PULMOZYME® (dornase alfa)

PULMOZYME® (dornase alfa)

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PULMOZYME® (dornase alfa)

PULMOZYME is a recombinant human deoxyribonuclease I (rhDNase) an enzyme which selectively cleaves DNA. The protein is produced by genetically engineered Chinese Hamster Ovary (CHO) cells containing DNA encoding for the native human protein, deoxyribonuclease I (DNase). Fermentation is carried out in a nutrient medium containing the antibiotic gentamicin, 100–200 mg/L.

However, the presence of the antibiotic is not detectable in the final product. The product is purified by tangential flow filtration and column chromatography. The purified glycoprotein contains 260 amino acids with an approximate molecular weight of 37,000 daltons. The primary amino acid sequence is identical to that of the native human enzyme.

PULMOZYME is administered by inhalation of an aerosol mist produced by a compressed air driven nebulizer or an approved nebulizer system.

PULMOZYME is a sterile, clear, colorless, highly purified solution in single-use ampules. Each ampule delivers 2.5 mL of the solution to the nebulizer bowl. Each mL of aqueous solution contains 1 mg dornase alfa, calcium chloride dihydrate (0.15 mg) and sodium chloride (8.77 mg). The solution contains no preservative. The nominal pH of the solution is 6.3.

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.

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 alpha.

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

PULMOZYME (dornase alfa) is indicated for daily administration in conjunction with standard therapies for the management of cystic fibrosis (CF) patients 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.

Recommended Dosage

The recommended dosage for use in most cystic fibrosis patients is one 2.5 mg single-use ampule inhaled once daily using a recommended jet nebulizer/compressor system or eRapid™ Nebulizer System. Some patients may benefit from twice daily administration.

Directions for Use

Administer PULMOZYME via the eRapid Nebulizer System or via a jet nebulizer connected to an air compressor with an adequate air flow and equipped with a mouthpiece or suitable face mask. No data are currently available to support the administration of PULMOZYME with other nebulizer systems.

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.

Contraindications

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

Use in special populations

Pregnancy: 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).

Lactation: 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.

Pediatric Use: The safety and effectiveness of PULMOZYME have been established in pediatric patients 5 years of age and older. While clinical trial data are limited in pediatric patients younger than 5 years of age, the use of PULMOZYME should be considered for pediatric CF patients who may experience potential benefit in pulmonary function or who may be at risk of respiratory tract infection.

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.

Overdosage

Single-dose inhalation studies in rats and monkeys at doses up to 180-times higher than doses routinely used in clinical studies are well tolerated. Single dose oral administration of PULMOZYME in doses up to 200 mg/kg are also well tolerated by rats.

Cystic fibrosis patients have received up to 20 mg BID for up to 6 days and 10 mg BID intermittently (2 weeks on/2 weeks off drug) for 168 days. These doses were well tolerated.

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