DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Inhalation powder: 40 mg mannitol per capsule; clear, colorless hard gelatin capsule imprinted with PXS 40 mg. Inhalation powder: 40 mg mannitol per capsule (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. No formal drug interaction studies have been conducted with mannitol, the active ingredient in BRONCHITOL.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical trials of BRONCHITOL did not include sufficient numbers of patients with cystic fibrosis who were 65 years of age and older to allow evaluation of safety and efficacy in this population.

HEALTH CARE PROVIDER LETTER SECTION.

HEALTHCARE PRACTITIONER INSTRUCTIONS FOR USE. Healthcare Practitioner Instructions.

HEPATIC IMPAIRMENT SUBSECTION.

8.6 Hepatic and Renal Impairment. Clinical trials of BRONCHITOL did not include patients with hepatic or renal impairment. No specific dose recommendations for these patient populations are available. 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.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling: Bronchospasm [see Warnings and Precautions (5.1)] Hemoptysis [see Warnings and Precautions (5.2)] Bronchospasm [see Warnings and Precautions (5.1)] Hemoptysis [see Warnings and Precautions (5.2)] Most common adverse reactions (>=3%) include cough, hemoptysis, oropharyngeal pain, vomiting, bacteria sputum identified, pyrexia, and arthralgia. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Chiesi USA, Inc. at 1-888-661-9260 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 drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The overall safety profile for BRONCHITOL is based on data from 1,020 CF patients from three 26-week, randomized, double-blind, controlled trials (Trials 1, 2, and 3). While CF patients aged to 17 years were included in two of the three trials, BRONCHITOL is not indicated for use in this age group [see Indications (1), Use in Specific Populations (8)]. The safety data described below are based on 761 adult patients who received at least one dose of study drug in the three trials. Of the 761 adult patients, 45% of patients were female and 98% were Caucasian; 414 received BRONCHITOL and 347 received control (50 mg inhaled mannitol) for up to 26 weeks. Adult patients treated with BRONCHITOL were ages 18 to 59 years with mean baseline FEV1 of 62.0% of predicted. In these three trials, the proportion of adult patients who prematurely discontinued study drug due to adverse reactions was 12.3% for patients treated with BRONCHITOL and 8.6% for patients treated with control. Serious adverse reactions occurred in 18.8% of patients treated with BRONCHITOL and 18.4% of patients treated with control. Serious adverse reactions occurring with greater than 1% incidence and more frequently in BRONCHITOL-treated adult patients compared to control-treated patients were CF exacerbations (13.3% vs. 11.2%), hemoptysis (1.4% vs. 1.2%) and lower respiratory tract infection (1.2% vs 0.9%).The incidence of Adverse Reactions in adults during the 26 week treatment period with BRONCHITOL across the three trials is shown in Table 1. Table 1. Adverse Reactions Occurring With >=3% Incidence and More Common Than Control in Adult CF Patients (Trials 1, 2, and 3) Primary System Organ Class Preferred TermBRONCHITOLN 414%CONTROLN 347%Respiratory, thoracic, and mediastinal disordersCough15.010.7Hemoptysis10.49.5Oropharyngeal pain7.04.3Gastrointestinal disordersVomiting3.11.4InvestigationsBacteria sputum identified6.84.6General disorders and administrative site conditionsPyrexia4.62.3Musculoskeletal and connective tissue disordersArthralgia3.12.6In Trials 1, 2, and 3, exacerbations of cystic fibrosis (reported as condition aggravated) occurred in 132 of 414 (32%) adult patients receiving BRONCHITOL and in 114 of 347 (33%) adult patients receiving control (50 mg inhaled mannitol). Exacerbations of cystic fibrosis reported as serious adverse reactions occurred in 55 of 414 adult patients (13%) receiving BRONCHITOL and in 39 of 347 adult patients (11%) receiving control. Within the U.S. adult subgroup (comprising 27% of adults enrolled), exacerbations of cystic fibrosis reported as serious adverse reactions occurred in 23 of 110 (21%) patients receiving BRONCHITOL and in 10 of 93 (11%) patients receiving control. Among the non-U.S. adult subgroup (comprising 73% of adults enrolled), exacerbations of cystic fibrosis reported as serious adverse reactions occurred in 11% of patients in each treatment arm.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisIn 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 mg/kg basis). These doses were approximately 55 and 30 times the MRHDID, respectively, on mg/m2 basis. MutagenesisMannitol 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. Impairment of FertilityThe effect of inhaled mannitol on fertility has not been investigated.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The precise mechanism of action of BRONCHITOL in improving pulmonary function in cystic fibrosis patients is unknown.. 12.2 Pharmacodynamics. The pharmacodynamics of mannitol are unknown.. 12.3 Pharmacokinetics. AbsorptionFollowing 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 mcgohr/mL. The mean time to peak plasma concentration (Tmax) after oral inhalation was 1.5 hour. DistributionBased on intravenous administration, the volume of distribution of mannitol was 34.3 L. EliminationMetabolismMannitol is metabolized in CYP-independent manner through the glycolytic pathway via dehydrogenation to fructose. The extent of metabolism of mannitol appears to be small. This is evident from urinary excretion of about 87% of unchanged drug after an intravenous dose to healthy patients. ExcretionFollowing 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 patients, about 55% of the total dose was excreted in the urine as unchanged mannitol. Following oral or intravenous administration of 500 mg dose, the corresponding values were 54% and 87% of the dose, respectively. Specific PopulationsPatients with Hepatic and Renal Impairment: Formal pharmacokinetic studies using BRONCHITOL 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. Drug Interaction StudiesNo formal drug interaction studies have been conducted with BRONCHITOL.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The efficacy of BRONCHITOL for the treatment of cystic fibrosis (CF) was evaluated in randomized, double-blind, controlled trials (Trials 1, 2, and 3).All three trials were 26-week, randomized, double-blind, controlled studies in patients with CF. Trial (NCT02134353) evaluated patients 18 years of age or older with baseline FEV1 >40% to <90% of predicted. Trial (NCT00446680) evaluated patients years of age or older with baseline FEV1 >30% to <90% of predicted. Trial (NCT00630812) evaluated pateints years of age or older with baseline FEV1 >40% to <90% of predicted. All three trials excluded CF patients with an episode of hemoptysis (>60 mL) in the months prior to enrollment. The use of inhaled hypertonic saline was not permitted in any of the three trials, but continued use of their other standard of care CF therapies were allowed (e.g., bronchodilators, inhaled antibiotics, and dornase alfa). While CF patients aged to 17 years were included in Trials and 3, BRONCHITOL is not indicated for use in this age group [see Indications (1), Warnings and Precautions (5), Adverse Reactions (6), Use in Specific Populations (8)]. Patients were randomized to receive either BRONCHITOL 400 mg or control (50 mg inhaled mannitol) twice daily. Each dose of BRONCHITOL was preceded by use of an inhaled short-acting bronchodilator (albuterol or equivalent) taken to 15 minutes prior to initiation of BRONCHITOL dosing. The primary efficacy endpoint in all three studies was improvement in lung function as determined by the mean change from baseline in pre-dose FEV1 (mL) over 26 weeks of treatment and was analyzed using the pattern mixture model with multiple imputation. Trial evaluated 423 adult patients with mean age of 28 years and mean FEV1 63.9% predicted (range: 40.3% minimum, 89.6% maximum). Treatment with BRONCHITOL resulted in statistically significant improvement in FEV1. In Trial 1, the treatment difference between BRONCHITOL and control for the adjusted mean change in FEV1 from baseline over 26 weeks was 51 mL (95% CI to 97 mL) shown in Table 2. Table 2: Change in FEV1 (mL) from Baseline Over 26 weeks by Treatment Group (Trial 1, intention to treat population)Control (N=214)BRONCHITOL (N=209)Adjusted mean change from baseline12 mL63 mLAdjusted mean difference (95% CI), p-value51 mL (6 to 97 mL), p=0.028 Trials and evaluated 295 and 305 patients, respectively. For the adjusted mean difference in the change from baseline in FEV1 over 26 weeks in the intention-to-treat population in Trials and 3, the treatment difference between BRONCHITOL and Control was 68 mL (95% CI: 24 to 113 mL) and 52 mL (95% CI: -3 to 107 mL), respectively. Post-hoc descriptive analyses of the adult subgroups from Trials and were performed. The adult subgroup analyses in Trial and evaluated 209 and 157 adult patients, respectively. In Trial 2, there was an adjusted mean difference in the change from baseline in FEV1 over 26 weeks in the intention-to-treat population of adults of 78 mL (95% CI: 21 to 135 mL). In Trial 3, there was an adjusted mean difference in the change from baseline in FEV1 over 26 weeks in the intention-to-treat population of adults of 78 mL (95% CI: to 153 mL).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. BRONCHITOL is contraindicated in the following conditions:Hypersensitivity to mannitol or to any of the capsule componentsFailure to pass the BRONCHITOL Tolerance Test (BTT). Hypersensitivity to mannitol or to any of the capsule components. Failure to pass the BRONCHITOL Tolerance Test (BTT). Hypersensitivity to mannitol or to any of the capsule components. (4)Failure to pass the BRONCHITOL Tolerance Test. (4). Hypersensitivity to mannitol or to any of the capsule components. (4). Failure to pass the BRONCHITOL Tolerance Test. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. BRONCHITOL (mannitol) inhalation powder contains D-Mannitol (referred to throughout as mannitol) as the active ingredient. Mannitol is hexahydric sugar alcohol, with the following chemical name hexane-1,2,3,4,5,6-hexol and chemical structure: Mannitol is white or almost white crystalline powder or free-flowing granules with an empirical formula of C6H14O6 and molecular weight of 182.2. Mannitol is freely soluble in water, and very slightly soluble in alcohol. Mannitol shows polymorphism. BRONCHITOL contains mannitol powder spray dried into particles of respirable size filled into clear, colorless hard gelatin capsules. There are no inactive ingredients in BRONCHITOL. The accompanying white plastic inhaler is comprised of mouthpiece, blue piercing buttons, capsule chamber, and removable cap. blister pack consists of 10 capsules, each containing 40 mg mannitol. After capsule is placed in the capsule chamber and pierced by firmly pressing and releasing the buttons on the side of the device, the powder within the capsule becomes exposed and ready for dispersion into the airstream generated by the patient upon inhalation through the mouthpiece. Under standardized in vitro test conditions, the inhaler delivers 32.2 mg of mannitol per inhalation when tested at flow rate of 60 L/min for seconds. The actual amount of drug delivered to the lungs will depend on patient factors, such as inspiratory flow profile. Bronchitol.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. For Oral Inhalation Only. (2.1)The BRONCHITOL Tolerance Test is administered to identify patients who are appropriate for inhaled mannitol use. (2.1)Treatment of cystic fibrosis: 400 mg of BRONCHITOL (10 capsules) twice day by oral inhalation, in the morning and evening, with the later dose taken 2-3 hours before bedtime. (2.2). For Oral Inhalation Only. (2.1). The BRONCHITOL Tolerance Test is administered to identify patients who are appropriate for inhaled mannitol use. (2.1). Treatment of cystic fibrosis: 400 mg of BRONCHITOL (10 capsules) twice day by oral inhalation, in the morning and evening, with the later dose taken 2-3 hours before bedtime. (2.2). 2.1 Required Testing and Evaluation Prior to Prescribing BRONCHITOL (BRONCHITOL Tolerance Test). Prior to prescribing BRONCHITOL for treatment of cystic fibrosis, the BRONCHITOL Tolerance Test (BTT) must be administered and performed under the supervision of healthcare practitioner who is able to manage acute bronchospasm, to identify patients who are suitable candidates for BRONCHITOL maintenance therapy.Perform BTT to identify patients who experience bronchospasm, decrease in FEV1, or decrease in oxygen saturation with administration of BRONCHITOL. If patient experiences any of these events during the BTT, the patient has failed the BTT. Do not prescribe BRONCHITOL. If patient does not experience any of these events during BTT, the patient has passed the BTT and is candidate for BRONCHITOL therapy. Ensure that rescue medication and resuscitation equipment are available for immediate use during the BTT. Do not perform the BTT if the patient is considered clinically unstable. See the BTT Healthcare Practitioner (HCP) Instructions for Use (IFU) for complete instructions and to avoid medication errors associated with BTT dosing and procedures.Do not use BRONCHITOL add-on maintenance therapy in patients who fail the BTT [see Contraindications (4)].. Perform BTT to identify patients who experience bronchospasm, decrease in FEV1, or decrease in oxygen saturation with administration of BRONCHITOL. If patient experiences any of these events during the BTT, the patient has failed the BTT. Do not prescribe BRONCHITOL. If patient does not experience any of these events during BTT, the patient has passed the BTT and is candidate for BRONCHITOL therapy. Ensure that rescue medication and resuscitation equipment are available for immediate use during the BTT. Do not perform the BTT if the patient is considered clinically unstable. 2.2 Recommended Dosage for Treatment of Cystic Fibrosis. For patients who have passed the BTT, the recommended dosage of BRONCHITOL is 400 mg twice day by oral inhalation (the contents of 10 capsules administered individually) via the inhaler [see Dosage and Administration (2.1)]. short-acting bronchodilator should be administered by oral inhalation, 5-15 minutes before every dose of BRONCHITOL. BRONCHITOL should be taken once in the morning and once in the evening, with the later dose taken at least 2-3 hours before bedtime. 2.3 Use and Maintenance of Inhaler. Instruct patients on safe hygiene practices (clean and dry hands thoroughly) and correct inhaler use, including loading of capsules and proper inhalation technique per the Patient Instructions for Use.The BRONCHITOL inhaler should be discarded and replaced after days of use. If the inhaler does need to be washed, the patient should allow the inhaler to thoroughly air dry before next use.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. BRONCHITOL (mannitol) inhalation powder: 40 mg of mannitol per capsulecapsules are clear, colorless and imprinted in black with PXS on cap and 40 mg on bodysupplied in cartons containing 10, 140 or 560 capsules in blister packs co-packaged with 1, 1, and inhalers respectively in cartonBRONCHITOL is provided in commercial presentations:Pack QuantitiesInhalersCapsulesNDC Number4-week Treatment Pack(4 7-day treatment packs)456010122-212-567-day Treatment Pack114010122-212-14Bronchitol Tolerance Test 11010122-212-04BRONCHITOL should be stored between 68F-77F (20C-25C) with excursions permitted between 59F-86F (15C-30C). [See USP Controlled Room Temperature]. Do not refrigerate. Do not freeze. The Training Kit (NDC 10122-216-01), containing empty gelatin capsules, should be stored between 68F-77F (20C-25C) with excursions permitted from 59F-86F (15C-30C). BRONCHITOL should only be used with the provided inhaler, which is white plastic inhaler comprised of mouthpiece, blue piercing buttons, capsule chamber, and removable cap. All remaining unused (opened and unopened) blister packs and the inhalers should be properly discarded. Be sure to read the accompanying BRONCHITOL instructions completely before administration. If you have any questions, contact the supplier at 1-888-661-9260. 40 mg of mannitol per capsule. capsules are clear, colorless and imprinted in black with PXS on cap and 40 mg on body. supplied in cartons containing 10, 140 or 560 capsules in blister packs co-packaged with 1, 1, and inhalers respectively in carton.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. BRONCHITOL is indicated as add-on maintenance therapy to improve pulmonary function in adult patients 18 years and older with Cystic Fibrosis. Use BRONCHITOL only for adults who have passed the BRONCHITOL Tolerance Test [see Dosage and Administration (2.1)]. BRONCHITOL is sugar alcohol indicated as add-on maintenance therapy to improve pulmonary function in adult patients 18 years of age and older with cystic fibrosis. Use BRONCHITOL only in adults who have passed the BRONCHITOL Tolerance Test. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information and Patient Instructions for Use).BRONCHITOL Tolerance TestInform patients that BRONCHITOL Tolerance Test is required prior to beginning treatment with BRONCHITOL. The BRONCHITOL Tolerance Test must be performed by healthcare practitioner equipped to monitor oxygen saturation (SpO2), perform spirometry (FEV1), and manage acute bronchospasm. Inhaled Short-Acting Bronchodilator Use Instruct patients that an inhaled short-acting bronchodilator such as albuterol must always be administered to 15 minutes prior to every dose of BRONCHITOL. Bronchospasm Prior to administration, inform patients that bronchospasm can occur with inhalation of BRONCHITOL. If patient experiences bronchospasm, instruct the patient to discontinue BRONCHITOL and contact their healthcare practitioner right away. HemoptysisInform patients that hemoptysis can occur with inhalation of BRONCHITOL. If patient experiences hemoptysis, instruct patients to discontinue BRONCHITOL and contact their healthcare practitioner right away.AdministrationInstruct patients on the proper administration of BRONCHITOL with the inhaler. The recommended dosage is 10 capsules (400 mg) twice day. This requires inhaling the contents of 10 capsules administered individually once in the morning and once at least 2-3 hours before bed. Manufactured by: Pharmaxis Ltd20 Rodborough Rd Frenchs Forest NSW 2086 AUSTRALIAManufactured for: Chiesi USA, Inc. Cary, NC 27518 USABRONCHITOL(R) is registered trademark of Pharmaxis LtdCTBR-001-1120-01-SPL.

INSTRUCTIONS FOR USE SECTION.

PATIENT INSTRUCTIONS FOR USE BRONCHITOL(R) (mannitol) inhalation powder for oral inhalation use This Patient Instructions for Use contains information on how to take BRONCHITOL. Each BRONCHITOL box contains: 7-Day Treatment Pack140 Capsules (14 blister packs)1 InhalerPrescribing Information4-Week Treatment Pack560 Capsules (56 blister packs)4 InhalersPrescribing Information Important Information You Need to Know Before Using BRONCHITOLDo not use BRONCHITOL until your healthcare provider has performed the BRONCHITOL Tolerance Test (BTT) and approved you for treatment. This is to make sure you get the right treatment if you have severe reaction.For oral inhalation onlyDo not swallow BRONCHITOL capsules.Use an inhaled short-acting bronchodilator to 15 minutes before every dose of BRONCHITOLUse BRONCHITOL times each day. Inhale through your mouth (oral inhalation) the capsule contents in 10 single BRONCHITOL capsules:1 time in the morning1 time at least to hours before bedtime Preparing to use BRONCHITOL BRONCHITOL is supplied to people in cartons containing 140 or 560 capsules in blister packs. Supplies you will need to use BRONCHITOL: Blister pack1 InhalerBronchodilator (and spacer for bronchodilator if needed)Sink or hand washing station Before using BRONCHITOL: Use an inhaled bronchodilator to15 minutes before using BRONCHITOL (See Figure A). Clean and dry hands well (See Figure B).Inhaler use steps for inhalation of the contents of single capsule:Step 1. Remove cap (See Figure C) Step 2. Twist open inhaler by turning the mouthpiece to the right. (See Figure D). Step 3. Take capsule out of the blister pack and put it in the chamber.(See Figure E). Do not place capsule into the mouthpiece of the inhaler. Step 4. Hold inhaler upright and turn the mouthpiece to the left until it locks in place. (See Figure F). Step 5. Push both piercing buttons at the same time. Release both piercing buttons at the same time (See Figure G). Keep inhaler upright. Never keep piercing buttons pressed. Step 6. Breathe out (exhale) fully (See Figure H). Do not breathe out into inhaler. Step 7. Close lips around the mouthpiece and take steady deep breath in through your mouth. Do not breathe through your nose. Remove inhaler from mouth. Hold breath for seconds before exhaling, do not breathe out (exhale) into inhaler (See Figure I). You should hear rattling sound while breathing in. If you do not, tap bottom of inhaler firmly and repeat steps and 7. Step 8. Open the inhaler by turning the cap to the right. If powder is left in capsule, repeat steps and 7. After the capsule is empty, throw away. (See Figure J). Step 9. Repeat steps to for all 10 capsules in blister pack (See Figure K). Breathe in (inhale) contents of each capsule one after another until all 10 capsules in the blister pack are used. Step 10. After inhaling contents of all 10 capsules, close mouthpiece and place cap on inhaler (See Figure L). Step 11. Continue using BRONCHITOL for days then throw away (discard) the inhaler (See Figure M). How should store BRONCHITOL Store BRONCHITOL at room temperature between 68F to77F (20C to 25C).If your BRONCHITOL capsules are stored at temperatures more than 86F (30C), throw them away.Do not freeze BRONCHITOL.Do not refrigerate BRONCHITOL.Keep BRONCHITOL and all medicines out of the reach of children. Cleaning your BRONCHITOL inhaler. Your inhaler should give you the correct dose of medicine for days without needing cleaning. However, if your inhaler does need cleaning: Make sure your inhaler is empty.Wash your inhaler in warm water with the mouthpiece open.Shake it until there are no large water droplets left in the inhaler.Leave it to dry in the air by laying it on its side with the mouthpiece open.Allow the inhaler to dry fully (or completely) after it has been washed. Caring for your BRONCHITOL inhaler. Keep your inhaler dry and always make sure your hands are completely dry before using it.Do not breathe or cough into your inhaler.Do not take your inhaler apart.Do not place capsule directly into the mouthpiece of your inhaler.Do not leave used capsule in your inhaler chamber.Use new inhaler after days.If your inhaler breaks, call to your healthcare provider. For more information about BRONCHITOL or how to use your inhaler, call 1-888-661-9260. Manufactured by: Pharmaxis Ltd 20 Rodborough Road Frenchs Forest NSW 2086 AUSTRALIA Manufactured for: Chiesi USA, Inc. Cary, NC 27518 USA 1-888-661-9260 BRONCHITOL is registered in the US Patent and Trademark Office. This Patient Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: 10/2020 CTBR-009-0817-00-SPL 140 Capsules (14 blister packs). Inhaler. Prescribing Information. 560 Capsules (56 blister packs). Inhalers. Prescribing Information. Do not use BRONCHITOL until your healthcare provider has performed the BRONCHITOL Tolerance Test (BTT) and approved you for treatment. This is to make sure you get the right treatment if you have severe reaction.. For oral inhalation only. Do not swallow BRONCHITOL capsules.. Use an inhaled short-acting bronchodilator to 15 minutes before every dose of BRONCHITOL. Use BRONCHITOL times each day. Inhale through your mouth (oral inhalation) the capsule contents in 10 single BRONCHITOL capsules:1 time in the morning1 time at least to hours before bedtime 1 time in the morning. time at least to hours before bedtime. Blister pack. Inhaler. Bronchodilator (and spacer for bronchodilator if needed). Sink or hand washing station. Store BRONCHITOL at room temperature between 68F to77F (20C to 25C).. If your BRONCHITOL capsules are stored at temperatures more than 86F (30C), throw them away.. Do not freeze BRONCHITOL.. Do not refrigerate BRONCHITOL.. Keep BRONCHITOL and all medicines out of the reach of children.. Your inhaler should give you the correct dose of medicine for days without needing cleaning. However, if your inhaler does need cleaning:. Make sure your inhaler is empty.. Wash your inhaler in warm water with the mouthpiece open.. Shake it until there are no large water droplets left in the inhaler.. Leave it to dry in the air by laying it on its side with the mouthpiece open.. Allow the inhaler to dry fully (or completely) after it has been washed.. Keep your inhaler dry and always make sure your hands are completely dry before using it.. Do not breathe or cough into your inhaler.. Do not take your inhaler apart.. Do not place capsule directly into the mouthpiece of your inhaler.. Do not leave used capsule in your inhaler chamber.. Use new inhaler after days.. If your inhaler breaks, call to your healthcare provider.. Blister Pack and Inhaler. Figure A. Figure B. Figure C. Figure D. Figure E. Figure F. Figure G. Figure H. Figure I. Figure I. Figure K. Figure L. Figure M.

LACTATION SECTION.

8.2 Lactation. Risk Summary It is not known whether BRONCHITOL is excreted in human breast milk. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for BRONCHITOL and any potential adverse effects on the breastfed child from BRONCHITOL or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. The precise mechanism of action of BRONCHITOL in improving pulmonary function in cystic fibrosis patients is unknown.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisIn 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 mg/kg basis). These doses were approximately 55 and 30 times the MRHDID, respectively, on mg/m2 basis. MutagenesisMannitol 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. Impairment of FertilityThe effect of inhaled mannitol on fertility has not been investigated.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Susceptible persons may experience bronchoconstriction from an overdosage. If excessive coughing and bronchoconstriction occurs, immediately administer an inhaled short-acting bronchodilator and other medical treatments as necessary.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Principal Display Panel 40 mg Week Carton LabelRx OnlyNDC 10122-212-56Caution: Federal Law Prohibits Dispensing Without PrescriptionBronchitol(R)(mannitol) inhalation powder40 mg per capsuleFOR ORAL INHALATION ONLYDo Not Swallow Bronchitol CapsulesComplete entire package (56 Blister Packs) for 28 days treatmentContents:56 Blister Cards: 560 capsules (40 mg each)4 Bronchitol devices: For use with enclosed capsules onlySee package insert for complete dosage informationFor more information, call 1-888-661-9260.. Principal Display Panel 40 mg Week Carton Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. BRONCHITOL is not indicated for use in children and adolescents. The safety and effectivenss of BRONCHITOL have not been established in pediatric patients for cystic fibrosis. Patients aged years to 17 years were included in two 26-week, double-blind clinical trials (Trials and 3). In these trials, 154 patients under 18 years of age received BRONCHITOL and 105 patients received control (50 mg inhaled mannitol). Hemoptysis was reported in 12 of 154 (7.8%) patients who received BRONCHITOL and in of 105 (1.9%) patients who received control.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. The pharmacodynamics of mannitol are unknown.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionFollowing 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 mcgohr/mL. The mean time to peak plasma concentration (Tmax) after oral inhalation was 1.5 hour. DistributionBased on intravenous administration, the volume of distribution of mannitol was 34.3 L. EliminationMetabolismMannitol is metabolized in CYP-independent manner through the glycolytic pathway via dehydrogenation to fructose. The extent of metabolism of mannitol appears to be small. This is evident from urinary excretion of about 87% of unchanged drug after an intravenous dose to healthy patients. ExcretionFollowing 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 patients, about 55% of the total dose was excreted in the urine as unchanged mannitol. Following oral or intravenous administration of 500 mg dose, the corresponding values were 54% and 87% of the dose, respectively. Specific PopulationsPatients with Hepatic and Renal Impairment: Formal pharmacokinetic studies using BRONCHITOL 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. Drug Interaction StudiesNo formal drug interaction studies have been conducted with BRONCHITOL.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are no adequate and well-controlled studies of BRONCHITOL in pregnant women. The available data on BRONCHITOL use in pregnant women are not sufficient to inform any drug-associated risks for major birth defects and miscarriage. Based on animal reproduction studies, no evidence of structural alterations was observed when mannitol was 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]. There are risks to the mother associated with cystic fibrosis in pregnancy [see Clinial Considerations]. BRONCHITOL should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 to 4% and 15 to 20%, respectively.Clinical ConsiderationsDisease-Associated Maternal and/or Embryo/Fetal RiskCystic fibrosis may increase the risk for preterm delivery.DataAnimal DataIn 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 mg/m2 basis at maternal doses of 1600 mg/kg/day in both species).

SPL PATIENT PACKAGE INSERT SECTION.

Patient InformationBRONCHITOL(R) (BRONK-ih-tol)(mannitol) inhalation powderfor oral inhalation useWhat is BRONCHITOLBRONCHITOL is prescription medicine that is used along with other therapies to improve lung function in people 18 years of age and older with cystic fibrosis (CF).BRONCHITOL is only for adults who have passed the BRONCHITOL Tolerance Test (BTT). Your first dose of BRONCHITOL is given during the BTT by your healthcare provider and tests if BRONCHITOL is right for you. Your healthcare provider will use equipment to monitor you and have medicine ready if you have bronchospasms during the test. If you have bronchospasms during your BTT, then you should not be prescribed BRONCHITOL.BRONCHITOL should not be used in children and adolescents. It is not known if BRONCHITOL is safe and effective in children under 18 years of age.Do not take BRONCHITOL if you:have had an allergic reaction to mannitol or any parts of the BRONCHITOL capsule. See the end of this Patient Information leaflet for complete list of ingredients in BRONCHITOL.do not pass the BTT. Before you use BRONCHITOL, tell your healthcare provider about all your medical conditions, including if you:have ever coughed up blood or had blood in your mucus (sputum).are pregnant or planning on becoming pregnant. It is not known if BRONCHITOL will harm your unborn baby. Tell your healthcare provider right away if you become pregnant while using BRONCHITOL.are breastfeeding or plan to breastfeed. It is not known if BRONCHITOL passes into your breast milk or if it can harm your baby. Talk to your healthcare provider about the best way to feed your baby while using BRONCHITOL. Tell your healthcare provider about all medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.Know the medicines you take. Keep list of the medicines you take and show it to your healthcare provider and pharmacist when you get new medicine.How should use BRONCHITOLSee the step-by-step Patient Instructions for Use at the end of this Patient Information leaflet. BRONCHITOL is for oral inhalation only.Do not use BRONCHITOL until your healthcare provider has given you the BTT and approved you for treatment. Ask your healthcare provider or pharmacist if you have any questions.Use BRONCHITOL exactly as your healthcare provider tells you to use it. Do not swallow BRONCHITOL capsules. BRONCHITOL capsules should be used only with the provided inhaler device. An inhaled short-acting bronchodilator should be used to15 minutes before every dose of BRONCHITOL. Use BRONCHITOL times each day. Breathe in (inhale) through your mouth (oral inhalation) the capsule contents in 10 single BRONCHITOL capsules using the BRONCHITOL inhaler:1 time in the morning time at least to hours before bedtime If you use too much BRONCHITOL, call your healthcare provider or go to the nearest emergency room right away if you have any unusual symptoms, such as feelings that you cannot breathe, have wheezing, or cough lot.Do not stop using BRONCHITOL or any other medicines unless told to do so by your healthcare provider because your symptoms might get worse. Your healthcare provider may change your medicines as needed.Call your healthcare provider or get emergency medical care right away if your breathing problems get worse while taking BRONCHITOL.What are the possible side effects of BRONCHITOL BRONCHITOL may cause serious side effects, including:sudden breathing problems immediately after inhaling your medicine. Use your short-acting bronchodilator or rescue medicine if you have sudden breathing problems. Get emergency medical care right away if your bronchodilator or rescue medicine does not relieve the symptoms.coughing up of blood (hemoptysis). This is serious but common side effect. Coughing up blood in your mucus can happen while you are using BRONCHITOL. Call your healthcare provider or get emergency medical care right away if you cough up large amount of blood. The most common side effects of BRONCHITOL include:coughcoughing up of blood pain or irritation in the back of your mouth and throat and discomfort when swallowingvomitingfeverjoint painbacteria in your sputumTell your healthcare provider if you have any side effect that bothers you or that does not go away.These are not all the possible side effects of BRONCHITOL. You can ask your healthcare provider or pharmacist for more information.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Chiesi USA, Inc. at 1-888-661-9260.How should store BRONCHITOLStore BRONCHITOL at room temperature between 68F to 77F (20C to 25C).If your BRONCHITOL capsules are stored at temperatures more than 86F (30C), throw them away.Do not freeze BRONCHITOL.Do not refrigerate BRONCHITOL.Throw away the BRONCHITOL inhaler after days and get new one.Keep BRONCHITOL and all medicines out of the reach of children.General information about the safe and effective use of BRONCHITOL.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use BRONCHITOL for condition for which it was not prescribed. Do not give BRONCHITOL to other people, even if they have the same symptoms that you have. It may harm them.This leaflet summarizes the most important information about BRONCHITOL. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about BRONCHITOL that is written for health professionals.What are the ingredients in BRONCHITOL Active ingredient: mannitolInactive ingredients: There are no inactive ingredients in BRONCHITOL. Capsules: gelatin and water. The imprinting ink contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, purified water, strong ammonia solution, potassium hydroxide and black iron oxide E172.Manufactured by:Pharmaxis Ltd20 Rodborough Road Frenchs Forest NSW 2086 AUSTRALIAManufactured for: Chiesi USA, Inc. Cary, NC 27518 USA 1-888-661-9260BRONCHITOL is registered in the US Patent and Trademark Office.All trademarks referenced herein are the property of their prospective owners. For more information about BRONCHITOL or how to use your inhaler, call 1-888-661-9260.This Patient Information has been approved by the U.S. Food and Drug Administration 10/2020. BRONCHITOL is prescription medicine that is used along with other therapies to improve lung function in people 18 years of age and older with cystic fibrosis (CF).. BRONCHITOL is only for adults who have passed the BRONCHITOL Tolerance Test (BTT). Your first dose of BRONCHITOL is given during the BTT by your healthcare provider and tests if BRONCHITOL is right for you. Your healthcare provider will use equipment to monitor you and have medicine ready if you have bronchospasms during the test. If you have bronchospasms during your BTT, then you should not be prescribed BRONCHITOL.. have had an allergic reaction to mannitol or any parts of the BRONCHITOL capsule. See the end of this Patient Information leaflet for complete list of ingredients in BRONCHITOL.. do not pass the BTT. have ever coughed up blood or had blood in your mucus (sputum).. are pregnant or planning on becoming pregnant. It is not known if BRONCHITOL will harm your unborn baby. Tell your healthcare provider right away if you become pregnant while using BRONCHITOL.. are breastfeeding or plan to breastfeed. It is not known if BRONCHITOL passes into your breast milk or if it can harm your baby. Talk to your healthcare provider about the best way to feed your baby while using BRONCHITOL. BRONCHITOL is for oral inhalation only.. Do not use BRONCHITOL until your healthcare provider has given you the BTT and approved you for treatment. Ask your healthcare provider or pharmacist if you have any questions.. Use BRONCHITOL exactly as your healthcare provider tells you to use it. Do not swallow BRONCHITOL capsules. BRONCHITOL capsules should be used only with the provided inhaler device. An inhaled short-acting bronchodilator should be used to15 minutes before every dose of BRONCHITOL. Use BRONCHITOL times each day. Breathe in (inhale) through your mouth (oral inhalation) the capsule contents in 10 single BRONCHITOL capsules using the BRONCHITOL inhaler:1 time in the morning time at least to hours before bedtime 1 time in the morning. time at least to hours before bedtime. If you use too much BRONCHITOL, call your healthcare provider or go to the nearest emergency room right away if you have any unusual symptoms, such as feelings that you cannot breathe, have wheezing, or cough lot.. Do not stop using BRONCHITOL or any other medicines unless told to do so by your healthcare provider because your symptoms might get worse. Your healthcare provider may change your medicines as needed.. sudden breathing problems immediately after inhaling your medicine. Use your short-acting bronchodilator or rescue medicine if you have sudden breathing problems. Get emergency medical care right away if your bronchodilator or rescue medicine does not relieve the symptoms.. coughing up of blood (hemoptysis). This is serious but common side effect. Coughing up blood in your mucus can happen while you are using BRONCHITOL. Call your healthcare provider or get emergency medical care right away if you cough up large amount of blood. cough. coughing up of blood pain or irritation in the back of your mouth and throat and discomfort when swallowing. vomiting. fever. joint pain. bacteria in your sputum. Store BRONCHITOL at room temperature between 68F to 77F (20C to 25C).. If your BRONCHITOL capsules are stored at temperatures more than 86F (30C), throw them away.. Do not freeze BRONCHITOL.. Do not refrigerate BRONCHITOL.. Throw away the BRONCHITOL inhaler after days and get new one.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThere are no adequate and well-controlled studies of BRONCHITOL in pregnant women. The available data on BRONCHITOL use in pregnant women are not sufficient to inform any drug-associated risks for major birth defects and miscarriage. Based on animal reproduction studies, no evidence of structural alterations was observed when mannitol was 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]. There are risks to the mother associated with cystic fibrosis in pregnancy [see Clinial Considerations]. BRONCHITOL should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 to 4% and 15 to 20%, respectively.Clinical ConsiderationsDisease-Associated Maternal and/or Embryo/Fetal RiskCystic fibrosis may increase the risk for preterm delivery.DataAnimal DataIn 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 mg/m2 basis at maternal doses of 1600 mg/kg/day in both species).. 8.2 Lactation. Risk Summary It is not known whether BRONCHITOL is excreted in human breast milk. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for BRONCHITOL and any potential adverse effects on the breastfed child from BRONCHITOL or from the underlying maternal condition.. 8.4 Pediatric Use. BRONCHITOL is not indicated for use in children and adolescents. The safety and effectivenss of BRONCHITOL have not been established in pediatric patients for cystic fibrosis. Patients aged years to 17 years were included in two 26-week, double-blind clinical trials (Trials and 3). In these trials, 154 patients under 18 years of age received BRONCHITOL and 105 patients received control (50 mg inhaled mannitol). Hemoptysis was reported in 12 of 154 (7.8%) patients who received BRONCHITOL and in of 105 (1.9%) patients who received control.. 8.5 Geriatric Use. Clinical trials of BRONCHITOL did not include sufficient numbers of patients with cystic fibrosis who were 65 years of age and older to allow evaluation of safety and efficacy in this population. 8.6 Hepatic and Renal Impairment. Clinical trials of BRONCHITOL did not include patients with hepatic or renal impairment. No specific dose recommendations for these patient populations are available. 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. BRONCHITOL can cause bronchospasm, which can be severe in susceptible patients. Because of the risk of bronchospasm, prior to prescribing BRONCHITOL, perform the BRONCHITOL tolerance test (BTT). The BTT must be administered under the supervision of healthcare practitioner who can treat severe bronchospasm. Do not prescribe BRONCHITOL if the patient fails the BTT. Patients who pass the BTT may experience bronchospasm with maintenance use of BRONCHITOL. Advise patients to premedicate with an inhaled short-acting bronchodilator prior to each administration of BRONCHITOL. If bronchospasm occurs, immediately discontinue BRONCHITOL. Treat bronchospasm with an inhaled short-acting bronchodilator. (2.1, 5.1)Hemoptysis can occur with BRONCHITOL use. Monitor patients with history of episodes of hemoptysis. If hemoptysis occurs, discontinue use of BRONCHITOL (5.2). BRONCHITOL can cause bronchospasm, which can be severe in susceptible patients. Because of the risk of bronchospasm, prior to prescribing BRONCHITOL, perform the BRONCHITOL tolerance test (BTT). The BTT must be administered under the supervision of healthcare practitioner who can treat severe bronchospasm. Do not prescribe BRONCHITOL if the patient fails the BTT. Patients who pass the BTT may experience bronchospasm with maintenance use of BRONCHITOL. Advise patients to premedicate with an inhaled short-acting bronchodilator prior to each administration of BRONCHITOL. If bronchospasm occurs, immediately discontinue BRONCHITOL. Treat bronchospasm with an inhaled short-acting bronchodilator. (2.1, 5.1). Hemoptysis can occur with BRONCHITOL use. Monitor patients with history of episodes of hemoptysis. If hemoptysis occurs, discontinue use of BRONCHITOL (5.2). 5.1 Bronchospasm. BRONCHITOL Tolerance TestBRONCHITOL can cause bronchospasm, which can be severe in susceptible individuals. Because of the risk of bronchospasm, prior to prescribing BRONCHITOL, perform the BRONCHITOL Tolerance Test (BTT), to identify patients who are appropriate for maintenance treatment with BRONCHITOL. The BTT must be administered under the supervision of healthcare practitioner who can treat severe bronchospasm. In clinical trials, 896 adult patients with cystic fibrosis underwent the BTT and 72 patients (8%) failed or did not complete the BTT. Do not prescribe BRONCHITOL if the patient fails the BTT. Maintenance TherapyBronchospasm may occur during inhalation of BRONCHITOL, even in patients who have passed the BTT. An inhaled short-acting bronchodilator must be administered 5-15 minutes before administration of each dose during maintenance therapy. In clinical studies, bronchospasm or bronchial hyperreactivity was reported in of 414 adult patients (1.0%) receiving BRONCHITOL as maintenance therapy and in of 347 adult patients (0.6%) receiving control (50 mg inhaled mannitol), even though these patients had passed the BTT. If bronchospasm occurs following dosing of BRONCHITOL, it should immediately be discontinued and treated with an inhaled short-acting bronchodilator or as medically appropriate. 5.2 Hemoptysis. Hemoptysis may occur with BRONCHITOL use. Hemoptysis was reported in 43 (10.4%) adult patients receiving BRONCHITOL and in 33 (9.5%) adult patients receiving control (50 mg inhaled mannitol) during clinical studies. In patients aged years to 17 years, hemoptysis was reported in 12 of 154 (7.8%) patients who received BRONCHITOL and in of 105 (1.9%) patients who received control. BRONCHITOL has not been studied in patients with history of episodes of significant hemoptysis (volume greater than 60 mL) in the previous months. BRONCHITOL should be discontinued in the event of hemoptysis. BRONCHITOL is not indicated for use in children and adolescents.