部分中文Pulmozyme处方资料（仅供参考） 中文药名：阿法脱氧核糖核酸酶 英文药名：Dornase alfa(Pulmozyme) 别名 胰去氧核糖核酸酶, 脱氧核糖核酸酶，Streptodornase，Panceratic Dornase，Dornavac，Deoxyribonuclease。 药理作用 本品是在治疗肺囊性纤维化(Cystic fibrosis, CF)方面的一项重要进展，也是30年来第一个治疗这种疾病的新药。 本品是从哺乳动物胰腺或溶血性链球菌培养基中分离提取的酶制品，随着生物技术的进展而开发的，现多为天然人脱氧核糖核酸酶（也称DNA酶或重组人DNA酶）的重组形式，它含有260个氨基酸，在排列顺序上与天然人的DNA酶完全一样。 本品的作用好似一把“分子剪刀”，直接作用于脓性痰，选择性切开细胞外的脱氧核糖核酸，迅速降低痰液粘度，使分泌物粘性降低并易于咳出。其次由于脓痰中脱氧核糖核酸与蛋白结合，使白细胞中的蛋白溶解酶不能发挥作用，减少了蛋白的自然溶解，而在本药溶解脱氧核糖核酸后。痰中蛋白失去保护，易被白细胞中的蛋白溶解酶分解。产生继发的蛋白溶解作用，这在粘痰的溶解中也起很大作用。 本药不仅可使脓痰的粘度下降，而且与抗生素合用时，可使抗生素易于到达感染灶，能充分发挥作用。本品不能穿透正常的细胞膜，因此它不损伤在活细胞内的DNA。 适应症 本品适用于与常规治疗方法结合在一起治疗肺囊性纤维化。单纯本品不能代替常规的抗菌治疗，用于呼吸系统感染有大量脓痰的患者，能减少应用抗菌素的次数并减轻呼吸道感染，从而减少抗菌素用量，减少住院和其它有关的卫生保健服务的花费。 剂量与用法 本品溶液经压缩空气驱动的雾化器产生气溶胶，大多数病人每日吸入1次（2.5mg）（雾化吸入：每次5万～10万U（溶于生理盐水）），每天3～4次，一般连续用药4～6天。气管内滴入：每次5万U（溶于2mL生理盐水），适量滴入。 一些研究提示，本品对较大年龄（20岁以上）的病人疗效比年龄小的差，较大年龄的病人每天须要两倍的剂量，而另一些研究认为，1天大于2.5mg两倍的剂量并无任何益处。 临床评价 许多轻到中度肺功能衰竭的病人应用本品后出现肺功能和生命质量的改善，如呼吸困难，咳嗽和夜间因咳嗽觉醒及端坐呼吸次数的减少。还观察到这些病人在学校和其它活动时间的延长。最近的研究表明，本品明显减低慢性支气管炎急性加重住院病人的死亡率并减少病人复发和再住院天数，尽管这类疾病 现在还不是本品规定的适应症，但是这个研究揭示了本品在严重呼吸道疾病洽疗中是有益的。 包装规格 2.5毫克/2.5毫升/安瓿 6包，30包/盒 生产厂家：罗氏制药公司 Pulmozyme 2500 U/ 2.5ml, nebuliser solution 1. Name of the medicinal product Pulmozyme 2500 U/ 2.5 ml, nebuliser solution 2. Qualitative and quantitative composition Each ampoule contains 2500 U (corresponding to 2.5 mg) of dornase alfa* per 2.5 ml corresponding to 1000 U/ml or 1 mg/ml**. *phosphorylated glycosylated protein human deoxyribonuclease 1 produced in Chinese Hamster Ovary Cell Line CHO A14.16-1 MSB #757 by recombinant DNA technology 1 Genentech unit/ml = 1µg/ml For a full list of excipients, see section 6.1. 3. Pharmaceutical form Nebuliser solution Clear, colourless to slightly yellowish solution 4. Clinical particulars 4.1 Therapeutic indications Management of cystic fibrosis patients with a forced vital capacity (FVC) of greater than 40% of predicted and over 5 years of age to improve pulmonary function. 4.2 Posology and method of administration Posology 2.5 mg (corresponding to 2500 U) deoxyribonuclease l by inhalation once daily. Some patients over the age of 21 years may benefit from twice daily dosage. Most patients gain optimal benefit from regular daily use of Pulmozyme. In studies in which Pulmozyme was given in an intermittent regimen, improvement in pulmonary function was lost on cessation of therapy. Patients should therefore be advised to take their medication every day without a break. Patients should continue their regular medical care, including their standard regimen of chest physiotherapy. Administration can be safely continued in patients who experience exacerbation of respiratory tract infection. Safety and efficacy have not yet been established in patients with forced vital capacity less than 40% of predicted. Paediatric population Safety and efficacy have not yet been established in patients under the age of 5 years. Method of administration Inhale the content of one ampoule (2.5 ml of solution) undiluted using a recommended nebuliser system (see section 6.6). 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use Traceability of PULMOZYME: In order to improve the traceability of Pulmozyme the trade name of the administered dornase alfa and the batch number should be clearly recorded in the patient file. 4.5 Interaction with other medicinal products and other forms of interaction Pulmozyme can be effectively and safely used in conjunction with standard cystic fibrosis therapies such as antibiotics, bronchodilators, pancreatic enzymes, vitamins, inhaled and systemic corticosteroids, and analgesics. 4.6 Pregnancy and lactation Pregnancy The safety of dornase alfa has not been established in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, or embryofoetal development (see section 5.3). Caution should be exercised when prescribing dornase alfa to pregnant women. Breastfeeding When dornase alfa is administered to humans according to the dosage recommendation, there is minimal systemic absorption; therefore no measurable concentrations of dornase alfa would be expected in human milk. Nevertheless, caution should be exercised when dornase alfa is administered to a breast-feeding woman (see section 5.3). 4.7 Effects on ability to drive and use machines Pulmozyme has no or negligible influence on the ability to drive and use machines. 4.8 Undesirable effects The adverse event data reflect the clinical trial and post-marketing experience of using Pulmozyme at the recommended dose regimen. Adverse reactions attributed to Pulmozyme are rare (< 1/1000). In most cases, the adverse reactions are mild and transient in nature and do not require alterations in Pulmozyme dosing. Eye disorders: Conjunctivitis. Respiratory, thoracic and mediastinal disorders: Dysphonia, dyspnea, pharyngitis, laryngitis, rhinitis (all non-infectious). Gastrointestinal disorders: Dyspepsia. Skin and subcutaneous tissue disorders: Rash, urticaria. General disorders: Chest pain (pleuritic/non-cardiac), pyrexia. Investigations: Pulmonary function tests decreased. Patients who experience adverse events common to cystic fibrosis can, in general, safely continue administration of Pulmozyme as evidenced by the high percentage of patients completing clinical trials with Pulmozyme. In clinical trials, few patients experienced adverse events resulting in permanent discontinuation from dornase alfa, and the discontinuation rate was observed to be similar between placebo (2%) and dornase alfa (3%). Upon initiation of dornase alfa therapy, as with any aerosol, pulmonary function may decline and expectoration of sputum may increase. Less than 5% of patients treated with dornase alfa have developed antibodies to dornase alpha and none of these patients have developed IgE antibodies to dornase alfa. Improvement in pulmonary function tests has still occurred even after the development of antibodies to dornase alfa. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Malta: ADR Reporting, at Website: www.medicinesauthority.gov.mt/adrportal, United Kingdom: Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard. 4.9 Overdose The effect of Pulmozyme overdosage has not been established. In clinical studies, cystic fibrosis patients have inhaled up to 20 mg Pulmozyme twice daily (16 times the recommended daily dose) for up to 6 days and 10 mg twice daily (8 times the recommended dose) intermittently (2 weeks on/2 weeks off drug) for 168 days. Six adult non-cystic fibrosis patients received a single intravenous dose of 125 μg/kg of dornase alfa, followed 7 days later by 125 μg/kg subcutaneously for two consecutive 5-day periods, without either neutralising antibodies to DNase or any change in serum antibodies against double-stranded DNA being detected. All of these doses were well tolerated. Systemic toxicity of Pulmozyme has not been observed and is not expected due to the poor absorption and short serum half-life of dornase alfa. Systemic treatment of overdose is therefore unlikely to be necessary (see section 5.2). 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: respiratory system, ATC code: R 05 C B13. Mechanism of action Recombinant human DNase is a genetically engineered version of a naturally occurring human enzyme which cleaves extracellular DNA. Retention of viscous purulent secretions in the airways contributes both to reduced pulmonary function and to exacerbations of infection. Purulent secretions contain very high concentrations of extracellular DNA, a viscous polyanion released by degenerating leukocytes, which accumulate in response to infection. In vitro, dornase alfa hydrolyses DNA in sputum and greatly reduces the viscoelasticity of cystic fibrosis sputum. Clinical efficacy and safety Efficacy and safety was established in double-blind, placebo-controlled studies (Z0342/Z0343) in which patients over 5 years of age and with FVC over 40% predicted received 2.5 mg Pulmozyme once or twice daily over a 24-week period. Overall, 968 patients (mean age of 19 years) with a mean baseline FVC of 78% were randomised in these trials. Another placebo-controlled double-blind study (Z0713) evaluated the effect of Pulmozyme (2.5 mg once daily for 2 years) on pulmonary function in young patients (aged 6-11 years) with minimum evidence of lung disease as defined by FVC of ≥ 85% predicted. Overall, 474 patients (mean age of 8.4 years) with a mean baseline FVC of 102.3% were randomised in this trial. Results of the main endpoints are shown in the following tables. A significant increase in FEV1 was observed in the beginning of treatment with Pulmozyme and subsided over time, especially after the first year of treatment; however, the difference with placebo remained statistically significant. Pulmozyme reduced the relative risk of respiratory tract exacerbations requiring parenteral antibiotics by about 30%; this reduction did not correlate with the improvement in FEV1 measured during the first weeks of therapy. Studies Z0342/Z0343 Placebo 2.5mg QD 2.5mg BID N = 325 N = 322 N = 321 FEV1 (% predicted) Mean % change from baseline Day 8 - 0.5% 7.9% 9.0% Week 24 0.1% 5.1% 3.6% Overall 0.0% 5.8% 5.6% p < 0.001 p < 0.001 % patients with exacerbations over 24 weeks 43% 34% 33% Relative risk (95% CI) 0.73 (0.57 - 0.94) 0.71 (0.55 - 0.91) p = 0.015 p = 0.007 Study Z0713 Placebo 2.5mg QD N = 235 N = 237 Spirometry Mean change from baseline (at Week 96) FEV1 (% predicted) - 3.10 0.03 p = 0.008 FVC (% predicted) - 2.88 - 2.23 p = 0.54 FEF 25-75 (% predicted) - 4.05 3.83 p = 0.0008 % patients with exacerbations over 96 weeks 24% 17% Relative risk (95% CI) 0.66 (0.44 - 0.996) p = 0.048 Post-hoc analysis of the data suggests that the effects of Pulmozyme on respiratory tract exacerbations in older patients (>21 years) may be smaller than in younger patients, and that twice daily dosing may be required in the older patients. The percentage of older patients developing exacerbations over 24 weeks was 44% on placebo, 48% and 39% on Pulmozyme 2.5 mg daily and twice daily, respectively. 5.2 Pharmacokinetic properties Absorption Inhalation studies conducted in rats and non-human primates show a low percentage of dornase alfa systemic absorption, < 15% for rats and < 2% for monkeys. Consistent with the results of these animal studies, dornase alfa administered to patients as an inhaled aerosol shows low systemic exposure. Absorption of dornase alfa from the gastrointestinal tract following oral administration to rats is negligible. DNase is normally present in human serum. Inhalation of up to 40 mg of dornase alfa for up to 6 days did not result in a significant elevation of serum DNase concentration above normal endogenous levels. No increase in serum DNase concentration greater than 10ng/ml was observed. Following administration of 2500 U (2.5 mg) of dornase alfa twice daily for 24 weeks, mean serum DNase concentrations were no different from the mean pre-treatment baseline value of 3.5 ± 0.1 ng/ml; suggesting low systemic absorption or accumulation. Distribution Studies in rats and monkeys have shown that, following intravenous administration, dornase alfa was cleared rapidly from the serum. The initial volume of distribution was similar to serum volume in these studies. Inhalation of 2500 U (2.5 mg) dornase alfa results in a mean sputum concentration of dornase alfa of approximately 3 µg/ml within 15 minutes in cystic fibrosis patients. Concentrations of dornase alfa in sputum rapidly decline following inhalation. Metabolism Dornase alfa is expected to be metabolised by proteases present in biological fluids. Elimination Studies in rats and monkeys have shown that, following intravenous administration, rhDNase is cleared rapidly from the serum. Human intravenous studies suggested an elimination half-life from serum of 3-4 hours. Studies in rats indicate that, following aerosol administration the disappearance half-life of dornase alfa from the lungs is 11 hours. In humans, sputum DNase levels declined below half of those detected immediately post-administration within 2 hours but effects on sputum rheology persisted beyond 12 hours. Paediatric population Pulmozyme, 2.5 mg by inhalation, was administered daily for 2 weeks to 98 patients aged 3 months to 9 years (65 aged 3 months to <5 years, 33 aged 5 to 9 years), and bronchoalveolar lavage (BAL) fluid was obtained within 90 minutes of the first dose. The Pari Baby reusable nebuliser (which uses a facemask instead of a mouthpiece) was utilised 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). 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 9 year age group. The incidence of fever was more frequent in the younger than older age group (41% vs. 24%, respectively); fever is a known complication of bronchoscopy. 5.3 Preclinical safety data Non-clinical data based on standard studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction do not indicate a specific safety risk for humans. In a study performed in lactating cynomolgus monkeys, receiving high doses of dornase alfa by the intravenous route (100 µg/kg bolus followed by 80 µg/kg/hour for 6 hours), low concentrations (< 0.1% of the concentrations seen in the maternal serum of cynomolgus monkeys), were detectable in the maternal milk. A four-week inhalation toxicity study in juvenile rats commenced dosing 22 days after parturition at doses to the LRT of 0, 51, 102 and 260 µg/kg/day. Dornase alfa was well tolerated, and no lesions were found in the respiratory tract. 6. Pharmaceutical particulars 6.1 List of excipients Sodium Chloride Calcium Chloride Dihydrate Water for Injections 6.2 Incompatibilities Pulmozyme is an unbuffered aqueous solution and should not be diluted or mixed with other drugs or solutions in the nebuliser bowl. Mixing of this solution could lead to adverse structural and/or functional changes in Pulmozyme or the admixed compound. 6.3 Shelf life 2 years. 6.4 Special precautions for storage Store in a refrigerator (2°C - 8°C). Keep the ampoule in the outer carton in order to protect from light. A single brief exposure to elevated temperatures (less than or equal to 24 hours at up to 30°C) does not affect product stability. 6.5 Nature and contents of container 2.5 ml of nebuliser solution in an ampoule (low density polyethylene plastic). Pack sizes of 6 and 30. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling The contents of one 2.5 mg (2500 U) single-use ampoule of Pulmozyme sterile solution for inhalation should be inhaled once a day using a recommended nebuliser. Pulmozyme should not be mixed with other drugs or solutions in the nebuliser (see section 6.2). • Pulmozyme may be used in conjunction with a jet nebuliser/compressor system, such as the Hudson T Up-draft II/Pulmo-Aide, Airlife Misty/Pulmo-Aide, customised Respirgard/Pulmo-Aide, or AcornII/Pulmo-Aide. • Pulmozyme may also be used in conjunction with a reusable jet nebuliser/compressor system, such as the Pari LL/Inhalierboy, Pari LC/Inhalierboy or Master, Aiolos/2 Aiolos, Side Stream/CR50 or MobilAire or Porta-Neb. • The Pari eFlow Rapid nebuliser, a general purpose electronic vibrating membrane nebuliser may be used. Parity between the eFlow Rapid electronic nebuliser and the LC Plus jet nebuliser has been demonstrated in vitro and in vivo. The average droplet size distribution of the aerosol generated by the eFlow Rapid nebuliser compared with the LC Plus jet nebuliser is shown below, using an adult breath simulator profile. The mass median aerodynamic diameter (MMAD) was 4.8 ± 0.4 µm (n=16) for e Flow Rapid and 4.6 ± 0.4 µm (n=12) for LC Plus. The geometric standard deviation (GSD) was 1.80 ± 0.11 for eFlow Rapid and 2.14 ± 0.04 for LC Plus. The drug delivery rate was 380 ± 60 µg/min (n=88) for eFlow Rapid and 93 ± 16 µg/min (n=40) for LC Plus. The total drug delivered was 567 ± 62 µg for eFlow Rapid and 570 ± 80 µg for LC Plus. The Pari eFlow Rapid nebuliser should be used with the Pari EasyCare cleaning accessory and cleaning should be performed every seventh nebulisation cycle (a cycle being defined as a nebulisation of a single ampoule of Pulmozyme followed by cleaning and disinfecting in accordance with the PARI eFlow Rapid nebuliser system instruction for use). Using the eFlow Rapid nebuliser without EasyCare cleaning accessory may lead to lower and more variable dose delivery. • Ultrasonic nebulisers may be unsuitable for delivery of Pulmozyme because they may inactivate Pulmozyme or have unacceptable aerosol delivery characteristics. The manufacturers' instructions on the use and maintenance of the nebuliser and compressor should be followed. Containment of the aerosol is not necessary. Pulmozyme ampoules are for single administration only. Any unused product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Roche Products Limited 6 Falcon Way Shire Park Welwyn Garden City AL7 1TW United Kingdom 8. Marketing authorisation number(s) PL00031/0335 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 12 January 1994 Date of latest renewal: 11 March 2009 10. Date of revision of the text 12 November 2015 -------------------------------------------- 产地国家：英国 原产地英文商品名: Pulmozyme nebuliser solution 2500U 2.5mg/2.5ml/bag 6bags/box 原产地英文药品名: Dornase alfa 中文参考商品译名: Pulmozyme吸入剂 2500单位 2.5毫克/2.5毫升/包 6包/盒 中文参考药品译名: 阿法脱氧核糖核酸酶 生产厂家中文参考译名: 罗氏制药 生产厂家英文名: Roche -------------------------------------------- 产地国家：英国 原产地英文商品名: Pulmozyme nebuliser solution 2500U 2.5mg/2.5ml/bag 30bags/box 原产地英文药品名: Dornase alfa 中文参考商品译名: Pulmozyme吸入剂 2500单位 2.5毫克/2.5毫升/包 30包/盒 中文参考药品译名: 阿法脱氧核糖核酸酶 生产厂家中文参考译名: 罗氏制药 生产厂家英文名: Roche -------------------------------------------- 产地国家：德国 原产地英文商品名: Pulmozyme 2.5mg /2.5ml/bag 6bags/box 原产地英文药品名: Dornase alfa 中文参考商品译名: Pulmozyme吸入剂 2.5毫克/2.5毫升/包 6包/盒 中文参考药品译名: 阿法脱氧核糖核酸酶 生产厂家中文参考译名: 罗氏制药 生产厂家英文名: Roche -------------------------------------------- 产地国家：德国 原产地英文商品名: Pulmozyme 2.5mg /2.5ml/bag 30bags/box 原产地英文药品名: Dornase alfa 中文参考商品译名: Pulmozyme吸入剂 2.5毫克/2.5毫升/包 30包/盒 中文参考药品译名: 阿法脱氧核糖核酸酶 生产厂家中文参考译名: 罗氏制药 生产厂家英文名: Roche