Included as part of the PRECAUTIONS section.
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. Subjects should be monitored until
fully recovered to within baseline.
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.
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
Use In Specific Populations
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.
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].
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
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.
A total of 246 children and adolescents ages 6 to 17
years were studied in the two clinical trials [see Clinical Studies].
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].
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.
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.