Bronchitol (Page 3 of 5)

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 FEV1 >40% to <90% of predicted. Trial 2 (NCT00446680) evaluated patients 6 years of age or older with baseline FEV1 >30% to <90% of predicted. Trial 3 (NCT00630812) evaluated pateints 6 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 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 FEV1 (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 FEV1 63.9% predicted (range: 40.3% = minimum, 89.6% = maximum).

Treatment with BRONCHITOL resulted in a 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 6 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 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 FEV1 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 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: 2 to 153 mL).

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.

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 (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 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

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