Mannitol

ARIDOL is indicated for the assessment of bronchial hyperresponsiveness in adult and pediatric patients 6 years of age or older who do not have clinically apparent asthma. Limitations of Use: ARIDOL is not a standalone 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. ARIDOL is a sugar alcohol indicated for the assessment of bronchial hyperresponsiveness in adult and pediatric patients 6 years of age or older who do not have clinically apparent asthma. ( 1 ) Limitations of Use: ARIDOL is not a standalone 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.

Inhalation powder: 0 mg, 5 mg, 10 mg, 20 mg, and 40 mg of mannitol dry powder per capsule in a bronchial challenge test kit. Each kit contains one, single patient use, dry powder inhaler device and 3 consecutively numbered foil blister packs containing a total of 19 capsules of mannitol for oral inhalation as described below: Blister pack "1" : Marked 1 – 1 x empty clear capsule printed with two white bands Marked 2 – 1 x 5 mg white/clear capsule printed with 5 mg Marked 3 – 1 x 10 mg yellow/clear capsule printed with 10 mg Marked 4 – 1 x 20 mg pink/clear capsule printed with 20 mg Blister pack "2" : Marked 5 – 1 x 40 mg red/clear capsule printed with 40 mg Marked 6 – 2 x 40 mg red/clear capsules printed with 40 mg Marked 7 – 4 x 40 mg red/clear capsules printed with 40 mg Blister pack "3" : Marked 8 – 4 x 40 mg red/clear capsules printed with 40 mg Marked 9 – 4 x 40 mg red/clear capsules printed with 40 mg Inhalation powder: 0mg, 5mg, 10mg, 20mg, and 40mg of mannitol dry powder per capsule in a bronchial challenge test kit ( 2 , 3 )

ARIDOL is contraindicated in: Patients with known hypersensitivity to mannitol or to the gelatin used to make the capsules Patients with conditions that may be compromised by induced bronchospasm or repeated spirometry maneuvers. Some examples include: aortic or cerebral aneurysm, uncontrolled hypertension, recent myocardial infarction or cerebral vascular accident [ see Warnings and Precautions ( 5.2 )]. Known hypersensitivity to mannitol or to the gelatin used to make the capsules ( 4 ) Conditions that may be compromised by induced bronchospasm or repeated spirometry maneuvers ( 4 )

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. 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.

The following clinically significant adverse reaction is described elsewhere in the labeling:

• Severe Bronchospasm [ 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 Methapharm, Inc. at 1-866-701-4636 or email at medinfo@methapharm.com 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. 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. 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. 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 FEV 1 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 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.

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

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.

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