U.S. BL 103532 Supplement: Pulmozyme? (dornase alfa)?Genentech, Inc. 1 of 12/Quality (PAS): PZ PI - Final Word for CORA.doc 1.14.1.3 1 Pulmozyme? 2 (dornase alfa) 3 Inhalation Solution 4 DESCRIPTION 5 Pulmozyme is a sterile, clear, colorless, highly purified solution of recombinant human 6 deoxyribonuclease I (rhDNase), an enzyme which selectively cleaves DNA. The protein is 7 produced by genetically engineered Chinese Hamster Ovary (CHO) cells containing DNA 8 encoding for the native human protein, deoxyribonuclease I (DNase). Fermentation is 9 carried out in a nutrient medium containing the antibiotic gentamicin, 100–200 mg/L. 10 However, the presence of the antibiotic is not detectable in the final product. The product is 11 purified by tangential flow filtration and column chromatography. The purified glycoprotein 12 contains 260 amino acids with an approximate molecular weight of 37,000 daltons (1). 13 The primary amino acid sequence is identical to that of the native human enzyme. 14 Pulmozyme is administered by inhalation of an aerosol mist produced by a compressed air 15 driven nebulizer system (see Clinical Experience, DOSAGE AND ADMINISTRATION). 16 Each Pulmozyme single-use ampule will deliver 2.5 mL of the solution to the nebulizer bowl. 17 The aqueous solution contains 1.0 mg/mL dornase alfa, 0.15 mg/mL calcium chloride 18 dihydrate and 8.77 mg/mL sodium chloride. The solution contains no preservative. 19 The nominal pH of the solution is 6.3. 20 CLINICAL PHARMACOLOGY 21 General 22 In cystic fibrosis (CF) patients, retention of viscous purulent secretions in the airways 23 contributes both to reduced pulmonary function and to exacerbations of infection (2, 3). 24 Purulent pulmonary secretions contain very high concentrations of extracellular DNA 25 released by degenerating leukocytes that accumulate in response to infection (4). In vitro, 26 Pulmozyme hydrolyzes the DNA in sputum of CF patients and reduces sputum 27 viscoelasticity (1). 28 U.S. BL 103532 Supplement: Pulmozyme? (dornase alfa)?Genentech, Inc. 2 of 12/Quality (PAS): PZ PI - Final Word for CORA.doc Pharmacokinetics 29 When 2.5 mg Pulmozyme was administered by inhalation to eighteen CF patients, mean 30 sputum concentrations of 3 ?g/mL DNase were measurable within 15 minutes. Mean 31 sputum concentrations declined to an average of 0.6 ?g/mL two hours following inhalation. 32 Inhalation of up to 10 mg TID of Pulmozyme by 4 CF patients for six consecutive days, did 33 not result in a significant elevation of serum concentrations of DNase above normal 34 endogenous levels (5, 6). After administration of up to 2.5 mg of Pulmozyme twice daily for 35 six months to 321 CF patients, no accumulation of serum DNase was noted. 36 Pulmozyme, 2.5 mg by inhalation, was administered daily to 98 patients aged 3 months to 37 ≤10 years, and bronchoalveolar lavage (BAL) fluid was obtained within 90 minutes of the 38 first dose. BAL DNase concentrations were detectable in all patients but showed a broad 39 range, from 0.007 to 1.8 ?g/mL. Over an average of 14 days of exposure, serum DNase 40 concentrations (mean ± s.d.) increased by 1.3 ± 1.3 ng/mL for the 3 months to <5 year age 41 group and by 0.8 ± 1.2 ng/mL for the 5 to ≤10 year age group. The relationship between 42 BAL or serum DNase concentration and adverse experiences and clinical outcomes is 43 unknown. 44 Clinical Experience 45 Pulmozyme has been evaluated in a randomized, placebo-controlled trial of clinically stable 46 cystic fibrosis patients, 5 years of age and older, with baseline forced vital capacity (FVC) 47 greater than or equal to 40% of predicted and receiving standard therapies for cystic fibrosis 48 (7). Patients were treated with placebo (325 patients), 2.5 mg of Pulmozyme once a day 49 (322 patients), or 2.5 mg of Pulmozyme twice a day (321 patients) for six months 50 administered via a Hudson T Up-draft II? nebulizer with a Pulmo-Aide? compressor. 51 Both doses of Pulmozyme resulted in significant reductions when compared with the placebo 52 group in the number of patients experiencing respiratory tract infections requiring use of 53 parenteral antibiotics. Administration of Pulmozyme reduced the relative risk of developing 54 a respiratory tract infection by 27% and 29% for the 2.5 mg daily dose and the 2.5 mg twice 55 daily dose, respectively (see Table 1). The data suggest that the effects of Pulmozyme on 56 respiratory tract infections in older patients (>21 years) may be smaller than in younger 57 patients, and that twice daily dosing may be required in the older patients. Patients with 58 baseline FVC >85% may also benefit from twice a day dosing (see Table 1). The reduced 59 U.S. BL 103532 Supplement: Pulmozyme? (dornase alfa)?Genentech, Inc. 3 of 12/Quality (PAS): PZ PI - Final Word for CORA.doc risk of respiratory infection observed in Pulmozyme treated patients did not directly correlate 60 with improvement in FEV1 during the initial two weeks of therapy. 61 Within 8 days of the start of treatment with Pulmozyme, mean FEV1 increased 7.9% in those 62 treated once a day and 9.0% in those treated twice a day compared to the baseline values. 63 The overall mean FEV1 during long-term therapy increased 5.8% from baseline at the 2.5 mg 64 daily dose level and 5.6% from baseline at the 2.5 mg twice daily dose level. Placebo 65 recipients did not show significant mean changes in pulmonary function testing (see 66 Figure 1). 67 For patients 5 years of age or older, with baseline FVC greater than or equal to 40%, 68 administration of Pulmozyme decreased the incidence of occurrence of first respiratory tract 69 infection requiring parenteral antibiotics, and improved mean FEV1, regardless of age or 70 baseline FVC. 71 Table 1 Incidence of First Respiratory Tract Infection Requiring Parenteral Antibiotics in Patients with FVC ≥40% of Predicted Placebo N=325 2.5 mg QD N=322 2.5 mg BID N=321 Percent of Patients Infected 43% 34% 33% Relative Risk (vs placebo) 0.73 0.71 p-value (vs placebo) 0.015 0.007 Subgroup by Age and Baseline FVC Placebo (N) 2.5 mg QD (N) 2.5 mg BID (N) Age 5?20 years 42% (201) 25% (199) 28% (184) 21 years and older 44% (124) 48% (123) 39% (137) Baseline FVC 40?85% Predicted 54% (194) 41% (201) 44% (203) >85% Predicted 27% (131) 21% (121) 14% (118) 72 U.S. BL 103532 Supplement: Pulmozyme? (dornase alfa)?Genentech, Inc. 4 of 12/Quality (PAS): PZ PI - Final Word for CORA.doc Figure 1: 73 Mean Percent Change from Baseline FEV1 in Patients with FVC ≥40% of Predicted 74 75 76 Pulmozyme has also been evaluated in a second randomized, placebo-controlled study in 77 clinically stable patients with baseline FVC <40% of predicted (8). Patients were enrolled 78 and treated with placebo (162 patients) or Pulmozyme 2.5 mg QD (158 patients) for 79 twelve weeks. In patients who received Pulmozyme, there was an increase in mean change 80 (as percent of baseline) compared to placebo in FEV1 (9.4% vs. 2.1%, p<0.001) and in FVC 81 (12.4% vs. 7.3%, p<0.01). Pulmozyme did not significantly reduce the risk of developing a 82 respiratory tract infection requiring parenteral antibiotics (54% of Pulmozyme patients vs. 83 55% of placebo patients had experienced a respiratory tract infection by 12 weeks, relative 84 risk=.93, p=0.62). 85 The effect of Pulmozyme on exercise tolerance has not been established in adults and 86 children. 87 Other Studies 88 Clinical trials have indicated that Pulmozyme therapy can be continued or initiated during an 89 acute respiratory exacerbation. 90 Short-term dose ranging studies demonstrated that doses in excess of 2.5 mg BID did not 91 provide further improvement in FEV1. Patients who have received drug on a cyclical 92 regimen (i.e., administration of Pulmozyme 10 mg BID for 14 days, followed by a 14 day 93 U.S. BL 103532 Supplement: Pulmozyme? (dornase alfa)?Genentech, Inc. 5 of 12/Quality (PAS): PZ PI - Final Word for CORA.doc wash out period) showed rapid improvement in FEV1 with the initiation of each cycle and a 94 return to baseline with each Pulmozyme withdrawal. 95 INDICATIONS AND USAGE 96 Daily administration of Pulmozyme? (dornase alfa) Inhalation Solution in conjunction with 97 standard therapies is indicated in the management of cystic fibrosis patients to improve 98 pulmonary function. In patients with an FVC ≥40% of predicted, daily administration of 99 Pulmozyme has also been shown to reduce the risk of respiratory tract infections requiring 100 parenteral antibiotics. 101 Safety and efficacy of daily administration have not been demonstrated in patients for longer 102 than twelve months. 103 CONTRAINDICATIONS 104 Pulmozyme is contraindicated in patients with known hypersensitivity to dornase alfa, 105 Chinese Hamster Ovary cell products, or any component of the product. 106 WARNINGS 107 None. 108 PRECAUTIONS 109 General 110 Pulmozyme should be used in conjunction with standard therapies for CF. 111 Information for Patients 112 Pulmozyme must be stored in the refrigerator at 2–8°C (36–46°F) and protected from strong 113 light. It should be kept refrigerated during transport and should not be exposed to room 114 temperatures for a total time of 24 hours. The solution should be discarded if it is cloudy or 115 discolored. Pulmozyme contains no preservative and, once opened, the entire contents of the 116 ampule must be used or discarded. Patients should be instructed in the proper use and 117 maintenance of the nebulizer and compressor system used in its delivery. 118 Pulmozyme should not be diluted or mixed with other drugs in the nebulizer. Mixing of 119 Pulmozyme with other drugs could lead to adverse physicochemical and/or functional 120 changes in Pulmozyme or the admixed compound. 121 U.S. BL 103532 Supplement: Pulmozyme? (dornase alfa)?Genentech, Inc. 6 of 12/Quality (PAS): PZ PI - Final Word for CORA.doc Drug Interactions 122 Clinical trials have indicated that Pulmozyme can be effectively and safely used in 123 conjunction with standard cystic fibrosis therapies including oral, inhaled and/or parenteral 124 antibiotics, bronchodilators, enzyme supplements, vitamins, oral or inhaled corticosteroids, 125 and analgesics. No formal drug interaction studies have been performed. 126 Carcinogenesis, Mutagenesis, Impairment of Fertility 127 Carcinogenesis: Lifetime studies in Sprague Dawley rats showed no carcinogenic effect 128 when Pulmozyme was administered at doses up to 246 ?g/kg body weight per day. 129 Pulmozyme was administered to rats as an aerosol for up to 30 minutes per day, daily for 130 two years, with resulting lower respiratory tract doses of up to 246 ?g/kg per day, which 131 represents up to a 28.8-fold multiple of the clinical dose. There was no increase in the 132 development of benign or malignant neoplasms and no occurrence of unusual tumor types in 133 rats after lifetime exposure. 134 Mutagenesis: Ames tests using six different tester strains of bacteria (4 of S. typhimurium 135 and 2 of E. coli) at concentrations up to 5000 ?g/plate, a cytogenetic assay using human 136 peripheral blood lymphocytes at concentrations up to 2000 ?g/plate, and a mouse lymphoma 137 assay at concentrations up to 1000 ?g/plate, with and without metabolic activation, revealed 138 no evidence of mutagenesis potential. Pulmozyme was tested in a micronucleus (in vivo) 139 assay for its potential to produce chromosome damage in bone marrow cells of mice 140 following a bolus intravenous dose of 10 mg/kg on two consecutive days. No evidence of 141 chromosomal damage was noted. 142 Impairment of Fertility: In studies with rats receiving up to 10 mg/kg/day, a dose 143 representing systemic exposures greater than 600 times that expected following the 144 recommended human dose, fertility and reproductive performance of both males and females 145 was not affected. 146 Pregnancy (Category B) 147 Reproduction studies have been performed in rats and rabbits with intravenous doses up to 148 10 mg/kg/day, representing systemic exposures greater than 600 times that expected 149 following the recommended human dose. These studies have revealed no evidence of 150 impaired fertility, harm to the fetus, or effects on development due to Pulmozyme. There 151 are, however, no adequate and well-controlled studies in pregnant women. Because animal 152 U.S. BL 103532 Supplement: Pulmozyme? (dornase alfa)?Genentech, Inc. 7 of 12/Quality (PAS): PZ PI - Final Word for CORA.doc reproductive studies are not always predictive of the human response, this drug should be 153 used during pregnancy only if clearly needed. 154 Nursing Mothers 155 It is not known whether Pulmozyme is excreted in human milk. Small amounts of dornase 156 alfa were detected in maternal milk of cynomolgus monkeys when administered a bolus dose 157 (100 ?g/kg) of dornase alfa followed by a six hour intravenous infusion (80 ?g/kg/hr). Little 158 or no measurable dornase alfa would be expected in human milk after chronic aerosol 159 administration of recommended doses. Because many drugs are excreted in human milk, 160 caution should still be exercised when Pulmozyme is administered to a nursing woman. 161 Pediatric Use 162 Because of the limited experience with the administration of Pulmozyme to patients younger 163 than 5 years of age, its use should be considered only for those patients in whom there is a 164 potential for benefit in pulmonary function or in risk of respiratory tract infection. 165 Geriatric Use 166 Cystic fibrosis is primarily a disease of pediatrics and young adults. Clinical studies of 167 Pulmozyme did not include sufficient numbers of subjects aged 65 or older to determine 168 whether they respond differently from younger subjects. 169 ADVERSE REACTIONS 170 Patients have been exposed to Pulmozyme for up to 12 months in clinical trials. 171 In a randomized, placebo-controlled clinical trial in patients with FVC ≥40% of predicted, 172 over 600 patients received Pulmozyme once or twice daily for six months; most adverse 173 events were not more common on Pulmozyme than on placebo and probably reflected the 174 sequelae of the underlying lung disease. In most cases events that were increased were mild, 175 transient in nature, and did not require alterations in dosing. Few patients experienced 176 adverse events resulting in permanent discontinuation from Pulmozyme, and the 177 discontinuation rate was similar for placebo (2%) and Pulmozyme (3%). Events that were 178 more frequent (greater than 3%) in Pulmozyme treated patients than in placebo-treated 179 patients are listed in Table 2. 180 U.S. BL 103532 Supplement: Pulmozyme? (dornase alfa)?Genentech, Inc. 8 of 12/Quality (PAS): PZ PI - Final Word for CORA.doc In a randomized, placebo-controlled trial of patients with advanced disease (FVC <40% of 181 predicted) the safety profile for most adverse events was similar to that reported for the trial 182 in patients with mild to moderate disease. For this study, adverse events that were reported 183 with a higher frequency (greater than 3%) in the Pulmozyme treated patients, are also listed 184 in Table 2. 185 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 7% 12% 16% 6% 18% Pharyngitis 33% 36% 40% 28% 32% Rash 7% 10% 12% 1% 3% Laryngitis 1% 3% 4% 1% 3% Chest Pain 16% 18% 21% 23% 25% Conjunctivitis 2% 4% 5% 0% 1% Rhinitis 24% 30% FVC decrease of ≥10% of predicted° 17% 22% Fever 28% 32% Dyspepsia Differences were less than 3% for these adverse events in the Trial in mild to moderate CF patients 0% 3% Dyspnea (when reported as serious) Differences were less than 3% for this adverse event in the Trial in mild to moderate CF patients 12%? 17%? ° 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. 186 Events Observed at Similar Rates in Pulmozyme? (dornase alfa) Inhalation 187 Solution and Placebo Treated Patients with FVC ≥ 40% of Predicted 188 Body as a Whole Abdominal pain, Asthenia, Fever, Flu syndrome, 189 Malaise, Sepsis 190 Digestive System Intestinal Obstruction, Gall Bladder disease, Liver 191 disease, Pancreatic disease 192 U.S. BL 103532 Supplement: Pulmozyme? (dornase alfa)?Genentech, Inc. 9 of 12/Quality (PAS): PZ PI - Final Word for CORA.doc Metabolic Nutritional System Diabetes Mellitus, Hypoxia, Weight Loss 193 Respiratory System Apnea, Bronchiectasis, Bronchitis, Change in Sputum, 194 Cough Increase, Dyspnea, Hemoptysis, Lung Function 195 Decrease, Nasal Polyps, Pneumonia, Pneumothorax, 196 Rhinitis, Sinusitis, Sputum Increase, Wheeze 197 Mortality rates observed in controlled trials were similar for the placebo and Pulmozyme 198 treated patients. Causes of death were consistent with progression of cystic fibrosis and 199 included apnea, cardiac arrest, cardiopulmonary arrest, cor pulmonale, heart failure, massive 200 hemoptysis, pneumonia, pneumothorax, and respiratory failure. 201 The safety of Pulmozyme, 2.5 mg by inhalation, was studied with 2 weeks of daily 202 administration in 98 patients with cystic fibrosis (65 aged 3 months to <5 years, 33 aged 5 to 203 ≤10 years). The PARI BABY? reusable nebulizer (which uses a facemask instead of a 204 mouthpiece) was utilized in patients unable to demonstrate the ability to inhale or exhale 205 orally throughout the entire treatment period (54/65, 83% of the younger and 2/33, 6% of the 206 older patients). The number of patients reporting cough was higher in the younger age group 207 as compared to the older age group (29/65, 45% compared to 10/33, 30%) as was the number 208 reporting moderate to severe cough (24/65, 37% as compared to 6/33, 18%). Other events 209 tended to be of mild to moderate severity. The number of patients reporting rhinitis was 210 higher in the younger age group as compared to the older age group (23/65, 35% compared 211 to 9/33, 27%) as was the number reporting rash (4/65, 6% as compared to 0/33). The nature 212 of adverse events was similar to that seen in the larger trials of Pulmozyme. 213 Allergic Reactions 214 There have been no reports of anaphylaxis attributed to the administration of Pulmozyme to 215 date. Urticaria, mild to moderate, and mild skin rash have been observed and have been 216 transient. Within all of the studies, a small percentage (average of 2?4%) of patients treated 217 with Pulmozyme developed serum antibodies to Pulmozyme. None of these patients 218 developed anaphylaxis, and the clinical significance of serum antibodies to Pulmozyme is 219 unknown. 220 U.S. BL 103532 Supplement: Pulmozyme? (dornase alfa)?Genentech, Inc. 10 of 12/Quality (PAS): PZ PI - Final Word for CORA.doc OVERDOSAGE 221 Single-dose inhalation studies in rats and monkeys at doses up to 180-times higher than doses 222 routinely used in clinical studies are well tolerated. Single dose oral administration of 223 Pulmozyme in doses up to 200 mg/kg are also well tolerated by rats. 224 Cystic fibrosis patients have received up to 20 mg BID for up to 6 days and 10 mg BID 225 intermittently (2 weeks on/2 weeks off drug) for 168 days. These doses were well tolerated. 226 DOSAGE AND ADMINISTRATION 227 The recommended dose for use in most cystic fibrosis patients is one 2.5 mg single-use 228 ampule inhaled once daily using a recommended nebulizer. Some patients may benefit from 229 twice daily administration (see Clinical Experience, Table 1). Clinical trial results and 230 laboratory information are only available to support use of the following 231 nebulizer/compressor systems (see Table 3). 232 Table 3 Recommended Nebulizer/Compressor Systems 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. 233 Patients who use the Sidestream? Nebulizer with the MOBILAIRE? compressor should turn 234 the compressor control knob fully to the right and then turn on the compressor. At this 235 setting, the needle on the pressure gauge should vibrate between 35 and 45 pounds per square 236 inch (highest pressure output). 237 No data are currently available that support the administration of Pulmozyme with other 238 nebulizer systems. The patient should follow the manufacturer's instructions on the use and 239 maintenance of the equipment. 240 U.S. BL 103532 Supplement: Pulmozyme? (dornase alfa)?Genentech, Inc. 11 of 12/Quality (PAS): PZ PI - Final Word for CORA.doc Pulmozyme should not be diluted or mixed with other drugs in the nebulizer. Mixing of 241 Pulmozyme with other drugs could lead to adverse physicochemical and/or functional 242 changes in Pulmozyme or the admixed compound. Patients should be advised to squeeze 243 each ampule prior to use in order to check for leaks. 244 HOW SUPPLIED 245 Pulmozyme is supplied in single-use ampules. Each ampule delivers 2.5 mL of a sterile, 246 clear, colorless, aqueous solution containing 1.0 mg/mL dornase alfa, 0.15 mg/mL calcium 247 chloride dihydrate and 8.77 mg/mL sodium chloride with no preservative. The nominal pH 248 of the solution is 6.3. 249 Pulmozyme is supplied in: 250 ? 30 unit cartons containing 5 foil pouches of 6 single-use ampules: NDC 50242-100-40. 251 Storage 252 Pulmozyme should be stored under refrigeration (2?8°C/36?46°F). Ampules should be 253 protected from strong light. Do not use beyond the expiration date stamped on the ampule. 254 Unused ampules should be stored in their protective foil pouch under refrigeration. 255 REFERENCES 256 1. Shak S, Capon DJ, Hellmiss R, Marsters SA, Baker CL. Recombinant human DNase I 257 reduces the viscosity of cystic fibrosis sputum. Proc Natl Acad Sci USA 258 1990;87:9188–92. 259 2. Boat TF. Cystic Fibrosis. In: Murray JF, Nadel JA, editors. Textbook of respiratory 260 medicine. Philadelphia: Saunders WB, 1988;1:1126–52. 261 3. Collins FS. Cystic Fibrosis: molecular biology and therapeutic implications. Science 262 1992;256:774–9. 263 4. Potter JL, Spector S, Matthews LW, Lemm J. Studies of pulmonary secretions. Am 264 Rev Respir Dis 1969;99:909–15. 265 5. Hubbard RC, McElvaney NG, Birrer P, Shak S, Robinson WW, Jolley C, et al. A 266 preliminary study of aerosolized recombinant human deoxyribonuclease I in the 267 treatment of cystic fibrosis. N Engl J Med 1992;326:812–5. 268 6. Aitken ML, Burke W, McDonald G, Shak S, Montgomery AB, Smith A. Recombinant 269 human DNase inhalation in normal subjects and patients with cystic fibrosis. JAMA 270 1992;267(14):1947–51. 271 U.S. BL 103532 Supplement: Pulmozyme? (dornase alfa)?Genentech, Inc. 12 of 12/Quality (PAS): PZ PI - Final Word for CORA.doc 7. Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, et al. 272 Effect of aerosolized recombinant human DNase on exacerbations of respiratory 273 symptoms and on pulmonary function in patients with cystic fibrosis. N Engl J Med 274 1994;331:637–42. 275 8. McCoy K, Hamilton S, Johnson C. Effects of 12-week administration of dornase alfa 276 in patients with advanced cystic fibrosis lung disease. Chest 1996;110:889–95. 277 278 Pulmozyme? (dornase alfa) Inhalation Solution Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990 LE0339 7061805 (4824302) Code Revision Date: October 2010 FDA Approval Date: January 2001 ?2010 Genentech, Inc. Pulmozyme? is a trademark of Genentech, Inc. 279
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U.S. BL 103532 Supplement: Pulmozyme? (dornase alfa)?Genentech, Inc. 1 of 12/Quality (PAS): PZ PI - Final Word for CORA.doc 1.14.1.3 1 Pulmozyme? 2 (dornase alfa) 3 Inhalation Solution 4 DESCRIPTION 5 Pulmozyme is a sterile, clear, colorless, highly purified solution of recombinant human 6 deoxyribonuclease I (rhDNase), an enzyme which selectively cleaves DNA. The protein is 7 produced by genetically engineered Chinese Hamster Ovary (CHO) cells containing DNA 8 encoding for the native human protein, deoxyribonuclease I (DNase). Fermentation is 9 carried out in a nutrient medium containing the antibiotic gentamicin, 100–200 mg/L. 10 However, the presence of the antibiotic is not detectable in the final product. The product is 11 purified by tangential flow filtration and column chromatography. The purified glycoprotein 12 contains 260 amino acids with an approximate molecular weight of 37,000 daltons (1). 13 The primary amino acid sequence is identical to that of the native human enzyme. 14 Pulmozyme is administered by inhalation of an aerosol mist produced by a compressed air 15 driven nebulizer system (see Clinical Experience, DOSAGE AND ADMINISTRATION). 16 Each Pulmozyme single-use ampule will deliver 2.5 mL of the solution to the nebulizer bowl. 17 The aqueous solution contains 1.0 mg/mL dornase alfa, 0.15 mg/mL calcium chloride 18 dihydrate and 8.77 mg/mL sodium chloride. The solution contains no preservative. 19 The nominal pH of the solution is 6.3. 20 CLINICAL PHARMACOLOGY 21 General 22 In cystic fibrosis (CF) patients, retention of viscous purulent secretions in the airways 23 contributes both to reduced pulmonary function and to exacerbations of infection (2, 3). 24 Purulent pulmonary secretions contain very high concentrations of extracellular DNA 25 released by degenerating leukocytes that accumulate in response to infection (4). In vitro, 26 Pulmozyme hydrolyzes the DNA in sputum of CF patients and reduces sputum 27 viscoelasticity (1). 28 U.S. BL 103532 Supplement: Pulmozyme? (dornase alfa)?Genentech, Inc. 2 of 12/Quality (PAS): PZ PI - Final Word for CORA.doc Pharmacokinetics 29 When 2.5 mg Pulmozyme was administered by inhalation to eighteen CF patients, mean 30 sputum concentrations of 3 ?g/mL DNase were measurable within 15 minutes. Mean 31 sputum concentrations declined to an average of 0.6 ?g/mL two hours following inhalation. 32 Inhalation of up to 10 mg TID of Pulmozyme by 4 CF patients for six consecutive days, did 33 not result in a significant elevation of serum concentrations of DNase above normal 34 endogenous levels (5, 6). After administration of up to 2.5 mg of Pulmozyme twice daily for 35 six months to 321 CF patients, no accumulation of serum DNase was noted. 36 Pulmozyme, 2.5 mg by inhalation, was administered daily to 98 patients aged 3 months to 37 ≤10 years, and bronchoalveolar lavage (BAL) fluid was obtained within 90 minutes of the 38 first dose. BAL DNase concentrations were detectable in all patients but showed a broad 39 range, from 0.007 to 1.8 ?g/mL. Over an average of 14 days of exposure, serum DNase 40 concentrations (mean ± s.d.) increased by 1.3 ± 1.3 ng/mL for the 3 months to <5 year age 41 group and by 0.8 ± 1.2 ng/mL for the 5 to ≤10 year age group. The relationship between 42 BAL or serum DNase concentration and adverse experiences and clinical outcomes is 43 unknown. 44 Clinical Experience 45 Pulmozyme has been evaluated in a randomized, placebo-controlled trial of clinically stable 46 cystic fibrosis patients, 5 years of age and older, with baseline forced vital capacity (FVC) 47 greater than or equal to 40% of predicted and receiving standard therapies for cystic fibrosis 48 (7). Patients were treated with placebo (325 patients), 2.5 mg of Pulmozyme once a day 49 (322 patients), or 2.5 mg of Pulmozyme twice a day (321 patients) for six months 50 administered via a Hudson T Up-draft II? nebulizer with a Pulmo-Aide? compressor. 51 Both doses of Pulmozyme resulted in significant reductions when compared with the placebo 52 group in the number of patients experiencing respiratory tract infections requiring use of 53 parenteral antibiotics. Administration of Pulmozyme reduced the relative risk of developing 54 a respiratory tract infection by 27% and 29% for the 2.5 mg daily dose and the 2.5 mg twice 55 daily dose, respectively (see Table 1). The data suggest that the effects of Pulmozyme on 56 respiratory tract infections in older patients (>21 years) may be smaller than in younger 57 patients, and that twice daily dosing may be required in the older patients. Patients with 58 baseline FVC >85% may also benefit from twice a day dosing (see Table 1). The reduced 59 U.S. BL 103532 Supplement: Pulmozyme? (dornase alfa)?Genentech, Inc. 3 of 12/Quality (PAS): PZ PI - Final Word for CORA.doc risk of respiratory infection observed in Pulmozyme treated patients did not directly correlate 60 with improvement in FEV1 during the initial two weeks of therapy. 61 Within 8 days of the start of treatment with Pulmozyme, mean FEV1 increased 7.9% in those 62 treated once a day and 9.0% in those treated twice a day compared to the baseline values. 63 The overall mean FEV1 during long-term therapy increased 5.8% from baseline at the 2.5 mg 64 daily dose level and 5.6% from baseline at the 2.5 mg twice daily dose level. Placebo 65 recipients did not show significant mean changes in pulmonary function testing (see 66 Figure 1). 67 For patients 5 years of age or older, with baseline FVC greater than or equal to 40%, 68 administration of Pulmozyme decreased the incidence of occurrence of first respiratory tract 69 infection requiring parenteral antibiotics, and improved mean FEV1, regardless of age or 70 baseline FVC. 71 Table 1 Incidence of First Respiratory Tract Infection Requiring Parenteral Antibiotics in Patients with FVC ≥40% of Predicted Placebo N=325 2.5 mg QD N=322 2.5 mg BID N=321 Percent of Patients Infected 43% 34% 33% Relative Risk (vs placebo) 0.73 0.71 p-value (vs placebo) 0.015 0.007 Subgroup by Age and Baseline FVC Placebo (N) 2.5 mg QD (N) 2.5 mg BID (N) Age 5?20 years 42% (201) 25% (199) 28% (184) 21 years and older 44% (124) 48% (123) 39% (137) Baseline FVC 40?85% Predicted 54% (194) 41% (201) 44% (203) >85% Predicted 27% (131) 21% (121) 14% (118) 72 U.S. BL 103532 Supplement: Pulmozyme? (dornase alfa)?Genentech, Inc. 4 of 12/Quality (PAS): PZ PI - Final Word for CORA.doc Figure 1: 73 Mean Percent Change from Baseline FEV1 in Patients with FVC ≥40% of Predicted 74 75 76 Pulmozyme has also been evaluated in a second randomized, placebo-controlled study in 77 clinically stable patients with baseline FVC <40% of predicted (8). Patients were enrolled 78 and treated with placebo (162 patients) or Pulmozyme 2.5 mg QD (158 patients) for 79 twelve weeks. In patients who received Pulmozyme, there was an increase in mean change 80 (as percent of baseline) compared to placebo in FEV1 (9.4% vs. 2.1%, p<0.001) and in FVC 81 (12.4% vs. 7.3%, p<0.01). Pulmozyme did not significantly reduce the risk of developing a 82 respiratory tract infection requiring parenteral antibiotics (54% of Pulmozyme patients vs. 83 55% of placebo patients had experienced a respiratory tract infection by 12 weeks, relative 84 risk=.93, p=0.62). 85 The effect of Pulmozyme on exercise tolerance has not been established in adults and 86 children. 87 Other Studies 88 Clinical trials have indicated that Pulmozyme therapy can be continued or initiated during an 89 acute respiratory exacerbation. 90 Short-term dose ranging studies demonstrated that doses in excess of 2.5 mg BID did not 91 provide further improvement in FEV1. Patients who have received drug on a cyclical 92 regimen (i.e., administration of Pulmozyme 10 mg BID for 14 days, followed by a 14 day 93 U.S. BL 103532 Supplement: Pulmozyme? (dornase alfa)?Genentech, Inc. 5 of 12/Quality (PAS): PZ PI - Final Word for CORA.doc wash out period) showed rapid improvement in FEV1 with the initiation of each cycle and a 94 return to baseline with each Pulmozyme withdrawal. 95 INDICATIONS AND USAGE 96 Daily administration of Pulmozyme? (dornase alfa) Inhalation Solution in conjunction with 97 standard therapies is indicated in the management of cystic fibrosis patients to improve 98 pulmonary function. In patients with an FVC ≥40% of predicted, daily administration of 99 Pulmozyme has also been shown to reduce the risk of respiratory tract infections requiring 100 parenteral antibiotics. 101 Safety and efficacy of daily administration have not been demonstrated in patients for longer 102 than twelve months. 103 CONTRAINDICATIONS 104 Pulmozyme is contraindicated in patients with known hypersensitivity to dornase alfa, 105 Chinese Hamster Ovary cell products, or any component of the product. 106 WARNINGS 107 None. 108 PRECAUTIONS 109 General 110 Pulmozyme should be used in conjunction with standard therapies for CF. 111 Information for Patients 112 Pulmozyme must be stored in the refrigerator at 2–8°C (36–46°F) and protected from strong 113 light. It should be kept refrigerated during transport and should not be exposed to room 114 temperatures for a total time of 24 hours. The solution should be discarded if it is cloudy or 115 discolored. Pulmozyme contains no preservative and, once opened, the entire contents of the 116 ampule must be used or discarded. Patients should be instructed in the proper use and 117 maintenance of the nebulizer and compressor system used in its delivery. 118 Pulmozyme should not be diluted or mixed with other drugs in the nebulizer. Mixing of 119 Pulmozyme with other drugs could lead to adverse physicochemical and/or functional 120 changes in Pulmozyme or the admixed compound. 121 U.S. BL 103532 Supplement: Pulmozyme? (dornase alfa)?Genentech, Inc. 6 of 12/Quality (PAS): PZ PI - Final Word for CORA.doc Drug Interactions 122 Clinical trials have indicated that Pulmozyme can be effectively and safely used in 123 conjunction with standard cystic fibrosis therapies including oral, inhaled and/or parenteral 124 antibiotics, bronchodilators, enzyme supplements, vitamins, oral or inhaled corticosteroids, 125 and analgesics. No formal drug interaction studies have been performed. 126 Carcinogenesis, Mutagenesis, Impairment of Fertility 127 Carcinogenesis: Lifetime studies in Sprague Dawley rats showed no carcinogenic effect 128 when Pulmozyme was administered at doses up to 246 ?g/kg body weight per day. 129 Pulmozyme was administered to rats as an aerosol for up to 30 minutes per day, daily for 130 two years, with resulting lower respiratory tract doses of up to 246 ?g/kg per day, which 131 represents up to a 28.8-fold multiple of the clinical dose. There was no increase in the 132 development of benign or malignant neoplasms and no occurrence of unusual tumor types in 133 rats after lifetime exposure. 134 Mutagenesis: Ames tests using six different tester strains of bacteria (4 of S. typhimurium 135 and 2 of E. coli) at concentrations up to 5000 ?g/plate, a cytogenetic assay using human 136 peripheral blood lymphocytes at concentrations up to 2000 ?g/plate, and a mouse lymphoma 137 assay at concentrations up to 1000 ?g/plate, with and without metabolic activation, revealed 138 no evidence of mutagenesis potential. Pulmozyme was tested in a micronucleus (in vivo) 139 assay for its potential to produce chromosome damage in bone marrow cells of mice 140 following a bolus intravenous dose of 10 mg/kg on two consecutive days. No evidence of 141 chromosomal damage was noted. 142 Impairment of Fertility: In studies with rats receiving up to 10 mg/kg/day, a dose 143 representing systemic exposures greater than 600 times that expected following the 144 recommended human dose, fertility and reproductive performance of both males and females 145 was not affected. 146 Pregnancy (Category B) 147 Reproduction studies have been performed in rats and rabbits with intravenous doses up to 148 10 mg/kg/day, representing systemic exposures greater than 600 times that expected 149 following the recommended human dose. These studies have revealed no evidence of 150 impaired fertility, harm to the fetus, or effects on development due to Pulmozyme. There 151 are, however, no adequate and well-controlled studies in pregnant women. Because animal 152 U.S. BL 103532 Supplement: Pulmozyme? (dornase alfa)?Genentech, Inc. 7 of 12/Quality (PAS): PZ PI - Final Word for CORA.doc reproductive studies are not always predictive of the human response, this drug should be 153 used during pregnancy only if clearly needed. 154 Nursing Mothers 155 It is not known whether Pulmozyme is excreted in human milk. Small amounts of dornase 156 alfa were detected in maternal milk of cynomolgus monkeys when administered a bolus dose 157 (100 ?g/kg) of dornase alfa followed by a six hour intravenous infusion (80 ?g/kg/hr). Little 158 or no measurable dornase alfa would be expected in human milk after chronic aerosol 159 administration of recommended doses. Because many drugs are excreted in human milk, 160 caution should still be exercised when Pulmozyme is administered to a nursing woman. 161 Pediatric Use 162 Because of the limited experience with the administration of Pulmozyme to patients younger 163 than 5 years of age, its use should be considered only for those patients in whom there is a 164 potential for benefit in pulmonary function or in risk of respiratory tract infection. 165 Geriatric Use 166 Cystic fibrosis is primarily a disease of pediatrics and young adults. Clinical studies of 167 Pulmozyme did not include sufficient numbers of subjects aged 65 or older to determine 168 whether they respond differently from younger subjects. 169 ADVERSE REACTIONS 170 Patients have been exposed to Pulmozyme for up to 12 months in clinical trials. 171 In a randomized, placebo-controlled clinical trial in patients with FVC ≥40% of predicted, 172 over 600 patients received Pulmozyme once or twice daily for six months; most adverse 173 events were not more common on Pulmozyme than on placebo and probably reflected the 174 sequelae of the underlying lung disease. In most cases events that were increased were mild, 175 transient in nature, and did not require alterations in dosing. Few patients experienced 176 adverse events resulting in permanent discontinuation from Pulmozyme, and the 177 discontinuation rate was similar for placebo (2%) and Pulmozyme (3%). Events that were 178 more frequent (greater than 3%) in Pulmozyme treated patients than in placebo-treated 179 patients are listed in Table 2. 180 U.S. BL 103532 Supplement: Pulmozyme? (dornase alfa)?Genentech, Inc. 8 of 12/Quality (PAS): PZ PI - Final Word for CORA.doc In a randomized, placebo-controlled trial of patients with advanced disease (FVC <40% of 181 predicted) the safety profile for most adverse events was similar to that reported for the trial 182 in patients with mild to moderate disease. For this study, adverse events that were reported 183 with a higher frequency (greater than 3%) in the Pulmozyme treated patients, are also listed 184 in Table 2. 185 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 7% 12% 16% 6% 18% Pharyngitis 33% 36% 40% 28% 32% Rash 7% 10% 12% 1% 3% Laryngitis 1% 3% 4% 1% 3% Chest Pain 16% 18% 21% 23% 25% Conjunctivitis 2% 4% 5% 0% 1% Rhinitis 24% 30% FVC decrease of ≥10% of predicted° 17% 22% Fever 28% 32% Dyspepsia Differences were less than 3% for these adverse events in the Trial in mild to moderate CF patients 0% 3% Dyspnea (when reported as serious) Differences were less than 3% for this adverse event in the Trial in mild to moderate CF patients 12%? 17%? ° 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. 186 Events Observed at Similar Rates in Pulmozyme? (dornase alfa) Inhalation 187 Solution and Placebo Treated Patients with FVC ≥ 40% of Predicted 188 Body as a Whole Abdominal pain, Asthenia, Fever, Flu syndrome, 189 Malaise, Sepsis 190 Digestive System Intestinal Obstruction, Gall Bladder disease, Liver 191 disease, Pancreatic disease 192 U.S. BL 103532 Supplement: Pulmozyme? (dornase alfa)?Genentech, Inc. 9 of 12/Quality (PAS): PZ PI - Final Word for CORA.doc Metabolic Nutritional System Diabetes Mellitus, Hypoxia, Weight Loss 193 Respiratory System Apnea, Bronchiectasis, Bronchitis, Change in Sputum, 194 Cough Increase, Dyspnea, Hemoptysis, Lung Function 195 Decrease, Nasal Polyps, Pneumonia, Pneumothorax, 196 Rhinitis, Sinusitis, Sputum Increase, Wheeze 197 Mortality rates observed in controlled trials were similar for the placebo and Pulmozyme 198 treated patients. Causes of death were consistent with progression of cystic fibrosis and 199 included apnea, cardiac arrest, cardiopulmonary arrest, cor pulmonale, heart failure, massive 200 hemoptysis, pneumonia, pneumothorax, and respiratory failure. 201 The safety of Pulmozyme, 2.5 mg by inhalation, was studied with 2 weeks of daily 202 administration in 98 patients with cystic fibrosis (65 aged 3 months to <5 years, 33 aged 5 to 203 ≤10 years). The PARI BABY? reusable nebulizer (which uses a facemask instead of a 204 mouthpiece) was utilized in patients unable to demonstrate the ability to inhale or exhale 205 orally throughout the entire treatment period (54/65, 83% of the younger and 2/33, 6% of the 206 older patients). The number of patients reporting cough was higher in the younger age group 207 as compared to the older age group (29/65, 45% compared to 10/33, 30%) as was the number 208 reporting moderate to severe cough (24/65, 37% as compared to 6/33, 18%). Other events 209 tended to be of mild to moderate severity. The number of patients reporting rhinitis was 210 higher in the younger age group as compared to the older age group (23/65, 35% compared 211 to 9/33, 27%) as was the number reporting rash (4/65, 6% as compared to 0/33). The nature 212 of adverse events was similar to that seen in the larger trials of Pulmozyme. 213 Allergic Reactions 214 There have been no reports of anaphylaxis attributed to the administration of Pulmozyme to 215 date. Urticaria, mild to moderate, and mild skin rash have been observed and have been 216 transient. Within all of the studies, a small percentage (average of 2?4%) of patients treated 217 with Pulmozyme developed serum antibodies to Pulmozyme. None of these patients 218 developed anaphylaxis, and the clinical significance of serum antibodies to Pulmozyme is 219 unknown. 220 U.S. BL 103532 Supplement: Pulmozyme? (dornase alfa)?Genentech, Inc. 10 of 12/Quality (PAS): PZ PI - Final Word for CORA.doc OVERDOSAGE 221 Single-dose inhalation studies in rats and monkeys at doses up to 180-times higher than doses 222 routinely used in clinical studies are well tolerated. Single dose oral administration of 223 Pulmozyme in doses up to 200 mg/kg are also well tolerated by rats. 224 Cystic fibrosis patients have received up to 20 mg BID for up to 6 days and 10 mg BID 225 intermittently (2 weeks on/2 weeks off drug) for 168 days. These doses were well tolerated. 226 DOSAGE AND ADMINISTRATION 227 The recommended dose for use in most cystic fibrosis patients is one 2.5 mg single-use 228 ampule inhaled once daily using a recommended nebulizer. Some patients may benefit from 229 twice daily administration (see Clinical Experience, Table 1). Clinical trial results and 230 laboratory information are only available to support use of the following 231 nebulizer/compressor systems (see Table 3). 232 Table 3 Recommended Nebulizer/Compressor Systems 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. 233 Patients who use the Sidestream? Nebulizer with the MOBILAIRE? compressor should turn 234 the compressor control knob fully to the right and then turn on the compressor. At this 235 setting, the needle on the pressure gauge should vibrate between 35 and 45 pounds per square 236 inch (highest pressure output). 237 No data are currently available that support the administration of Pulmozyme with other 238 nebulizer systems. The patient should follow the manufacturer's instructions on the use and 239 maintenance of the equipment. 240 U.S. BL 103532 Supplement: Pulmozyme? (dornase alfa)?Genentech, Inc. 11 of 12/Quality (PAS): PZ PI - Final Word for CORA.doc Pulmozyme should not be diluted or mixed with other drugs in the nebulizer. Mixing of 241 Pulmozyme with other drugs could lead to adverse physicochemical and/or functional 242 changes in Pulmozyme or the admixed compound. Patients should be advised to squeeze 243 each ampule prior to use in order to check for leaks. 244 HOW SUPPLIED 245 Pulmozyme is supplied in single-use ampules. Each ampule delivers 2.5 mL of a sterile, 246 clear, colorless, aqueous solution containing 1.0 mg/mL dornase alfa, 0.15 mg/mL calcium 247 chloride dihydrate and 8.77 mg/mL sodium chloride with no preservative. The nominal pH 248 of the solution is 6.3. 249 Pulmozyme is supplied in: 250 ? 30 unit cartons containing 5 foil pouches of 6 single-use ampules: NDC 50242-100-40. 251 Storage 252 Pulmozyme should be stored under refrigeration (2?8°C/36?46°F). Ampules should be 253 protected from strong light. Do not use beyond the expiration date stamped on the ampule. 254 Unused ampules should be stored in their protective foil pouch under refrigeration. 255 REFERENCES 256 1. Shak S, Capon DJ, Hellmiss R, Marsters SA, Baker CL. Recombinant human DNase I 257 reduces the viscosity of cystic fibrosis sputum. Proc Natl Acad Sci USA 258 1990;87:9188–92. 259 2. Boat TF. Cystic Fibrosis. In: Murray JF, Nadel JA, editors. Textbook of respiratory 260 medicine. Philadelphia: Saunders WB, 1988;1:1126–52. 261 3. Collins FS. Cystic Fibrosis: molecular biology and therapeutic implications. Science 262 1992;256:774–9. 263 4. Potter JL, Spector S, Matthews LW, Lemm J. Studies of pulmonary secretions. Am 264 Rev Respir Dis 1969;99:909–15. 265 5. Hubbard RC, McElvaney NG, Birrer P, Shak S, Robinson WW, Jolley C, et al. A 266 preliminary study of aerosolized recombinant human deoxyribonuclease I in the 267 treatment of cystic fibrosis. N Engl J Med 1992;326:812–5. 268 6. Aitken ML, Burke W, McDonald G, Shak S, Montgomery AB, Smith A. Recombinant 269 human DNase inhalation in normal subjects and patients with cystic fibrosis. JAMA 270 1992;267(14):1947–51. 271 U.S. BL 103532 Supplement: Pulmozyme? (dornase alfa)?Genentech, Inc. 12 of 12/Quality (PAS): PZ PI - Final Word for CORA.doc 7. Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW, et al. 272 Effect of aerosolized recombinant human DNase on exacerbations of respiratory 273 symptoms and on pulmonary function in patients with cystic fibrosis. N Engl J Med 274 1994;331:637–42. 275 8. McCoy K, Hamilton S, Johnson C. Effects of 12-week administration of dornase alfa 276 in patients with advanced cystic fibrosis lung disease. Chest 1996;110:889–95. 277 278 Pulmozyme? (dornase alfa) Inhalation Solution Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990 LE0339 7061805 (4824302) Code Revision Date: October 2010 FDA Approval Date: January 2001 ?2010 Genentech, Inc. Pulmozyme? is a trademark of Genentech, Inc. 279