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注射用达托霉素|CUBICIN(daptomycin for injection)

2015-01-02 12:02:12  作者:新特药房  来源:互联网  浏览次数:220  文字大小:【】【】【
简介: 部分中文CUBICIN处方资料(仅供参考)药品英文名 Daptomycin 药品别名 Cidecin、Cubicin 药物剂型 注射用达托霉素:350mg/支;500mg/支。2~8℃冷藏保存。 药理作用 本品是从reseosporus链霉菌发酵液中 ...

部分中文CUBICIN处方资料(仅供参考)
药品英文名
Daptomycin
药品别名
Cidecin、Cubicin
药物剂型
注射用达托霉素:350mg/支;500mg/支。2~8℃冷藏保存。
药理作用
本品是从reseosporus链霉菌发酵液中提取得到的一个环酯肽类抗生素,具有新颖的化学结构。通过多方面破坏细菌细胞膜的功能,达到抗菌的作用,包括扰乱细胞膜对氨基酸的转运,从而阻碍细菌细胞壁肽聚糖和胞壁酸酯的生物合成,改变细胞膜电位。
另外,本品还能通过破坏细菌的细胞膜,使其内容物外泄而达到杀灭细菌的目的。对甲氧西林耐药的葡萄球菌和万古霉素耐药的肠球菌,应用本品的效果大于万古霉素或替考拉宁。本品仅对革兰阳性菌敏感,如对糖肽类敏感的葡萄球菌、对甲氧西林耐药的肠球菌、对甲氧西林敏感和耐药的金黄色葡萄球菌、凝固酶阴性葡萄球菌、对苯唑青霉素耐药的金黄色葡萄球菌和表皮葡萄球菌、对青霉素敏感和耐药的肺炎链球菌、草绿色链球菌、化脓性链球菌、无乳链球菌、C族和G族链球菌、嗜酸性乳酸杆菌、嗜酪蛋白乳酸杆菌鼠李糖亚种、万古霉素敏感和耐药的粪肠球菌。本品对单核细胞增多性李斯特杆菌的效果相对较差,对于革兰阴性病原体基本无效。
药动学
静脉给药治疗白色念珠菌血症48h起效。健康志愿者一日分别静脉给药4mg/kg、6mg/kg和8mg/kg,7日后,本品的平均血浆峰浓度分别是57.8μg/ml、98.6μg/ml和133μg/ml,达峰时间分别是0.8h、0.5h和0.5h,平均稳态谷浓度分别是5.9μg/ml、9.4μg/m1和14.9μg/ml,药时曲线下面积(AUC)分别是494μg·h/ml、747μg·h/ml和1130μg·h/ml。肾功能不全患者的平均AUC较大。本品与蛋白可逆性结合,总蛋白结合率为90%~95%,与药物浓度大小无关。药代学研究表明,本品组织穿透性弱,分布体积小,心内膜炎和菌血症患者分布容积是0.21L/kg,健康受试者分布容积是0.12L/kg。
本品可能通过肾脏代谢而不通过肝脏代谢。静脉给药(0.5~6mg/kg)后,在尿中检测到本品的代谢物。给药总量约有80%从肾脏排出,5%~5.7%从粪便排泄。消除半衰期为7~11h,没有剂量依赖性的证据,肾损害时,半衰期延长。本品可经血透和腹透清除。
适应证
本品用于复杂性皮肤及皮肤软组织感染。
禁忌证
对本品过敏者禁用。
注意事项
1.有肌肉骨骼病史者使用本品有恶化的可能,应慎用。
2.肾脏损害者慎用。
3.本品是否通过乳汁排泄尚不清楚,哺乳期妇女慎用。4.18岁以下患者,尚未确定本品的安全性和有效性。5.本品的妊娠安全性分级为B级。
6.应将本品稀释于O.9%的氯化钠注射液中,静脉给药时间应持续30min。
7.本品组织穿透性弱,可能对深层感染疗效不佳(如心内膜炎、骨感染),即使高剂量也如此(如6mg/kg)。8.用药前后及用药时应当定期进行血常规、肾功能、血生化、肌酸磷酸激酶项目检查
不良反应
1.心血管系统 可发生低血压(2.4%)、高血压(1.1%)、水肿、心衰和室上性心律失常。2.中枢神经系统 可发生头昏(2.2%)、头痛(5.4%)、失眠(4.5%)、焦虑、意识错乱、眩晕和感觉异常。3.代谢/内分泌系统 可发生低血钾、高血糖、低血镁、血清碳酸盐增加和电解质紊乱。4.呼吸系统 可发生呼吸困难(2.1%)。5.肌肉骨骼系统 可发生肢体痛(1.5%)、关节痛(0.9%)、肌痛、肌痉挛、肌无力和骨髓炎。6.肾脏 可发生肾衰(2.2%)。7.肝脏 可发生肝功能异常(3%),如碱性磷酸酶和乳酸脱氢酶升高以及黄疸。8.胃肠道 可发生恶心(5.8%)、呕吐(3.2%)、腹泻(5.2%)、便秘(6.2%)、消化不良(0.9%)、腹痛、食欲下降、口腔炎和腹胀。9.血液 可发生贫血(2.1%)、白细胞增多、血小板减少(或增多)、嗜曙红细胞增多和国际标准化比值升高。10.皮肤 可发生皮疹(4.3%)、瘙痒(2.8%)和湿疹。11.其他 可有注射部位反应(5.8%)、发烧(1.9%)和过敏反应。
用法用量
静注,每次4~6mg/kg,每日1次,连续用药7~14日。肌酐清除率低于30ml/min者(包括接受血液透析或连续门诊腹膜透析者),每次4mg/kg,每2日1次。
药物相应作用
1.本品与庆大霉素或阿贝卡星合用,抗葡萄球菌和肠球菌时,有协同作用。
2.与3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶抑制剂合用,可能会增加肌病的风险。


Cubicin powder for concentrate for solution for injection or infusion
1. Name of the medicinal product
Cubicin® 350 mg powder for solution for injection or infusion
Cubicin® 500 mg powder for solution for injection or infusion
2. Qualitative and quantitative composition
Cubicin 350 mg powder for solution for infusion or injection: Each vial contains 350 mg daptomycin.
One ml provides 50 mg of daptomycin after reconstitution with 7 ml of sodium chloride 9 mg/ml (0.9%) solution.
Cubicin 500 mg powder for solution for infusion or injection: Each vial contains 500 mg daptomycin.
One ml provides 50 mg of daptomycin after reconstitution with 10 ml of sodium chloride 9 mg/ml (0.9%) solution.
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Powder for solution for injection or infusion
A pale yellow to light brown lyophilised cake or powder.
4. Clinical particulars
4.1 Therapeutic indications
Cubicin is indicated for the treatment of the following infections in adults (see sections 4.4 and 5.1).
- Complicated skin and soft-tissue infections (cSSTI).
- Right-sided infective endocarditis (RIE) due to Staphylococcus aureus. It is recommended that the decision to use daptomycin should take into account the antibacterial susceptibility of the organism and should be based on expert advice. See sections 4.4 and 5.1.
- Staphylococcus aureus bacteraemia (SAB) when associated with RIE or with cSSTI.
Daptomycin is active against Gram positive bacteria only (see section 5.1). In mixed infections where Gram negative and/or certain types of anaerobic bacteria are suspected, Cubicin should be co-administered with appropriate antibacterial agent(s).
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
4.2 Posology and method of administration
Clinical studies in patients employed infusion of daptomycin over 30 minutes. There is no clinical experience in patients with the administration of daptomycin as an injection over 2 minutes. This mode of administration was only studied in healthy subjects. However, when compared with the same doses given as intravenous infusions over 30 minutes there were no clinically important differences in the pharmacokinetics and safety profile of daptomycin (see also sections 4.8 and 5.2).
Posology
- cSSTI without concurrent Staphylococcus aureus bacteraemia: Cubicin 4 mg/kg is administered once every 24 hours for 7-14 days or until the infection is resolved (see section 5.1).
- cSSTI with concurrent Staphylococcus aureus bacteraemia: Cubicin 6 mg/kg is administered once every 24 hours. See below for dose adjustments in patients with renal impairment. The duration of therapy may need to be longer than 14 days in accordance with the perceived risk of complications in the individual patient.
- Known or suspected right-sided infective endocarditis due to Staphylococcus aureus: Cubicin 6 mg/kg is administered once every 24 hours. See below for dose adjustments in patients with renal impairment. The duration of therapy should be in accordance with available official recommendations.
Cubicin is administered intravenously in 0.9% sodium chloride (see section 6.6). Cubicin should not be used more frequently than once a day.
Renal impairment
Daptomycin is eliminated primarily by the kidney.
Due to limited clinical experience (see table and footnotes below) Cubicin should only be used in patients with any degree of renal impairment (CrCl < 80 ml/min) when it is considered that the expected clinical benefit outweighs the potential risk. The response to treatment, renal function and creatine phosphokinase (CPK) levels should be closely monitored in all patients with any degree of renal impairment (see also sections 4.4 and 5.2).
Dose adjustments in patients with renal impairment by indication and creatinine clearance

Indication for use

Creatinine clearance

Dose recommendation

Comments

cSSTI without S. aureus bacteraemia

≥ 30 ml/min

4 mg/kg once daily

See section 5.1

 

< 30 ml/min

4 mg/kg every 48 hours

(1, 2)

RIE or cSSTI associated with S. aureus bacteraemia

≥ 30 ml/min

6 mg/kg once daily

See section 5.1

 

< 30 ml/min

6 mg/kg every 48 hours

(1, 2)

(1) The safety and efficacy of the dose interval adjustment have not been evaluated in controlled clinical trials and the recommendation is based on pharmacokinetic studies and modelling results (see sections 4.4 and 5.2).
(2) The same dose adjustments, which are based on pharmacokinetic data in volunteers including PK modelling results, are recommended for patients on haemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). Whenever possible, Cubicin should be administered following the completion of dialysis on dialysis days (see section 5.2).
Hepatic impairment
No dose adjustment is necessary when administering Cubicin to patients with mild or moderate hepatic impairment (Child-Pugh Class B) (see section 5.2). No data are available in patients with severe hepatic impairment (Child-Pugh Class C). Therefore caution should be exercised if Cubicin is given to such patients.
Elderly patients
The recommended doses should be used in elderly patients except those with severe renal impairment (see above and section 4.4).
Paediatric population
The safety and efficacy of Cubicin in children and adolescents aged below 18 years have not been established. Currently available data are described in section 5.2 but no recommendation on a posology can be made.
Method of administration
Cubicin is given by intravenous infusion (see section 6.6) and administered over a 30-minute period or by intravenous injection (see section 6.6) and administered over a 2-minute period.
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
General
If a focus of infection other than cSSTI or RIE is identified after initiation of Cubicin therapy consideration should be given to instituting alternative antibacterial therapy that has been demonstrated to be efficacious in the treatment of the specific type of infection(s) present.
Anaphylaxis/hypersensitivity reactions
Anaphylaxis/hypersensitivity reactions have been reported with Cubicin. If an allergic reaction to Cubicin occurs, discontinue use and institute appropriate therapy.
Pneumonia
It has been demonstrated in clinical studies that Cubicin is not effective in the treatment of pneumonia. Cubicin is therefore not indicated for the treatment of pneumonia.
RIE due to Staphylococcus aureus
Clinical data on the use of Cubicin to treat RIE due to Staphylococcus aureus are limited to 19 patients (see “Information from clinical trials” in section 5.1).
The efficacy of Cubicin in patients with prosthetic valve infections or with left-sided infective endocarditis due to Staphylococcus aureus has not been demonstrated.
Deep-seated infections
Patients with deep-seated infections should receive any required surgical interventions (e.g. debridement, removal of prosthetic devices, valve replacement surgery) without delay.
Enterococcal infections
There is insufficient evidence to be able to draw any conclusions regarding the possible clinical efficacy of Cubicin against infections due to enterococci, including Enterococcus faecalis and Enterococcus faecium. In addition, dose regimens of daptomycin that might be appropriate for the treatment of enterococcal infections, with or without bacteraemia, have not been identified. Failures with daptomycin in the treatment of enterococcal infections that were mostly accompanied by bacteraemia have been reported. In some instances treatment failure has been associated with the selection of organisms with reduced susceptibility or frank resistance to daptomycin (see section 5.1).
Non-susceptible micro-organisms
The use of antibacterials may promote the overgrowth of non-susceptible micro-organisms. If superinfection occurs during therapy, appropriate measures should be taken.
Clostridium difficile-associated diarrhoea
Clostridium difficile-associated diarrhoea (CDAD) has been reported with Cubicin (see section 4.8). If CDAD is suspected or confirmed, Cubicin may need to be discontinued and appropriate treatment instituted as clinically indicated.
Drug/laboratory test interactions
False prolongation of prothrombin time (PT) and elevation of international normalised ratio (INR) have been observed when certain recombinant thromboplastin reagents are utilised for the assay (see also section 4.5).
Creatine phosphokinase and myopathy
Increases in plasma creatine phosphokinase (CPK; MM isoenzyme) levels associated with muscular pains and/or weakness and cases of myositis, myoglobinaemia and rhabdomyolysis have been reported during therapy with Cubicin (see also sections 4.5, 4.8 and 5.3). In clinical studies, marked increases in plasma CPK to > 5x Upper Limit of Normal (ULN) without muscle symptoms occurred more commonly in Cubicin-treated patients (1.9%) than in those that received comparators (0.5%). Therefore, it is recommended that:
• Plasma CPK should be measured at baseline and at regular intervals (at least once weekly) during therapy in all patients.
• CPK should be measured more frequently (e.g. every 2-3 days at least during the first two weeks of treatment) in patients who are at higher risk of developing myopathy. For example, patients with any degree of renal impairment (creatinine clearance < 80 ml/min; see also section 4.2), including those on haemodialysis or CAPD, and patients taking other medicinal products known to be associated with myopathy (e.g. HMG-CoA reductase inhibitors, fibrates and ciclosporin).
• It cannot be ruled out that those patients with CPK greater than 5 times upper limit of normal at baseline may be at increased risk of further increases during daptomycin therapy. This should be taken into account when initiating daptomycin therapy and, if daptomycin is given, these patients should be monitored more frequently than once weekly.
• Cubicin should not be administered to patients who are taking other medicinal products associated with myopathy unless it is considered that the benefit to the patient outweighs the risk.
• Patients should be reviewed regularly while on therapy for any signs or symptoms that might represent myopathy.
• Any patient that develops unexplained muscle pain, tenderness, weakness or cramps should have CPK levels monitored every 2 days. Cubicin should be discontinued in the presence of unexplained muscle symptoms if the CPK level reaches greater than 5 times upper limit of normal.
Peripheral neuropathy
Patients who develop signs or symptoms that might represent a peripheral neuropathy during therapy with Cubicin should be investigated and consideration should be given to discontinuation of daptomycin (see sections 4.8 and 5.3).
Eosinophilic pneumonia
Eosinophilic pneumonia has been reported in patients receiving Cubicin (see section 4.8). In most reported cases associated with Cubicin, patients developed fever, dyspnoea with hypoxic respiratory insufficiency, and diffuse pulmonary infiltrates. The majority of cases occurred after more than 2 weeks of treatment with Cubicin and improved when Cubicin was discontinued and steroid therapy was initiated. Recurrence of eosinophilic pneumonia upon re-exposure has been reported. Patients who develop these signs and symptoms while receiving Cubicin should undergo prompt medical evaluation, including, if appropriate, bronchoalveolar lavage, to exclude other causes (e.g. bacterial infection, fungal infection, parasites, other medicinal products). Cubicin should be discontinued immediately and treatment with systemic steroids should be initiated when appropriate.
Renal impairment
Renal impairment has been reported during treatment with Cubicin. Severe renal impairment may in itself also pre-dispose to elevations in daptomycin levels which may increase the risk of development of myopathy (see above).
An adjustment of Cubicin dose interval is needed for patients whose creatinine clearance is < 30 ml/min (see sections 4.2 and 5.2). The safety and efficacy of the dose interval adjustment have not been evaluated in controlled clinical trials and the recommendation is mainly based on pharmacokinetic modelling data. Cubicin should only be used in such patients when it is considered that the expected clinical benefit outweighs the potential risk.
Caution is advised when administering Cubicin to patients who already have some degree of renal impairment (creatinine clearance < 80 ml/min) before commencing therapy with Cubicin. Regular monitoring of renal function is advised (see also section 5.2).
In addition, regular monitoring of renal function is advised during concomitant administration of potentially nephrotoxic agents, regardless of the patient's pre-existing renal function (see also section 4.5).
Obesity
In obese subjects with Body Mass Index (BMI) > 40 kg/m2 but with creatinine clearance > 70 ml/min, the AUC0-∞ daptomycin was significantly increased (mean 42% higher) compared with non-obese matched controls. There is limited information on the safety and efficacy of daptomycin in the very obese and so caution is recommended. However, there is currently no evidence that a dose reduction is required (see section 5.2).
4.5 Interaction with other medicinal products and other forms of interaction
Daptomycin undergoes little to no Cytochrome P450 (CYP450)-mediated metabolism. It is unlikely that daptomycin will inhibit or induce the metabolism of medicinal products metabolised by the P450 system.
Interaction studies for Cubicin were performed with aztreonam, tobramycin, warfarin and probenecid. Daptomycin had no effect on the pharmacokinetics of warfarin or probenecid, nor did these medicinal products alter the pharmacokinetics of daptomycin. The pharmacokinetics of daptomycin were not significantly altered by aztreonam.
Although small changes in the pharmacokinetics of daptomycin and tobramycin were observed during coadministration by intravenous infusion over a 30-minute period using a Cubicin dose of 2 mg/kg, the changes were not statistically significant. The interaction between daptomycin and tobramycin with an approved dose of Cubicin is unknown. Caution is warranted when Cubicin is co-administered with tobramycin.
Experience with the concomitant administration of Cubicin and warfarin is limited. Studies of Cubicin with anticoagulants other than warfarin have not been conducted. Anticoagulant activity in patients receiving Cubicin and warfarin should be monitored for the first several days after therapy with Cubicin is initiated.
There is limited experience regarding concomitant administration of daptomycin with other medicinal products that may trigger myopathy (e.g. HMG-CoA reductase inhibitors). However, some cases of marked rises in CPK levels and cases of rhabdomyolysis occurred in patients taking one of these medicinal products at the same time as Cubicin. It is recommended that other medicinal products associated with myopathy should if possible be temporarily discontinued during treatment with Cubicin unless the benefits of concomitant administration outweigh the risk. If co-administration cannot be avoided, CPK levels should be measured more frequently than once weekly and patients should be closely monitored for any signs or symptoms that might represent myopathy. See sections 4.4, 4.8 and 5.3.
Daptomycin is primarily cleared by renal filtration and so plasma levels may be increased during co-administration with medicinal products that reduce renal filtration (e.g. NSAIDs and COX-2 inhibitors). In addition, there is a potential for a pharmacodynamic interaction to occur during co-administration due to additive renal effects. Therefore, caution is advised when daptomycin is co-administered with any other medicinal product known to reduce renal filtration.
During post–marketing surveillance, cases of interference between daptomycin and particular reagents used in some assays of prothrombin time/international normalised ratio (PT/INR) have been reported. This interference led to a false prolongation of PT and elevation of INR. If unexplained abnormalities of PT/INR are observed in patients taking daptomycin, consideration should be given to a possible in vitro interaction with the laboratory test. The possibility of erroneous results may be minimised by drawing samples for PT or INR testing near the time of trough plasma concentrations of daptomycin (see section 4.4).
4.6 Fertility, pregnancy and lactation
Pregnancy
No clinical data on pregnancies are available for daptomycin. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).
Cubicin should not be used during pregnancy unless clearly necessary i.e., only if the expected benefit outweighs the possible risk.
Breast-feeding
In a single human case study, Cubicin was intravenously administered daily for 28 days to a nursing mother at a dose of 500 mg/day, and samples of the patient's breast milk were collected over a 24-hour period on day 27. The highest measured concentration of daptomycin in the breast milk was 0.045 mcg/ml, which is a low concentration. Therefore, until more experience is gained, breast-feeding should be discontinued when Cubicin is administered to nursing women.
Fertility
No clinical data on fertility are available for daptomycin. Animal studies do not indicate direct or indirect harmful effects with respect to fertility (see section 5.3).
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed.
On the basis of reported adverse drug reactions, Cubicin is presumed to be unlikely to produce an effect on the ability to drive or use machinery.
4.8 Undesirable effects
Summary of the safety profile
In clinical studies, 2,011 subjects received Cubicin. Within these trials, 1,221 subjects received a daily dose of 4 mg/kg, of whom 1,108 were patients and 113 were healthy volunteers; 460 subjects received a daily dose of 6 mg/kg, of whom 304 were patients and 156 were healthy volunteers. Adverse reactions (i.e. considered by the investigator to be possibly, probably, or definitely related to the medicinal product) were reported at similar frequencies for Cubicin and comparator regimens.
The most frequently reported adverse reactions (frequency common (≥ 1/100 to < 1/10)) are:
Fungal infections, urinary tract infection, candida infection, anaemia, anxiety, insomnia, dizziness, headache, hypertension, hypotension, gastrointestinal and abdominal pain, nausea, vomiting, constipation, diarrhoea, flatulence, bloating and distension, liver function tests abnormal (increased alanine aminotransferase (ALT), aspartate aminotransferase (AST) or alkaline phosphatase (ALP)), rash, pruritus, limb pain, serum creatine phosphokinase (CPK) increased, infusion site reactions, pyrexia, asthenia.
Less frequently reported, but more serious, adverse reactions include hypersensitivity reactions, eosinophilic pneumonia, drug rash with eosinophilia and systemic symptoms (DRESS), angioedema and rhabdomyolysis.
Tabulated list of adverse reactions
The following adverse reactions were reported during therapy and during follow-up with frequencies corresponding to 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); very rare (< 1/10,000); not known (cannot be estimated from the available data):
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 1 Adverse reactions from clinical studies and post-marketing reports

System organ class

Frequency

Adverse reactions

Infections and infestations

Common:

Fungal infections, urinary tract infection, candida infection

Uncommon:

Fungaemia

Not known*:

Clostridium difficile-associated diarrhoea**

Blood and lymphatic system disorders

Common:

Anaemia

Uncommon:

Thrombocythaemia, eosinophilia, international normalised ratio (INR) increased

Rare:

Prothrombin time (PT) prolonged

Immune system disorders

Not known*:

Hypersensitivity**, manifested by isolated spontaneous reports including, but not limited to angioedema, drug rash with eosinophilia and systemic symptoms (DRESS), pulmonary eosinophilia, vesicobullous rash with mucous membrane involvement and sensation of oropharyngeal swelling

Not known*:

Anaphylaxis**

Not known*:

Infusion reactions including the following symptoms: tachycardia, wheezing, pyrexia, rigors, systemic flushing, vertigo, syncope and metallic taste

Metabolism and nutrition disorders

Uncommon:

Decreased appetite, hyperglycaemia, electrolyte imbalance

Psychiatric disorders

Common:

Anxiety, insomnia

Nervous system disorders

Common:

Dizziness, headache

Uncommon:

Paraesthesia, taste disorder, tremor

Not known*:

Peripheral neuropathy**

Ear and labyrinth disorders

Uncommon:

Vertigo

Cardiac disorders

Uncommon:

Supraventricular tachycardia, extrasystole

Vascular disorders

Common:

Hypertension, hypotension

Uncommon:

Flushes

Respiratory, thoracic and mediastinal disorders

Not known*:

Eosinophilic pneumonia1**, cough

Gastrointestinal disorders

Common:

Gastrointestinal and abdominal pain, nausea, vomiting, constipation, diarrhoea, flatulence, bloating and distension

Uncommon:

Dyspepsia, glossitis

Hepatobiliary disorders

Common:

Liver function tests abnormal2 (increased alanine aminotransferase (ALT), aspartate aminotransferase (AST) or alkaline phosphatase (ALP))

Rare:

Jaundice

Skin and subcutaneous tissue disorders

Common:

Rash, pruritus

Uncommon:

Urticaria

Musculoskeletal and connective tissue disorders

Common:

Limb pain, serum creatine phosphokinase (CPK)2 increased

Uncommon:

Myositis, increased myoglobin, muscular weakness, muscle pain, arthralgia, serum lactate dehydrogenase (LDH) increased

Not known*:

Rhabdomyolysis3 **

Renal and urinary disorders

Uncommon:

Renal impairment, including renal failure and renal insufficiency, serum creatinine increased

Reproductive system and breast disorders

Uncommon:

Vaginitis

General disorders and administration site conditions

Common:

Infusion site reactions, pyrexia, asthenia

Uncommon:

Fatigue, pain

* Based on post-marketing reports. Since these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorised as not known.
** See section 4.4.
1 While the exact incidence of eosinophilic pneumonia associated with daptomycin is unknown, to date the reporting rate of spontaneous reports is very low (< 1/10,000).
2 In some cases of myopathy involving raised CPK and muscle symptoms, the patients also presented with elevated transaminases. These transaminase increases were likely to be related to the skeletal muscle effects. The majority of transaminase elevations were of Grade 1-3 toxicity and resolved upon discontinuation of treatment.
3 When clinical information on the patients was available to make a judgement, approximately 50% of the cases occurred in patients with pre-existing renal impairment, or in those receiving concomitant medicinal products known to cause rhabdomyolysis.
The safety data for the administration of daptomycin via 2-minute intravenous injection are derived from two pharmacokinetic studies in healthy volunteers. Based on these study results, both methods of daptomycin administration, the 2-minute intravenous injection and the 30-minute intravenous infusion, had a similar safety and tolerability profile. There was no relevant difference in local tolerability or in the nature and frequency of adverse reactions.
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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9 Overdose
In the event of overdose, supportive care is advised. Daptomycin is slowly cleared from the body by haemodialysis (approximately 15% of the administered dose is removed over 4 hours) or by peritoneal dialysis (approximately 11% of the administered dose is removed over 48 hours).
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antibacterials for systemic use, Other antibacterials, ATC code: J01XX09
Mechanism of action
Daptomycin is a cyclic lipopeptide natural product that is active against Gram positive bacteria only.
The mechanism of action involves binding (in the presence of calcium ions) to bacterial membranes of both growing and stationary phase cells causing depolarisation and leading to a rapid inhibition of protein, DNA, and RNA synthesis. This results in bacterial cell death with negligible cell lysis.
PK/PD relationship
Daptomycin exhibits rapid, concentration dependent bactericidal activity against Gram positive organisms in vitro and in in vivo animal models. In animal models AUC/MIC and Cmax/MIC correlate with efficacy and predicted bacterial kill in vivo at single doses equivalent to human doses of 4 mg/kg and 6 mg/kg once daily.
Mechanisms of resistance
Strains with decreased susceptibility to daptomycin have been reported especially during the treatment of patients with difficult-to-treat infections and/or following administration for prolonged periods. In particular, there have been reports of treatment failures in patients infected with Staphylococcus aureus, Enterococcus faecalis or Enterococcus faecium, including bacteraemic patients, that have been associated with the selection of organisms with reduced susceptibility or frank resistance to daptomycin during therapy.
The mechanism(s) of daptomycin resistance is (are) not fully understood.
Breakpoints
Minimum inhibitory concentration (MIC) breakpoint established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for Staphylococci and Streptococci (except S. pneumoniae) are Susceptible ≤ 1 mg/l and Resistant > 1 mg/l.
Susceptibility
The prevalence of resistance may vary geographically and over 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

Staphylococcus aureus *

Staphylococcus haemolyticus

Coagulase negative staphylococci

Streptococcus agalactiae*

Streptococcus dysgalactiae subsp equisimilis*

Streptococcus pyogenes*

Group G streptococci

Clostridium perfringens

Peptostreptococcus spp

Inherently resistant organisms

Gram negative organisms

* denotes species against which it is considered that activity has been satisfactorily demonstrated in clinical studies.
Clinical efficacy and safety
In two clinical trials in complicated skin and soft tissues infections, 36% of patients treated with Cubicin met the criteria for systemic inflammatory response syndrome (SIRS). The most common type of infection treated was wound infection (38% of patients), while 21% had major abscesses. These limitations of the patients population treated should be taken into account when deciding to use Cubicin.
In a randomised controlled open-label study in 235 patients with Staphylococcus aureus bacteraemia (i.e, at least one positive blood culture of Staphylococcus aureus prior to receiving the first dose) 19 of 120 patients treated with Cubicin met the criteria for RIE. Of these 19 patients 11 were infected with methicillin-susceptible and 8 with methicillin-resistant Staphylococcus aureus. The success rates in RIE patients are shown in the table below.

Population

Daptomycin

Comparator

Differences in Success

 

n/N (%)

n/N (%)

Rates (95% CI)

ITT (intention to treat) Population

     

RIE

8/19 (42.1%)

7/16 (43.8%)

-1.6% (-34.6, 31.3)

PP (per protocol) Population

     

RIE

6/12 (50.0%)

4/8 (50.0%)

0.0% (-44.7, 44.7)

Failure of treatment due to persisting or relapsing Staphylococcus aureus infections was observed in 19/120 (15.8%) patients treated with Cubicin, 9/53 (16.7%) patients treated with vancomycin and 2/62 (3.2%) patients treated with an anti-staphylococcal semi-synthetic penicillin. Among these failures six patients treated with Cubicin and one patient treated with vancomycin were infected with Staphylococcus aureus that developed increasing MICs of daptomycin on or following therapy (see “Mechanisms of resistance” above). Most patients who failed due to persisting or relapsing Staphylococcus aureus infection had deep-seated infection and did not receive necessary surgical intervention.
5.2 Pharmacokinetic properties
Daptomycin pharmacokinetics are generally linear and time-independent at doses of 4 to 12 mg/kg administered as a single daily dose by 30-minute intravenous infusion for up to 14 days in healthy volunteers. Steady-state concentrations are achieved by the third daily dose.
Daptomycin administered as a 2-minute intravenous injection also exhibited dose proportional pharmacokinetics in the approved therapeutic dose range of 4 to 6 mg/kg. Comparable exposure (AUC and Cmax) was demonstrated in healthy subjects following administration of daptomycin as a 30-minute intravenous infusion or as a 2-minute intravenous injection.
Animal studies showed that daptomycin is not absorbed to any significant extent after oral administration.
Distribution
The volume of distribution at steady state of daptomycin in healthy adult subjects was approximately 0.1 l/kg and was independent of dose. Tissue distribution studies in rats showed that daptomycin appears to only minimally penetrate the blood-brain barrier and the placental barrier following single and multiple doses.
Daptomycin is reversibly bound to human plasma proteins in a concentration independent manner. In healthy volunteers and patients treated with daptomycin, protein binding averaged about 90% including subjects with renal impairment.
Biotransformation
In in vitro studies, daptomycin was not metabolised by human liver microsomes. In vitro studies with human hepatocytes indicate that daptomycin does not inhibit or induce the activities of the following human cytochrome P450 isoforms: 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4. It is unlikely that daptomycin will inhibit or induce the metabolism of medicinal products metabolised by the P450 system.
After infusion of 14C-daptomycin in healthy adults, the plasma radioactivity was similar to the concentration determined by microbiological assay. Inactive metabolites were detected in urine, as determined by the difference in total radioactive concentrations and microbiologically active concentrations. In a separate study, no metabolites were observed in plasma, and minor amounts of three oxidative metabolites and one unidentified compound were detected in urine. The site of metabolism has not been identified.
Elimination
Daptomycin is excreted primarily by the kidneys. Concomitant administration of probenecid and daptomycin has no effect on daptomycin pharmacokinetics in humans suggesting minimal to no active tubular secretion of daptomycin.
Following intravenous administration, plasma clearance of daptomycin is approximately 7 to 9 ml/h/kg and its renal clearance is 4 to 7 ml/h/kg.
In a mass balance study using radiolabelled material, 78% of the administered dose was recovered from the urine based on total radioactivity, whilst urinary recovery of unchanged daptomycin was approximately 50% of the dose. About 5% of the administered radiolabel was excreted in the faeces.
Special populations
Elderly
Following administration of a single 4 mg/kg intravenous dose of Cubicin over a 30-minute period, the mean total clearance of daptomycin was approximately 35% lower and the mean AUC0-∞ was approximately 58% higher in elderly subjects (≥ 75 years of age) compared with those in healthy young subjects (18 to 30 years of age). There were no differences in Cmax. The differences noted are most likely due to the normal reduction in renal function observed in the geriatric population.
No dose adjustment is necessary based on age alone. However, renal function should be assessed and the dose should be reduced if there is evidence of severe renal impairment.
Children and adolescents (< 18 years of age)
The pharmacokinetics of daptomycin after a single 4 mg/kg dose of Cubicin were evaluated in three groups of paediatric patients with proven or suspected Gram-positive infection (2-6 years, 7-11 years and 12-17 years). The pharmacokinetics of daptomycin following a single 4 mg/kg dose in adolescents aged 12-17 years are generally similar to those of healthy adult subjects with normal renal function with trends towards lower AUC and Cmax in adolescents. In the younger age groups (2-6 years and 7-11 years), total clearance was higher compared with that in adolescents, resulting in a lower level of exposure (AUC and Cmax) and elimination half-life. Efficacy was not assessed in this study.
A separate study was conducted to evaluate the pharmacokinetics of daptomycin after a single 8 mg/kg or 10 mg/kg dose of Cubicin as either a 1 or 2 hour infusion in paediatric subjects aged 2 to 6 years, inclusive, with proven or suspected Gram-positive infection who were receiving standard antibacterial therapy.
The mean exposure (AUC0-∞) was approximately 429 and 550 μg*hr/ml after the administration of 8 and 10 mg/kg single doses, respectively, similar to the exposure seen in adults at the 4 mg/kg dose at steady state (495 μg*hr/ml). The pharmacokinetics of daptomycin appears to be linear in the dose range studied. The half life, clearance and volume of distribution were similar at both dose levels.
Obesity
Relative to non-obese subjects daptomycin systemic exposure measured by AUC was about 28% higher in moderately obese subjects (Body Mass Index of 25-40 kg/m2) and 42% higher in extremely obese subjects (Body Mass Index of > 40 kg/m2). However, no dose adjustment is considered to be necessary based on obesity alone.
Gender
No clinically significant gender-related differences in daptomycin pharmacokinetics have been observed.
Renal impairment
Following administration of a single 4 mg/kg or 6 mg/kg intravenous dose of daptomycin over a 30-minute period to subjects with various degrees of renal impairment, total daptomycin clearance (CL) decreased and systemic exposure (AUC) increased as renal function (creatinine clearance) decreased.
Based on pharmacokinetic data and modelling, the daptomycin AUC during the first day after administration of a 6 mg/kg dose to patients on HD or CAPD was 2-fold higher than that observed in patients with normal renal function who received the same dose. On the second day after administration of a 6 mg/kg dose to HD and CAPD patients the daptomcyin AUC was approximately 1.3-fold higher than that observed after a second 6 mg/kg dose in patients with normal renal function. On this basis, it is recommended that patients on HD or CAPD receive daptomycin once every 48 hours at the dose recommended for the type of infection being treated (see section 4.2).
Hepatic impairment
The pharmacokinetics of daptomycin is not altered in subjects with moderate hepatic impairment (Child-Pugh B classification of hepatic impairment) compared with healthy volunteers matched for gender, age and weight following a single 4 mg/kg dose. No dosage adjustment is necessary when administering daptomycin in patients with moderate hepatic impairment. The pharmacokinetics of daptomycin in patients with severe hepatic impairment (Child-Pugh C classification) have not been evaluated.
5.3 Preclinical safety data
In studies of clinically-relevant duration (14-28 days), daptomycin administration was associated with minimal to mild degenerative/regenerative changes in skeletal muscle in the rat and dog. Microscopic changes in skeletal muscle were minimal (approximately 0.05% of myofibres affected) and at the higher doses were accompanied by elevations in CPK. No fibrosis or rhabdomyolysis was observed. Depending on the study duration, all muscle effects, including microscopic changes, were fully reversible within 1-3 months following cessation of dosing. No functional or pathological changes in smooth or cardiac muscle were observed.
The lowest observable effect level (LOEL) for myopathy in rats and dogs occurred at exposure levels of 0.8 to 2.3-fold the human therapeutic levels at 6 mg/kg (30-minute intravenous infusion) for patients with normal renal function. As the pharmacokinetics (see section 5.2) is comparable, the safety margins for both methods of administration are very similar.
A study in dogs demonstrated that skeletal myopathy was reduced upon once daily administration as compared to fractionated dosing at same total daily dose, suggesting that myopathic effects in animals were primarily related to time between doses.
Effects on peripheral nerves were observed at higher doses than those associated with skeletal muscle effects in adult rats and dogs, and were primarily related to plasma Cmax. Peripheral nerve changes were characterised by minimal to slight axonal degeneration and were frequently accompanied by functional changes. Reversal of both the microscopic and functional effects was complete within 6 months post-dose. Safety margins for peripheral nerve effects in rats and dogs are 8- and 6-fold, respectively, based on comparison of Cmax values at the No Observed Effect Level (NOEL) with the Cmax achieved on dosing with 30-minute intravenous infusion of 6 mg/kg once daily in patients with normal renal function.
The findings of in vitro and some in vivo studies designed to investigate the mechanism of daptomycin myotoxicity indicate that the plasma membrane of differentiated spontaneously contracting muscle cells is the target of toxicity. The specific cell surface component directly targeted has not been identified. Mitochondrial loss/damage was also observed; however the role and significance of this finding in the overall pathology are unknown. This finding was not associated with an effect on muscle contraction.
In contrast to adult dogs, juvenile dogs appeared to be more sensitive to peripheral nerve lesions as compared to skeletal myopathy. Juvenile dogs developed peripheral and spinal nerve lesions at doses lower than those associated with skeletal muscle toxicity.
Reproductive toxicity testing showed no evidence of effects on fertility, embryofetal, or postnatal development. However, daptomycin can cross the placenta in pregnant rats (see section 5.2). Excretion of daptomycin into milk of lactating animals has not been studied.
Long-term carcinogenicity studies in rodents were not conducted. Daptomycin was not mutagenic or clastogenic in a battery of in vivo and in vitro genotoxicity tests.
6. Pharmaceutical particulars
6.1 List of excipients
Sodium hydroxide
6.2 Incompatibilities
Cubicin is not physically or chemically compatible with glucose-containing solutions. This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
6.3 Shelf life
3 years
After reconstitution: Chemical and physical in-use stability of the reconstituted solution in the vial has been demonstrated for 12 hours at 25°C and up to 48 hours at 2°C – 8°C. Chemical and physical stability of the diluted solution in infusion bags is established as 12 hours at 25°C or 24 hours at 2°C – 8°C.
For the 30-minute intravenous infusion, the combined storage time (reconstituted solution in vial and diluted solution in infusion bag; see section 6.6) at 25°C must not exceed 12 hours (or 24 at 2°C – 8°C).
For the 2-minute intravenous injection, the storage time of the reconstituted solution in the vial (see section 6.6) at 25°C must not exceed 12 hours (or 48 at 2°C – 8°C).
However, from a microbiological point of view the product should be used immediately. No preservative or bacteriostatic agent is present in this product. If not used immediately, in-use storage times are the responsibility of the user and would not normally be longer than 24 hours at 2°C – 8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.
6.4 Special precautions for storage
Store in a refrigerator (2°C – 8°C).
For storage conditions after reconstitution and after reconstitution and dilution of the medicinal product see section 6.3.
6.5 Nature and contents of container
Single use 10 ml type I clear glass vials with type I rubber stoppers and aluminium closures with yellow (350 mg) or blue (500 mg) plastic flip off caps.
Available in packs containing 1 vial or 5 vials.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Daptomycin may be administered intravenously as an infusion over 30 minutes or as an injection over 2 minutes (see sections 4.2 and 5.2). Preparation of the solution for infusion requires an additional dilution step as detailed below.
Cubicin 350mg powder for solution for injection or infusion
Cubicin given as 30-minute intravenous infusion
A 50 mg/ml concentration of Cubicin for infusion is obtained by reconstituting the lyophilised product with 7 ml of sodium chloride 9 mg/ml (0.9%) solution for injection.
The lyophilised product takes approximately 15 minutes to dissolve. The fully reconstituted product will appear clear and may have a few small bubbles or foam around the edge of the vial.
To prepare Cubicin for intravenous infusion, please adhere to the following instructions:
Aseptic technique should be used throughout to reconstitute lyophilised Cubicin.
1. The polypropylene flip off cap should be removed to expose the central portions of the rubber stopper. Draw 7 ml of sodium chloride 9 mg/ml (0.9%) solution for injection into a syringe, then slowly inject through the centre of the rubber stopper into the vial pointing the needle towards the wall of the vial.
2. The vial should be gently rotated to ensure complete wetting of the product and then allowed to stand for 10 minutes.
3. Finally the vial should be gently rotated/swirled for a few minutes as needed to obtain a clear reconstituted solution. Vigorous shaking/agitation should be avoided to prevent foaming of the product.
4. The reconstituted solution should be checked carefully to ensure that the product is in solution and visually inspected for the absence of particulates prior to use. Reconstituted solutions of Cubicin range in colour from pale yellow to light brown.
5. The reconstituted solution should then be diluted with sodium chloride 9 mg/ml (0.9%) (typical volume 50 ml).
6. Invert the vial in order to allow the solution to drain towards the stopper. Using a new syringe, insert the needle into the inverted vial. Keeping the vial inverted, position the needle tip at the very bottom of the solution in the vial when drawing the solution into the syringe. Before removing the needle from the vial, pull the plunger all the way back to the end of the syringe barrel in order to remove all of the solution from the inverted vial.
7. Replace needle with a new needle for the intravenous infusion.
8. Expel air, large bubbles, and any excess solution in order to obtain the required dose.
9. The reconstituted and diluted solution should then be infused intravenously over 30 minutes as directed in section 4.2.
The following have been shown to be compatible when added to Cubicin containing infusion solutions: aztreonam, ceftazidime, ceftriaxone, gentamicin, fluconazole, levofloxacin, dopamine, heparin and lidocaine.
Cubicin given as 2-minute intravenous injection
Water should not be used for reconstitution of Cubicin for intravenous injection. Cubicin should only be reconstituted with sodium chloride 9 mg/ml (0.9%).
A 50 mg/ml concentration of Cubicin for injection is obtained by reconstituting the lyophilised product with 7 ml of sodium chloride 9 mg/ml (0.9%) solution for injection.
The lyophilised product takes approximately 15 minutes to dissolve. The fully reconstituted product will appear clear and may have a few small bubbles or foam around the edge of the vial.
To prepare Cubicin for intravenous injection, please adhere to the following instructions:
Aseptic technique should be used throughout to reconstitute lyophilised Cubicin.
1. The polypropylene flip off cap should be removed to expose the central portions of the rubber stopper. Draw 7 ml of sodium chloride 9 mg/ml (0.9%) solution for injection into a syringe, then slowly inject through the centre of the rubber stopper into the vial pointing the needle towards the wall of the vial.
2. The vial should be gently rotated to ensure complete wetting of the product and then allowed to stand for 10 minutes.
3. Finally the vial should be gently rotated/swirled for a few minutes as needed to obtain a clear reconstituted solution. Vigorous shaking/agitation should be avoided to prevent foaming of the product.
4. The reconstituted solution should be checked carefully to ensure that the product is in solution and visually inspected for the absence of particulates prior to use. Reconstituted solutions of Cubicin range in colour from pale yellow to light brown.
5. Invert the vial in order to allow the solution to drain towards the stopper. Using a new syringe, insert the needle into the inverted vial. Keeping the vial inverted, position the needle tip at the very bottom of the solution in the vial when drawing the solution into the syringe. Before removing the needle from the vial, pull the plunger all the way back to the end of the syringe barrel in order to remove all of the solution from the inverted vial.
6. Replace needle with a new needle for the intravenous injection.
7. Expel air, large bubbles, and any excess solution in order to obtain the required dose.
8. The reconstituted solution should then be injected intravenously slowly over 2 minutes as directed in section 4.2.
Cubicin vials are for single-use only.
From a microbiological point of view, the product should be used immediately after reconstitution (see section 6.3).
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Cubicin 500mg powder for solution for injection or infusion
Cubicin given as 30-minute intravenous infusion
A 50 mg/ml concentration of Cubicin for infusion is obtained by reconstituting the lyophilised product with 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection.
The lyophilised product takes approximately 15 minutes to dissolve. The fully reconstituted product will appear clear and may have a few small bubbles or foam around the edge of the vial.
To prepare Cubicin for intravenous infusion, please adhere to the following instructions:
Aseptic technique should be used throughout to reconstitute lyophilised Cubicin.
1. The polypropylene flip off cap should be removed to expose the central portions of the rubber stopper. Draw 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection into a syringe, then slowly inject through the centre of the rubber stopper into the vial pointing the needle towards the wall of the vial.
2. The vial should be gently rotated to ensure complete wetting of the product and then allowed to stand for 10 minutes.
3. Finally the vial should be gently rotated/swirled for a few minutes as needed to obtain a clear reconstituted solution. Vigorous shaking/agitation should be avoided to prevent foaming of the product.
4. The reconstituted solution should be checked carefully to ensure that the product is in solution and visually inspected for the absence of particulates prior to use. Reconstituted solutions of Cubicin range in colour from pale yellow to light brown.
5. The reconstituted solution should then be diluted with sodium chloride 9 mg/ml (0.9%) (typical volume 50 ml).
6. Invert the vial in order to allow the solution to drain towards the stopper. Using a new syringe, insert the needle into the inverted vial. Keeping the vial inverted, position the needle tip at the very bottom of the solution in the vial when drawing the solution into the syringe. Before removing the needle from the vial, pull the plunger all the way back to the end of the syringe barrel in order to remove all of the solution from the inverted vial.
7. Replace needle with a new needle for the intravenous infusion.
8. Expel air, large bubbles, and any excess solution in order to obtain the required dose.
9. The reconstituted and diluted solution should then be infused intravenously over 30 minutes as directed in section 4.2.
The following have been shown to be compatible when added to Cubicin containing infusion solutions: aztreonam, ceftazidime, ceftriaxone, gentamicin, fluconazole, levofloxacin, dopamine, heparin and lidocaine.
Cubicin given as 2-minute intravenous injection
Water should not be used for reconstitution of Cubicin for intravenous injection. Cubicin should only be reconstituted with sodium chloride 9 mg/ml (0.9%).
A 50 mg/ml concentration of Cubicin for injection is obtained by reconstituting the lyophilised product with 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection.
The lyophilised product takes approximately 15 minutes to dissolve. The fully reconstituted product will appear clear and may have a few small bubbles or foam around the edge of the vial.
To prepare Cubicin for intravenous injection, please adhere to the following instructions:
Aseptic technique should be used throughout to reconstitute lyophilised Cubicin.
1. The polypropylene flip off cap should be removed to expose the central portions of the rubber stopper. Draw 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection into a syringe, then slowly inject through the centre of the rubber stopper into the vial pointing the needle towards the wall of the vial.
2. The vial should be gently rotated to ensure complete wetting of the product and then allowed to stand for 10 minutes.
3. Finally the vial should be gently rotated/swirled for a few minutes as needed to obtain a clear reconstituted solution. Vigorous shaking/agitation should be avoided to prevent foaming of the product.
4. The reconstituted solution should be checked carefully to ensure that the product is in solution and visually inspected for the absence of particulates prior to use. Reconstituted solutions of Cubicin range in colour from pale yellow to light brown.
5. Invert the vial in order to allow the solution to drain towards the stopper. Using a new syringe, insert the needle into the inverted vial. Keeping the vial inverted, position the needle tip at the very bottom of the solution in the vial when drawing the solution into the syringe. Before removing the needle from the vial, pull the plunger all the way back to the end of the syringe barrel in order to remove all of the solution from the inverted vial.
6. Replace needle with a new needle for the intravenous injection.
7. Expel air, large bubbles, and any excess solution in order to obtain the required dose.
8. The reconstituted solution should then be injected intravenously slowly over 2 minutes as directed in section 4.2.
Cubicin vials are for single-use only.
From a microbiological point of view, the product should be used immediately after reconstitution (see section 6.3).
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. Marketing authorisation holder
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
8. Marketing authorisation number(s)
Cubicin 350mg powder for solution for injection or infusion: EU/1/05/328/001 & 003
Cubicin 500mg powder for solution for injection or infusion: EU/1/05/328/002 & 004
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 19 January 2006
Date of latest renewal: 19 January 2011
10. Date of revision of the text
23 April 2014
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu

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