Consumer medicine information

Bronchitol

Mannitol

BRAND INFORMATION

Brand name

Bronchitol

Active ingredient

Mannitol

Schedule

Unscheduled

What is in this leaflet

This leaflet answers some common questions about Bronchitol.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Bronchitol against the benefits they expect it will have for you.

If you have any concerns about taking Bronchitol, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Bronchitol is used for

Bronchitol is used to treat Cystic Fibrosis.

Bronchitol is inhaled into the lungs to relieve the symptoms of cystic fibrosis. It does this by helping to clear mucus from the lungs.

Bronchitol contains the active ingredient mannitol.

It works by increasing the amount of water on the surface of your airways and in your mucus. This helps your lungs to clear mucus more easily. It also helps improve the condition of your lungs and your breathing. As a result, you may get a ‘productive cough’, which also helps to remove mucus from your lungs.

Your doctor may have prescribed Bronchitol for another reason. Ask your doctor if you have any questions about why Bronchitol has been prescribed for you.

There is no evidence that Bronchitol is addictive.

This medicine is available only with a doctor’s prescription.

Before you take Bronchitol

Before you are started on Bronchitol, your doctor will check whether your airways are too sensitive to mannitol.

This is done by giving your first (initiation) dose of Bronchitol under strictly controlled conditions.

Your doctor will monitor you while you take your initiation dose and determine if you are sensitive to mannitol.

If you are too sensitive to mannitol, your airways will become narrower, and you may find it harder to breathe.

When you must not take it

Do not take Bronchitol if you have an allergy to Bronchitol (mannitol) or gelatin or any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

shortness of breath
wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin.

Do not take Bronchitol if:

your doctor has not tested if you are sensitive to mannitol.
you have previously experienced severe symptoms of difficulty breathing, wheezing or coughing after inhaling mannitol.

If any of the above apply to you (or you are not sure), talk to your doctor before using Bronchitol.

Do not give Bronchitol to a child under 6 years, unless directed to by the child’s doctor. Bronchitol is not recommended for use in children under 6 years because there have not been any studies in children of this age group.

Do not take Bronchitol after the expiry date (EXP) printed on the pack. If you take this medicine after the expiry date has passed, it may not work (as well).

Do not take Bronchitol if the packaging is torn or shows signs of tampering.

If you are not sure whether you should start using Bronchitol, contact your doctor or pharmacist.

Tell your doctor if:

you have allergies to any other medicines, foods, preservatives or dyes.

Your doctor may want to take special precautions if you have any of these conditions.

Take special care with Bronchitol if:

you have ever coughed up blood or had blood in your sputum
you have asthma
you have severe cystic fibrosis, in particular if your lung function (FEV1) is usually less than 30%

If any of the above apply to you (or you are not sure), talk to your doctor or pharmacist before using Bronchitol.

Tell your doctor or pharmacist if you are pregnant or plan to become pregnant or are breast-feeding. Your doctor can discuss the possible risks involved.

Taking other medicines

Tell your doctor or pharmacist if you are using any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

You can carry on using your medicines for cystic fibrosis when you are using Bronchitol. If you are not sure, talk to your doctor or pharmacist before using Bronchitol.

How to take Bronchitol

Do not swallow the capsules.

The powder in the capsules must only be inhaled using the inhaler device included in the carton. Each pack of Bronchitol contains an instruction leaflet that tells you the correct way to use the inhaler device. Please read this carefully.

Follow all directions given to you by your doctor carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

If you are not sure how to use an inhaler, ask your doctor or pharmacist.

Children should only use their inhaler with the help of an adult.

How much to take

The usual dose of Bronchitol is the contents of 10 capsules (400 mg) inhaled twice a day.

How to take it

Full instructions on how to use the inhaler device are provided in a leaflet with the pack. Follow the instructions in the leaflet carefully.

If you have any problems inhaling Bronchitol using the inhaler device, ask your doctor or pharmacist for assistance.

When to take it

Take Bronchitol in the morning and 2-3 hours before bedtime. You should take your bronchodilator 5-15 minutes before taking Bronchitol, and physiotherapy is usually done after taking Bronchitol.

If you forget to take it

If you forget to take a dose of Bronchitol, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect. If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

How long to take it

Keep taking your medicine for as long as your doctor or pharmacist tells you.

Bronchitol helps treat the symptoms of cystic fibrosis but does not cure it.

Do not stop using it unless your doctor or pharmacist tells you to - even if you feel better.

If you take too much (overdose)

Telephone your doctor or pharmacist or the Poisons Information Centre (telephone Australia 13 11 26, or go to Accident and Emergency at your nearest hospital if you think that you or anyone else may have taken too much Bronchitol.

Do this even if there are no signs of discomfort or poisoning.

If you take too much Bronchitol, you may feel that you cannot breathe, become wheezy or cough. These symptoms are usually mild side effects of using Bronchitol. However, if they are severe or do not go away, it may be that you have taken too much Bronchitol. If large quantities of Bronchitol capsules are swallowed it may cause diarrhoea.

While you are using Bronchitol

Things you must do

Continue using Bronchitol for as long as your doctor tells you.

If your breathing becomes more difficult while you are taking Bronchitol, stop taking it, and tell your doctor immediately.

Visit your doctor regularly to check on your condition.

Tell any other doctors, dentists, and pharmacists who are treating you that you are using Bronchitol.

If you are about to be started on any new medicine, tell your doctor or pharmacist that you are using Bronchitol.

If you plan to have surgery, tell your doctor or dentist that you are using Bronchitol.

If you become pregnant while using Bronchitol, tell your doctor.

Things you must not do

Do not give Bronchitol to anyone else, even if they have the same condition as you.

Do not take Bronchitol to treat any other complaints unless your doctor tells you to.

Do not stop using Bronchitol, or lower the dosage, without checking with your doctor.

When taken as recommended, and when there are no side effects, Bronchitol is not known to have any effect on the ability to drive or operate machinery.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using Bronchitol. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

If you get any side effects, do not stop using Bronchitol without first talking to your doctor or pharmacist.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

Common (likely to affect less than 1 in 10 but more than 1 in 100 people):

cough
headache
blood in your sputum
tightening or restriction of your airway
mouth, tongue or throat pain
vomiting
chest discomfort

It is important to understand that Bronchitol works by making the mucus in your lungs more fluid and thus easier to cough up. A productive cough may actually be a helpful side effect.

Other side effects not listed above may occur in some patients. Tell your doctor or pharmacist if you notice anything else that is making you feel unwell. This is not a complete list of side effects. Other side effects not listed above may also occur in some people and there may be some side effects not yet known.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After using Bronchitol

Cleaning

Replace the inhaler device after you have used it for 1 week. If for some reason you feel the need to clean the inhaler, wash it in warm water and allow it to thoroughly air dry for 24 hours before use.

Storage

Keep Bronchitol in a cool dry place where the temperature stays below 30°C.

Do not store Bronchitol or any other medicine in the bathroom or near a sink.

Do not leave it in the car on hot days or on window sills. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

The inhaler device should be thrown away after 7 days of use.

If your doctor or pharmacist tells you to stop using Bronchitol or it has passed its expiry date, ask your pharmacist what to do with any that is left over.

Product Description

What it looks like

Bronchitol capsules are clear capsules containing white powder with “PXS 40 mg” imprinted on them.

The capsules are supplied in blister strips of 10 capsules.

The inhaler is off-white with blue buttons.

The Initiation Dose pack contains:

1 blister strip (10 capsules)
1 Inhaler

The 7-day pack contains:

14 blister strips (140 capsules)
1 Inhaler

The 14-day pack contains:

28 blister strips (280 capsules)
2 Inhalers

Ingredients

Active Ingredients

Bronchitol capsules contain 40 mg of the active ingredient mannitol.

Inactive Ingredients

There are no inactive ingredients in the Bronchitol powder.

The capsules containing the powder are made from gelatin. The capsules are not inhaled or swallowed.

Bronchitol does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Supplier

Bronchitol is manufactured in Australia by:

Pharmaxis Ltd
20 Rodborough Road
Frenchs Forest NSW 2086

Bronchitol is distributed in Australia by:

BTC Speciality Health
Level 1, 10 Oxley Road
Hawthorn Vic 3122
www.btchealth.com.au
Tel: 1800 100 282

Australian Registration Number

AUST R 168002

This leaflet was last updated on 22 March 2022

® Registered Trademark

Published by MIMS May 2023

BRAND INFORMATION

Brand name

Bronchitol

Active ingredient

Mannitol

Schedule

Unscheduled

1 Name of Medicine

Mannitol.

2 Qualitative and Quantitative Composition

Bronchitol contains 40 mg of mannitol.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for inhalation in hard capsules.
White powder in a clear hard capsule and imprinted with "PXS 40 mg".

4 Clinical Particulars

4.1 Therapeutic Indications

Bronchitol is indicated for the treatment of cystic fibrosis (CF) in both paediatric and adult populations six years and above as either an add-on therapy to dornase alfa or in patients intolerant to, or inadequately responsive to dornase alfa.

4.2 Dose and Method of Administration

Before commencing treatment with Bronchitol, all patients should be assessed for bronchial hyper-responsiveness to inhaled mannitol during administration of their initiation dose (see Section 4.3 Contraindications). Patients who are contraindicated for spirometry and cannot therefore undergo the initiation dose assessment must not be prescribed Bronchitol.

Initiation dose assessment.

The patient's initiation dose of Bronchitol (400 mg) must be used under the supervision and monitoring of an experienced physician or another health professional appropriately trained and equipped to monitor oxygen saturation (SpO₂), perform spirometry and manage acute bronchospasm, including appropriate use of resuscitation equipment.
The patient should be premedicated with a bronchodilator 5-15 minutes prior to the initiation dose but after the baseline FEV₁ and SpO₂ measurement. All FEV₁ measurements and SpO₂ monitoring should be performed 60 seconds after dose inhalation.
The initiation dose assessment must be performed according to the following steps.
Step 1: Patient's baseline FEV₁ and SpO₂ are measured prior to the initiation dose.
Step 2: Patient inhales 40 mg (1 x 40 mg capsules) and SpO₂ is monitored.
Step 3: Patient inhales 80 mg (2 x 40 mg capsules) and SpO₂ is monitored.
Step 4: Patient inhales 120 mg (3 x 40 mg capsules), FEV₁ is measured and SpO₂ is monitored.
Step 5: Patient inhales 160 mg (4 x 40 mg capsules), FEV₁ is measured and SpO₂ is monitored.
Step 6: Patient's FEV₁ is measured 15 minutes after last dose.
Training the patient to practice correct inhaler technique during this initiation dose assessment is important.
Patients are defined as hyper-responsive to mannitol and must not be prescribed the therapeutic dose regimen if they experience any of the following:
≥ 10% fall in SpO₂ at any point of the assessment;
FEV₁ fall is ≥ 20% at 240 mg cumulative dose;
FEV₁ has fallen ≥ 20% (from baseline) at the end of the assessment and does not return to within < 20% of baseline, within 15 minutes;
FEV₁ has fallen ≥ 50% (from baseline) at the end of the assessment.
All patients should be monitored until their FEV₁ has returned to baseline levels.

Therapeutic dose regimen.

The therapeutic dose regimen should not be prescribed until the initiation dose assessment has been performed. The patient must complete and pass the initiation dose assessment before starting treatment with Bronchitol.
The recommended dosage of Bronchitol is 400 mg twice a day.
This requires the inhalation of the contents of 10 x 40 mg capsules via the inhaler device, twice a day. Each capsule delivers a dose of approximately 32 mg. The doses should be taken morning and night with the evening dose taken 2-3 hours before bedtime.

Method of administration.

Bronchitol is for inhalation use, using the inhaler provided in the pack. It must not be administered by any other route or using any other inhaler. The capsules must not be swallowed.
Each of the capsules is loaded into the device separately. The contents of the capsules are inhaled via the inhaler device with one or two breaths. After inhalation, each empty capsule is discarded before inserting the next capsule into the inhaler device.
The inhaler device is to be replaced after one week of use. If the inhaler does require cleaning, ensure the device is empty then wash in warm water and before re-use, allow the inhaler to thoroughly air dry.
A bronchodilator must be administered 5-15 minutes before Bronchitol is used. The recommended order of treatment is: bronchodilator, Bronchitol, physiotherapy/ exercise, then dornase alfa (if applicable), inhaled antibiotics (if applicable).

4.3 Contraindications

Hypersensitivity to mannitol or to any of the capsule ingredients.
Bronchial hyper-responsiveness to inhaled mannitol.

4.4 Special Warnings and Precautions for Use

Haemoptysis.

Haemoptysis has been commonly reported with Bronchitol in clinical studies in CF.
Bronchitol has not been studied in patients with a history of significant episodes of haemoptysis (> 60 mL) in the previous 3 months. As a consequence, these patients should be carefully monitored, and Bronchitol should be withheld in the event of massive haemoptysis. A massive/ serious haemoptysis is considered to be: acute bleeding ≥ 240 mL in a 24 hour period; recurrent bleeding ≥ 100 mL/day over several days.
The reinstitution or withholding of Bronchitol following smaller episodes of haemoptysis should be based on clinical judgment. (Please also see Section 4.8 Adverse Effects (Undesirable Effects)).

Asthma.

The efficacy/ safety of Bronchitol in patients with asthma has not been formally studied. Patients with asthma must be carefully monitored for worsening signs and symptoms of asthma after the initiation dose of Bronchitol.
Patients must be advised to report worsening signs and symptoms of asthma during therapeutic use of Bronchitol to their physician. If there is evidence of therapy induced bronchospasm, the physician should carefully evaluate whether the benefits of continued use of Bronchitol outweigh the risks to the patient. Bronchospasm should be treated with a bronchodilator or as medically appropriate.

Hyper-responsiveness to mannitol.

Patients must be monitored for bronchial hyper-responsiveness to inhaled mannitol during their initiation dose assessment before commencing the therapeutic dose regimen of Bronchitol. If patients are unable to perform spirometry or complete the initiation dose assessment, they must not be prescribed Bronchitol. If patients are hyper-responsive, they should not be prescribed the therapeutic dose regimen of Bronchitol. The usual precautions regarding bronchial hyper-responsiveness monitoring apply. If a therapy induced hyperresponsive reaction is suspected, Bronchitol should be discontinued.

Bronchospasm.

Bronchitol may cause bronchoconstriction/ bronchospasm requiring treatment, even in patients who were not hyper-responsive to the initiation dose of inhaled mannitol. Bronchospasm should be treated with a bronchodilator or as medically appropriate.
If there is evidence of therapy induced bronchospasm, the physician should carefully evaluate the benefits of continued use of Bronchitol outweigh the risks to the patient.
All patients should be formally reviewed after approximately six weeks of Bronchitol treatment to assess for signs and symptoms suggestive of drug induced bronchospasm. The initiation dose assessment should be repeated if uncertainty exists.

Cough.

Cough was commonly reported with use of Bronchitol in clinical studies.
Productive cough may be a beneficial component of mucus clearance.
Patients should be trained to practice correct inhaler technique during treatment and advised to report persistent cough with the use of Bronchitol to their physician.

Impaired lung function.

Safety and efficacy have not yet been demonstrated in patients with a FEV₁ of less than 30% of predicted. The use of Bronchitol is not recommended in these patients.

Non-CF bronchiectasis.

Efficacy and safety have not been established in non-CF bronchiectasis patients. Therefore, treatment with Bronchitol is not recommended.

Use in hepatic impairment.

Bronchitol has not formally been studied in patients with impaired hepatic function. No specific dose recommendations for this patient population are available.

Use in renal impairment.

Bronchitol has not formally been studied in patients with impaired renal function. No specific dose recommendations for this patient population are available.

Use in the elderly.

In Phase 2 and 3 studies the mean patient age was approximately 22 years. The oldest patient from the Phase 3 studies was 78 years of age. No specific dose recommendations for use in the elderly are available.

Paediatric use.

Bronchitol is not recommended for use in children below 6 years of age due to insufficient data on safety and efficacy.

Effects on laboratory tests.

No effects were observed on haematology, liver function test, or urea and electrolyte parameters.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Bronchitol has been used in clinical studies in conjunction with standard cystic fibrosis therapies such as mucolytics, antibiotics, bronchodilators, pancreatic enzymes, vitamins, inhaled and systemic corticosteroids, and analgesics. However, no formal interaction studies have been conducted.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effect of inhaled mannitol on fertility has not been investigated.
(Category B2)
Animal reproduction studies have not been carried out with inhaled mannitol. However, studies with orally administered mannitol indicate no teratogenic effects in mice or rats at daily doses up to 1.6 g/kg, or in hamsters at 1.2 g/kg/day.
As effects of a possible hyper-responsiveness reaction on the mother and/or the foetus are unknown, caution should be exercised when prescribing Bronchitol to pregnant women. As a precautionary measure, it is preferable to avoid the use of Bronchitol during pregnancy.
It is unknown whether mannitol is excreted in human breast milk. The excretion of mannitol in milk has not been studied in animals.
A decision on whether to continue/ discontinue breastfeeding or to continue/ discontinue therapy with Bronchitol should be made taking into account the benefit of breastfeeding to the child and the benefit of Bronchitol therapy to the woman.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Initiation dose assessment.

The most commonly observed adverse reaction associated with the use of Bronchitol during the initiation dose assessment is cough.
The most important adverse reaction associated with the use of Bronchitol during the initiation dose assessment is bronchospasm.

Therapeutic dose regimen.

The most commonly observed adverse reaction associated with the use of Bronchitol is cough. Cough which led to cessation of treatment was also commonly experienced.
The most important adverse reaction associated with the use of Bronchitol is haemoptysis.
Table 1 provides a summary of the most commonly reported treatment-emergent adverse events from Phase 3 clinical studies.

Frequencies provided in Table 2 are based on clinical review of the observations on the day of screening and prior to the day of study drug dosing (if any) in patients undertaking the initiation dose assessment in the 3 phase III comparative clinical studies investigating the effect of Bronchitol.
Frequencies are defined as: Very common (≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100); Rare (≥ 1/10,000 to < 1/1,000); Very rare (< 1/10,000); Not known (cannot be estimated from the available data).
Table 2 contains a selected list of adverse reactions. Other than asthma, only adverse events reported in > 2 patients are included.

Post-marketing.

Adverse reactions from the initiation dose assessment seen in the post-marketing setting but not observed in the clinical trials include Dyspnoea.
Frequencies provided in Table 3 are based on clinical review of the observations during the treatment phase of 3 phase III comparative clinical trials investigating the effect of Bronchitol.

Haemoptysis.

An important adverse event associated with the use of Bronchitol is haemoptysis (Table 4). From the pooled data from DPM-CF-301 and DPM-CF-302, haemoptysis (reported as an adverse event) occurred in 9.4% of patients in the Bronchitol arm versus 5.4% in the control arm. The percentages stratified by age were (Bronchitol versus control): 6-11 years (6.1% versus 0.0%); 12-17 years (9.1% versus 3.1%); ≥ 18 years (10.6% versus 8.2%).

In DPM-CF-303, the number of patients reporting haemoptysis as a treatment emergent adverse event occurred in 10.1% of patients in the Bronchitol arm versus 10.3% in the control arm.

Cough.

Cough is a commonly reported adverse reaction. Although uncommonly reported as an adverse reaction, productive cough is a beneficial component of mucus clearance.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Incidences of overdose were not observed in the clinical studies. Susceptible persons may suffer bronchoconstriction in the event of an inhaled overdose. If excessive coughing and bronchoconstriction occurs, a β₂-agonist should be given, and oxygen if necessary.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Bronchitol contains mannitol that has been spray dried to achieve a respirable form. The spray dried mannitol is to be delivered by use of a specific inhaler device. The inhalation of mannitol is intended to improve lung hygiene by correcting the impaired mucociliary clearance that is characteristic of cystic fibrosis. While the exact mechanism of action is unknown, inhaled mannitol may change the viscoelastic properties of mucus, increase the hydration of the periciliary fluid layer and contribute to increased mucociliary and cough clearance of the retained secretions.

Clinical trials.

Three Phase-3 randomised, double-blind, parallel, controlled trials of 26 weeks duration have been conducted in patients with cystic fibrosis. In the DPM-CF-301 and DPM-CF-302 trials, patients aged 6 years or older were randomised in a 3:2 ratio to either: (1) inhaled mannitol 400 mg twice daily or (2) control (inhaled mannitol 50 mg twice daily). In the third study (DPM-CF-303), 423 adult patients were randomised in a 1:1 ratio to inhaled mannitol 400 mg twice daily or to control.
Enrolled patients who were not randomised because of a failed mannitol tolerance test (MTT) were 27/389 (7%) in study DPF-CF-301, 14/342 (4%) in study DPM-CF-302 and 25/486 (5.1%) in study DPM-CF-303. Additionally, 4% (n=27) patients from the first two studies and 1.4% (7/486) from study DPM-CF-303 had an incomplete MTT and were not randomised.
The number of patients who were randomised but withdrew before they received any study drug was 29 (mannitol: 15; control: 14) in study DPM-CF-301, 13 (mannitol: 8; control: 5) in study DPM-CF-302, and 3 (mannitol: 2; control: 1) in study DPM-CF-303.
A further 50 (16.9%) patients in study DPM-CF-301, 20 (6.6%) in study DPM-CF-302 and 25 (5.9%) in study DPM-CF-303 withdrew consent during the 26-week, randomised phase.
Of the patients who received the study drug in study DPM-CF-301, 28/177 (15.8%) patients in the mannitol arm and 10/118 (8.5) in the control arm experienced an adverse event leading to study withdrawal. The corresponding numbers in study DPM-CF-302 were 13/184 (7.1%) patients in the mannitol arm and 5/121 (4.1%) in the control arm; and in study DPM-CF-303, 8/207 (3.9%) patients in the mannitol arm and 7/213 (3.3%) in the control arm. The most common adverse events leading to study withdrawal were increased cough, condition aggravated and haemoptysis.
Table 5 shows the results for the pre-specified primary endpoint (control-subtracted change from baseline in FEV₁).

For dornase alfa users in DPM-CF-301, the control-subtracted change in FEV₁ after 26 weeks was 77.6 mL (95% CI 18.2, 137.1); non-users: 89.6 mL (95% CI 25.4, 153.8). The corresponding results for DPM-CF-302 were: dornase alfa users: 43.5 mL (95% CI -19.8, 106.8); non-users: 86.5 mL (95% CI -23.8, 196.8); and for DPM-CF-303: dornase alfa users: 29 mL (95% CI -23, 81); non-users: 112 mL (95% CI 22, 202).
The number of study participants with at least one protocol-defined pulmonary exacerbation (≥ 4 symptoms and signs plus IV antibiotics) in DPM-CF-301 was 18.1% in the mannitol group and 28% in the control group; in DPM-CF-302 15.2% versus 19.0%; and in DPM-CF-303, 13.4% versus 13.6%.

5.2 Pharmacokinetic Properties

Absorption.

In a study of 18 healthy male adult volunteers, using an Aridol inhaler, the absolute bioavailability of mannitol powder for inhalation by comparison to mannitol administered intravenously was 0.59 ± 0.15. The rate and extent of absorption of mannitol after inhaled administration was very similar to that observed after oral administration. The T_max after inhaled administration was 1.5 ± 0.5 hours.
In a study of 9 cystic fibrosis patients (6 adults, 3 adolescents), using 400 mg inhaled mannitol as a single dose (day 1) then twice a day for 7 days (days 2-7), pharmacokinetic parameters were similar for adults and adolescents, except for a longer average apparent terminal half-life for adolescents (day 1 = 7.29 hr, day 7 = 6.52 hr) compared with adults (day 1 = 6.10 hr, day 7 = 5.42 hr). Overall, the comparison of AUCs between day 1 and day 7 showed a time independence of pharmacokinetics, indicating linearity at the dose level administered in this study.

Distribution.

Lung deposition studies have demonstrated a 24.7% deposition of inhaled mannitol confirming its distribution to the target organ. Nonclinical toxicology studies indicate that mannitol inhaled into the lungs is absorbed into the bloodstream, with the maximum serum concentration being achieved within 1 hour. In a pharmacokinetic study of mannitol in 18 healthy adults, the volume of distribution was 34.3 ± 13.8 L following a 500 mg intravenous dose. There is no evidence that mannitol is accumulated in the body, therefore distribution of inhaled mannitol was not examined in PK studies.

Metabolism.

Mannitol is metabolised after oral/ inhaled administration (by gut microflora), but little metabolism is observed following intravenous administration. A small percentage of systemically absorbed mannitol undergoes hepatic metabolism to glycogen and carbon dioxide. Studies in rats, mice and humans have demonstrated that mannitol has no toxic metabolites. The metabolic pathway of inhaled mannitol was not examined in PK studies.

Excretion.

The cumulative amount of mannitol filtered into the urine over the 24 hr collection period was similar for inhaled (55%) and oral (54%) mannitol. When administered intravenously, mannitol is eliminated largely unchanged by glomerular filtration and 87% of the dose is excreted in the urine within 24 hours. The mean terminal half-life in adults was approximately 4-5 hours from serum and approximately 3.66 hours from urine.

5.3 Preclinical Safety Data

Genotoxicity.

No mutagenic or clastogenic effect has been revealed when mannitol was assayed in a standard battery of genotoxicity tests.

Carcinogenicity.

No evidence of carcinogenicity was observed when dietary mannitol (≤ 5%) was administered to mice and rats for 2 years. Carcinogenicity studies have not been carried out with inhaled mannitol.

6 Pharmaceutical Particulars

6.1 List of Excipients

Capsule shell component: Gelatin.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Bronchitol 40 mg capsules are presented in Aluminium/Aluminium blisters. Each blister strip contains 10 hard capsules.

Pack sizes.

The initiation pack: cartons containing 1 blister strip and one inhaler device.
The 7 day pack: cartons containing 14 blister strips and one inhaler device.
The 14 day pack: cartons containing 28 blister strips and two inhaler devices.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Also known as D-mannitol. Mannitol is a hexahydric alcohol. The powder is a white or almost white, crystalline powder of free-flowing granules. Mannitol is freely soluble in water, and very slightly soluble in alcohol. Mannitol shows polymorphism.
The empirical formula is C₆H₁₄O₆. Molecular weight is 182.2.

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