rdless of whether the easycare cleaning aid is used. since delivery data are not available for pulmozyme administered with the erapid handset beyond 90 administrations, delivery of the appropriate therapeutic dose of pulmozyme cannot be assured beyond 90 administrations. the erapid nebulizer system should only be used by adults and pediatric patients who can use a mouthpiece, and not by younger patients who need a mask to take pulmozyme. the patient should follow the manufacturer's instructions on the use and maintenance of the equipment, including cleaning and disinfection procedures. for additional information, refer to recommended nebulizer manufacturers' instructions for use. table 1 recommended jet nebulizers and nebulizer systems jet nebulizer follow manufacturer's instructions for use compressor hudson t up-draft ii ® pulmo-aide® or legally marketed compressor of identical pressure and flow rate (maximum 30 psi, 12 lpm). marquest acorn ii ® pari lc ® plus pari proneb® or legally marketed compressor of identical pressure and flow rate (maximum 24 psi, 9 lpm). patients who are unable to inhale or exhale orally throughout the entire nebulization period may use the pari baby™ nebulizer. pari baby™ durable sidestream ® mobilaire™, porta-neb® or legally marketed compressor of identical pressure and flow rate (maximum 45 psi, 7 lpm). nebulizer system erapid™ nebulizer system consisting of the erapid™ nebulizer handset with ebase™ controller. pulmozyme information each pulmozyme ampule should be squeezed prior to use in order to check for leaks. discard ampules if the solution is cloudy or discolored. once opened, the entire contents of the ampule must be used or discarded. do not dilute or mix pulmozyme 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.

=804 and n=98). the population of patients in placebo-controlled trials was with fvc ≥ 40% of predicted (n=643) or with more advanced pulmonary disease, fvc < 40% of predicted (n=161). the population in the uncontrolled trial included 98 pediatric patients with cf ranging from 3 months to 10 years of age. more than half of the patients received pulmozyme 2.5 mg by inhalation once a day (n=581), while the rest of patients (n=321) received pulmozyme 2.5 mg by inhalation twice a day. placebo-controlled trials trial 1 : trial 1 was a randomized, placebo-controlled clinical trial in patients with fvc ≥ 40% of predicted. in this trial, over 600 patients received pulmozyme once or twice daily for six months. the most common adverse reaction (risk difference ≥5%) was voice alteration. the proportion of most adverse events was similar for patients on pulmozyme and on placebo, probably reflecting the sequelae of the underlying lung disease. in most cases reactions that were increased were mild, transient in nature, and did not require alterations in dosing. few patients experienced adverse reactions resulting in permanent discontinuation from pulmozyme, and the proportion of discontinuations were similar for placebo (2%) and pulmozyme (3%). adverse reactions occurring in a higher proportion (greater than 3%) of pulmozyme treated patients than in placebo-treated patients are listed in table 2 . trial 2 : trial 2 was a randomized, placebo-controlled trial in patients with more advanced pulmonary disease (fvc < 40% of predicted) who were treated for 12 weeks. in this trial, the safety profile of pulmozyme was similar to that reported in patients with less advanced pulmonary disease (fvc ≥ 40% of predicted). adverse reactions that were reported in this trial with a higher proportion (greater than 3%) in the pulmozyme treated patients are listed in table 2 . table 2. adverse reactions increased 3% or more in pulmozyme treated patients over placebo in cf clinical trials adverse reactions (of any severity or seriousness) trial 1 cf patients with fvc ≥ 40% of predicted treated for 24 weeks trial 2 cf patients with fvc <40% of predicted treated for 12 weeks 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 differences were less than 3% 24% 30% fvc decrease of ≥ 10% of predicted single measurement only, does not reflect overall fvc changes. 17% 22% fever 28% 32% dyspepsia 0% 3% dyspnea (when reported as serious) differences were less than 3% 12% total reports of dyspnea (regardless of severity or seriousness) had a difference of less than 3% in trial 2. 17% 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. uncontrolled trial trial 3: the safety of pulmozyme, 2.5 mg by inhalation, was studied with 2 weeks of daily administration in 98 pediatric patients with cystic fibrosis 3 months to 10 years of age (65 aged 3 months to < 5 years, 33 aged 5 to ≤ 10 years). the pari baby™ reusable nebulizer (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). overall, the nature of adverse reactions was similar to that seen in the placebo-controlled trials. 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%). 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). allergic reactions there have been no reports of anaphylaxis attributed to the administration of pulmozyme. 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.

hen dornase alfa was administered to dams throughout organogenesis (gestation days 6 to 17). dornase alfa did not elicit adverse effects on fetal or neonatal growth when administered to dams throughout most of gestation and delivery (gestation days 6 to 25) and nursing (post-partum days 6 to 21). a pharmacokinetic study in cynomolgus monkeys found no detectable levels of dornase alfa in fetal blood or amniotic fluid on gestation day 150 (end of gestation) from mothers that were administered an intravenous bolus dose (0.1 mg/kg) followed by an intravenous infusion dose (0.080 mg/kg) over a 6-hour period during pregnancy. 8.2 lactation risk summary it is not known whether pulmozyme is present in human milk. in a pharmacokinetic study in cynomolgus monkeys, levels of dornase alfa detected in milk were less than 0.1% of the maternal serum concentration at 24 hours after dosing [intravenous bolus dose (0.1 mg/kg) of dornase alfa followed by an intravenous infusion (0.080 mg/kg/hr) over a 6-hour period] on post-partum day 14. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for pulmozyme and any potential adverse effects on the breastfed child from pulmozyme or from the underlying maternal condition. 8.4 pediatric use the safety and effectiveness of pulmozyme in conjunction with standard therapies for cystic fibrosis have been established in pediatric patients. use of pulmozyme in pediatric patients is supported by evidence in the following age groups: patients 5 to 17 years of age: use of pulmozyme in patients 5 to 17 years of age is supported by evidence from a randomized, placebo-controlled trial of 303 of clinically stable cystic fibrosis patients 5 to 17 years of age who received pulmozyme [see clinical studies (14) ]. patients less than 5 years : use of pulmozyme in patients less than 5 years of age is supported by extrapolation of efficacy data in patients 5 years of age and older with additional safety data in 65 pediatric patients aged 3 months to less than 5 years who received pulmozyme 2.5 mg daily by inhalation for 2 weeks [ see adverse reactions (6) and clinical studies (14) ] . 8.5 geriatric use cystic fibrosis is primarily a disease of children 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.

red to dams throughout organogenesis (gestation days 6 to 17). dornase alfa did not elicit adverse effects on fetal or neonatal growth when administered to dams throughout most of gestation and delivery (gestation days 6 to 25) and nursing (post-partum days 6 to 21). a pharmacokinetic study in cynomolgus monkeys found no detectable levels of dornase alfa in fetal blood or amniotic fluid on gestation day 150 (end of gestation) from mothers that were administered an intravenous bolus dose (0.1 mg/kg) followed by an intravenous infusion dose (0.080 mg/kg) over a 6-hour period during pregnancy.

f serum concentrations of dnase above normal endogenous levels. 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. 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 for dornase alfa. pulmozyme, 2.5 mg by inhalation, was administered daily to 98 patients aged 3 months to ≤ 10 years, and bronchoalveolar 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 exposure, serum dnase concentrations (mean ± s.d.) increased by 1.1 ± 1.6 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.

ncentrations 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 exposure, serum dnase concentrations (mean ± s.d.) increased by 1.1 ± 1.6 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.

ble 3 ). 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 benefit from twice a day dosing (see table 3 ). the reduced risk of respiratory infection observed in pulmozyme treated patients did not directly correlate with improvement in fev 1 during the initial two weeks of therapy. within 8 days of the start of treatment with pulmozyme, mean fev 1 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 fev 1 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 fev 1 , regardless of age or baseline fvc. table 3. 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) figure 1. mean percent change from baseline fev 1 in patients with fvc ≥40% of predicted figure 1 trial in cf patients with fvc <40% of predicted pulmozyme has also been evaluated in a second randomized, placebo-controlled trial in clinically stable patients with baseline fvc < 40% of predicted. 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 fev 1 (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 experienced a respiratory tract infection by 12 weeks, relative risk = .93, p = 0.62). the effect of pulmozyme on exercise tolerance has not been established in adult and pediatric patients. other studies clinical trials have indicated that pulmozyme 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 bid did not provide further improvement in fev 1 . 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 fev 1 with the initiation of each cycle and a return to baseline with each pulmozyme withdrawal.

r functional changes in pulmozyme or the admixed compound. use with the erapid nebulizer system instruct patients and caregivers to read and follow the directions in both the pulmozyme instructions for use and in the manufacturer's erapid nebulizer system instruction booklet. instruct patients and caregivers to clean the handset, including the medication reservoir, medicine cap, aerosol head, and mouthpiece, after each use. instruct patients and caregivers to disinfect the handset, including the medication reservoir, medicine cap, aerosol head, and mouthpiece, after each day of use. instruct patients to replace the handset after 90 uses, regardless of whether the easycare cleaning aid is used. since delivery data are not available for pulmozyme administered with the erapid handset beyond 90 administrations, delivery of the appropriate therapeutic dose of pulmozyme cannot be assured beyond 90 administrations.

ons for use). read and follow the manufacturer's instructions. do not use any other inhaled medicines in the nebulizer at the same time. keep all other inhaled medicine systems completely separate from pulmozyme. use the mouthpiece or face mask provided with the nebulizer kit. if your child cannot breathe in or breathe out by mouth, you may use the pari baby reusable nebulizer, but you should discuss it with your doctor first. the pari baby nebulizer is the same as the pari lc plus jet system, except the mouthpiece is replaced by a tight-fitting face mask connected to an elbow piece. follow the steps on this side of the sheet to give pulmozyme using the following jet nebulizer systems nebulizer compressor hudson t up-draft ii a compressor with the following specifications is recommended: approximate air flow of 3.5 l/min to 9 l/min at approximately 20 psi to 45 psi pressure marquest acorn ii pari lc plus pari baby durable sidestream for additional information on an appropriate compressor to use with pulmozyme, read the manufacturer's instructions for the recommended nebulizer. important information you need to know before using pulmozyme supplies you will need to give a dose of pulmozyme (see figure a ): 1 pulmozyme ampule compressor nebulizer cup and cap (screw-on or snap-on) plastic t (not needed for sidestream nebulizer or pari baby) flexible aerosol tube (not needed for sidestream nebulizer or pari baby) mouthpiece (clean) or pari baby facemask long connecting tube nose clip (optional, not needed for pari baby) preparing the jet nebulizer and compressor: step 1. clean a flat table surface and wash your hands. clean a flat table surface. wash your hands well with soap and water before using the pulmozyme ampule and nebulizer. this helps prevent infection (see figure b ) . step 2. gather the nebulizer and test the compressor. place the nebulizer parts on a clean, flat table surface within reach. test the compressor by turning it on and putting your finger in front of the "air out" or "air" port to feel air flowing. turn off the compressor (see figure c ) . step 3. gather the pulmozyme ampule and check the expiration date. remove 1 foil pouch of pulmozyme from the refrigerator. open the foil pouch and remove 1 ampule of pulmozyme. put the remaining ampules back in the foil pouch and return them to the refrigerator. check the expiration (exp.) date printed on the ampule (see figure d ) . do not use the pulmozyme ampule if the expiration date has passed. step 4. check the pulmozyme ampule. check the ampule for leaks by turning it upside down and gently squeezing (see figure e ) . do not use the ampule if it is leaking. throw it away and get a new one. check the pulmozyme liquid in the ampule and make sure it is clear and free of particles. do not use pulmozyme if the liquid is cloudy or discolored. take the pulmozyme back to the pharmacy, hospital, or clinic that gave you the medicine. step 5. attach the long connecting tube to the compressor. attach the long connecting tube to the "air out" or "air" port on the compressor (see figure f ) . step 6. attach the mouthpiece. skip to step 7 if you use the sidestream nebulizer or the pari baby nebulizer. push the mouthpiece into the wider end of the plastic t. attach the flexible aerosol tube to the other end of the t (see figure g ) . step 7. remove the cap from the cup. unscrew or unsnap the cap from the nebulizer cup (see figure h ) . put the nebulizer cup on the table face up and place the cap upside down on a clean surface (see figure i ) . step 8. open the pulmozyme ampule. hold the tab at the bottom of the pulmozyme ampule firmly. twist off the top. do not squeeze the body of the ampule (see figure j ) . step 9. pour the full pulmozyme dose into the nebulizer cup. turn the ampule upside down and squeeze gently to empty the medicine into the nebulizer cup. keep squeezing until the ampule is empty. it is very important you squeeze all of the medicine out of the ampule (see figure k ) . screw or snap the cap onto the nebulizer cup (see figure l ) . step 10. connect the plastic t. connect the plastic t to the nebulizer cap (see figure m ) . if you are using the sidestream nebulizer, attach the mouthpiece to the top of the nebulizer (see figure n ). if you are using the pari baby nebulizer, connect the elbow piece and mask to the nebulizer outlet (see figure o ). step 11. attach the long connecting tube to the cup. connect the open end of the long connecting tube to the port on the bottom of the nebulizer cup by pushing up firmly (see figure p ) . step 12. turn on the compressor. turn on the compressor and check to see that mist is coming out of the nebulizer (see figure q ) . taking your dose of pulmozyme with a nebulizer: step 13. breathe through the mouthpiece. skip to step 14 if you are using the pari baby to give pulmozyme to your child. place the mouthpiece between your teeth and on top of your tongue (see figure r ) . breathe slowly in and out through your mouth. do not block the airflow with your tongue. do not breathe through your nose. if you have problems breathing only through your mouth, use a nose clip (see figure s ) . do not be concerned if liquid droplets form in the long connecting tube during treatment. when the nebulizer begins spitting, gently tap the nebulizer cup and continue breathing until the nebulizer cup is empty or stops making mist (see figure t ) . if you need to stop treatment before you are finished, or you begin coughing, turn off the compressor and do not spill any of the medicine. to start treatment again, turn on the compressor and continue breathing slowly in and out through your mouth. the complete treatment usually takes from 10 to 15 minutes for most nebulizers. if you are using the sidestream nebulizer, treatment usually takes from 2 to 6 minutes. it is important to inhale the full dose of pulmozyme. if you find a leak or feel any moisture coming from the nebulizer during treatment, turn off the compressor and check to make sure the nebulizer cap is sealed correctly before continuing (see figure u ) . if you are using the pari baby nebulizer to give pulmozyme to your child, follow the instructions below in step 14. if not, go to step 15 step 14. breathing through the facemask during the treatment your child may sit, lie down or stand. place the facemask gently but firmly over your child's nose and mouth (see figure v ) . make sure there are no air gaps between the mask and your child's face. this will help make sure that your child will get the full dose of pulmozyme. it is important that you try to keep the body of the nebulizer upright during the entire treatment (see figure v ) . the elbow piece will allow you to move the mask for a good fit while keeping the nebulizer body upright. when the nebulizer begins "spitting," gently tap the nebulizer cup and continue treatment until the nebulizer is empty or stops making a mist (see figure w ) . if you need to stop the treatment or your child begins to cough during treatment, turn the compressor off. do not spill any pulmozyme. if you have not removed the mask and you want to begin the treatment again, turn on the compressor. if you have removed the mask, repeat the steps above to replace the mask on your child's face and restart the compressor. the complete treatment usually takes from 10 to 15 minutes. it is important that your child inhale the full dose of pulmozyme. if you find a leak or feel moisture coming from the nebulizer during the treatment, turn off the compressor and make sure the nebulizer cap is sealed correctly before starting the compressor again (see figure x ) . after your treatment with pulmozyme: step 15. prepare the nebulizer for cleaning and storage. turn off the compressor and take apart the nebulizer system. set aside the flexible aerosol tube and the long connecting tube. note: the sidestream nebulizer does not use a flexible aerosol tube. throw away the pulmozyme ampule in your household trash. follow the manufacturer's recommendations for care of your nebulizer and compressor. how should i store pulmozyme? store pulmozyme in its foil pouch in the refrigerator between 36°f to 46°f (2°c to 8°c) until you are ready to use it. when traveling, pulmozyme should be kept cold in its foil pouch. protect pulmozyme from excessive heat and light. do not use pulmozyme if it has been left at room temperature for a total time of 24 hours or if it becomes cloudy or discolored. do not use pulmozyme past the expiration date printed on the ampule. this instructions for use has been approved by the u.s. food and drug administration. genentech, inc. a member of the roche group 1 dna way south san francisco, ca 94080-4990 us license no. 1048 this instructions for use has been approved by the u.s. food and drug administration. revised: 04/2022 figure a figure b figure c figure d figure e figure f figure g figure h figure i figure j figure k figure l figure m figure n figure o figure p figure q figure r figure s figure t figure u figure v figure w figure x figure a figure b figure c figure d figure e figure f figure g figure h figure i figure j figure k figure l figure m figure n figure o figure p figure q