dose and excessive bronchoconstriction. Drug Interactions: Precaution should be taken when the inhalation challenge is performed in patients receiving any $-adrenergic blocking agents, as it is possible that bronchoconstriction may not reverse as readily. The following asthma and hay fever medications inhibit the response of airways to METHACHOLINE OMEGA aerosol, and should be withheld before the test, for their duration of action: $-agonists, anticholinergics and theophylline. Corticosteroids, cromoglycate and nedocromil, after regular use, may alter METHACHOLINE OMEGA responsiveness but they do not do this acutely; thus, they may be continued in their regular dose before any test. The effects of other newer medications have not been investigated.

Information for Patients: To assure the safe and effective use of the METHACHOLINE OMEGA inhalation challenge, the following instructions and information should be given to patients:

1. Patients should be educated in the symptoms that may occur as a result of the test, and instructed to alert the test administrator of these symptoms so that the test can be stopped before pulmonary function is reduced to less than 1.5 litres or less than 70% of the predicted value.

2. Women of child-bearing age should be questioned on the possibility of pregnancy (See PRECAUTIONS: Pregnancy).

Laboratory Personnel: METHACHOLINE OMEGA (Methacholine chloride powder for inhalation solution) aerosol may cause bronchoconstriction in laboratory personnel and others in the same room as the patient undergoing the test. Laboratory personnel with asthma or hay fever should take appropriate precautions when handling the material. (See PHARMACEUTICAL INFORMATION: SPECIAL INSTRUCTIONS.)

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.

Pregnancy

: Teratogenic Effects: Animal reproduction studies have not been conducted with

Methacholine Chloride. It is not known whether Methacholine Chloride can cause fetal harm when administered to a pregnant patient or affect reproductive capacity. METHACHOLINE OMEGA (Methacholine chloride powder for inhalation solution) should be given to a pregnant woman only when the benefits clearly outweigh the risks.

Nursing Mothers

: It is not known if Methacholine Chloride when inhaled is excreted in breast milk. Methacholine Chloride inhalation challenge should be administered to nursing mothers only when the benefits clearly outweigh the risks.

Pediatric Use: The safety and efficacy of METHACHOLINE OMEGA inhalation challenge have not been established in children below the age of 5 years.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

METHACHOLINE OMEGA METHACHOLINE OMEGA

(Methacholine Chloride Powder for inhalation solution) is to be administered only for inhalation. When administered orally or by injection, overdosage with

(Methacholine chloride powder for inhalation solution) can result in a syncopal reaction, with cardiac arrest and loss of consciousness. Serious toxic reactions should be treated with 0.5 mg to 1 mg of atropine sulfate, administered I.M. or I.V.

DOSAGE AND ADMINISTRATION

Two methods of administration of the METHACHOLINE OMEGA (Methacholine chloride powder for inhalation solution) inhalation challenge test have been widely used in current clinical practice, the tidal breathing method and the dosimeter method. The tidal breathing technique requires the patient to breathe normally, over a two-minute period, a constantly generated aerosol of METHACHOLINE OMEGA. By contrast, the dosimeter method requires the patient to take five full breaths of METHACHOLINE OMEGA aerosol generated to produce a specific dose per breath. With either technique, the test is stopped if the FEV1 falls by more than 20% from the mean baseline FEV1. The concentration at dose and the percent fall in FEV1 are then used to calculate either the provocative concentration to cause a fall in FEV1 of 20% (PC20), or the provocation dose (PD20). DOSAGES Adults and children (5 years or older) are exposed to the following increasing concentrations of METHACHOLINE OMEGA (Methacholine chloride powder for inhalation solution): 0.03, 0.06, 0.125, 0.25, 0.5, 1, 2, 4, 8 and 16 mg/mL. (See Table 1.) PREPARATION OF DILUTIONS All dilutions should be made with 0.9% sodium chloride injection containing 0.9% benzyl alcohol, as suggested in Table 1 for METHACHOLINE OMEGA 100 mg/vial, in sterile USP Type I Glass vials. After adding the 0.9% sodium chloride injection, shake each vial to obtain a clear solution. Check the date of preparation or expiry before using dilutions that are not freshly prepared. For the preparation of dilutions for METHACHOLINE OMEGA 480 mg/vial, add 30 mL of 0.9% sodium chloride injection containing 0.9% benzyl alcohol to the vial to obtain a 16 mg/mL solution and follow the Table 1 for the subsequent dilutions. For the preparation of dilutions for METHACHOLINE OMEGA 1600 mg/vial, add 50 mL of 0.9% sodium chloride injection containing 0.9% benzyl alcohol to the vial. Use 3 mL of the prepared solution in an empty vial and add 3 mL of the same diluent to obtain a 16 mg/mL solution. From this 16 mg/mL solution, follow the Table 1 for the preparation of the subsequent dilutions.

METHACHOLINE OMEGA

(Methacholine chloride powder for inhalation solution) solutions prepared using aseptic technique may be stored in a refrigerator (2 to 8/C) for up to 2 weeks. After this time, discard the vials and prepare new dilutions. Do not freeze the dilutions. Since the temperature of the solution affects nebulizer output, solutions should be taken out of the refrigerator and allowed to equilibrate to room temperature (approximately 30 minutes) before use.

Discard used solution from the nebulizer after each concentration used. Table 1 describes a method of producing appropriate dilutions, using a single vial containing 100 mg of METHACHOLINE OMEGA (Methacholine chloride powder for inhalation solution).

Table 1: Preparation of Serial Dilutions Using a Single 100 mg Vial of METHACHOLINE OMEGA

(Methacholine chloride powder for inhalation solution)

A sterile bacterial-retentive filter (porosity 0.22 :m) should be used when transferring a solution from each vial (at least 2 mL) to a nebulizer

.

ADMINISTRATION - GENERAL PROCEDURES The challenge test must be conducted in a pulmonary function laboratory or clinic, by adequately trained personnel, for safety and accuracy. The FEV1 value should be established before and after diluent inhalation. After determination of the post-diluent baseline pulmonary function, the predicted value of a positive response is then calculated from the mean before diluent inhalation. The challenge is performed by giving a subject increasing serial concentrations of METHACHOLINE OMEGA (Methacholine chloride powder for inhalation solution), after determining baseline FEV1 with inhaled normal saline control containing 0.9% benzyl alcohol. A subject to be challenged must have an FEV1 of at least 70% of the predicted value. A common error giving inaccurate results is caused by not taking a full inspiratory breath prior to baseline FEV1 determination. Consult a physician if the FEV1 falls below 1.5 litres. Do not leave the patient unattended at any time. An inhaled $-agonist must be administered after METHACHOLINE OMEGA challenge to expedite the return of the FEV1 to baseline and to relieve any discomfort of the subject. Most patients revert to normal pulmonary function within 10 to 20 minutes following administration of a $-agonist. In order to produce interpretable results, it is important to calibrate nebulizers to produce a standard output, and validate the reproducibility of the delivery system. Suitable nebulizers and standard settings are discussed in published sources. ADMINISTRATION - TIDAL BREATHING METHOD The following method is based on the use of the Wright nebulizer. If using other nebulizer models, consult published sources on Methacholine inhalation challenge for the appropriate operation of alternate nebulizers.

1. Using a 3-mL syringe and needle, draw up 3 mL of diluent (0.9% NaCl solution for injection with 0.9% benzyl alcohol as preservative) and place it in the nebulizer vial. Attach the vial firmly to the nebulizer.

2. At this time, the subject should be told that subsequent aerosols may produce mild cough, chest tightness or shortness of breath. Tell the subject that if these symptoms become uncomfortable, to remove the face mask (mouthpiece) and to stop inhaling the aerosol immediately. Try to avoid suggesting that these symptoms will definitely develop, as suggestion alone can lower the FEV1. Remember that perception of airway narrowing can vary considerably between subjects, making it advisable to watch and listen for other signs such as wheeze and an altered pattern of breathing. Instructions to cease inhaling the aerosol if symptoms become troublesome should be repeated before every dose.

3. Instruct the patient to relax and breathe the aerosol quietly (tidal breathing) for 2 minutes.

4. Keeping the nebulizer well away from the patient, adjust the flow meter so that the nebulizer is operating at the calibrated output (0.13 mL/min for the Wright nebulizer).

5. Apply a nose clip and place the face mask loosely over the nose and mouth (or the mouthpiece in the mouth). Start the stopwatch immediately. The vial nebulizer should be kept vertical. The patient should hold the nebulizer and not the vial so as to avoid warming the solution, and subsequently altering the output.

6. After exactly two minutes, remove the nebulizer from the patient's mouth, turn off the flow meter, and discard the solution.

7. Measure the FEV1 30 and 90 seconds after the end of the inhalation. These values may be left at ATPS. If the FEV1 at 90 seconds is the same or lower than that at 30 seconds, the measurement must be repeated at 3 minutes and, if needed, at 2-minute intervals until the FEV1 starts to rise. To avoid tiring the patient, the FEV1 should only be measured once on each occasion. If it is not technically satisfactory, it should be repeated after 10 seconds.

8. If the FEV1 falls by more than 20% from the mean baseline FEV1 (ATPS) or to less than 1.0 litre, no further inhalations are given. (A physician should be consulted if the FEV1 falls below 1.5 litres.) If the FEV1 has fallen by 16% or more from baseline, it is unwise to give further doses. The PC20 may be extrapolated from the last two points of the dose response curve.

9. The concentration of the first aerosol of METHACHOLINE OMEGA (Methacholine chloride powder for inhalation solution) is 0.03 mg/mL. Subsequent ones are given at approximately 5-minute intervals in doubling concentrations (0.06, 0.125, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0 and

16.0 mg/mL). NOTE: The initial dilution of the 1600 mg vial to obtain a solution of 32 mg/mL is NOT to be administered to the patient during the Methacholine inhalation challenge test. It is only used in the preparation of the 16 mg/mL and 8 mg/mL dilutions. Repeat steps 1 through 8 with each increasing concentration of METHACHOLINE OMEGA (Methacholine chloride powder for inhalation solution) until the FEV1 has fallen by 20% from baseline, or the FEV1 is 1.5 litres or less, or the highest concentration has been given. Do not give any further aerosols of METHACHOLINE OMEGA. Once the FEV1 stops falling after the last inhalation, give the patient 2 puffs of a $-agonist. Wait 10 minutes and measure the FEV1 and VC. Patients should not be allowed to leave the laboratory until their FEV1 has returned to within 90% of baseline. After the test, wash the nebulizer thoroughly in clean water. Allow to dry completely before storing. ADMINISTRATION - DOSIMETER METHOD The following method is based on the use of a DeVilbiss jet nebulizer attached to a Rosenthal- French dosimeter operating at 20 psi and for a period of 0.6 second. If using other nebulizers or dosimeters, consult published sources on Methacholine inhalation challenge for the appropriate operation of alternate nebulizers and dosimeters. The dosimeter should be calibrated to ensure accurate duration of delivery, and re-calibrated whenever the length of the tubing is changed. All solutions are delivered from functional residual capacity to inspiratory capacity. Factors that influence the response to inhalation challenge, and which should be consistent, are nebulizer output and inspiratory time. Baseline FEV1 value is established before and after diluent inhalation. The target for a positive response to achieve a 20% reduction in baseline pulmonary function is calculated using standard nomograms. Solution is put in the nebulizer, and the plumbing tube attached to the compressed air reservoir. (The volume of solution does not affect the output.) The aerosol is generated by the compressed air delivered at 20 psi through the nebulizer. The input is controlled by a solenoid valve that is triggered by the inspiration and is kept open for 0.6 second. A nose clip is used. The subjects are instructed to inhale slowly from the functional residual capacity (FRC) to total lung capacity. During the inhalation, the vent of the nebulizer should be kept open. Baseline pulmonary function is established with five inhalations of diluent (0.9% NaCl injection with 0.9% benzyl alcohol as preservative), and the baseline FEV1 noted. A subject to be challenged must have an FEV1 of at least 70% of the predicted value, when tested with the diluent. Spirometry is measured within 5 minutes of the fifth inspiration of control solution. At this time, the subject should be told that subsequent aerosols may produce mild cough, chest tightness or shortness of breath. Tell the subject that if these symptoms become uncomfortable, to remove the mouthpiece immediately. Try to avoid suggesting that these symptoms will definitely develop, as suggestion alone can lower the FEV1. Remember that perception of airway narrowing can vary considerably between subjects, making it advisable to watch and listen for other signs such as wheeze and an altered pattern of breathing. Instructions to cease inhaling the aerosol if symptoms become troublesome should be repeated before every step up in concentration. As with the tidal breathing technique, serial concentrations of METHACHOLINE OMEGA (Methacholine chloride powder for inhalation solution) are administered. Five inhalations of each concentration are taken, followed by measurement of FEV1 within 5 minutes of the last inhalation at each dosage. One inhalation unit is defined as one inhalation of a solution of METHACHOLINE OMEGA containing 1 mg/mL. Because doses are taken in rapid succession, the units are expressed as cumulative units, as shown in Table 2, below.

Table 2: Cumulative Inhalation Units

If the FEV1 falls by more than 20% from the mean baseline FEV1 (ATPS) or less than 1.0 litre, no further inhalations are given. (A physician should be consulted if the FEV1 falls below 1.5 litres.) Partial doses (fewer than 5 inhalations) may be given if the FEV1 is between 15% and 20% less than baseline control, in order to protect against an excessive fall in pulmonary function. Once the FEV1 stops falling after the last inhalation, give the patient 2 puffs of a $-agonist. Wait 10 minutes and measure the FEV1. Patients should not be allowed to leave the laboratory until their FEV1 has returned to within 90% of baseline. After the test, wash the nebulizer thoroughly in clean water. Allow it to dry completely before storing. SHORTENING THE TEST PROCEDURE Technicians should be well versed on the longer procedure before attempting a shorter version. Shortening the test does run the risk of inadvertently giving the patient too high a dose; always err on the side of safety and give a lower dose when in doubt. If clinical history suggests that the patient may not have asthma or that their asthma is very mild, then the lowest concentration may be omitted, as described below:

1. Starting Concentrations in Adults

As a guide, the first concentration of METHACHOLINE OMEGA (Methacholine chloride powder for inhalation solution) can be based on the following criteria:

1. If FEV1/VC > 80% AND FEV1 > 70% predicted AND FEV1 falls < 10% after the diluent inhalation AND the patient's symptoms are well controlled on the following medications, use these starting concentrations:

Medication Starting

Inhaled or ingested corticosteroids 0.125 mg/mL Daily bronchodilators 0.25 mg/mL Occasional bronchodilators (< once/day) 1.0 mg/mL No medications 2.0 mg/mL If FEV1/VC < 80% OR FEV1 < 70% predicted AND FEV1 falls < 10% after the diluent inhalation AND the patient's symptoms are well controlled on the following medications, use these starting concentrations:

Medication Starting Concentration

Inhaled or ingested corticosteroids 0.03 mg/mL

Other or no medications 0.125 mg/mL If a patient's FEV1 falls by 10% or more after the diluent inhalation, or if asthma symptoms do not appear to be well controlled, DO NOT omit any concentrations, and start all patients at 0.03 mg/mL.

Starting Concentrations in Children

1. If FEV1/VC > 80% AND the child's symptoms are well controlled on the following medications, use these starting concentrations:

Medication Starting Concentration

Inhaled or ingested corticosteroids 0.03 mg/mL

Daily or occasional bronchodilators 0.06 mg/mL No medications 0.25 mg/mL If FEV1/VC < 80% OR if asthma symptoms do not appear to be well controlled, DO NOT omit any concentrations, and start all patients at 0.03 mg/mL.

Omission of Concentrations

If, after the first concentration of METHACHOLINE OMEGA (Methacholine chloride powder for inhalation solution), there has been no evidence of any significant fall in the FEV1 (less than 5% from mean baseline) and there is NO clinical evidence of any bronchoconstriction (chest tightness, cough or wheezing), the next dose may be omitted. As soon as there is any evidence of symptoms or a fall greater than 5% from mean baseline FEV1, DO NOT omit any further concentrations. If a concentration is omitted, it is important to stress before every 2-minute inhalation that the subject should remove the face mask/mouthpiece as soon as they experience any breathing or chest discomfort. CALCULATION AND INTERPRETATION OF RESULTS Either the provocative concentration or the provocative dose causing a 20% fall in FEV1 (PC20 or PD20) may be calculated as described below:

1. Calculation of PC20

With either the tidal breathing method or the dosimeter method, airway responsiveness may be expressed as that concentration of METHACHOLINE OMEGA (Methacholine chloride powder for inhalation solution) provoking a fall in FEV1 of 20% (PC20). The percent fall in FEV1 can be calculated using the mean baseline FEV1, as shown below: % fall in FEV1 = mean baseline FEV1 - lowest FEV1 post-METHACHOLINE OMEGA x 100 mean baseline FEV1 The percent fall in FEV1 is then plotted against the rising concentration of METHACHOLINE OMEGA (Methacholine Chloride Powder for inhalation solution) (log scale). The PC20 is obtained by linear interpolation between the last two points, as shown in Figure 1. Figure 1: Calculation of PC20 Alternatively, the PC20 may be calculated as follows: PC20 = antilog log C1 + (log C2 - log C1) (20 - R1) (R2 - R1) where: C1 = second last concentration (< 20% FEV1 fall) C2 = last concentration (> 20% FEV1 fall) R1 = % fall FEV1 after C1 R2 = % fall FEV1 after C2

Calculation of PD20 The FEV1 from the best spirogram at each dose is plotted on semilog paper (see example Figure 2, below) and a dose response curve constructed. The dose is expressed as cumulative units, either :moles or breath units, where 1 mg/mL is equal to 0.5 :moles or 10 breath units. The curve starts at 100%, and the last data point should be at 80% of saline control or lower. From this curve, the PD20, the provocation dose of agonist necessary for a 20% drop in FEV1, can be interpolated. The PD20 is the measure of the sensitivity to METHACHOLINE OMEGA (Methacholine chloride powder for inhalation solution). Patients who do not respond to five inhalations of METHACHOLINE OMEGA at the 16 mg/mL concentration can be said to have a negative challenge. Figure 2: Airway responsiveness to METHACHOLINE OMEGA (PD20), expressed as cumulative units (either :moles or breath units)

Interpretation of Results

In clinical trials, most asthmatics had a positive response at the 10 mg/mL concentration or less. Results can be interpreted with respect to the presence or absence of asthma only if the FEV1/VC is > 70%. The cut-off point between normal and increased responsiveness is a PC20 of 8 mg/mL, or a PD20 of 4 cumulative :moles or 80 cumulative breath units. (Figure 3). Increased responsiveness is arbitrarily graded as borderline if between 4 and 8 mg/mL (2 and 4 :moles or 40 and 80 breath units), as mild between 2 and < 4 mg/mL (1 and < 2 :moles or 20 and 40 breath units), as moderate if between 0.25 and < 2 mg/mL (0.125 and < 1 :mole or 5 and < 20 breath units), and as severe if < 0.25 mg/mL (< 0.125 :moles or < 2.5 breath units). Patients with a PC20 > 16 mg/mL (or a PD20 > 8 :moles or > 160 cumulative breath units) are unlikely to have current symptoms due to asthma. When the PC20 is between 2 and 16 mg/mL, or the PD20 is between 1 and 8 :moles or 20 and 160 cumulative breath units, current symptoms due to asthma are likely to be mild, infrequent or absent. Current symptoms of asthma are usual when the PC20 is < 2 mg/mL, or the PD20 is < 1:moles or < 20 cumulative breath units. Figure 3: Comparison of METHACHOLINE OMEGA (Methacholine chloride powder for inhalation solution) airway responsiveness expressed as PC20 (mg/mL) using the tidal breathing method, and expressed as PD20 (cumulative :moles and cumulative breath units) using the dosimeter method. DRUG SUBSTANCE

PHARMACEUTICAL INFORMATION

Proper Name: Methacholine chloride Chemical Name: 1-Propanaminium, 2-(acetyloxy)-N,N,N-trimethyl-, chloride Structural Formula:

CH3 Cl

N3

CH

+ CH3 Molecular Formula: C8H18ClNO2 Molecular Weight: 195.69 Description: METHACHOLINE OMEGA is a white to practically white deliquescent compound that is soluble in water, alcohol and chloroform and insoluble in ether. Aqueous solutions are neutral to litmus. COMPOSITION Each vial of METHACHOLINE OMEGA contains 100 mg, 480 mg or 1600 mg of Methacholine Chloride powder to be reconstituted before use. STABILITY AND STORAGE RECOMMENDATIONS Unopened vials may be stored at 15 to 30/C. RECONSTITUTED SOLUTIONS

METHACHOLINE OMEGA

(Methacholine chloride powder for inhalation solution) solutions prepared with 0.9% NaCl solution for injection with 0.9% benzyl alcohol as preservative, using aseptic technique, may be stored in a refrigerator (2 to 8/C) for up to 2 weeks. After this time, discard the vials and prepare new dilutions. Do not freeze the dilutions..

SPECIAL INSTRUCTIONS

METHACHOLINE OMEGA METHACHOLINE OMEGA

(Methacholine chloride powder for inhalation solution) is a potent bronchoconstrictor. Do not inhale the powder. Do not handle this material if you have asthma or hay fever. A low resistance filter should be applied to an expiratory port of any dosing apparatus, as necessary, to prevent

aerosol from being released into the air of the room.

AVAILABILITY OF DOSAGE FORMS

METHACHOLINE OMEGA METHACHOLINE OMEGA

(Methacholine chloride powder for inhalation solution) is packaged in 30- mL amber glass vials containing 100 mg of

, in boxes 6 vials.

METHACHOLINE OMEGA METHACHOLINE OMEGA

(Methacholine chloride powder for inhalation solution) is packaged in 30- mL amber glass vials containing 480 mg of

, in boxes 1 vial.

METHACHOLINE OMEGA METHACHOLINE OMEGA

(Methacholine chloride powder for inhalation solution) is packaged in 50- mL amber glass vials containing 1600 mg of

, in boxes 1 vial.

Animal Studies

PHARMACOLOGY

In vitro

studies with tracheal, bronchial or lung tissue from several species indicate that Methacholine Chloride consistently produced a dose-related contraction. Lung tissue appeared to be less sensitive than other portions of the respiratory tract.

Pharmacologic studies of the pulmonary effects of Methacholine aerosol in the guinea pig, dog and monkey showed dose-related increases in pulmonary resistance and decreased dynamic compliance.

Clinical Trials

In 1,500 patients with asthma and 500 nonasthmatics (either atopic or nonatopic), over 90% of asthmatics had high- or medium-positive responsiveness to Methacholine Chloride. Less than 5% of individuals with hay fever or nonatopic normal subjects showed a high-positive response. Twenty-seven percent of hay fever patients had a negative response compared to 49% of normals. Hay fever patients and normals had about the same incidence of low-positive responses. Thirty percent of hay fever patients had a medium-positive response compared to 18% of normals from families with a history of asthma and 8% of normals from control families. Asthmatics were different from all other groups. Hay fever patients were different from normals of normal families only. Among current asthmatics, the severity of asthma determined the bronchial sensitivity of subjects to methacholine challenge. This sensitivity varied from 100 to several thousand times that of normal subjects. However, in former asthmatics, the degree of bronchoconstriction was also related to the severity of past asthma symptoms. The mean sensitivity of former asthmatics was approximately one tenth that of current asthmatics. In population-based studies, the prevalence of Methacholine Chloride hyperresponsiveness is 8 to 15%. While the degree of responsiveness of asthmatics does not distinguish them from nonasthmatics, asthmatics repond to a lower mean dose. Asthmatics who are less responsive generally have milder and more stable disease. Interpretation is easiest when the result is either substantially positive (a PC20 < 1 mg/mL or a PD20 < 10 cumulative breath units), or decidedly negative (minimal change in the FEV1 with the highest dose delivered). The cutt-off point between normal and increased responsiveness is considered to be a PC20 of 8 mg/mL or a PD20 of 4 :moles (cumulative). A dosimeter technique was used to test 766 children aged 9 years, who showed symptoms of asthma but had normal resting pulmonary function. Within two months, the dosimeter method was used to retest 79 of these patients. A further 30, 22 of whom showed reactivity, were challenged with the tidal breathing method. Twenty-five percent of the children had evidence of airway reactivity, revealed either by resting airflow obstruction relieved by salbutamol or by responsiveness to inhalation of Methacholine Chloride. The dosimeter method was suitably repeatable, and the tidal breathing method was equally sensitive in detecting reactivity to Methacholine Chloride. In only four children was the difference in PC20 between the two techniques greater than a twofold concentration step. A paired t test showed no bias from one method to the other. The usefulness of the challenge test in confirming suspected asthma was determined in 1,105 subjects of 5 to 80 years of age; 189 were current asthmatics and 916 were nonasthmatics. Nonasthmatics were further categorized as: 143 atopics from asthma families; 66 atopics from normal families; 326 nonatopics from asthma families; and 381 nonatopics from normal families. Subjects were challenged with Methacholine Chloride, using the dosimeter method. Methacholine Chloride challenge was shown to be helpful tool in affirming the pretest probability of asthma.

METHACHOLINE OMEGA

(Methacholine chloride powder for inhalation solution) challenge test is used to help investigate whether asthma is of occupational or nonoccupational origin. The incidence of cough, wheezing, and shortness of breath in the workplace ranges from 2 to 15 percent in various series. Increases in airway responsiveness associated with periods at work provide useful supportive evidence to pulmonary function records.

TOXICOLOGY

The acute (24-hour) oral LD50 of Methacholine Chloride and related compounds is 1100 mg/kg in the mouse and 750 mg/kg in the rat. Cynomolgus monkeys were exposed to a 2% (20 mg/mL) aerosol of Methacholine Chloride in acute (10-minute) and subchronic (7-day) inhalation toxicity studies. In the former study, animals exposed to the aerosol for up to 10-minutes demonstrated an increase in respiratory rate and decrease in tidal volume after 30 seconds. These changes peaked at 2 minutes and were followed by a rise in pulmonary resistance and a decrease in compliance. Pulmonary function returned to normal 20 to 25 minutes after exposure ended. In the 7-day study, monkeys were given daily inhalations equivalent to the maximum and roughly five times the maximum standard human dose. Although the typical pulmonary response/recovery sequence was observed, distinct changes in airway resistance were noted at the end of the study. These changes were not rapidly reversed in the maximum equivalent standard-dose group, which was observed for 9 weeks.

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