BRONCHITOL

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)] 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 Pharmaxis Europe Limited at 1-888-276-0618 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 06/2024

4 CONTRAINDICATIONS BRONCHITOL is contraindicated in the following conditions: 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)

11 DESCRIPTION BRONCHITOL (mannitol) inhalation powder contains D-Mannitol (referred to throughout as mannitol) as the active ingredient. Mannitol is a hexahydric sugar alcohol, with the following chemical name hexane-1,2,3,4,5,6-hexol and chemical structure: Mannitol is a 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 a mouthpiece, blue piercing buttons, capsule chamber, and a removable cap. A blister pack consists of 10 capsules, each containing 40 mg mannitol. After a 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 a flow rate of 60 L/min for 2 seconds. The actual amount of drug delivered to the lungs will depend on patient factors, such as inspiratory flow profile. chemical structure

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 a 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 a 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, a decrease in FEV1, or a decrease in oxygen saturation with administration of BRONCHITOL. If a patient experiences any of these events during the BTT, the patient has failed the BTT. Do not prescribe BRONCHITOL. If a patient does not experience any of these events during BTT, the patient has passed the BTT and is a 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)] . 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 a day by oral inhalation (the contents of 10 capsules administered individually) via the inhaler [see Dosage and Administration (2.1)] . A 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 7 days of use. If the inhaler does need to be washed, the patient should allow the inhaler to thoroughly air dry before next use.

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.

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

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 Absorption 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. Distribution Based on intravenous administration, the volume of distribution of mannitol was 34.3 L. Elimination Metabolism Mannitol is metabolized in a 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 a urinary excretion of about 87% of unchanged drug after an intravenous dose to healthy patients. Excretion 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 patients, 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. Specific Populations Patients 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 Studies No formal drug interaction studies have been conducted with BRONCHITOL.

20240903

1

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

BRONCHITOL Mannitol MANNITOL MANNITOL Clear capsule with white powder PXS;40;mg CAPSULE

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis 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/m 2 basis. Mutagenesis 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. Impairment of Fertility The effect of inhaled mannitol on fertility has not been investigated.

NDA202049

BRONCHITOL

Mannitol

84639-212

HUMAN PRESCRIPTION DRUG

RESPIRATORY (INHALATION)

Principle Display Panel - 40 mg 4 Week Carton Principal Display Panel - 40 mg 4 Week Carton Label Rx Only NDC 84639-212-56 Caution: Federal Law Prohibits Dispensing Without A Prescription Bronchitol® (mannitol) inhalation powder 40 mg per capsule FOR ORAL INHALATION ONLY Do Not Swallow Bronchitol Capsules Complete entire package (56 Blister Packs) for 28 days treatment Contents: 56 Blister Cards: 560 capsules (40 mg each) 4 Bronchitol devices: For use with enclosed capsules only See package insert for complete dosage information For more information, call 1-888-661-9260. Bronchitol 4 Week Carton image

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Patient Instructions for Use). BRONCHITOL Tolerance Test Inform patients that a BRONCHITOL Tolerance Test is required prior to beginning treatment with BRONCHITOL. The BRONCHITOL Tolerance Test must be performed by a healthcare practitioner equipped to monitor oxygen saturation (SpO 2 ), perform spirometry (FEV 1 ), and manage acute bronchospasm. Inhaled Short-Acting Bronchodilator Use Instruct patients that an inhaled short-acting bronchodilator such as albuterol must always be administered 5 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. Hemoptysis Inform patients that hemoptysis can occur with inhalation of BRONCHITOL. If a patient experiences hemoptysis, instruct patients to discontinue BRONCHITOL and contact their healthcare practitioner right away. Administration Instruct patients on the proper administration of BRONCHITOL with the inhaler. The recommended dosage is 10 capsules (400 mg) twice a 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: Arna Pharma Pty Ltd. 20 Rodborough Rd Frenchs Forest NSW 2086 AUSTRALIA Manufactured for: Pharmaxis Europe Limited 108 Q House Furze Road, Sandyford Dublin 18, D18AY29 Ireland BRONCHITOL® is a registered trademark of Pharmaxis Europe Limited.

14 CLINICAL STUDIES Control (N=214) BRONCHITOL (N=209) Adjusted mean change from baseline 12 mL 63 mL Adjusted mean difference (95% CI), p-value 51 mL (6 to 97 mL), p=0.028 intention-to-treat population of adults of 78 mL (95% CI: 2 to 153 mL).

8 ​USE IN SPECIFIC POPULATIONS 8.1 ​Pregnancy Risk Summary There 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 a background risk of birth defect, loss, or other adverse outcomes. In the United States general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Cystic fibrosis may increase the risk for preterm delivery. Data Animal Data In animal reproduction studies, oral administration of mannitol to pregnant rats and mice during the period of organogenesis did not cause fetal structural alterations. The mannitol dose in rats and mice was approximately 20 and 10 times the maximum recommended human daily inhalation dose (MRDID) in humans, respectively, (on a mg/m 2 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 mother’s 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 6 years to 17 years were included in two 26- week, double-blind clinical trials (Trials 2 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 2 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.

16 HOW SUPPLIED/STORAGE AND HANDLING BRONCHITOL (mannitol) inhalation powder: 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 4 inhalers respectively in a carton BRONCHITOL is provided in 3 commercial presentations: Pack Quantities Inhalers Capsules NDC Number 4-week Treatment Pack (4 x 7-day treatment packs) 4 560 84639-212-56 7-day Treatment Pack 1 140 84639-212-14 Bronchitol Tolerance Test 1 10 84639-212-04 BRONCHITOL should be stored between 68°F-77°F (20°C-25°C) with excursions permitted between 59°F-86°F (15°C- 30°C). [See USP Controlled Room Temperature]. Do not refrigerate. Do not freeze. BRONCHITOL should only be used with the provided inhaler, which is a white plastic inhaler comprised of a mouthpiece, blue piercing buttons, capsule chamber, and a 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 1-888-276-2144.