PULMOZYME

General Administration Information
For storage information, see the specific product information within How Supplied section.

Route-Specific Administration

Injectable Administration
Other Injectable Administration
Intrapleural catheter injection*
NOTE: Dornase Alfa is not FDA-approved for injectable administration.
Preparation
-Dilute 5 mg in 10 to 30 mL of 0.9% Sodium Chloride Injection.

Intrapleural Instillation

-Inject via chest tube followed by 5 mL 0.9% Sodium Chloride flush and clamp chest tube for 1 hour, then allow to drain for 1 hour.



Inhalation Administration
Nebulization Administration
-The manufacturer recommends that 1 of the following jet nebulizers/compressors or nebulizer systems be used to deliver dornase alfa. There are no data available to support the administration of dornase alfa with other nebulizer systems.
--Hudson T Up-draft II in conjunction with a Pulmo-Aide or legally marketed compressor of identical pressure and flow rate (max 30 psi, 12 LPM);
-Marquest Acorn II in conjunction with a Pulmo-Aide or legally marketed compressor of identical pressure and flow rate (max 30 psi, 12 LPM);
-PARI LC Plus in conjunction with a PARI PRONEB or legally marketed compressor of identical pressure and flow rate (max 24 psi, 9 LPM);
-PARI BABY nebulizer in conjunction with a PARI PRONEB or legally marketed compressor of identical pressure and flow rate (max 24 psi, 9 LPM); this nebulizer can be used in patients unable to inhale or exhale orally throughout the treatment period;
-Durable Sidestream in conjunction with a MOBILAIRE, Porta-NEB, or legally marketed compressor of identical pressure and flow rate (max 45 psi, 7 LPM);
-eRapid Nebulizer System consisting of the eRapid Nebulizer Handset with eBase Controller. Only use in patients who can use a mouthpiece; do not use for patients who require a mask for administration.
-Innospire Go
-Pulmogine Vibrating Mesh Nebulizer
-AireHealth Nebulizer
-Intelligent Mesh Nebulizer

-Each ampule should be squeezed prior to use in order to check for leaks. Discard the solution if it is cloudy or discolored.
-Empty entire contents of the single-use ampule into the nebulizer cup and attach cup to the nebulizer according to the manufacturer's instruction. Discard any unused portions because the inhalation solution contains no preservatives.
-In order to avoid adverse physicochemical and/or functional changes, do not dilute or mix dornase alfa with other drugs in the nebulizer.
-Instruct patient on proper inhalation technique (see manufacturer's labeling). Breathe through the mouth; do not breathe through the nose. A nose clip may be used in patients unable to breathe correctly. Patients who are unable to inhale or exhale orally through a mouthpiece may use the PARI BABY nebulizer, which utilizes a facemask. Continue therapy until nebulizer cup is empty or the nebulizer stops producing a mist.
-Advise the patient to follow the manufacturer's instructions for use and maintenance of equipment.
-Storage: Unused ampules should be stored in the original protective foil pouch and refrigerated. Do not allow dornase alfa to be exposed to room temperature for more than a total of 60 hours.

The safety profile of dornase alfa was evaluated in both placebo-controlled (n = 804) and uncontrolled (n = 98) trials, with exposures ranging from 2 weeks of daily administration up to once or twice daily administration for 6 months. Most patients (n = 581) received dornase alfa 2.5 mg once daily via nebulization, while the rest received 2.5 mg twice daily. Placebo-controlled trials evaluated 643 patients with mild to moderate disease, defined as a forced vital capacity (FVC) >= 40% predicted, and 161 patients with advanced disease, defined as a FVC < 40% predicted. The population in the uncontrolled trial included 98 pediatric patients with cystic fibrosis (CF) ranging from 3 months to 10 years of age. Overall, the trials showed similar safety profiles. Adverse events observed at similar rates in placebo treated patients were consistent with sequelae of CF. Most adverse events were mild, transient in nature, and did not require dose adjustments. Mortality rates observed were similar in both arms and consistent with CF progression. Spontaneous post-marketing reports and prospective safety data from observational studies confirm the safety profile of dornase alfa to be as described in clinical trials.

Adverse reactions reported in patients treated with dornase alfa in clinical trials include: chest pain (unspecified) (18% to 25%), conjunctivitis (1% to 5%), pharyngitis (32% to 40%), laryngitis (3% to 4%), and hoarseness/voice alterations (12% to 18%). Rhinitis (30%), fever (32%), dyspnea (17%), and dyspepsia (3%) were reported more frequently in patients with advanced disease. Advanced disease patients also reported 10% or more predicted decrease in forced vital capacity (22% vs. 17% placebo). The incidence of adverse reactions was slightly greater in patients receiving dornase alfa twice daily than in those receiving once daily treatment. Ninety-eight pediatric patients (65 patients 3 months to 4 years; 33 patients 5 to 10 years) with cystic fibrosis (CF) were evaluated in a 2-week safety trial of dornase alfa 2.5 mg once daily. Cough (18% to 45%) and rhinitis (27% to 35%) were reported at a higher incidence in the younger age group. Of note, this study did not include a control arm so it is difficult to determine to what degree cough can be attributed to dornase alfa and what amount of cough was a result of the underlying CF. Headache (5% to 36%) was reported more frequently in the older age group. Other adverse reactions observed at similar rates in both dornase alfa and placebo treated patients include: abdominal pain, asthenia, flu-like syndrome, malaise, sepsis, intestinal obstruction, gall bladder disease, liver disease, pancreatic disease, diabetes mellitus, hypoxia, weight loss, apnea, bronchiectasis, bronchitis, sputum changes, hemoptysis, decreased pulmonary function, nasal polyps, pneumonia, pneumothorax, sinusitis, and wheeze.

According to the manufacturer, there have been no reports of anaphylaxis attributed to the use of dornase alfa. Mild to moderate urticaria and a mild skin rash (unspecified) have been observed, but have been transient in nature. In addition, rash (unspecified) was reported in 0-12% of pediatric patients. A small percentage of patients (2-4%) had serum antibody formation to dornase alfa; however, none of these patients developed anaphylaxis and the significance is unknown.

Use dornase alfa in conjunction with standard cystic fibrosis therapies.
Until sufficient clinical trial data is available, caution should be used when prescribing chronic dornase alfa therapy for disease states other than cystic fibrosis (CF). One multicenter randomized, double-blind, placebo-controlled trial including 349 stable adult outpatients with idiopathic bronchiectasis examined the use of aerosolized dornase alfa 2.5mg twice daily for 24 weeks. Patients in the dornase alfa group experienced more pulmonary exacerbations compared to placebo. The treatment group also experienced a statistically significant decrease in FEV1. These results were consistent with an in vitro study in non-CF patients showing that dornase alfa had a detrimental effect on sputum transportability.

Dornase alfa is contraindicated in patients with known hypersensitivity to dornase alfa or any component of the product. Dornase alfa is manufactured using Chinese hamster ovary cells and is contraindicated in patients who have previously demonstrated hamster protein hypersensitivity.

Because of there is limited data for administration of dornase alfa to neonates, infants, and children < 5 years, the manufacturer recommends limiting therapy to patients in whom there is a potential for benefit in pulmonary function or risk of respiratory tract infection.

Description: Dornase alfa is recombinant human deoxyribonuclease (rh-DNase) administered via inhalation to assist in the clearance of bronchial secretions in patients with cystic fibrosis (CF). It is produced by genetically engineered Chinese hamster ovary cells, and the primary amino acid sequence is identical to the human enzyme. In a randomized controlled trial, 105 CF patients 5 years of age and older with normal lung function received dornase alfa 2.5 mg daily or no treatment for 3 years. Bronchoalveolar lavage (BAL) fluid samples were taken and assessed for concentrations of neutrophilic airway inflammation markers (neutrophils, elastase activities, and interleukin-8); after 3 years, pooled BAL fluid samples from the treatment group demonstrated no change in concentrations, while the pooled samples from the untreated patients showed significant increases in inflammatory markers. Dornase alfa has been associated with both an improvement in pulmonary function and a decrease in the risk of pulmonary exacerbations and respiratory infections in CF patients. When compared to inhaled hypertonic saline for mucolytic therapy in CF patients, dornase alfa has demonstrated a significantly greater improvement in pulmonary function. The Cystic Fibrosis Foundation guidelines recommend chronic use of dornase alfa in children with mild, moderate, or severe lung disease. Although there is limited data available, the use of dornase alfa in non-CF disease states such as asthma, idiopathic bronchiectasis, plastic bronchitis, respiratory syncytial virus (RSV) bronchiolitis, and pulmonary mucus plugging in premature infants has been described with conflicting results. The potential role for dornase alfa in non-CF disease states remains unclear. Dornase alfa is FDA approved for use in children 5 years and older.

For the treatment of cystic fibrosis in combination with standard therapies to improve pulmonary function:
Respiratory (Inhalation) dosage:
Infants and Children 3 months to 4 years: 2.5 mg inhaled by nebulizer once daily. Use in this age group is supported by extrapolation of efficacy data in patients 5 years and older; additional safety data is available for 65 pediatric patients aged 3 months to 4 years who received 2.5 mg by nebulizer once daily for 2 weeks.
Children and Adolescents 5 to 17 years: 2.5 mg inhaled by nebulizer once daily; some persons with baseline forced vital capacity (FVC) more than 85% may benefit from twice daily administration. Guidelines recommend use in persons with mild, moderate, and severe disease.

For mucolysis in the management of atelectasis* and/or pulmonary mucus plugging in non-cystic fibrosis disease states*:
NOTE: Limited data is available for the use of dornase alfa in non-cystic fibrosis disease states. The optimal dose for these conditions has not been determined.
Pulmonary administration dosage:
Premature Neonates: Small case series have described the use of dornase alfa for the treatment of severe atelectasis and mucus plugging in premature neonates as young as 25 weeks postmenstrual age. Nebulized doses have ranged from 1.25 mg as a single dose to 2.5 mg twice daily. Intratracheal doses have ranged from 1 mg/m2 as a single dose to 2.5 mg three times daily. One case series of 7 premature infants reported clinical improvement in all patients after the administration of dornase alfa. The initial dose used was 2.5 mg intratracheally twice daily for 3 to 6 days, followed by daily therapy for an additional 3 days in some patients. The clinical condition of 2 infants deteriorated when the dornase alfa was discontinued. No adverse events were reported.
Infants, Children, and Adolescents: Small studies and case reports have utilized a variety of doses administered via nebulization or intratracheally. Pediatric studies most often included infants younger than 6 months of age with a primary diagnosis of congenital heart disease; however, patients up to 16 years and those with varying underlying conditions (e.g., bronchiolitis, pneumonia) have also been studied. Those treated with nebulized dornase alfa received 2.5 mg once or twice daily for up to 3 days or until clinical improvement was noted. One retrospective study suggested nebulized dornase alfa was most effective within 10 doses of therapy for amelioration of atelectasis in mechanically ventilated patients. Studies utilizing intratracheal dornase alfa for resolution of atelectasis used 0.1 mg/kg/dose (Max: 1.25 mg) twice daily or 0.25 mg/dose, diluted to 5 mL with 0.9% NaCl Injection, twice daily until clinical improvement and/or extubation. Case reports of intratracheal administration have described larger single doses of 2.5 mg or 10 mg, both diluted to 10 to 20 mL with 0.9% NaCl Injection, in children 7 to 8 years of age; in 1 patient, the 10 mg dose was repeated in 8 hours resulting in clinical improvement and no adverse effects. In a study evaluating the use of dornase alfa for the prevention of atelectasis in post-operative cardiac patients, a prophylactic intratracheal dose of 0.2 mg/kg/dose for patients weighing less than 5 kg and 0.1 mg/kg/dose for those weighing more than 5 kg, administered every 12 hours was used.

For the treatment of pleural empyema*:
Intrapleural dosage*:
Infants, Children, and Adolescents: 5 mg intrapleurally twice daily for 3 days in combination with alteplase.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established; however, doses up to 2.5 mg via inhalation twice daily or 2.5 mg intratracheally 3 times daily have been used off-label.
-Infants
1 to 2 months: Safety and efficacy have not been established; however, doses up to 2.5 mg via inhalation twice daily or 2.5 mg intratracheally 3 times daily have been used off-label.
3 to 11 months: 2.5 mg via inhalation twice daily.
-Children
2.5 mg via inhalation twice daily.
-Adolescents
2.5 mg via inhalation twice daily.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.


Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Dornase alfa hydrolyzes extracellular deoxyribonucleic acid (DNA). The exact mechanism of hydrolysis is unknown. There is no effect on intracellular DNA. Patients with cystic fibrosis (CF) experience chronic bacterial lung infections and inflammation. One characteristic feature of this inflammation is a significant influx of neutrophils. When these neutrophils degenerate, their DNA is released, increasing the viscosity and decreasing the patient's ability to clear the sputum. In vitro studies show that by cleaving extracellular DNA, dornase alfa decreases the viscosity of the sputum which then improves mucociliary clearance of sputum. Also, in these patients, dornase alfa reduces the incidence of recurrent bacterial infections. Clinical trials report that patients given dornase alfa have an increase in general perception of well-being and a decreased perception of dyspnea, frequency of cough and chest congestion. Beneficial effects subside within several days after discontinuation.

Pharmacokinetics: Dornase alfa is administered via inhalation with minimal systemic absorption. Administration of dornase alfa 2.5mg to 18 cystic fibrosis (CF) patients resulted in a mean sputum concentration of 3 mcg/mL within 15 minutes. Two hours after administration, concentrations declined to an average of 0.6 mcg/mL. After 6 months of twice daily administration (n = 321), no accumulation of serum deoxyribonuclease (DNase) occurred. However, when dornase alfa 2.5 mg was administered once daily to 98 pediatric patients (age 3 months to <= 10 years) for 14 days, serum DNase concentrations increased by 1.3 +/- 1.3 ng/mL and 0.8 +/- 1.2 ng/mL in the 3 month to < 5 years age group and 5 to <= 10 years age group, respectively. The slight elevation in serum concentration is consistent with other studies. Bronchoalveolar lavage (BAL) fluid concentrations of DNase obtained 90 minutes after administration ranged from 0.007 to 1.8 mcg/mL. Though serum concentrations are not believed to be clinically useful, the relationship between BAL concentrations and clinical outcomes is unknown. 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 to 4 hours. Dornase alfa has demonstrated improvements in forced expiratory volume (FEV1) and forced vital capacity (FVC) by day 3 to 8 of administration. Improvement in symptoms from baseline has been observed for up to 4 days after treatment discontinuation.

Affected cytochrome P450 isoenzymes: none