2.1 Bronchial Challenge Test Kit Overview

ARIDOL is a bronchial challenge test kit containing the required capsules of dry powder mannitol for oral inhalation in graduated doses with the supplied single patient use inhaler necessary to perform one bronchial challenge test. Do not swallow ARIDOL capsules.

The airway response to bronchial challenge testing with ARIDOL is measured using forced expiratory volume in one second (FEV1).

Prior to bronchial challenge testing with ARIDOL, standard spirometry should be performed and the reproducibility of the resting FEV1 established.

2.2 Administration Instructions

An overview of the testing procedure can be found below. The ARIDOL bronchial challenge test should only be used with the provided inhaler. All remaining unused (opened and unopened) blister packs and the inhaler should be properly discarded at the completion of the test. See the ARIDOL Bronchial Challenge Test Kit instructions for complete instructions on the dosing and spirometry procedures.

a. A nose clip may be used if preferred. If so, apply nose clip to the patient and direct the patient to breathe through the mouth

b. Insert 0 mg capsule into inhalation device. Puncture capsule by depressing buttons on side of device slowly, and ONCE ONLY (a second puncture may fragment the capsules)

c. The patient should exhale completely, before inhaling from device in a controlled deep inspiration

d. At the end of deep inspiration, start 60 second timer, subject should hold breath for 5 seconds and exhale through mouth before removal of nose clip

e. At the end of 60 seconds, measure the FEV1 in duplicate (the measurement after inhaling the 0 mg capsule is the baseline FEV1)

f. Repeat steps a-e following the mannitol capsule dose steps from Table 1 below until the patient has a positive response or 635 mg of mannitol has been administered (negative test)

2.3 Bronchial Challenge Test Response and Patient Management

A positive response is achieved when the patient experiences a 15% reduction in FEV1 from (0 mg) baseline (or a 10% incremental reduction in FEV1 between consecutive doses). The test result is expressed as a PD15.

Patients with either a positive response to bronchial challenge testing with ARIDOL or significant respiratory symptoms should receive a standard dose of a short-acting inhaled beta-agonist and monitored until fully recovered to within baseline.

5.1 Severe Bronchospasm

Mannitol, the active ingredient in ARIDOL, acts as a bronchoconstrictor and may cause severe bronchospasm in susceptible patients. The test should only be conducted by trained professionals under the supervision of a physician familiar with all aspects of the bronchial challenge test and the management of acute bronchospasm. Patients should not be left unattended during the bronchial challenge test. Medications and equipment to treat severe bronchospasm must be present in the testing area.

If a patient has a ≥10% reduction in FEV1 (from pre-challenge FEV1) on administration of the 0 mg capsule, the ARIDOL Bronchial Challenge Test should be discontinued and the patient should be given a dose of a short-acting inhaled beta-agonist and monitored accordingly.

Patients with either a positive response to bronchial challenge testing with ARIDOL or significant respiratory symptoms should receive a short-acting inhaled beta-agonist. Patients should be monitored until fully recovered to within baseline.

5.2 Subjects with Co-morbid Conditions

Bronchial challenge testing with ARIDOL should be performed with caution in patients with conditions that may increase sensitivity to the bronchoconstricting or other potential effects of ARIDOL such as severe cough, ventilatory impairment, spirometry-induced bronchoconstriction, hemoptysis of unknown origin, pneumothorax, recent abdominal or thoracic surgery, recent intraocular surgery, unstable angina, or active upper or lower respiratory tract infection.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety population for the ARIDOL bronchial challenge test consisted of 1,082 subjects (577 females and 505 males) including patients with asthma, symptoms suggestive of asthma, and healthy individuals from 6 to 83 years of age who participated in the two clinical trials (Studies 1 and 2). The racial distribution of subjects was 84% Caucasian, 5% Asian, 4% Black, and 7% Other. Pediatric and adolescents patients comprised 23% of the total study population with 118 pediatric patients aged 6-11 years and 128 adolescents aged 12-17 years.

Adverse reactions were reported at the time of the testing procedure and for one day thereafter. No serious adverse reactions were reported following bronchial challenge testing with ARIDOL in either trial.

Five adult subjects (0.6%) discontinued from the studies within a day following bronchial challenge testing with ARIDOL because of cough, decreased lung function, feeling jittery, sore throat, and throat irritation. One adult subject (0.3%) discontinued following the methacholine bronchial challenge test because of dizziness. One pediatric subject (0.4%) discontinued from the studies within a day following bronchial challenge testing with ARIDOL because of retching.

Table 2 displays the combined common adverse reactions (≥1%) within a day after bronchial challenge testing with ARIDOL or methacholine in the overall population for Studies 1 and 2.

The maximum reduction in FEV1 following bronchial challenge testing with ARIDOL was 46%, compared to 54% for exercise testing and 67% for the methacholine challenge. The incidences in decreases in FEV1 ≥30% and ≥60% following ARIDOL, methacholine, and exercise challenges for Studies 1 and 2 is shown in Table 3.

There were no differences in the incidence of adverse reactions based on gender or race. The clinical trials did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently compared to subjects below 65 years of age.

Pediatric Patients Aged 6 to 17 Years: Overall, the types and severities of adverse reactions in children were similar to those observed in the adult population. As in the adult population, the adverse reactions of pharyngolaryngeal pain, nausea, and headache were the more common with incidences of 4%, 3%, and 3%, respectively. There were no major differences in the types of adverse reactions observed in children 6-11 years of age compared to adolescents 12-17 years old.

The decrease in FEV1 in pediatric patients and adolescents who received the ARIDOL bronchial challenge test was similar to that of the adult population with 5%, 15% and 9% of pediatric patients who had bronchial challenge testing with ARIDOL, methacholine and exercise, respectively, experiencing reduction in FEV1 ≥30%. No patient who had bronchial challenge testing with ARIDOL or exercise had a decrease in FEV1 ≥60%, whereas, one adolescent patient (aged 12 years) who received methacholine had a decrease in FEV1 ≥60%.

6.2 Post-Marketing Experience

The following adverse reactions have been identified post approval outside the U.S. of the ARIDOL Bronchial Challenge Test Kit: cough, gagging, wheeze, and decreased forced expiratory volume. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

8.1 Pregnancy

Risk Summary

There are no available human data regarding inhaled mannitol to evaluate a drug-associated risk for major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Based on animal reproduction studies, no evidence of structural alterations was observed when mannitol was orally administered to pregnant rats and mice during organogenesis at doses up to approximately 20 and 10 times, respectively, the maximum recommended daily inhalation dose (MRDID) in humans (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a 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 2-4% and 15-20%, respectively

Data

Animal Data

In animal reproduction studies, oral administration of mannitol to pregnant rats and mice during the period of organogenesis did not cause fetal structural alterations. The mannitol dose in rats and mice was approximately 20 and 10 times the maximum recommended human daily inhalation dose (MRDID) in humans, respectively, (on a mg/m2 basis at maternal doses of 1600 mg/kg/day in both
species).

8.2 Lactation

Risk Summary

There are no data on the presence of mannitol in human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ARIDOL bronchial challenge test and any potential adverse effects on the breastfed child from ARIDOL or from the underlying maternal condition.

8.4 Pediatric Use

The safety and effectiveness of ARIDOL for the assessment of bronchial hyperresponsiveness in adult and pediatric patients 6 years of age or older who do not have clinically apparent asthma have been established. The use of ARIDOL for this indication is supported by evidence from two clinical studies that included 246 pediatric patients 6 to 17 years of age [see Clinical Studies (14)].

The mean and median maximum percentage reduction in FEV1 in patients with a positive ARIDOL challenge test in pediatric patients 6 to 17 years of age (19% and 18%, respectively) showed no apparent difference compared to the adult population (19% and 18%, respectively).

The safety profile of the ARIDOL bronchial challenge test in pediatric patients 6 to 17 years of age was similar to the adult population in two clinical studies [see Adverse Reactions (6)].

Safety and effectiveness of ARIDOL have not been established in pediatric patients less than 6 years old. Bronchial challenge testing with ARIDOL should not be performed in children less than 6 years of age due to their inability to provide reliable spirometric measurements.

8.5 Geriatric Use

Clinical studies of ARIDOL did not include sufficient numbers of patients 50 years of age and older to determine whether they respond differently from younger adult patients.

8.6 Hepatic and Renal Impairment

Formal pharmacokinetic studies with mannitol, the active ingredient, in ARIDOL, have not been conducted in patients with hepatic or renal impairment. However, an increase in systemic exposure of mannitol can be expected in patients with renal impairment based on the kidney being its primary route of elimination.

Given parenterally, mannitol is used as an osmotic diuretic in a variety of clinical situations including acute renal failure where the osmotic effects of mannitol inhibit the rate of water re-absorption and maintain the rate of urine production.

12.1 Mechanism of Action

The precise mechanisms through which inhaled mannitol causes bronchoconstriction are not known.

12.2 Pharmacodynamics

The response to inhaled mannitol is reported as the delivered dose of mannitol causing a 15% reduction in FEV1 and is expressed as PD15.

12.3 Pharmacokinetics

Absorption: The rate and extent of absorption of mannitol after oral inhalation was generally similar to that observed after oral administration. In a study of 18 healthy adult male subjects the absolute bioavailability of mannitol powder following oral inhalation was 59% while the relative bioavailability of inhaled mannitol in comparison to orally administered mannitol was 96%. Following oral inhalation of 635 mg, the mean mannitol peak plasma concentration (Cmax) was 13.71 mcg/mL while the mean extent of systemic exposure (AUC) was 73.15 mcg•hr/mL. The mean time to peak plasma concentration (Tmax) after oral inhalation was 1.5 hour.

Distribution: Based on intravenous administration, the volume of distribution of mannitol was 34.3 L.

Elimination: Following oral inhalation, the elimination half-life of mannitol was 4.7 hours. The mean terminal elimination half-life for mannitol in plasma remained unchanged regardless of the route of administration (oral, inhalation, and intravenous). The urinary excretion rate versus time profile for mannitol was consistent for all routes of administration. The total clearance after intravenous administration was 5.1 L/hr while the renal clearance was 4.4 L/hr. Therefore, the clearance of mannitol was predominately via the kidney. Following inhalation of 635 mg of mannitol in 18 healthy subjects, about 55% of the total dose was excreted in the urine as unchanged mannitol. Following oral or intravenous administration of a 500 mg dose, the corresponding values were 54% and 87% of the dose, respectively.

Metabolism: The extent of metabolism of mannitol appears to be small. This is evident from a urinary excretion of about 87% of unchanged drug after an intravenous dose to healthy subjects.

Specific Populations

Patients with Hepatic and Renal Impairment: Formal pharmacokinetic studies using ARIDOL have not been conducted in patients with hepatic or renal impairment. Since the drug is eliminated primarily via the kidney, an increase in systemic exposure can be expected in renally impaired patients.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In 2-year carcinogenicity studies in rats and mice, mannitol did not show evidence of carcinogenicity at oral dietary concentrations up to 5% (or 7,500 mg/kg on a mg/kg basis). These doses were approximately 55 and 30 times the MRHDID, respectively, on a mg/m2 basis.

Mannitol tested negative in the following assays: bacterial gene mutation assay, in vitro mouse lymphoma assay, in vitro chromosomal aberration assay in WI-38 human cells, in vivo chromosomal aberration assay in rat bone marrow, in vivo dominant lethal assay in rats, and in vivo mouse micronucleus assay.

The effect of inhaled mannitol on fertility has not been investigated.