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Overview
Dornase alfa is a Mucolytic enzyme that is FDA approved for the treatment of cystic fibrosis (CF) patients. Common adverse reactions include voice alteration, pharyngitis, rash, laryngitis, chest pain, conjunctivitis, rhinitis, decrease in FVC of ≥10%, fever, and dyspnea.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Indications
PULMOZYME® (dornase alfa) is indicated for daily administration in conjunction with standard therapies for the management of cystic fibrosis (CF) patients to improve pulmonary function.
In CF 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.
Recommended Dosage
The recommended dosage for use in most cystic fibrosis patients is one 2.5 mg single-use ampule inhaled once daily using a recommended jet nebulizer/compressor system or eRapid™ Nebulizer System.
Some patients may benefit from twice daily administration
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dornase alfa in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Dornase alfa in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Dornase alfa in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Dornase alfa in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Dornase alfa in pediatric patients.
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
None
Adverse Reactions
Clinical Trials Experience
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described below reflect exposure to PULMOZYME in 902 patients, with exposures ranging from 2 weeks of daily administration up to once or twice daily administration for six months. PULMOZYME was studied in both placebo-controlled and uncontrolled trials (n=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.
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.
Postmarketing Experience
Postmarketing spontaneous reports and prospectively collected safety data from observational studies confirm the safety profile to be as described in clinical trials
Drug Interactions
Available data indicate there are no clinically important drug-drug interactions with PULMOZYME.
There are no adequate and well-controlled studies with PULMOZYME in pregnant women. However, animal reproduction studies have been conducted with dornase alfa. In these studies, no evidence of fetal harm was observed in rats and rabbits at doses of dornase alfa up to approximately 600 times the maximum recommended human dose (MRHD).
The background risk of major birth defects and miscarriage for the cystic fibrosis population is unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.
Data
Animal Data
Reproductive studies have been performed in rats and rabbits at intravenous doses of dornase alfa up to 10 mg/kg/day (approximately 600 times the MRHD in adults). In a combined embryo-fetal development and pre- and post-natal development study, no evidence of maternal toxicity, embryotoxicity, or teratogenicity was observed when 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.
Pregnancy Category (AUS):
Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dornase alfa in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Dornase alfa during labor and delivery.
Nursing Mothers
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.
Pediatric Use
The safety and effectiveness of PULMOZYME have been established in pediatric patients 5 years of age and older [see Adverse Reactions (6) and Clinical Studies (14)]. The safety of PULMOZYME, 2.5 mg by inhalation, was studied with 2 weeks of daily administration in 65 patients with cystic fibrosis aged 3 months to < 5 years [see Adverse Reactions (6.1)]. While clinical trial data are limited in pediatric patients younger than 5 years of age, the use of PULMOZYME should be considered for pediatric CF patients who may experience potential benefit in pulmonary function or who may be at risk of respiratory tract infection.
Geriatic 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.
Gender
There is no FDA guidance on the use of Dornase alfa with respect to specific gender populations.
Race
There is no FDA guidance on the use of Dornase alfa with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Dornase alfa in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Dornase alfa in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Dornase alfa in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Dornase alfa in patients who are immunocompromised.
Administration and Monitoring
Administration
Directions for Use
Administer PULMOZYME via the eRapid Nebulizer System or via a jet nebulizer connected to an air compressor with an adequate air flow and equipped with a mouthpiece or suitable face mask (see Table 1). No data are currently available to support the administration of PULMOZYME with other nebulizer systems.
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.
The patient should follow the manufacturer's instructions on the use and maintenance of the equipment, including cleaning and disinfection procedures.
When PULMOZYME is administered with the eRapid Nebulizer System, advise 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. The eRapid Nebulizer System should only be used by adults and children who can use a mouthpiece, and not by younger children who need a mask to take PULMOZYME.
2.3 Storage and Handling
Store PULMOZYME ampules in their protective foil pouch under refrigeration and protected from light. Refrigerate ampules during transport and do not expose to room temperatures for a total time of 24 hours.
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.
DOSAGE FORMS AND STRENGTHS
Inhalation Solution: 2.5 mg/2.5 mL in single-use ampules.
Monitoring
There is limited information regarding Monitoring of Dornase alfa in the drug label.
Description
IV Compatibility
There is limited information regarding IV Compatibility of Dornase alfa in the drug label.
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.
Pharmacology
There is limited information regarding Dornase alfa Pharmacology in the drug label.
