Promixin（多粘菌素E甲磺酸盐）已被英国批准用于治疗囊性纤维化患者的肺部感染，该药将在3月正式上市，promixin为吸入性抗菌素，主要作用于肺内的铜绿假单孢菌。 活性成分：  Colistina mesilato sodio多粘菌素钠甲磺酸  ATC: Colistina多粘菌素  生产厂家：PRAXIS PHARMACEUTICAL   PROMIXIN Polvo para sol. para inhal. 1000000 UI env. con 30 viales Clase terapéutica:  Virus, bacterias, parásitos  Principios activos:  Colistina mesilato sodio  ATC:  Colistina  Laboratorio:  PRAXIS PHARMACEUTICAL  Enfermedades: Tratamientos  Fibrosis quística 多粘菌素包括多粘菌素B（polymyxin　B）及多粘菌素E（polymyxin 　E；粘菌素，colistin），二者具有相似的药理作用。是多肽类抗生素，由于静脉给药可致严重肾毒性现已少用。 【体内过程】多粘菌素口服不易吸收。肌内注射50mg后2小时血药浓度达峰值（2～8mg/L），有效血药浓度可维持8～12小时，t1/2约6小时。肾功能不全者清除慢，t1/2可达2～3天。它分布于全身组织，以肝、肾为最高，并保持较长时间。多粘菌素不易弥散进入胸、腹腔、关节腔，即使在脑膜炎症时也不易透入脑脊液中，胆汁中浓度也较低。药物经肾缓慢排泄。 【抗菌作用及临床应用】对多数革兰阴性杆菌有杀灭作用。多肽类抗生素具有表面活性，含有带阳电荷的游离氨基，能与革兰阴性菌细胞膜的磷脂中带阴电荷的磷酸根结合，使细菌细胞膜面积扩大，通透性增加，细胞内的磷酸盐、核苷酸等成份外漏，导致细菌死亡。多粘菌素对生长繁殖期和静止期的细菌都有效，过去曾用于对其他抗生素耐药的绿脓杆菌和革兰阴性杆菌所致感染如败血症、脑膜炎、心内膜炎、烧伤后感染等。但现在已被疗效好、毒性低的其他抗生素所取代。仍可局部用于敏感菌的眼、耳、皮肤、粘膜感染及烧伤绿脓杆菌感染。多粘菌素口服用于肠道手术前准备。 【不良反应】毒性较大。主要表现在肾脏及神经系统两方面，其中多粘菌素B较E尤为多见，症状为蛋白尿、血尿等。大剂量、快速静脉滴注时，由于神经肌肉的阻滞可导致呼吸抑制。 制剂及用法 硫酸链霉素（streptomycin　sulfate）成人0.75～1.0g/日，儿童15～30mg/kg/日，分1～2次肌内注射。成人1～3g/日，儿童1mg/kg/日，分4次服。 硫酸庆大霉素（gentamicin　sulfate）成人16～24万单位/日，儿童3,000～5,000u/kg/日，分3～4次肌内注射。静脉滴注剂量同上，忌与青霉素等混合滴注。鞘内注射，成人每次5,000～10,000单位。口服，成人24万～64万单位/日，儿童1万～1.5万单位/kg/日，分四次服。 硫酸卡那霉素（kanamycin　sulfate）成人1.0～1.5g/日，儿童20～30mg/kg/日，分2～3次肌内注射。静脉滴注用，剂量同肌内注射。疗程一般不超过10～14天。 硫酸妥布霉素（tobramycin　sulfate）成人或儿童每次1.5mg/kg/日，每8小时一次，肌内或静脉注射，总量不超过5mg/kg/日，疗程一般不超过10～14天。 硫酸阿米卡星（amikacin　sulfate）成人1.0～1.5g/日，分2～3次肌内注射。 硫酸西索米星（sisomicin　sulfate）全身性感染用3mg/kg/日，分3次肌内注射，尿道感染可按2mg/kg/日，分2次肌内注射。 硫酸奈替米星（netilimicin　sulfate）成人用4～6mg/kg/日，严重感染7.5mg/kg/日，分2～3次肌内注射；儿童按6～7.5mg/kg/日，分3次给予。 硫酸新霉素（neomycin　sulfate）成人1～4g/日，儿童25～50mg/kg/日，分4次口服。 大观霉素（spectinomycin）2g溶于3.2ml特殊稀释液（0.9%苯甲醇溶液）深部肌注，每日1～2次。 硫酸多粘菌素B（polymyxin　B　sulfate）成人50～100万单位/日，儿童1.0～2.0万单位/日，分2～3次肌内注射或静脉滴注，疗程一般不超过7～14天，鞘内注射，成人1万单位/次，儿童5,000单位/次。 硫酸多粘菌素E（polymyxin　E　sulfate，colistin　sulfate）肌内注射，成人100～150万单位/日，儿童1.5～2.5万单位/kg/日，分2～3次。静脉滴注，成人50～100万单位/日，分2次；儿童1.5～2.5万单位/kg/日，分1～2次。疗程一般不超7天。口服，100～200万单位/日，分3～4次服。 Promixin 1million unit powder for nebuliser solution unit dose vials Promixin 1 million International Units (IU) Powder for Nebuliser Solution 1. NAME OF THE MEDICINAL PRODUCT Promixin, 1 million International Units (IU) Powder for Nebuliser Solution 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each vial contains 1 million International Units (IU) which is approximately equivalent to 80 mg of colistimethate sodium. 3. PHARMACEUTICAL FORM Powder for nebuliser solution. The powder is white to off-white 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Promixin is indicated for the treatment by nebulisation of colonisation and infections of the lung due to susceptible Pseudomonas aeruginosa in patients with cystic fibrosis. Consideration should be given to official guidance on the appropriate use of antibacterial agents. 4.2 Posology and method of administration Sputum cultures should be obtained to confirm colonisation with Pseudomonas aeruginosa sensitive to colistimethate sodium prior to initiating treatment with Promixin. The following information provides guidance on recommended doses and the dose should be adjusted according to clinical response. Recommended doses are: Children >2 years and adults: 1-2 million IU two or three times daily Children < 2 years: The safety and efficacy of Promixin has not been demonstrated in patients less than 2 years of age. The dosage is determined by the severity and type of infection. The dose may be varied across this range depending on the condition being treated. Initial colonisation with Pseudomonas aeruginosa sensitive to colistimethate sodium may be treated with a 3-week course of 2 million IU twice daily in conjunction with other parenteral or oral antibiotics. For frequent, recurrent infections (Less than three positive cultures of Pseudomonas aeruginosa sensitive to colistimethate sodium in a six month period) the dose may be increased up to a maximum of 2 million IU three times daily for up to 3 months, in conjunction with other parenteral or oral antibiotics. Chronic colonisation (Three or more positive cultures of Pseudomonas aeruginosa sensitive to colistimethate sodium in a six month period) may require long-term therapy with 1 to 2 million IU twice daily. Additional parenteral or oral antibiotics may need to be administered to treat acute exacerbations of pulmonary infection. Nebulised Promixin should be administered after physiotherapy and other inhaled treatments, where used. Other inhaled therapies may include agents to reduce the viscoelasticity of sputum and bronchodilators (see Section 4.4). Mode of administration Promixin for nebulisation is intended for administration by nebulisation using a suitable nebuliser. Drug delivery characteristics from in vitro studies with different nebuliser systems are detailed below; Characteristic Nebuliser system Respironics I-neb AAD Pari LC plus with Pari TurboBoy S compressor Respironics Sidestream with Portaneb compressor With 0.3 mL (grey) medication chamber With 0.5 mL (lilac) medication chamber (a) Droplet Size Distribution (µm) Median Particle Size: d50 4.34 4.81 4.78 3.32 (b) Total Drug Delivered from Nebuliser mouthpiece (Million IU) 0.333 0.579 0.407 0.239 (c) Fine Particle Fraction (% < 5µm) 59.55 53.01 52.67 76.07 (d) Total Drug Delivered to patient (Million IU < 5 µm) 0.198 0.307 0.214 0.182 (e) Delivery Time 3 minutes, 36 seconds 8 minutes, 29 seconds 7 minutes, 4 seconds 5 minutes, 18 seconds (f) Drug Delivery Rate to patient (Million IU/minute) 0.055 0.036 0.030 0.034 • Measured using 1 million IU of Promixin reconstituted using 1mL (I-neb AAD) and 3mL (Pari LC plus and Sidestream) of a 50:50 mixture of WFI and 0.9% saline to the recommended volume for each nebuliser system. • TurboBoy S operated at 1.2 bar pressure, 4.5 L/min flow rate. Portaneb operated at: 0.8 bar pressure, 6 L/min flow rate • (d) is calculated from (b) / 100 x (c) • (f) = (d) / (e) For special precautions for disposal and handling of reconstituted solutions, see Section 6.6 4.3 Contraindications Promixin is contraindicated in patients with known hypersensitivity to colistimethate sodium or other polymyxins. Colistimethate sodium is known to reduce the amount of acetylcholine released from the pre-synaptic neuromuscular junction and therefore should not be used in patients with myasthenia gravis. 4.4 Special warnings and precautions for use Bronchospasm Nebulisation of colistimethate sodium may induce coughing or bronchospasm. It is advisable to administer the first dose under medical supervision. Pre-dosing with a bronchodilator is recommended and should be routine, especially if this is part of the patient's current therapeutic regimen. FEV1 should be evaluated pre and post dosing. If there is evidence of colistimethate sodium induced bronchial hyperreactivity in a patient not receiving pre-treatment bronchodilators the test should be repeated on a separate occasion using a bronchodilator. Evidence of bronchial hyperreactivity in the presence of a bronchodilator may indicate an allergic response and Promixin should be discontinued. Bronchospasm that occurs should be treated as medically indicated. Bronchial hyperreactivity in response to colistimethate sodium may develop with continued use over time and it is recommended that pre and post treatment FEV1s are evaluated at regular clinic visits. Renal impairment Colistimethate sodium is renally excreted and is nephrotoxic if high serum concentrations are achieved. Whilst this is unlikely during inhalation therapy, serum concentration estimations are recommended especially in patients with renal impairment. Nephrotoxicity Impairment of renal function has been reported, usually following use of higher than recommended intravenous or intramuscular doses in patients with normal renal function, or failure to reduce the intravenous or intramuscular dosage in patients with renal impairment or when used concomitantly with other nephrotoxic drugs. The effect is usually reversible on discontinuation of therapy. Neurotoxicity High serum concentrations of colistimethate sodium after intravenous or intramuscular administration may be associated with overdosage or failure to reduce the dosage in patients with renal impairment, and this may lead to neurotoxicity. Concomitant use with either non-depolarising muscle relaxants or antibiotics with similar neurotoxic effects can also lead to neurotoxicity. Dose reduction of colistimethate sodium may relieve symptoms. Neurotoxic effects that have been reported include: vertigo, transient facial paraesthesia, slurred speech, vasomotor instability, visual disturbances, confusion, psychosis and apnoea. (see also Section 4.5) Porphyria Use with extreme caution in patients with porphyria. Microbial Resistance Colistimethate sodium acquired resistance in mucoid Pseudomonas aeruginosa during clinical use has been reported. Susceptibility testing should be performed on patients who are treated on a long term basis, at regular clinic visits, and whenever a patient experiences an exacerbation (see Section 5.1). 4.5 Interaction with other medicinal products and other forms of interaction Due to the effects of colistimethate sodium on the release of acetylcholine, non-depolarising muscle relaxants should be used with extreme caution in patients receiving Promixin as their effects could be prolonged (see Section 4.4). Concomitant use of inhaled colistimethate sodium with other medications that are nephrotoxic or neurotoxic (e.g. cephalothin sodium, aminoglycosides, non-depolarising muscle relaxants) including those which are administered by the i.v. or i.m. routes should only be undertaken with the greatest caution (see Section 4.4). 4.6 Pregnancy and lactation Safety in human pregnancy has not been established. Animal studies do not indicate a teratogenic potential. However there is evidence that colistimethate sodium crosses the placenta and consequently there is potential for foetal toxicity if administered during pregnancy. Promixin should only be given during pregnancy if the benefits outweigh any potential risk. Colistimethate sodium is excreted in breast milk; breast feedingisnotrecommended during therapy. 4.7 Effects on ability to drive and use machines Neurotoxicity, characterised by dizziness, confusion or visual disturbances have been reported following parenteral administration of colistimethate sodium. If these effects occur patients should be warned against driving or operating machinery. 4.8 Undesirable effects The commonest undesirable effects following nebulisation of colistimethate sodium are coughing and bronchospasm (indicated by chest tightness which may be detected by a decrease in FEV1) in approximately 10% of patients. (See also Section 4.4) Adverse reactions are tabulated below by system organ class and frequency. Frequencies are defined as Very common (1/10): common (1/100 to <1/10): uncommon (1/1,000 to <1/100): rare (1/10,000 to <1/1,000) and very rare (<1/10,000), not known (cannot be estimated from the available data) Body System Frequency Reported adverse reaction Immune system disorders Not known Hypersensitivity reactions such as skin rash Respiratory, thoracic and mediastinal disorders Very common Cough, chest tightness, bronchoconstriction or bronchospasm General disorders and administration site conditions Not known Sore throat and sore mouth. Should hypersensitivity reactions such asskinrashoccurtreatmentwithcolistimethate sodium should be withdrawn. Cases of sore throat or sore mouth may be due to hypersensitivityorsuperinfection with Candida species. 4.9 Overdose Overdosage may cause apnoea, muscle weakness, vertigo, transient facial paraesthesia, slurred speech, vasomotor instability, visual disturbances, confusion, psychosis and renal insufficiency. No antidote is available. Management of overdose is by means of supportive treatment and measures designed to increase clearance of colistimethate sodium such as inducing an osmotic diuresis with mannitol, peritoneal dialysis or prolonged haemodialysis. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: other antibacterials, Polymyxins. ATC code: J01XB01 General properties Mode of action Colistimethate sodium is a prodrug of colistin, a polymyxin antibiotic , (belonging to the polymyxin E group). It is a polypeptide structure and is derived from Bacillus polymyxa var. colistinus. The polymyxin antibiotics are surface active agents and act by binding to and changing the permeability of the bacterial cell membrane causing bacterial cell death. Polymyxins are bactericidal against Gram-negative bacteria with a hydrophobic outer membrane. PK/PD relationship Polymyxins have been reported to have a concentration-dependent bactericidal effect on susceptible bacteria. Mechanisms of resistance Resistance develops due to modifications of lipopolysaccharide (LPS) or other components in the bacterial cell membrane. Susceptibility The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable. Commonly susceptible species Acinetobacter species Haemophilus influenzae Klebsiella species Pseudomonas aeruginosa Species for which acquired resistance may be a problem Stenotrophomonas maltophilia Achromobacter xylosoxidans (formerly Alcaligenes xylosoxidans) Inherently resistant organisms Burkholderia cepacia and related species Proteus spp Providencia spp Serratia spp Resistance Colistimethate sodium acquired resistance in mucoid Pseudomonas aeruginosa has been reported to be approximately 3%. However, local rates of resistance may vary including higher rates (see Section 4.4). Cross resistance The resistance to polymyxins is not crossed with other antibiotic families. 5.2 Pharmacokinetic properties Absorption Gastrointestinal absorption is negligible hence the swallowing of colistimethate sodium deposited in the nasopharynx is unlikely to add to the systemic exposure. Absorption following lung administration is influenced by the nebuliser system, aerosol droplet size and disease state of the lungs. Pharmacokinetics A study in healthy volunteers, who inhaled colistimethate sodium, demonstrated the Cmax of polymyxin E1 (the active moiety) varied between 40.0 and 69.9 ng/mL and the AUC varied between 350 and 668 ng/mL/h depending on the nebuliser and the fill volume and concentration, which varied the dose from 0.3 million IU to 2 million IU. The half-life was approximately 5.2 hours. The absolute bioavailability was calculated to vary between 5% and 18% depending on the nebuliser. The AUC following an intravenous dose of 0.5 million IU was 3,352 ng/ml/h and the Cmax was 1,232 ng/mL. Biotransformation Colistimethate sodium undergoes conversion to its base in vivo. Elimination There is no information on the elimination of colistimethate sodium following nebulisation. Following i.v. administration excretion is primarily renal with 62% of a parenteral dose recovered in the urine within 8 hours and around 80% in 24 hours. 5.3 Preclinical safety data Animal studies with colistimethate do not indicate adverse effects on fertility or embryo-foetal development. Peri-postnatal studies have not been conducted. Data on potential genotoxicity and carcinogenicity for colistimethate sodium are lacking. Colistin has been shown to induce chromosomal aberrations in human lymphocytes in vitro an effect that might be related to a reduction in mitotic index, which was also observed. Colistin was not mutagenic in a set of other tests 6. PHARMACEUTICAL PARTICULARS None 6.2 Incompatibilities The addition of other antibiotics to solutions of Promixin may lead to precipitation. This medicinal product should not be mixed with other medicinal products except those mentioned in section 6.6. Unopened: 2 years. Once reconstituted: Use immediately. 6.5 Nature and contents of container The product is supplied in clear type I glass vials sealed with a siliconised chlorobutyl type I rubber stopper and protected by a 20 mm aluminium tear-off cap incorporating a red flip-up central plastic top. The product is supplied in packs of 30 vials. Each pack contains a Promixin Disc to enable use with the I-neb AAD System. 6.6 Special precautions for disposal and other handling Promixin may be reconstituted with Water for Injections (WFI) to produce a clear colourless to pale yellow hypotonic solution or a 50:50 mixture of WFI and 0.9% saline to produce a clear colourless to pale yellow isotonic solution. When reconstituted, Promixin may be used with any conventional nebuliser suitable for delivery of antibiotic solutions. Solutions should be used immediately after reconstitution. Any unused solution remaining in the nebuliser must be discarded following treatment. Promixin is supplied with a Promixin Disc, for use with the I-neb AAD System. For instructions on the use of Promixin with the I-neb AAD System, please refer to detailed instructions provided with the device. Conventional nebulisers operate on a continuous flow basis and it is likely that some nebulised drug will be released into the local environment. When used with a conventional nebuliser, Promixin should be administered in a well-ventilated room, particularly in hospitals where several patients may be using nebulisers at the same time. Tubing or filters may be used to prevent waste aerosol from entering the environment.