Bronchitol

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 a 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 )

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 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 a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The 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 6 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 a mean baseline FEV 1 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 Term BRONCHITOL N = 414 % CONTROL N = 347 % Respiratory, thoracic, and mediastinal disorders Cough 15.0 10.7 Hemoptysis 10.4 9.5 Oropharyngeal pain 7.0 4.3 Gastrointestinal disorders Vomiting 3.1 1.4 Investigations Bacteria sputum identified 6.8 4.6 General disorders and administrative site conditions Pyrexia 4.6 2.3 Musculoskeletal and connective tissue disorders Arthralgia 3.1 2.6 In 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.

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 C 6 H 14 O 6 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. Bronchitol

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 FEV 1 , 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.

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.

20240101

5

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 )

Bronchitol mannitol mannitol mannitol Clear capsule with white powder PXS;40;mg CAPSULE

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.

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

10122-212

HUMAN PRESCRIPTION DRUG

RESPIRATORY (INHALATION)

Principal Display Panel - 40 mg 4 Week Carton Label Rx Only NDC 10122-212-56 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. Principal Display Panel - 40 mg 4 Week Carton Label

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: Pharmaxis Ltd 20 Rodborough Rd Frenchs Forest NSW 2086 AUSTRALIA Manufactured for: Chiesi USA, Inc. Cary, NC 27518 USA BRONCHITOL ® is a registered trademark of Pharmaxis Ltd CTBR-001-1120-01-SPL-1

PATIENT INSTRUCTIONS FOR USE BRONCHITOL ® (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 Pack 140 Capsules (14 blister packs) 1 Inhaler Prescribing Information 4-Week Treatment Pack 560 Capsules (56 blister packs) 4 Inhalers Prescribing Information Important Information You Need to Know Before Using BRONCHITOL 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 a severe reaction. For oral inhalation only Do not swallow BRONCHITOL capsules. Use an inhaled short-acting bronchodilator 5 to 15 minutes before every dose of BRONCHITOL Use BRONCHITOL 2 times each day. Inhale through your mouth (oral inhalation) the capsule contents in 10 single BRONCHITOL capsules: 1 time in the morning 1 time at least 2 to 3 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: 1 Blister pack 1 Inhaler Bronchodilator (and spacer for bronchodilator if needed) Sink or hand washing station Before using BRONCHITOL: Use an inhaled bronchodilator 5 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 a 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 1 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 a steady deep breath in through your mouth. Do not breathe through your nose. Remove inhaler from mouth. Hold breath for 5 seconds before exhaling, do not breathe out (exhale) into inhaler (See Figure I ). You should hear a rattling sound while breathing in. If you do not, tap bottom of inhaler firmly and repeat steps 6 and 7. Step 8. Open the inhaler by turning the cap to the right. If powder is left in capsule, repeat steps 6 and 7. After the capsule is empty, throw away . (See Figure J ). Step 9 . Repeat steps 3 to 8 for all 10 capsules in 1 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 7 days then throw away (discard) the inhaler (See Figure M ). How should I store BRONCHITOL? Store BRONCHITOL at room temperature between 68°F to77°F (20°C to 25°C). If your BRONCHITOL capsules are stored at temperatures more than 86°F (30°C), 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 7 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 a capsule directly into the mouthpiece of your inhaler. Do not leave a used capsule in your inhaler chamber. Use a new inhaler after 7 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: 1/2024 CTBR-009-0817-00-SPL-1 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

14 CLINICAL STUDIES The efficacy of BRONCHITOL for the treatment of cystic fibrosis (CF) was evaluated in 3 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 1 (NCT02134353) evaluated patients 18 years of age or older with baseline FEV 1 >40% to <90% of predicted. Trial 2 (NCT00446680) evaluated patients 6 years of age or older with baseline FEV 1 > 30% to <90% of predicted. Trial 3 (NCT00630812) evaluated pateints 6 years of age or older with baseline FEV 1 > 40% to <90% of predicted. All three trials excluded CF patients with an episode of hemoptysis (>60 mL) in the 3 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 6 to 17 years were included in Trials 2 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 5 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 FEV 1 (mL) over 26 weeks of treatment and was analyzed using the pattern mixture model with multiple imputation. Trial 1 evaluated 423 adult patients with a mean age of 28 years and a mean FEV 1 63.9% predicted (range: 40.3% = minimum, 89.6% = maximum). Treatment with BRONCHITOL resulted in a statistically significant improvement in FEV 1 . In Trial 1, the treatment difference between BRONCHITOL and control for the adjusted mean change in FEV 1 from baseline over 26 weeks was 51 mL (95% CI 6 to 97 mL) shown in Table 2. Table 2: Change in FEV 1 (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 baseline 12 mL 63 mL Adjusted mean difference (95% CI), p-value 51 mL (6 to 97 mL), p=0.028 Trials 2 and 3 evaluated 295 and 305 patients, respectively. For the adjusted mean difference in the change from baseline in FEV 1 over 26 weeks in the intention-to-treat population in Trials 2 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 2 and 3 were performed. The adult subgroup analyses in Trial 2 and 3 evaluated 209 and 157 adult patients, respectively. In Trial 2, there was an adjusted mean difference in the change from baseline in FEV 1 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 FEV 1 over 26 weeks in the intention-to-treat population of adults of 78 mL (95% CI: 2 to 153 mL).

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.

8.4 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.

8.1 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 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 10122-212-56 7-day Treatment Pack 1 140 10122-212-14 Bronchitol Tolerance Test 1 10 10122-212-04 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. The Training Kit (NDC 10122-216-01), containing empty gelatin capsules, should be stored between 68°F-77°F (20°C-25°C) with excursions permitted from 59°F-86°F (15°C-30°C). 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 1-888-661-9260.