WARNING: RISK OF SEVERE BRONCHOSPASM Mannitol, the active ingredient in ARIDOL, acts as a bronchoconstrictor and may cause severe bronchospasm. Bronchial challenge testing with ARIDOL is for diagnostic purposes only. Bronchial challenge testing with ARIDOL 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. Medications (such as short acting inhaled beta-agonist) and equipment to treat severe bronchospasm must be present in the testing area. If severe bronchospasm occurs it should be treated immediately by administration of a short acting inhaled beta-agonist. Because of the potential for severe bronchoconstriction, the bronchial challenge testing with ARIDOL should not be performed in any patient with clinically apparent asthma or very low baseline pulmonary function tests (e.g., FEV 1 <1-1.5 liters or <70% of the predicted values) [ see Warnings and Precautions ( 5.1 )]. WARNING: RISK OF SEVERE BRONCHOSPASM See full prescribing information for complete boxed warning. Mannitol, the active ingredient in ARIDOL, acts as a bronchoconstrictor and may cause severe bronchospasm. Bronchial challenge testing with ARIDOL is for diagnostic purposes only. Only trained professionals under the supervision of a physician who are familiar with the management of acute bronchospasm should perform bronchial challenge testing with ARIDOL. Medications (such as short acting inhaled beta-agonist) and equipment to treat severe bronchospasm must be present in the testing area. Because of the potential for severe bronchoconstriction, bronchial challenge testing with ARIDOL should not be performed in any patient with clinically apparent asthma or very low baseline pulmonary function tests (e.g., FEV 1 <1-1.5 liters or <70% of the predicted values) ( 5.1 )
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warnings and cautions
5 WARNINGS & PRECAUTIONS Severe bronchospasm: ARIDOL may cause severe bronchospasm in susceptible patients. Administer by trained professionals under the supervision of a physician. Medications and equipment to treat severe bronchospasm must be present in the testing area. ( 5.1 ) Subjects with co-morbid conditions: Use 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, unstable angina, or active upper or lower respiratory tract infection that may worsen with use of a bronchial irritant. ( 5.2 ) 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 FEV 1 (from pre-challenge FEV 1 ) 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. Subjects 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 ADVERSE REACTIONS Mannitol, the active ingredient in ARIDOL, is a sugar alcohol that may cause severe bronchospasm in susceptible subjects [ see Warnings and Precautions ( 5.1 )]. Most common adverse reactions (rate ≥1%) were headache, pharyngolaryngeal pain, throat irritation, nausea, cough, rhinorrhea, dyspnea, chest discomfort, wheezing, retching and dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pharmaxis Inc. at 1-888-659-6396 or email at adverse.events@pharmaxis.com.au or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 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. 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. Table 2: Adverse reactions with an incidence ≥1% within a day after bronchial challenge testing (overall population, Studies 1 and 2 combined) Adverse Reactions Treatment ARIDOL (N=1046) n (%) Methacholine Challenge (N=420) n (%) Headache 59 (6) 4 (1) Pharyngolaryngeal pain 25 (2) 0 Throat irritation 19 (2) 1 (<1) Nausea 19 (2) 0 Cough 17 (2) 8 (2) Rhinorrhea 16 (2) 0 Dyspnea 15 (1) 21 (5) Chest discomfort 13 (1) 18 (4) Wheezing 8 (1) 6 (1) Retching 6 (1) 0 Dizziness 5 (1) 13 (3) The maximum reduction in FEV 1 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 FEV 1 ≥30% and ≥60% following ARIDOL, methacholine, and exercise challenges for Studies 1 and 2 is shown in Table 3. Table 3: Incidence of decreases in FEV 1 ≥30% or ≥60% (overall population, Studies 1 and 2) Challenge No. Exposed N (%) with Fall in FEV 1 ≥30% N (%) with Fall in FEV 1 ≥60% Study 1 Exercise 435 27 (6%) 0 Methacholine 420 51 (12%) 3 (1%) ARIDOL 419 3 (1%) 0 Study 2 ARIDOL asthmatics 536 23 (4%) 0 ARIDOL Non-asthmatics 91 0 0 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 FEV 1 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 FEV 1 ≥30%. No patient who had bronchial challenge testing with ARIDOL or exercise had a decrease in FEV 1 ≥60%, whereas, one adolescent patient (aged 12 years) who received methacholine had a decrease in FEV 1 ≥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.