RECENT MAJOR CHANGES SECTION

RECENT MAJOR CHANGES

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CLINICAL PHARMACOLOGY SECTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

PULMOZYME is recombinant human deoxyribonuclease I (rhDNase), an enzyme which selectively cleaves DNA. In preclinical in vitro studies, PULMOZYME hydrolyzes the DNA in sputum of CF patients and reduces sputum viscoelasticity. In CF patients, retention of viscous purulent secretions in the airways contributes both to reduced pulmonary function and to exacerbations of infection. Purulent pulmonary secretions contain very high concentrations of extracellular DNA released by degenerating leukocytes that accumulate in response to infection.

12.3 Pharmacokinetics

When 2.5 mg PULMOZYME was administered by inhalation to eighteen CF patients, mean sputum concentrations of 3 µg/mL DNase were measurable within 15 minutes. Mean sputum concentrations declined to an average of 0.6 µg/mL two hours following inhalation. Inhalation of up to 10 mg TID of PULMOZYME by 4 CF patients for six consecutive days, did not result in a significant elevation of serum concentrations of DNase above normal endogenous levels. After administration of up to 2.5 mg of PULMOZYME twice daily for six months to 321 CF patients, no accumulation of serum DNase was noted. Dornase alfa is expected to be metabolized by proteases present in biological fluids. A human intravenous dose study suggested an elimination half-life of 3-4 hours for dornase alfa.

PULMOZYME, 2.5 mg by inhalation, was administered daily to 98 patients aged 3 months to ≤ 10 years, and bronchoalveolar lavage (BAL) fluid was obtained within 90 minutes of the first dose. BAL DNase concentrations were detectable in all patients but showed a broad range, from 0.007 to 1.8 µg/mL. Over an average of 14 days of exposure, serum DNase concentrations (mean ± s.d.) increased by 1.1 ± 1.6 ng/mL for the 3 months to < 5 year age group and by 0.8 ± 1.2 ng/mL for the 5 to ≤ 10 year age group. The relationship between BAL or serum DNase concentration and adverse experiences and clinical outcomes is unknown.

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INDICATIONS & USAGE SECTION

Highlight: PULMOZYME is a recombinant DNase enzyme indicated in conjunction with standard therapies for the management of cystic fibrosis (CF) patients to improve pulmonary function. (1)

1 INDICATIONS AND USAGE

PULMOZYME® is indicated, in conjunction with standard therapies, for the management of pediatric and adult patients with cystic fibrosis (CF) to improve pulmonary function.

In CF patients with an FVC ≥ 40% of predicted, daily administration of PULMOZYME has also been shown to reduce the risk of respiratory tract infections requiring parenteral antibiotics.

DOSAGE & ADMINISTRATION SECTION

Highlight: * The recommended dosage is 2.5 mg (one single-dose ampule) inhaled once daily using a recommended nebulizer. (2.1)

• Some patients may benefit from twice daily administration. (2.1)
• See full prescribing information for the recommended nebulizers for use with PULMOZYME. (2.2)

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

The recommended dosage, in most cystic fibrosis patients, is 2.5 mg (one single-dose ampule) inhaled once daily using a recommended jet nebulizer connected to an air compressor system or via a vibrating mesh nebulizer [see Dosage and Administration (2.2)].

Some patients may benefit from twice daily administration [see Clinical Studies (14)].

2.2 Administration Instructions

Nebulizer Information

• Administer PULMOZYME via a jet nebulizer connected to an air compressor with an adequate air flow and equipped with a mouthpiece or suitable face mask, or via a vibrating mesh nebulizer. Refer to Table 1 for the recommended Jet Nebulizers or Vibrating Mesh Nebulizers for use with PULMOZYME. No data are currently available to support the administration of PULMOZYME with other nebulizer systems.
• The eRapid Nebulizer System should only be used by adults and pediatric patients who can use a mouthpiece, and not by younger patients who need a mask to inhale PULMOZYME.
• Use the selected nebulizer in accordance with the manufacturer's instruction manual.
• Refer to the manufacturer's instruction manual on the use, maintenance, and replacement of the equipment, including cleaning and disinfection procedures for the selected nebulizer.
• For additional information, refer to the selected nebulizer manufacturer's instruction manual.

Table 1. Recommended Jet Nebulizers or Vibrating Mesh Nebulizers for Use with PULMOZYME

PULMOZYME Information

• Each PULMOZYME ampule should be squeezed prior to use in order to check for leaks. Discard ampules if the solution is cloudy or discolored. Once opened, the entire contents of the ampule must be used or discarded.
• Do not dilute or mix PULMOZYME with other drugs in the nebulizer. Mixing of PULMOZYME with other drugs could lead to adverse physicochemical and/or functional changes in PULMOZYME or the admixed compound.

DOSAGE FORMS & STRENGTHS SECTION

Highlight: Inhalation solution: 2.5 mg/2.5 mL (1 mg/mL) clear, colorless solution in single-dose ampules (3)

3 DOSAGE FORMS AND STRENGTHS

Inhalation solution: 2.5 mg/2.5 mL (1 mg/mL) clear, colorless solution in single-dose ampules.

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CONTRAINDICATIONS SECTION

Highlight: PULMOZYME is contraindicated in patients with known hypersensitivity to dornase alfa, Chinese Hamster Ovary cell products, or any component of the product. (4)

4 CONTRAINDICATIONS

PULMOZYME is contraindicated in patients with known hypersensitivity to dornase alfa, Chinese Hamster Ovary cell products, or any component of the product.

WARNINGS AND PRECAUTIONS SECTION

Highlight: None. (5)

5 WARNINGS AND PRECAUTIONS

None.

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DRUG INTERACTIONS SECTION

7 DRUG INTERACTIONS

Available data indicate there are no clinically important drug-drug interactions with PULMOZYME.

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USE IN SPECIFIC POPULATIONS SECTION

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no adequate and well-controlled studies with PULMOZYME in pregnant women. However, animal reproduction studies have been conducted with dornase alfa. In these studies, no evidence of fetal harm was observed in rats and rabbits at doses of dornase alfa up to approximately 600 times the maximum recommended human dose (MRHD).

The background risk of major birth defects and miscarriage for the cystic fibrosis population is unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.

Data

Animal Data

Reproductive studies have been performed in rats and rabbits at intravenous doses of dornase alfa up to 10 mg/kg/day (approximately 600 times the MRHD in adults). In a combined embryo-fetal development and pre- and post-natal development study, no evidence of maternal toxicity, embryotoxicity, or teratogenicity was observed when dornase alfa was administered to dams throughout organogenesis (Gestation days 6 to 17). Dornase alfa did not elicit adverse effects on fetal or neonatal growth when administered to dams throughout most of gestation and delivery (Gestation days 6 to 25) and nursing (Post-partum days 6 to 21).

A pharmacokinetic study in Cynomolgus monkeys found no detectable levels of dornase alfa in fetal blood or amniotic fluid on gestation day 150 (end of gestation) from mothers that were administered an intravenous bolus dose (0.1 mg/kg) followed by an intravenous infusion dose (0.080 mg/kg) over a 6-hour period during pregnancy.

8.2 Lactation

Risk Summary

It is not known whether PULMOZYME is present in human milk. In a pharmacokinetic study in Cynomolgus monkeys, levels of dornase alfa detected in milk were less than 0.1% of the maternal serum concentration at 24 hours after dosing [intravenous bolus dose (0.1 mg/kg) of dornase alfa followed by an intravenous infusion (0.080 mg/kg/hr) over a 6-hour period] on post-partum day 14. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for PULMOZYME and any potential adverse effects on the breastfed child from PULMOZYME or from the underlying maternal condition.

8.4 Pediatric Use

The safety and effectiveness of PULMOZYME in conjunction with standard therapies for cystic fibrosis have been established in pediatric patients. Use of PULMOZYME in pediatric patients is supported by evidence in the following age groups:

• Patients 5 to 17 years of age: Use of PULMOZYME in patients 5 to 17 years of age is supported by evidence from a randomized, placebo-controlled trial of 303 of clinically stable cystic fibrosis patients 5 to 17 years of age who received PULMOZYME [see Clinical Studies (14)].
• Patients less than 5 years: Use of PULMOZYME in patients less than 5 years of age is supported by extrapolation of efficacy data in patients 5 years of age and older with additional safety data in 65 pediatric patients aged 3 months to less than 5 years who received PULMOZYME 2.5 mg daily by inhalation for 2 weeks [see Adverse Reactions (6.1) and Clinical Studies (14)].

8.5 Geriatric Use

Cystic fibrosis is primarily a disease of children and young adults. Clinical studies of PULMOZYME did not include sufficient numbers of subjects aged 65 or older to determine whether they respond differently from younger subjects.

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INSTRUCTIONS FOR USE SECTION

INSTRUCTIONS FOR USE

PULMOZYME**®**** (PULL-muh-zyme)**

(dornase alfa)

Inhalation Solution

This Instructions for Use contains information on how to use PULMOZYME with the following recommended vibrating mesh nebulizers:

See the other side of this Instructions for Use for****information on use with Jet Nebulizers and Compressors

Read and understand this Instructions for Use and the nebulizer manufacturer's instruction manual before you start taking Pulmozyme and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

This information does not take the place of the manufacturer's instruction manual for the vibrating mesh nebulizer.

The vibrating mesh nebulizer changes the Pulmozyme liquid medicine into a fine mist you inhale by breathing through a mouthpiece.

Do not use any other inhaled medicines in the nebulizer at the same time. Keep all other inhaled medication systems completely separate from Pulmozyme.

The eRapid Nebulizer System should only be used by adults and children who can use a mouthpiece, and not by younger children who need a mask to take Pulmozyme.

Follow the instructions on this side of the Instructions for Use to give Pulmozyme using a vibrating mesh nebulizer.

Important Information You Need to Know Before Using PULMOZYME

Read and follow the nebulizer manufacturer's instruction manual for correct use and maintenance:

• to clean the nebulizer before first use and after each use as recommended
• to disinfect the nebulizer parts by using the disinfecting method recommended
• to replace nebulizer parts as recommended

Supplies you will need to give a dose of PULMOZYME:

1 Pulmozyme ampule*(SeeFigure A)**

• Vibrating mesh nebulizer and its parts
• Manufacturer's instruction manual for the vibrating mesh nebulizer Nose clip (optional) (See**Figure B***)**

How should I store Pulmozyme?

*Store Pulmozyme ampules at a refrigerated temperature between 36°F to 46°F (2°C to 8°C) in their protective foil pouch to protect from light and heat until you are ready to use them. When the protective foil pouch is opened, the unused ampules must be kept refrigerated in the protective foil pouch to protect from light and heat.

• When traveling, Pulmozyme ampules should be kept refrigerated in their protective foil pouch to protect from light and heat.
• Protect Pulmozyme from excessive heat and light. *Do not use Pulmozyme if the ampules have been exposed to room temperature at 72°F to 82°F (22°C to 28°C) for more than a total of60 hours or if the solution has turned cloudy or discolored. *Do not use Pulmozyme past the expiration date printed on the ampule.

Genentech, Inc.

A Member of the Roche Group
1 DNA Way
South San Francisco, CA 94080-4990
US License No. 1048

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Revised: 02/2024

Representative sample of labeling (see the HOW SUPPLIED section for complete listing):

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SPL UNCLASSIFIED SECTION

Pulmozyme**®**** (dornase alfa)**
Inhalation Solution

Manufactured by:
Genentech, Inc.
A Member of the Roche Group
1 DNA Way
South San Francisco, CA 94080-4990

US License No. 1048

©2024 Genentech, Inc. All rights reserved

©2024 Genentech, Inc.
Pulmozyme® is a registered trademark of Genentech, Inc.

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