Aridol

Overdose

Mannitol, the active ingredient in ARIDOL (mannitol inhalation powder) , 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.  

Contraindications

ARIDOL (mannitol inhalation powder) use 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.

Undesirable effects

Mannitol, the active ingredient in ARIDOL (mannitol inhalation powder) , is a sugar alcohol that may cause severe bronchospasm in susceptible subjects.

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 (mannitol inhalation powder) 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 (mannitol inhalation powder) in either trial.

Five adult subjects (0.6%) discontinued from the studies within a day following bronchial challenge testing with ARIDOL (mannitol inhalation powder) 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 (mannitol inhalation powder) because of retching.

Table 2 displays the combined common adverse reactions ( ≥ 1%) within a day after bronchial challenge testing with ARIDOL (mannitol inhalation powder) 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)

The maximum reduction in FEV1 following bronchial challenge testing with ARIDOL (mannitol inhalation powder) 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 (mannitol inhalation powder) , methacholine, and exercise challenges for Studies 1 and 2 is shown in Table 3.

Table 3: Incidence of decreases in FEV1 ≥ 30% or ≥ 60% (overall population, Studies 1 and 2)

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.

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 (mannitol inhalation powder) 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 (mannitol inhalation powder) , methacholine and exercise, respectively, experiencing reduction in FEV1 ≥ 30%. No patient who had bronchial challenge testing with ARIDOL (mannitol inhalation powder) or exercise had a decrease in FEV1 ≥ 60%, whereas, one adolescent patient (aged 12 years) who received methacholine had a decrease in FEV1 ≥ 60%.

The following adverse reactions have been identified post approval outside the U.S. of the ARIDOL (mannitol inhalation powder) 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.

Therapeutic indications

Mannitol, the active ingredient in ARIDOL (mannitol inhalation powder) , 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.

ARIDOL (mannitol inhalation powder) is not a stand alone test or a screening test for asthma. Bronchial challenge testing with ARIDOL (mannitol inhalation powder) should be used only as part of a physician's

Pharmacodynamic properties

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

Pharmacokinetic properties

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.

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

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.

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.

Formal pharmacokinetic studies using ARIDOL (mannitol inhalation powder) 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.

Name of the medicinal product

Fertility, pregnancy and lactation

There are no adequate and well-controlled clinical studies of mannitol in pregnant women. Bronchial challenge testing with ARIDOL (mannitol inhalation powder) 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.

Qualitative and quantitative composition

ARIDOL (mannitol inhalation powder) is 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
• 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

ARIDOL (mannitol inhalation powder) is 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
• 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

NDC-44178-XXX-XX

ARIDOL (mannitol inhalation powder) should be stored below 77°F (25°C) with excursions permitted between 59-86°F (15-30°C).. Do not freeze. Do not refrigerate.

The ARIDOL (mannitol inhalation powder) 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. Be sure to read the accompanying ARIDOL (mannitol inhalation powder) bronchial challenge test kit instructions completely before test initiation. If you have any questions, contact the manufacturer support at 1-888-659-6396.

Manufactured by: Pharmaxis Ltd, Unit 2, 10 Rodborough Rd, Frenchs Forest NSW 2086, AUSTRALIA. Manufactured for: Pharmaxis, Inc. One East Uwchlan Avenue, Suite 405, Exton, PA 19341. 1-888-659-6396. www.aridol (mannitol inhalation powder).info

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

Mannitol, the active ingredient in ARIDOL (mannitol inhalation powder) , 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 (mannitol inhalation powder) 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 (mannitol inhalation powder) or significant respiratory symptoms should receive a short acting inhaled beta-agonist. Subjects should be monitored until fully recovered to within baseline.

Bronchial challenge testing with ARIDOL (mannitol inhalation powder) should be performed with caution in patients with conditions that may increase sensitivity to the bronchoconstricting or other potential effects of ARIDOL (mannitol inhalation powder) 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.

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.

There are no adequate and well-controlled clinical studies of mannitol in pregnant women. Bronchial challenge testing with ARIDOL (mannitol inhalation powder) 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.

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 (mannitol inhalation powder) should not be administered during labor or delivery.

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.

The mean and median maximum percentage reduction in FEV1 in patients with a positive ARIDOL (mannitol inhalation powder) 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 (mannitol inhalation powder) bronchial challenge test in children and adolescents 6 to 17 years of age was similar to the adult population in two clinical studies .

Bronchial challenge testing with ARIDOL (mannitol inhalation powder) 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 (mannitol inhalation powder) 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 (mannitol inhalation powder) exist between subjects 50 years of age and older and younger subjects.

Formal pharmacokinetic studies with mannitol, the active ingredient, in ARIDOL (mannitol inhalation powder) , 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.

Dosage (Posology) and method of administration

ARIDOL is a 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. The inhaler should be discarded after use.

Do not swallow ARIDOL (mannitol inhalation powder) capsules.

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

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

An overview of the testing procedure can be found below. See the ARIDOL (mannitol inhalation powder) bronchial challenge test instructions for complete instructions on the dosing and spirometry procedures.

1. A nose clip may be used if preferred. If so, apply nose clip to the subject and direct the subject to breathe through the mouth
2. 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)
3. The patient should exhale completely, before inhaling from device in a controlled rapid deep inspiration
4. 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
5. At the end of 60 seconds, measure the FEV1 in duplicate (the measurement after inhaling the 0 mg capsule is the baseline FEV1)
6. 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)

Table 1: Mannitol dose steps for bronchial challenge testing with ARIDOL (mannitol inhalation powder)

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 (mannitol inhalation powder) or significant respiratory symptoms should receive a standard dose of a short acting inhaled beta-agonist and monitored until fully recovered to within baseline.

Interaction with other medicinal products and other forms of interaction

Mannitol, the active ingredient in ARIDOL (mannitol inhalation powder) , is a sugar alcohol that may cause severe bronchospasm in susceptible subjects.

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 (mannitol inhalation powder) 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 (mannitol inhalation powder) in either trial.

Five adult subjects (0.6%) discontinued from the studies within a day following bronchial challenge testing with ARIDOL (mannitol inhalation powder) 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 (mannitol inhalation powder) because of retching.

Table 2 displays the combined common adverse reactions ( ≥ 1%) within a day after bronchial challenge testing with ARIDOL (mannitol inhalation powder) 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)

The maximum reduction in FEV1 following bronchial challenge testing with ARIDOL (mannitol inhalation powder) 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 (mannitol inhalation powder) , methacholine, and exercise challenges for Studies 1 and 2 is shown in Table 3.

Table 3: Incidence of decreases in FEV1 ≥ 30% or ≥ 60% (overall population, Studies 1 and 2)

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.

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 (mannitol inhalation powder) 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 (mannitol inhalation powder) , methacholine and exercise, respectively, experiencing reduction in FEV1 ≥ 30%. No patient who had bronchial challenge testing with ARIDOL (mannitol inhalation powder) or exercise had a decrease in FEV1 ≥ 60%, whereas, one adolescent patient (aged 12 years) who received methacholine had a decrease in FEV1 ≥ 60%.

The following adverse reactions have been identified post approval outside the U.S. of the ARIDOL (mannitol inhalation powder) 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 (mannitol inhalation powder).