Aridol Bronchial Challenge Test Kit

Mannitol, the active ingredient in ARIDOL, is a sugar alcohol indicated for the assessment of bronchial hyperresponsiveness in patients 6 years of age or older who do not have clinically apparent asthma.

Limitations of Use:
ARIDOL is not a stand alone test or a screening test for asthma. Bronchial challenge testing with ARIDOL should be used only as part of a physician's overall assessment of asthma.

Mannitol, the active ingredient in ARIDOL, is a sugar alcohol that may cause severe bronchospasm in susceptible subjects [see Warnings and Precautions (5.1)].

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. Children and adolescents comprised 23% of the total study population with 118 children 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.

Children and Adolescents 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 children and adolescents who received the ARIDOL bronchial challenge test was similar to that of the adult population with 5%, 15% and 9% of pediatric subjects 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%.

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.

No formal drug-drug interaction studies were conducted with mannitol, the active ingredient in ARIDOL.

Pregnancy

Pregnancy Category C: There are no adequate and well-controlled clinical studies of mannitol in pregnant women. Bronchial challenge testing with ARIDOL should be performed during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Teratogenic Effects: Mannitol was not teratogenic. Mannitol did not cause any embryofetal malformations when given to pregnant rats and mice at oral doses approximately 20 and 10 times the maximum recommended human daily inhalation dose (MRHDID) in adults, respectively, on a mg/m2 basis [see Animal Toxicology and/or Pharmacology (13.2)].

Labor and Delivery

The effects of a possible hyperresponsiveness reaction on a mother or child during labor or delivery are not known, and therefore bronchial challenge testing with ARIDOL should not be administered during labor or delivery.

Nursing Mothers

It is not known whether mannitol is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when mannitol is given to a nursing mother.

Pediatric Use

A total of 246 children and adolescents ages 6 to 17 years were studied in the two clinical trials [see Clinical Studies (14)].

The mean and median maximum percentage reduction in FEV1 in patients with a positive ARIDOL challenge test in children and adolescents 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 children and adolescents 6 to 17 years of age was similar to the adult population in two clinical studies [see Adverse Reactions (6)].

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.

Geriatric Use

There was insufficient number of subjects 50 years of age and older in the clinical program. Therefore, the safety and efficacy of bronchial challenge testing with ARIDOL in the older population cannot be adequately assessed. It is unknown whether any differences in the safety and efficacy of bronchial challenge testing with ARIDOL exist between subjects 50 years of age and older and younger subjects.

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.

Mannitol, the active ingredient in ARIDOL, is to be administered only by inhalation. Susceptible persons may experience excessive bronchospasm from an overdose. If such bronchospasm occurs, immediately administer a short acting inhaled beta-agonist and other medical treatments such as oxygen, as necessary.

D-mannitol (referred to throughout as mannitol), the active ingredient in ARIDOL is a hexahydric alcohol, that is a sugar alcohol, with the following chemical name (2R,3R,4R,5R)-hexane-1,2,3,4,5,6-hexol and chemical structure:

Mannitol is a white or almost white crystalline powder of free-flowing granules with an empirical formula of C6H14O6 and molecular weight of 182.2. Mannitol is freely soluble in water, and very slightly soluble in alcohol. Mannitol shows polymorphism.

The Aridol Bronchial Challenge Test Kit contains one single patient use dry powder inhaler and 3 consecutively numbered foil blister packs containing a total of 19 capsules of mannitol for oral inhalation. All except the 0 mg printed hard gelatin capsules contain dry powder mannitol for oral inhalation. The accompanying dry powder inhaler is a plastic device used for inhaling the capsules. All doses are to be administered using the same device supplied with each kit without washing or sterilizing the device at anytime during the test.

To use the delivery system, a mannitol capsule is placed in the well of the inhaler, and the capsule is pierced by pressing and releasing the buttons on the side of the device. The mannitol dry powder is dispersed into the air stream when the patient inhales rapidly and deeply through the mouthpiece.

There are no inactive ingredients in the mannitol capsules supplied with the Aridol Bronchial Challenge Test Kit. The 0 mg capsule and the bodies of the 5, 10, 20 and 40 mg capsules are clear. The white caps (5 mg) contain titanium dioxide. The yellow caps (10 mg) contain titanium dioxide and yellow iron oxide. The pink caps (20 mg) and red caps (40 mg) contain titanium dioxide and red iron dioxide. The inhaler is a plastic device used for administering mannitol to the lungs. The amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow rate and inspiratory time. Under standardized in vitro testing at a fixed flow rate of 60 L/min for 2 seconds, the delivered dose from the inhaler from each of the 5, 10, 20 and 40 mg capsules is approximately 3.4, 7.7, 16.5 and 34.1 mg, respectively. Peak inspiratory flow rates (PIFR) achievable through the inhaler were evaluated in healthy and asthmatic individuals ranging from 7 to 65 years of age and with % FEV1 of predicted ranging from 67% to 123%. PIFR achieved in the study was at least 70.8 L/min in all subjects assessed. The mean PIFR was 118.2 L/min and approximately ninety percent of each population studied generated a PIFR through the device exceeding 90 L/min.