Pulmozyme® (dornase alfa) Inhalation Solution
`
`Figure 1 Mean Percent Change from Baseline FEV1 in Patients with FVC ‡ 40% of Predicted
`
`10
`
`5
`
`0
`
`-5
`
`Mean Percent Change
`
` Baseline
`
`8 15
`
`29
`
`43
`
`57
`
`71
`
`85
`99
`Study Day
`
`113
`
`127
`
`141
`
`155
`
`169
`
`Treatment: Placebo rhDNase 2.5 mg QD rhDNase 2.5 mg BID
`
`Pulmozyme has also been evaluated in a second randomized, placebo-controlled study in clinically stable patients
`with baseline FVC <40% of predicted (8). Patients were enrolled and treated with placebo (162 patients) or
`Pulmozyme 2.5 mg QD (158 patients) for twelve weeks. In patients who received Pulmozyme, there was an
`increase in mean change (as percent of baseline) compared to placebo in FEV1 (9.4% vs. 2.1%, p <0.001) and in
`FVC (12.4% vs. 7.3%, p <0.01). Pulmozyme did not significantly reduce the risk of developing a respiratory tract
`infection requiring parenteral antibiotics (54% of Pulmozyme patients vs. 55% of placebo patients had experi-
`enced a respiratory tract infection by 12 weeks, relative risk = .93, p=0.62).
`
`Other Studies
`
`DESCRIPTION
`
`Pulmozyme is a sterile, clear, colorless, highly purified solution of 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 fil-
`tration and column chromatography. The purified glycoprotein contains 260 amino acids with an approximate
`molecular weight of 37,000 daltons (1). 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 sys-
`tem (see Clinical Experience, DOSAGE AND ADMINISTRATION). Each Pulmozyme single-use ampule will deliver
`2.5 mL of the solution to the nebulizer bowl. The aqueous solution contains 1.0 mg/mL dornase alfa, 0.15 mg/mL
`calcium chloride dihydrate and 8.77 mg/mL sodium chloride. The solution contains no preservative. The nominal
`pH of the solution is 6.3.
`
`CLINICAL PHARMACOLOGY
`
`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 (2,3).
`
`Clinical trials have indicated that Pulmozyme therapy can be continued or initiated during an acute respiratory
`exacerbation.
`
`Purulent pulmonary secretions contain very high concentrations of extracellular DNA released by degenerating
`leukocytes that accumulate in response to infection (4). In vitro, Pulmozyme hydrolyzes the DNA in sputum of CF
`patients and reduces sputum viscoelasticity (1).
`
`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 endoge-
`nous levels (5,6). 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.
`Pulmozyme, 2.5 mg by inhalation, was administered daily to 98 patients aged 3 months to ≤10 years, and bron-
`choalveolar 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 expo-
`sure, serum DNase concentrations (mean ± s.d.) increased by 1.3 ± 1.3 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.
`
`Clinical Experience
`
`Pulmozyme has been evaluated in a 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 pre-
`dicted and receiving standard therapies for cystic fibrosis (7). Patients were treated with placebo (325 patients),
`2.5 mg of Pulmozyme once a day (322 patients), or 2.5 mg of Pulmozyme twice a day (321 patients) for six
`months administered via a Hudson T Up-draft II® nebulizer with a Pulmo-Aide® compressor.
`
`Both doses of Pulmozyme resulted in significant reductions when compared with the placebo group in the num-
`ber of patients experiencing respiratory tract infections requiring use of parenteral antibiotics. Administration of
`Pulmozyme 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 (see Table 1). The data suggest that the effects of
`Pulmozyme on respiratory tract infections in older patients (>21 years) may be smaller than in younger patients,
`and that twice daily dosing may be required in the older patients. Patients with baseline FVC >85% may also ben-
`efit from twice a day dosing (see Table 1). The reduced risk of respiratory infection observed in Pulmozyme treat-
`ed patients did not directly correlate with improvement in FEV1 during the initial two weeks of therapy.
`
`Within 8 days of the start of treatment with Pulmozyme, mean FEV1 increased 7.9% in those treated once a day
`and 9.0% in those treated twice a day compared to the baseline values. The overall mean FEV1 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 (see
`Figure 1).
`
`For patients 5 years of age or older, with baseline FVC greater than or equal to 40%, administration of Pulmozyme
`decreased the incidence of occurrence of first respiratory tract infection requiring parenteral antibiotics, and
`improved mean FEV1, regardless of age or baseline FVC.
`
`Table 1
`Incidence of First Respiratory Tract Infection
`Requiring Parenteral Antibiotics in Patients with FVC ‡ 40% of Predicted
`
`Percent of Patients Infected
`Relative Risk (vs placebo)
`p-value (vs placebo)
`
`Placebo
`N=325
`
`43%
`
`2.5 mg QD
`N=322
`
`2.5 mg BID
`N=321
`
`34%
`0.73
`0.015
`
`33%
`0.71
`0.007
`
`Subgroup by Age and Baseline FVC
`
`Placebo (N)
`
`2.5 mg QD (N)
`
`2.5 mg BID (N)
`
`Age
`5-20 years
`21 years and older
`
`Baseline FVC
`40-85% Predicted
`>85% Predicted
`
`42% (201)
`44% (124)
`
`25% (199)
`48% (123)
`
`28% (184)
`39% (137)
`
`54% (194)
`27% (131)
`
`41% (201)
`21% (121)
`
`44% (203)
`14% (118)
`
`Short-term dose ranging studies demonstrated that doses in excess of 2.5 mg BID did not provide further
`improvement in FEV1. Patients who have received drug on a cyclical regimen (i.e., administration of Pulmozyme
`10 mg BID for 14 days, followed by a 14 day wash out period) showed rapid improvement in FEV1 with the initi-
`ation of each cycle and a return to baseline with each Pulmozyme withdrawal.
`
`INDICATIONS AND USAGE
`
`Daily administration of Pulmozyme® (dornase alfa) Inhalation Solution in conjunction with standard therapies is
`indicated in the management of cystic fibrosis patients to improve pulmonary function. In 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.
`
`Safety and efficacy of daily administration have not been demonstrated in patients for longer than twelve months.
`
`CONTRAINDICATIONS
`
`Pulmozyme is contraindicated in patients with known hypersensitivity to dornase alfa, Chinese Hamster Ovary cell
`products, or any component of the product.
`
`WARNINGS
`
`None.
`
`PRECAUTIONS
`
`General
`
`Pulmozyme should be used in conjunction with standard therapies for CF.
`
`Information for Patients
`
`Pulmozyme must be stored in the refrigerator at 2-8°C (36-46°F) and protected from strong 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 contents of the ampule must be used or discarded. Patients should be instructed in the prop-
`er 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 Pulmozyme can be effectively and safely used in conjunction with standard cys-
`tic fibrosis therapies including oral, inhaled and/or parenteral antibiotics, bronchodilators, enzyme supplements,
`vitamins, oral or inhaled corticosteroids, and analgesics. No formal drug interaction studies have been performed.
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`Carcinogenesis: Lifetime studies in Sprague Dawley rats showed no carcinogenic effect when Pulmozyme was
`administered at doses up to 246 µg/kg body weight per day. Pulmozyme was administered to rats as an aerosol
`for up to 30 minutes per day, daily for two years, with resulting lower respiratory tract doses of up to 246 µg/kg
`per day, which represents up to a 28.8-fold multiple of the clinical dose. There was no increase in the develop-
`ment of benign or malignant neoplasms and no occurrence of unusual tumor types in rats after lifetime exposure.
`
`Mutagenesis: Ames tests using six different tester strains of bacteria (4 of S. typhimurium and 2 of E. coli) at con-
`centrations up to 5000 µg/plate, a cytogenetic assay using human peripheral blood lymphocytes at concentrations
`up to 2000 µg/plate, and a mouse lymphoma assay at concentrations up to 1000 µg/plate, with and without meta-
`bolic activation, revealed no evidence of mutagenesis potential. Pulmozyme was tested in a micronucleus (in vivo)
`assay for its potential to produce chromosome damage in bone marrow cells of mice following a bolus intra-
`venous dose of 10 mg/kg on two 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 per-
`formance of both males and females was not affected.
`
`Pregnancy (Category B)
`
`Reproduction studies have been performed in rats and rabbits with intravenous doses up to 10 mg/kg/day, rep-
`resenting 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
`Pulmozyme. There are, however, no adequate and well-controlled studies in pregnant women. Because animal
`
`Liquidia's Exhibit 1050
`Page 1
`
`

`

`Pulmozyme® (dornase alfa) Inhalation Solution
`
`Pulmozyme® (dornase alfa) Inhalation Solution
`
`reproductive studies are not always predictive of the human response, this drug should be used during pregnan-
`cy only if clearly needed.
`
`Nursing Mothers
`
`It is not known whether Pulmozyme is excreted in human milk. Small amounts of dornase alfa were detected in
`maternal milk of cynomolgus monkeys when administered a bolus dose (100 µg/kg) of dornase alfa followed by
`a six hour intravenous infusion (80 µg/kg/hr). Little or no measurable dornase alfa would be expected in human
`milk after chronic aerosol administration of recommended doses. Because many drugs are excreted in human
`milk, caution should still be exercised when Pulmozyme is administered to a nursing woman.
`
`Pediatric Use
`
`Because of the limited experience with the administration of Pulmozyme to patients younger than 5 years of age,
`its use should be considered only for those patients in whom there is a potential for benefit in pulmonary function
`or in risk of respiratory tract infection.
`
`Allergic Reactions
`
`There have been no reports of anaphylaxis attributed to the administration of Pulmozyme to date. Urticaria, mild
`to moderate, and mild skin rash have been observed and have been transient. Within all of the studies, a small
`percentage (average of 2-4%) of patients treated with Pulmozyme developed serum antibodies to Pulmozyme.
`None of these patients developed anaphylaxis, and the clinical significance of serum antibodies to Pulmozyme is
`unknown.
`
`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.
`
`Geriatric Use
`
`DOSAGE AND ADMINISTRATION
`
`Cystic fibrosis is primarily a disease of pediatrics 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.
`
`ADVERSE REACTIONS
`
`The recommended dose for use in most cystic fibrosis patients is one 2.5 mg single-use ampule inhaled once
`daily using a recommended nebulizer. Some patients may benefit from twice daily administration (see Clinical
`Experience, Table 1). Clinical trial results and laboratory information are only available to support use of the fol-
`lowing nebulizer/compressor systems (see Table 3).
`
`Patients have been exposed to Pulmozyme for up to 12 months in clinical trials.
`In a randomized, placebo-controlled clinical trial in patients with FVC ‡ 40% of predicted, over 600 patients
`received Pulmozyme once or twice daily for six months; most adverse events were not more common on
`Pulmozyme 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 Pulmozyme, and the discontinuation rate
`was similar for placebo (2%) and Pulmozyme (3%). Events that were more frequent (greater than 3%) in
`Pulmozyme treated patients than in placebo-treated patients are listed in Table 2.
`
`In a randomized, placebo-controlled trial of patients with advanced disease (FVC <40% of predicted) the safety
`profile for most adverse events was similar to that reported for the trial in patients with mild to moderate disease.
`For this study, adverse events that were reported with a higher frequency (greater than 3%) in the Pulmozyme
`treated patients, are also listed in Table 2.
`
`Table 3
`Recommended Nebulizer/Compressor System
`
`Jet Nebulizer
`
`Compressor
`
`Hudson T Up-draft II® with Pulmo-Aide®
`
`Marquest Acorn II® with Pulmo-Aide®
`
`PARI LC Jet+ with PARI PRONEB®
`
`*PARI BABY™ with PARI PRONEB®
`
`Durable Sidestream® with MOBILAIRE™
`
`Durable Sidestream® with Porta-Neb®
`
`*Patients who are unable to inhale or exhale orally
`throughout the entire nebulization period may use
`the PARI BABY™ nebulizer.
`
`Table 2
`Adverse Events Increased 3% or More in Pulmozyme Treated Patients
`Over Placebo in CF Clinical Trials
`
`Trial in Mild to Moderate CF Patients
`(FVC ‡ 40% of predicted) treated
`for 24 weeks
`
`Trial in Advanced CF Patients
`(FVC < 40% of predicted)
`treated for 12 weeks
`
`Adverse Event (of any
`severity or seriousness)
`
`Placebo
`
`n=325
`
`Pulmozyme
`QD
`n=322
`
`Pulmozyme
`BID
`n=321
`
`Placebo
`
`n=159
`
`Pulmozyme
`QD
`n=161
`
`Voice alteration
`Pharyngitis
`Rash
`Laryngitis
`Chest Pain
`Conjunctivitis
`
`Rhinitis
`FVC decrease of ‡ 10%
`of predicted°
`
`Fever
`
`Dyspepsia
`
`7%
`33%
`7%
`1%
`16%
`2%
`
`12%
`36%
`10%
`3%
`18%
`4%
`
`16%
`40%
`12%
`4%
`21%
`5%
`
`Differences were less than 3% for these
`adverse events in the Trial in mild to
`moderate CF patients
`
`Dyspnea
`(when reported as serious)
`
`Differences were less than 3% for this
`adverse events in the Trial in mild to
`moderate CF patients
`
`6%
`28%
`1%
`1%
`23%
`0%
`
`24%
`
`17%
`
`28%
`
`0%
`
`18%
`32%
`3%
`3%
`25%
`1%
`
`30%
`
`22%
`
`32%
`
`3%
`
`Patients who use the Sidestream® Nebulizer with the MOBILAIRE™ compressor should turn the compressor
`control knob fully to the right and then turn on the compressor. At this setting, the needle on the pressure gauge
`should vibrate between 35 and 45 pounds per square inch (highest pressure output).
`
`No data are currently available that support the administration of Pulmozyme 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.
`Patients should be advised to squeeze each ampule prior to use in order to check for leaks.
`
`HOW SUPPLIED
`
`Pulmozyme is supplied in single-use ampules. Each ampule delivers 2.5 mL of a sterile, clear, colorless, aque-
`ous solution containing 1.0 mg/mL dornase alfa, 0.15 mg/mL calcium chloride dihydrate and 8.77 mg/mL sodi-
`um chloride with no preservative. The nominal pH of the solution is 6.3.
`
`Pulmozyme is supplied in:
`• 30 unit cartons containing 5 foil pouches of 6 single-use ampules: NDC 50242-100-40.
`
`Storage
`
`Pulmozyme should be stored under refrigeration (2-8°C/36-46°F). Ampules should be protected from strong light.
`Do not use beyond the expiration date stamped on the ampule. Unused ampules should be stored in their protec-
`tive foil pouch under refrigeration.
`
`REFERENCES
`
`12%†
`
`17%†
`
`1. Shak S, Capon DJ, Hellmiss R, Marsters SA, Baker CL. Recombinant human DNase I reduces the viscosity of
`cystic fibrosis sputum. Proc Natl Acad Sci USA. 1990;87:9188-92.
`
`°Single measurement only, does not reflect overall FVC changes.
`†Total reports of dyspnea (regardless of severity or seriousness) had a difference of less than 3% for the Trial in
`advanced CF patients.
`
`Events Observed at Similar Rates in Pulmozyme® (dornase alfa) Inhalation Solution and Placebo Treated
`Patients with FVC ‡ 40% of Predicted
`Body as a Whole
`Abdominal pain, Asthenia, Fever, Flu syndrome, Malaise, Sepsis
`
`Digestive System
`
`Intestinal Obstruction, Gall Bladder disease, Liver disease, Pancreatic disease
`
`Metabolic Nutritional System Diabetes Mellitus, Hypoxia, Weight Loss
`
`Respiratory System
`
`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 controlled trials were similar for the placebo and Pulmozyme treated patients. 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.
`The safety of Pulmozyme, 2.5 mg by inhalation, was studied with 2 weeks of daily administration in 98 patients
`with cystic fibrosis (65 aged 3 months to <5 years, 33 aged 5 to ≤10 years). The PARI BABY™ reusable nebuliz-
`er (which uses a facemask instead of a mouthpiece) was utilized in patients unable to demonstrate the ability to
`inhale or exhale orally throughout the entire treatment period (54/65, 83% of the younger and 2/33, 6% of the
`older patients). The number of patients reporting cough was higher in the younger age group as compared to the
`older age group (29/65, 45% compared to 10/33, 30%) as was the number reporting moderate to severe cough
`(24/65, 37% as compared to 6/33, 18%). Other events tended to be of mild to moderate severity. The number of
`patients reporting rhinitis was higher in the younger age group as compared to the older age group (23/65, 35%
`compared to 9/33, 27%) as was the number reporting rash (4/65, 6% as compared to 0/33). The nature of adverse
`events was similar to that seen in the larger trials of Pulmozyme.
`
`2. Boat TF. Cystic Fibrosis. In: Murray JF, Nadel JA, editors. Textbook of respiratory medicine. Philadelphia:
`Saunders WB, 1988;1:1126-52.
`
`3. Collins FS. Cystic Fibrosis: molecular biology and therapeutic implications. Science. 1992;256:774-9.
`
`4. Potter JL, Spector S, Matthews LW, Lemm J. Studies of pulmonary secretions. Am Rev Respir Dis. 1969;99:909-15.
`
`5. Hubbard RC, McElvaney NG, Birrer P, Shak S, Robinson WW, Jolley C, et al. A preliminary study of aerosolized
`recombinant human deoxyribonuclease I in the treatment of cystic fibrosis. N Engl J Med. 1992;326:812-5.
`
`6. Aitken ML, Burke W, McDonald G, Shak S, Montgomery AB, Smith A. Recombinant human DNase inhalation
`in normal subjects and patients with cystic fibrosis. JAMA. 1992;267(14):1947-51.
`
`7. Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, et al. Effect of aerosolized
`recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients
`with cystic fibrosis. N Engl J Med. 1994;331:637-42.
`
`8. McCoy K, Hamilton S, Johnson C. Effects of 12-week administration of dornase alfa in patients with advanced
`cystic fibrosis lung disease. Chest. 1996;110:889-95.
`
`Pulmozyme®
`(dornase alfa)
`Inhalation Solution
`
`Manufactured by
`GENENTECH, Inc.
`1 DNA Way
`South San Francisco, CA 94080-4990
`
`LE0339
`7061805
`(4824301)
`
`Code Revision Date: April 2005
`FDA Approval Date: January 2001
`©2005 Genentech, Inc.
`
`Liquidia's Exhibit 1050
`Page 2
`
`