Pulmozyme (Dornase Alfa)



Dornase Alfa Recombinant

Enzyme that Cleaves DNA

Action And Clinical Pharmacology: Dornase alfa for inhalation is a sterile, clear, colorless, highly purified solution of recombinant human deoxyribonuclease 1 (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 1 (Dnase). 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 system (see Dosage).

General: In cystic fibrosis (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. In vitro, dornase alfa hydrolyzes the DNA in sputum of CF patients and reduces sputum viscoelasticity.

Pharmacokinetics: When 2.5 mg dornase alfa was administered by inhalation to 18 CF patients, mean sputum concentrations of 3 g/mL DNase were measurable within 15 minutes. Mean sputum concentrations declined to an average of 0.6 g/mL 2 hours following inhalation. Inhalation of up to 10 mg t.i.d. of dornase alfa by 4 CF patients for 6 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 dornase alfa twice daily for 6 months to 321 CF patients, no accumulation of serum DNase was noted.

Clinical Experience: Phase III Studies: Dornase alfa has been evaluated in a large, randomized, placebo-controlled trial of clinically stable cystic fibrosis patients, 5 years of age and older, with baseline forced vital capacity (FVC) greater than or equal to 40% of predicted and receiving standard therapies for cystic fibrosis. Patients were treated with placebo (325 patients), 2.5 mg of dornase alfa once a day (322 patients), or 2.5 mg of dornase alfa twice a day (321 patients) for 6 months administered via a Hudson T Up-draft II nebulizer with a Pulmo-Aide compressor.

Both doses of dornase alfa resulted in significant reductions compared with the placebo group in the number of patients experiencing respiratory tract infections requiring use of parenteral antibiotics. Administration of dornase reduced the relative risk of developing a respiratory tract infection by 27% and 29% for the 2.5 mg daily dose and the 2.5 mg twice daily dose, respectively. The data suggest that the effects of dornase alfa on respiratory tract infections in older patients (>21 years) may be smaller than in young patients, and that twice daily dosing may be required in the older patients. Patients with baseline FVC>85% may also benefit from twice a day dosing (see Table I). The reduced risk of respiratory infection observed in dornase alfa treated patients did not directly correlate with improvement in FEV1, during the initial 2 weeks of therapy.

Within 8 days of the start of treatment with dornase alfa mean FEV1 increased 7.9% in those treated once a day and 9% in those treated twice a day compared to the baseline values. The overall mean FEV1 observed during long-term therapy increased 5.8% from baseline at the 2.5 mg daily dose level and 5.6% from baseline at the 2.5 mg twice daily dose level. Placebo recipients did not show significant mean changes in pulmonary function testing.

For patients 5 years of age or older, with baseline FVC greater than or equal to 40%, administration of dornase alfa decreased the incidence of occurrence of first respiratory tract infection requiring parenteral antibiotics, and improved mean FEV1 regardless of age or baseline FVC.

Other Studies: Dornase alfa did not produce a pulmonary function benefit in short-term usage in patients with FVC less than 40% of predicted. Studies are in progress to assess the impact of chronic use on pulmonary function and infection risk in this population.

Clinical trials have indicated that dornase alfa therapy can be continued or initiated during an acute respiratory exacerbation.

Short-term dose ranging studies demonstrated that doses in excess of 2.5 mg b.i.d. did not provide further improvement in FEV1. Patients who have received drug on a cyclical regimen (i.e., administration of dornase alfa 10 mg b.i.d. for 14 days followed by a 14-day wash out period) showed rapid improvement in FEV1 with the initiation of each cycle and a return to baseline with each dornase alfa withdrawal.

Indications And Clinical Uses: Daily administration of dornase alfa for inhalation in conjunction with standard therapies is indicated in the management of cystic fibrosis patients to reduce the frequency of respiratory infections requiring parenteral antibiotics and to improve pulmonary function. Safety and efficacy of daily administration have not been demonstrated in patients under the age of 5 years, or with FVC.

Contra-Indications: Patients with known hypersensitivity to dornase alfa, Chinese Hamster Ovary cell products or any component of the product.

Manufacturers’ Warnings In Clinical States: None.

Precautions: General: Dornase alfa should be used in conjunction with standard therapies for CF.

Information for the Patient: Pulmozyme must be stored in the refrigerator at 2 to 8°C and protected from light. It should be kept refrigerated during transport and should not be exposed to room temperatures for a total time of 24 hours. The solution should be discarded if it is cloudy or discolored. Pulmozyme contains no preservative and, once opened, the entire ampul must be used or discarded. Patients should be instructed in the proper use and maintenance of the nebulizer and compressor system used in its delivery.

Pulmozyme should not be diluted or mixed 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.

Drug Interactions: Clinical trials have indicated that dornase alfa can be effectively and safely used in conjunction with standard cystic fibrosis therapies including oral, inhaled and parenteral antibiotics, bronchodilators, enzyme supplements, vitamins, oral and inhaled corticosteroids and analgesics. No formal drug interaction studies have been performed.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: A 2-year inhalation (head-only) toxicity study of dornase alfa in rats to assess oncogenic potential is in progress.

Mutagenesis: Ames tests using 6 different tester strains of bacteria (4 of S. typhimurium and 2 of E. coli), at concentrations up to 5 000 g/plate, a cytogenetic assay using human peripheral blood lymphocytes at concentrations up to 2 000 g/plate, and a mouse lymphoma assay at concentrations up to 1 000 g/plate, with and without metabolic activation, revealed no evidence of mutagenesis potential. Dornase alfa was tested in a micronucleus (in vivo) assay for its potential to produce chromosome damage in bone marrow cells of mice following a bolus i.v. dose of up to 10 mg/kg on 2 consecutive days. No evidence of chromosomal damage was noted.

Impairment of Fertility: In studies with rats receiving up to 10 mg/kg/day, a dose representing systemic exposures greater than 600 times that expected following the recommended human dose, fertility and reproductive performance on both males and females was not affected.

Pregnancy: Reproduction studies have been performed in rats and rabbits with i.v. doses up to 10 mg/kg/day, representing systemic exposures greater than 600 times that expected following the recommended human dose. These studies have revealed no evidence of impaired fertility, harm to the fetus, or effects on development due to dornase alfa. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of the human response, this drug should be used during pregnancy only if clearly needed.

Lactation: It is not known whether the drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when dornase alfa is administered to a nursing woman.

Children: Safety and effectiveness in children under the age of 5 years has not been studied.

Adverse Reactions: Patients have been exposed to dornase alfa for up to 12 months in clinical trials. In a large, randomized, placebo-controlled clinical trial, over 600 patients received dornase alfa once or twice daily for 6 months; most adverse events were not more common on dornase alfa than on placebo and probably reflected the sequelae of the underlying lung disease. In most cases events that were increased were mild, transient in nature, and did not require alterations in dosing. Few patients experienced adverse events resulting in permanent discontinuation from dornase alfa and the discontinuation rate was similar between placebo (2%) and dornase alfa (3%).

Events Observed at Similar Rates in Pulmozyme and Placebo Treated Patients: Body as a Whole: abdominal pain, asthenia, fever, flu syndrome, malaise, sepsis.

Digestive: intestinal obstruction, gallbladder disease, liver disease, pancreatic disease.

Metabolic Nutritional: diabetes mellitus, hypoxia, weight loss.

Respiratory: apnea, bronchiectasis, bronchitis, change in sputum, cough increase, dyspnea, hemoptysis, lung function decrease, nasal polyps, pneumonia, pneumothorax, rhinitis, sinusitis, sputum increase, wheeze.

Mortality rates observed in a controlled trial were similar for the placebo (1%) and dornase alfa (1%). Causes of death were consistent with progression of cystic fibrosis and included apnea, cardiac arrest, cardiopulmonary arrest, cor pulmonale, heart failure, massive hemoptysis, pneumonia, pneumothorax and respiratory failure.

Allergic Reactions: There have been no reports of anaphylaxis attributed to the administration of dornase alfa to date. Skin rash and urticaria have been observed and were mild and transient in nature. Within all of the studies, a small percentage (average of 2 to 4%) of patients treated with dornase alfa developed serum antibodies to dornase alfa. None of these patients developed anaphylaxis, and the clinical significance of serum antibodies to dornase alfa is unknown.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: 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 dornase alfa in doses up to 200 mg/kg are also well tolerated by rats.

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

Dosage And Administration: The recommended dose for use in most cystic fibrosis patients is one 2.5 mg single-use ampul inhaled once daily using a recommended nebulizer. Some patients may benefit from twice daily administration. Clinical trials have been performed with the following nebulizers and compressors: the disposable jet nebulizer Hudson T Up-draft II and disposable jet nebulizer Marquest Acorn II in conjunction with a Pulmo-Aide compressor, and with the reusable PARI LC Jetnebulizer, in conjunction with the PARI PRONEB compressor. Safety and efficacy have been demonstrated only with these recommended nebulizer systems. No clinical data are currently available that support the safety and efficacy of administration of dornase alfa with other nebulizer systems. The patient should follow the manufacturer’s instructions on the use and maintenance of the equipment.

Pulmozyme should not be diluted or mixed 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.

Availability And Storage: Each mL of sterile, clear, colorless, aqueous solution contains: dornase alfa 1 mg. Nonmedicinal ingredients: calcium chloride dihydrate and sodium chloride. Nominal pH is 6.3. Preservative-free. Single-use ampuls of 2.5 mL. Cartons of 14 (each in a foil pouch) and 30 (5 foil pouches of 6 ampuls). Keep refrigerated during transport and do not expose to room temperatures for a total time of 24 hours. Store under refrigeration (2 to 8°C). Ampuls should be protected from light. Do not use beyond the expiration date stamped on the ampul. Unused ampuls should be stored in their protective foil pouch under refrigeration.

PULMOZYME™ Roche Dornase Alfa Recombinant Enzyme that Cleaves DNA

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