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  • CLASSES

    Cystic Fibrosis Agents

    DEA CLASS

    Rx

    DESCRIPTION

    Recombinant human deoxyribonuclease (rhDNase); selectively cleaves DNA
    Used in cystic fibrosis (CF) patients to aid clearance of bronchial secretions
    Recommended for use in children and adults with mild, moderate, or severe CF; role in non-CF disease states unclear

    COMMON BRAND NAMES

    Pulmozyme

    HOW SUPPLIED

    Pulmozyme Respiratory (Inhalation) Sol: 1mg, 1mL

    DOSAGE & INDICATIONS

    For mucolysis in patients with cystic fibrosis in conjunction with standard therapies to improve pulmonary function.
    Inhalation dosage
    Adults, Adolescents, and Children 5 years and older

    2.5 mg via oral inhalation once daily using a recommended nebulizer. Data suggests 2.5 mg twice daily may be beneficial in patients with a baseline forced vital capacity (FVC) > 85%. A randomized double-blind study of children and adults (n = 968) receiving dornase alfa 2.5 mg reported similar improvements in forced expiratory volume (FEV1) and forced vital capacity (FVC) with once or twice daily dosing. A randomized crossover trial of 48 children and adolescents suggested that alternate day therapy was as effective as once-daily dosing. Cystic fibrosis patients have tolerated nebulized doses up to 20 mg twice daily; however, short term dosage range studies showed doses in excess of 2.5 mg twice daily did not provide additional benefit.

    Infants and Children 3 months to 4 years

    Due to limited data, limit use to patients in whom there is a potential for benefit in pulmonary function or in risk of respiratory tract infection. Small studies using dornase alfa 2.5 mg via oral inhalation once daily in patients as young as 3 months have reported efficacy and safety profiles similar to those seen in older children.

    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
    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.[33011] [33010] [58319] [58412] One retrospective study suggested nebulized dornase alfa was most effective within 10 doses of therapy for amelioration of atelectasis in mechanically ventilated patients.[58319] 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.[33010] [58244] 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.[58326] [58328] [58329] 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.[58245]

    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.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    2.5 mg via inhalation twice daily.

    Geriatric

    Safety and efficacy have not been established.

    Adolescents

    2.5 mg via inhalation twice daily.

    Children

    2.5 mg via inhalation twice daily.

    Infants

    >= 3 months: 2.5 mg via inhalation twice daily.
    < 3 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.

    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.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

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

    Inhalation Administration

    Nebulization Administration:
    The manufacturer recommends that one of the following jet nebulizers/compressors or nebulizer systems be used to deliver dornase alfa:
    Hudson T Up-draft II in conjunction with a Pulmo-Aide compressor;
    Marquest Acorn II in conjunction with a Pulmo-Aide compressor;
    PARI LC Plus in conjunction with a PARI PRONEB compressor;
    PARI BABY nebulizer in conjunction with a PARI PRONEB compressor; this nebulizer can be used in young children unable to inhale or exhale orally throughout the treatment period; the PARI BABY nebulizer is identical to the PARI LC Jet system except the mouthpiece is replaced by a tight fitting face mask connected to an elbow piece;
    Durable Sidestream in conjunction with a MOBILAIRE compressor; when the MOBILAIRE compressor is used, the compressor control knob should be fully turned to the right and then the compressor may be turned on. The needle on the pressure gauge should vibrate between 35 and 45 pounds per square inch (highest pressure output);
    Durable Sidestream in conjunction with a Porta-Neb compressor;
    eRapid Nebulizer System consisting of the eRapid Nebulizer Handset with eBase Controller; this system should only be used by adults and children who can use a mouthpiece and not by younger children who require a mask. When used for dornase alfa administration, the handset should be replaced after 90 uses, regardless of whether the EasyCare cleaning aid is used. Delivery data is not available for dornase alfa administered beyond 90 administrations, and appropriate therapeutic dose delivery cannot be assured.
    Safety and efficacy have been demonstrated with these machines; there are no clinical data to support the use of dornase alfa (Pulmozyme) with other nebulizer systems.
    The patient should follow the manufacturer's instructions for use and maintenance of equipment.
    In order to avoid adverse physicochemical and/or functional changes, dornase alfa (Pulmozyme) should not be diluted or mixed with other drugs in the nebulizer.

    Oral Inhalation Administration

    Oral inhalation via nebulization:
    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.
    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. Continue therapy until nebulizer cup is empty or the nebulizer stops producing a mist.

    STORAGE

    Pulmozyme:
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Dornase alfa should be used in conjunction with standard cystic fibrosis therapies.
    Until more data are available, caution should be used when prescribing chronic dornase alfa therapy for disease states other than cystic fibrosis. One randomized, double-blind, placebo-controlled trial in 349 adult patients with idiopathic bronchiectasis examined the use of aerosolized dornase alfa 2.5mg twice daily. Patients in the dornase alfa group experienced more pulmonary exacerbations compared to placebo. The treatment group also experienced a statistically significant decrease in FEV1, although the authors question the clinical significance of the decline.

    Hamster protein hypersensitivity

    Dornase alfa is contraindicated in patients who have previously demonstrated hamster protein hypersensitivity. Dornase alfa is manufactured using Chinese hamster ovary cells. No contraindications other than hamster protein hypersensitivity or hypersensitivity to the product or its ingredients are known.

    Breast-feeding

    It is not known whether dornase alfa is distributed into human breast milk. Small amounts of dornase alfa were detected in the milk of cynomolgus monkeys after an intravenous bolus of 100 mcg/kg followed by a 6 hour infusion of 80 mcg/kg/hour. Per the manufacturer, little or no measurable concentrations of dornase alfa would be expected in human milk after chronic dosing at recommended nebulized doses. However, because many drugs are excreted in breast milk, caution should still be used in women who are breast-feeding.

    Pregnancy

    Dornase alfa is classified as FDA pregnancy risk category B. Animal studies have revealed no evidence of impaired fertility, harm to the fetus, or effects on development of the fetus. Adequate studies in humans have not been conducted; therefore, dornase alfa should be used during pregnancy only when clearly needed.

    Children, infants, neonates

    Because of the limited experience with administration of dornase alfa to neonates, infants, and children < 5 years, the risks and benefits of use should be considered carefully prior to initiation of therapy.

    ADVERSE REACTIONS

    Moderate

    chest pain (unspecified) / Early / 18.0-25.0
    dyspnea / Early / 17.0-17.0
    conjunctivitis / Delayed / 1.0-5.0
    antibody formation / Delayed / 2.0-4.0

    Mild

    cough / Delayed / 30.0-45.0
    pharyngitis / Delayed / 32.0-40.0
    headache / Early / 5.0-36.0
    rhinitis / Early / 27.0-35.0
    fever / Early / 32.0-32.0
    hoarseness / Early / 12.0-18.0
    rash / Early / 3.0-10.0
    laryngitis / Delayed / 3.0-4.0
    dyspepsia / Early / 3.0-3.0
    urticaria / Rapid / Incidence not known

    DRUG INTERACTIONS

    There are no drug interactions associated with Dornase Alfa products.

    PREGNANCY AND LACTATION

    Pregnancy

    Dornase alfa is classified as FDA pregnancy risk category B. Animal studies have revealed no evidence of impaired fertility, harm to the fetus, or effects on development of the fetus. Adequate studies in humans have not been conducted; therefore, dornase alfa should be used during pregnancy only when clearly needed.

    It is not known whether dornase alfa is distributed into human breast milk. Small amounts of dornase alfa were detected in the milk of cynomolgus monkeys after an intravenous bolus of 100 mcg/kg followed by a 6 hour infusion of 80 mcg/kg/hour. Per the manufacturer, little or no measurable concentrations of dornase alfa would be expected in human milk after chronic dosing at recommended nebulized doses. However, because many drugs are excreted in breast milk, caution should still be used in women who are breast-feeding.

    MECHANISM OF ACTION

    Dornase alfa hydrolyzes extracellular DNA. The exact mechanism of hydrolysis is unknown. There is no effect on intracellular DNA. Patients with 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 by inhalation.

    Inhalation Route

    Administration of a usual dose to cystic fibrosis patients results in sputum concentrations of approximately 3 mcg/mL within 15 minutes. Mean sputum concentrations declined to an average of 0.6 mcg/ml 2 hours following inhalation. Following 6 months of 2.5 mg twice daily administration in 321 CF patients, no accumulation of serum DNase occurred. However, when 2.5 mg once daily was administered to 98 children (age 3 months to <= 10 years) for 14 days, serum DNase concentrations increased by 1.3 +/- 1.3 ng/mL for the 3 month to < 5 years age group and by 0.8 +/- 1.2 ng/mL in the 5 to <= 10 years age group. In this same study, bronchoalveolar lavage (BAL) fluid concentrations of DNase 90 minutes following the first dose of dornase alfa varied from 0.007—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—4 hours. Dornase alfa has demonstrated improvements in forced expiratory volume (FEV1) and forced vital capacity (FVC) by day 3—8 of administration.