英文药名：ABRAXANE（paclitaxe powder for suspension for infusion） 中文药名：注射用混悬液（紫杉醇,白蛋白结合型） 生产厂家：Celgene 药品介绍 晚期胰腺癌属于难治性癌症，生存率在所有类型癌症中最低。所有胰腺癌患者中，相对5年生存率为5.5%。一项III期研究显示，白蛋白结合型紫杉醇（Abraxane）可改善晚期胰腺癌患者的总生存，差异有统计学意义。 Abraxane（紫杉醇蛋白质结合颗粒注射悬液）与吉西他滨联合治疗未接受治疗的晚期胰腺癌患者的III期研究达到了主要终点：总生存。该研究显示，Abraxane与吉西他滨联合治疗组的总生存优于吉西他滨单药治疗组，差异有统计学意义。 MPACT（转移性胰腺腺癌临床试验）研究是一项开放、随机、国际性研究，861例转移性胰腺癌患者随机接受白蛋白结合型紫杉醇（125mg/m2）联合吉西他滨（1000mg/m2），用药3周、休1周或吉西他滨单药（1000mg/m2，周疗、连续7周，休息1周；然后周疗连续3周、休1周）。 研究主要终点是总生存改善。次要终点包括该患者人群中该联合用药组的无进展生存、客观肿瘤缓解和安全性及耐受性。观察到的Abraxane与吉西他滨联合治疗的安全性接近Abraxane在胰腺癌中的其他临床试验。 Abraxane是紫杉醇的白蛋白结合形式，于2005年1月在美国首先获准用于治疗联合化疗无效的转移性乳腺癌或辅助化疗6个月内复发的乳腺癌。2012年10月，FDA批准Abraxane联合卡铂用于不适合治愈性手术或放疗的局部晚期或转移性非小细胞肺癌的一线治疗，但目前尚未获准用于治疗晚期胰腺癌。 ABRAXANE®注射用混悬液(紫杉醇[paclitaxel]蛋白质结合颗粒注射用混悬液) (白蛋白结合) 适应证和用途 ABRAXANE是一种微观抑制剂适用于为治疗： （1）转移乳癌，对转移疾病或辅助化疗6个月内复发联合化疗失败后。既往治疗应包括一种蒽环类除非临床禁忌。 （2）为不是治病手术或放射治疗被选患者，局部晚期或转移非小细胞肺癌(NSCLC)，与卡铂[carboplatin]联用作为一线治疗. （3）转移胰腺腺癌作为与吉西他滨[gemcitabine]联用一线治疗。 剂量和给药方法 （1）转移乳癌：ABRAXANE的推荐剂量为260 mg/m2历时30分钟静脉注射每3周。 （2）非小细胞肺癌：ABRAXANE推荐剂量为在每21天疗程的第1，8，和15天100mg/m2历时30分钟静脉注射；在每21天疗程的第1天ABRAXANE后立即给予卡铂[carboplatin]。 （3）胰腺腺癌：ABRAXANE推荐剂量是每28-天疗程第1，8和15天125mg/m2历时30-40分钟静脉注射；每28-天疗程第1，8和15天ABRAXANE后立即给予吉西他滨。 （4）有轻度肝损伤患者无需调整剂量。如AST>10×ULN或胆红素>5×ULN保留ABRAXANE。中度至严重肝损伤患者减低起始剂量。 （5）剂量减低：根据严重血液学，神经学，皮肤，或胃肠道毒性可能需要减低剂量或终止。 （6）当处理细胞毒药物谨慎使用。严密监视输注部位外渗和浸润。给药前无需预先给药。 剂型和规格 注射用混悬液: 为配制重建单次使用小瓶冰冻干燥粉含100mg紫杉醇。 禁忌证 （1）中性粒细胞计数< 1,500cells/mm3。 （2）对ABRAXANE严重超敏反应。 警告和注意事项 （1）ABRAXANE致骨髓抑制。监视CBC和保持和/或需要时减低剂量。 （2）频繁发生感觉神经病变和可能需要减低剂量或中断治疗。 （3）接受ABRAXANE与吉西他滨联用患者有或无中性粒细胞减少发生脓毒血症; 中断ABRAXANE和吉西他滨直至脓毒血症解决，和如果中性粒细胞减少，直至中性粒细胞至少 1500cells/mm3，然后在减低剂量水平恢复治疗。 （4）使用ABRAXANE与吉西他滨联合发生肺炎; 永久终止用ABRAXANE和吉西他滨治疗。 （5）曾报道严重超敏性反应与致命性结局。不要再用此药。 （6）有肝损伤患者紫杉醇暴露和毒性可能增加；因此谨慎给予。 （7）ABRAXANE含来自人血白蛋白，有病毒传播理论风险。 （8）给予妊娠妇女可能发生胎儿危害。建议生育潜能妇女接受ABRAXANE避免成为妊娠。 （9）建议当用ABRAXANE时不要成为父亲。 不良反应 （1）转移乳癌最常见不良反应(≥20%)是脱发，中性粒细胞减少，感觉神经病变，异常ECG，疲劳/虚弱，肌肉痛/关节痛，AST升高，碱性磷酸酶升高，贫血，恶心，感染，和腹泻。 （2）NSCLC最常见不良反应(≥ 20%)是贫血，中性粒细胞减少，血小板减少，突发，周边神经病变，恶心，和疲劳。 （3）在胰腺腺癌中ABRAXANE的最常见(≥ 20%)不良反应是中性粒细胞减少，疲劳，周边神经病变，恶心，脱发，周边水肿，腹泻，发热，呕吐，食欲减退，皮疹，和脱水。 药物相互作用 当同时给予ABRAXANE与或CYP2C8或CYP3A4抑制剂或诱导剂谨慎使用 Abraxane 5mg/ml powder for suspension for infusion 1. Name of the medicinal product Abraxane 5 mg/ml powder for suspension for infusion. 2. Qualitative and quantitative composition Each vial contains 100 mg of paclitaxel formulated as albumin bound nanoparticles. Each vial contains 250 mg of paclitaxel formulated as albumin bound nanoparticles. After reconstitution, each ml of suspension contains 5 mg of paclitaxel formulated as albumin bound nanoparticles. Excipients with known effect Each ml of concentrate contains 0.183 mmol sodium, which is 4.2 mg of sodium. For the full list of excipients, see section 6.1. 3. Pharmaceutical form Powder for suspension for infusion. The reconstituted suspension has a pH of 6-7.5 and an osmolality of 300-360 mOsm/kg. The powder is white to yellow. 4. Clinical particulars 4.1 Therapeutic indications Abraxane monotherapy is indicated for the treatment of metastatic breast cancer in adult patients who have failed first-line treatment for metastatic disease and for whom standard, anthracycline containing therapy is not indicated (see section 4.4). Abraxane in combination with gemcitabine is indicated for the first-line treatment of adult patients with metastatic adenocarcinoma of the pancreas. 4.2 Posology and method of administration Abraxane should only be administered under the supervision of a qualified oncologist in units specialised in the administration of cytotoxic agents. It should not be substituted for or with other paclitaxel formulations. Posology Breast cancer The recommended dose of Abraxane is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks. Dose adjustments during treatment of breast cancer Patients who experience severe neutropenia (neutrophil count < 500 cells/mm3 for a week or longer) or severe sensory neuropathy during Abraxane therapy should have the dose reduced to 220 mg/m2 for subsequent courses. Following recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m2. Abraxane should not be administered until neutrophil counts recover to >1500 cells/mm3. For grade 3 sensory neuropathy withhold treatment until resolution to grade 1 or 2, followed by a dose reduction for all subsequent courses. Pancreatic adenocarcinoma The recommended dose of Abraxane in combination with gemcitabine is 125 mg/m2 administered intravenously over 30 minutes on Days 1, 8 and 15 of each 28-day cycle. The concurrent recommended dose of gemcitabine is 1000 mg/m2 administered intravenously over 30 minutes immediately after the completion of Abraxane administration on Days 1, 8 and 15 of each 28-day cycle. Dose adjustments during treatment of pancreatic adenocarcinoma Table 1: Dose level reductions for patients with pancreatic adenocarcinoma Dose Level Abraxane Dose (mg/m2) Gemcitabine Dose (mg/m2) Full dose 125 1000 1st dose level reduction 100 800 2nd dose level reduction 75 600 If additional dose reduction required Discontinue treatment Discontinue treatment Table 2: Dose modifications for neutropenia and/or thrombocytopenia at the start of a cycle or within a cycle for patients with pancreatic adenocarcinoma Cycle Day ANC count (cells/mm3)   Platelet count (cells/mm3) Abraxane Dose Gemcitabine Dose Day 1 < 1500 OR < 100,000 Delay doses until recovery Day 8 ≥ 500 but < 1000 OR ≥ 50,000 but < 75,000 Reduce doses 1 dose level   < 500 OR < 50,000 Withhold doses Day 15: IF Day 8 doses were given without modification: Day 15 ≥ 500 but < 1000 OR ≥ 50,000 but < 75,000 Treat with Day 8 dose level and follow with WBC Growth Factors OR Reduce doses 1 dose level from Day 8 doses   < 500 OR < 50,000 Withhold doses Day 15: IF Day 8 doses were reduced: Day 15 ≥ 1000 AND ≥ 75,000 Return to the Day 1 dose levels and follow with WBC Growth Factors OR Treat with same doses as Day 8   ≥ 500 but < 1000 OR ≥ 50,000 but < 75,000 Treat with Day 8 dose levels and follow with WBC Growth Factors OR Reduce doses 1 dose level from Day 8 doses   < 500 OR < 50,000 Withhold doses Day 15: IF Day 8 doses were withheld: Day 15 ≥ 1000 AND ≥ 75,000 Return to Day 1 dose levels and follow with WBC Growth Factors OR Reduce doses 1 dose level from Day 1 doses   ≥ 500 but < 1000 OR ≥ 50,000 but < 75,000 Reduce 1 dose level and follow with WBC Growth Factors OR Reduce doses 2 dose levels from Day 1 doses   < 500 OR < 50,000 Withhold doses Abbreviations: ANC=Absolute Neutrophil Count; WBC=white blood cell Table 3: Dose modifications for other adverse drug reactions in patients with pancreatic adenocarcinoma Adverse Drug Reaction (ADR) Abraxane Dose Gemcitabine Dose Febrile Neutropenia: Grade 3 or 4 Withhold doses until fever resolves and ANC ≥ 1500; resume at next lower dose levela Peripheral Neuropathy: Grade 3 or 4 Withhold dose until improves to ≤ Grade 1; resume at next lower dose levela Treat with same dose Cutaneous Toxicity: Grade 2 or 3 Reduce to next lower dose levela; discontinue treatment if ADR persists Gastrointestinal Toxicity: Grade 3 mucositis or diarrhoea Withhold doses until improves to ≤ Grade 1; resume at next lower dose levela aSee Table 1 for dose level reductions Special populations Patients with hepatic impairment Insufficient data are currently available to recommend dose modifications in patients with mild to moderate hepatic impairment that ensure acceptable toxicity while maintaining efficacy of Abraxane. Patients with severe hepatic impairment should not be treated with paclitaxel (see sections 4.4.and 5.2). Patients with renal impairment Studies in patients with impaired renal function have not been performed and insufficient data are currently available to recommend dose modifications of Abraxane in patients with renal impairment (see section 5.2). Older people No additional dosage reductions, other than those for all patients, are recommended for patients 65 years and older. Of the 229 patients in the randomized study who received Abraxane monotherapy for breast cancer, 13% were at least 65 years of age and < 2% were 75 years and older. No toxicities occurred notably more frequently among patients at least 65 years of age who received Abraxane. Of the 421 patients with pancreatic adenocarcinoma in the randomized study who received Abraxane in combination with gemcitabine, 41% were 65 years and older and 10% were 75 years and older. In patients aged 75 years and older who received Abraxane and gemcitabine, there was a higher incidence of serious adverse reactions and adverse reactions that led to treatment discontinuation (see section 4.4). Patients with pancreatic adenocarcinoma aged 75 years and older should be carefully assessed before treatment is considered (see section 4.4). Paediatric population The safety and efficacy of Abraxane in children and adolescents aged 0-17 years has not been established. There is no relevant use of Abraxane in the paediatric population in the indication of metastatic breast cancer or pancreatic adenocarcinoma. Method of administration Administer reconstituted Abraxane suspension intravenously using an infusion set incorporating a 15 µm filter. For instructions on reconstitution of the medicinal product before administration, see section 6.6. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Lactation (see section 4.6). Patients who have baseline neutrophil counts <1500 cells/mm3. 4.4 Special warnings and precautions for use Abraxane is an albumin-bound nanoparticle formulation of paclitaxel, which may have substantially different pharmacological properties compared to other formulations of paclitaxel (see sections 5.1 and 5.2). It should not be substituted for or with other paclitaxel formulations. Hypersensitivity Rare occurrences of severe hypersensitivity reactions, including very rare events of anaphylactic reactions with fatal outcome, have been reported. If a hypersensitivity reaction occurs, the medicinal product should be discontinued immediately, symptomatic treatment should be initiated, and the patient should not be rechallenged with paclitaxel. Haematology Bone marrow suppression (primarily neutropenia) occurs frequently with Abraxane. Neutropenia is dose-dependent and a dose-limiting toxicity. Frequent monitoring of blood cell counts should be performed during Abraxane therapy. Patients should not be retreated with subsequent cycles of Abraxane until neutrophils recover to >1500 cells/mm3 and platelets recover to >100,000 cells/mm3 (see section 4.2). Neuropathy Sensory neuropathy occurs frequently with Abraxane, although development of severe symptoms is less common. The occurrence of grade 1 or 2 sensory neuropathy does not generally require dose reduction. When Abraxane is used as monotherapy, if grade 3 sensory neuropathy develops, treatment should be withheld until resolution to grade 1 or 2 followed by a dose reduction for all subsequent courses of Abraxane is recommended (see section 4.2). For combination use of Abraxane and gemcitabine, if grade 3 or higher peripheral neuropathy develops, withhold Abraxane; continue treatment with gemcitabine at the same dose. Resume Abraxane at reduced dose when peripheral neuropathy improves to Grade 0 or 1 (see section 4.2). Sepsis Sepsis was reported at a rate of 5% in patients with or without neutropenia who received Abraxane in combination with gemcitabine. Complications due to the underlying pancreatic cancer, especially biliary obstruction or presence of biliary stent, were identified as significant contributing factors. If a patient becomes febrile (regardless of neutrophil count), initiate treatment with broad spectrum antibiotics. For febrile neutropenia, withhold Abraxane and gemcitabine until fever resolves and ANC ≥ 1500 cells/mm3, then resume treatment at reduced dose levels (see section 4.2). Pneumonitis Pneumonitis occurred in 1% of patients when Abraxane was used as monotherapy and in 4% of patients when Abraxane was used in combination with gemcitabine. Closely monitor all patients for signs and symptoms of pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with Abraxane and gemcitabine and promptly initiate appropriate treatment and supportive measures (see section 4.2). Hepatic impairment Because the toxicity of paclitaxel can be increased with hepatic impairment, administration of Abraxane in patients with hepatic impairment should be performed with caution. Patients with hepatic impairment may be at increased risk of toxicity, particularly from myelosuppression, and such patients should be closely monitored for development of profound myelosuppression. Patients with severe hepatic impairment (bilirubin > 5 x ULN or AST/ALT > 10 x ULN) have not been studied and should not be treated with Abraxane. The appropriate dose regimen in patients with less severe hepatic impairment is unknown. A dose reduction in patients with bilirubin >2 ULN must be considered since paclitaxel clearance is decreased in patients with high bilirubin levels (see section 5.2). Cardiotoxicity Rare reports of congestive heart failure and left ventricular dysfunction have been observed among individuals receiving Abraxane. Most of the individuals were previously exposed to cardiotoxic medicinal products such as anthracyclines, or had underlying cardiac history. Thus patients receiving Abraxane should be vigilantly monitored by physicians for the occurrence of cardiac events. CNS metastases The effectiveness and safety of Abraxane in patients with central nervous system (CNS) metastases has not been established. CNS metastases are generally not well controlled by systemic chemotherapy. Gastrointestinal symptoms If patients experience nausea, vomiting and diarrhoea following the administration of Abraxane, they may be treated with commonly used anti-emetics and constipating agents. Patients 75 years and older For patients of 75 years and older, no benefit for the combination treatment of Abraxane and gemcitabine in comparison to gemcitabine monotherapy has been demonstrated. In the very elderly (≥75 years) who received Abraxane and gemcitabine, there was a higher incidence of serious adverse reactions and adverse reactions that led to treatment discontinuation including haematologic toxicities, peripheral neuropathy, decreased appetite and dehydration. Patients with pancreatic adenocarcinoma aged 75 years and older should be carefully assessed for their ability to tolerate Abraxane in combination with gemcitabine with special consideration to performance status, co-morbidities and increased risk of infections (see section 4.2 and 4.8) Other Although limited data is available, no clear benefit in terms of prolonged overall survival has been demonstrated in pancreatic adenocarcinoma patients with normal CA 19-9 levels prior to start of treatment with Abraxane and gemcitabine (see section 5.1). Erlotinib should not be coadministered to Abraxane plus gemcitabine (see section 4.5). Excipients When reconstituted, each ml of Abraxane concentrate contains 0.183 mmol sodium, which is 4.2 mg of sodium. To be taken into consideration by patients on a controlled sodium diet. 4.5 Interaction with other medicinal products and other forms of interaction No interaction studies have been performed. The metabolism of paclitaxel is catalysed, in part, by cytochrome P450 isoenzymes CYP2C8 and CYP3A4 (see section 5.2). Therefore, caution should be exercised when administering paclitaxel concomitantly with medicines known to inhibit (e.g. ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g. rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine) either CYP2C8 or CYP3A4. Paclitaxel and gemcitabine do not share a common metabolic pathway. Paclitaxel clearance is primarily determined by CYP2C8 and CYP3A4 mediated metabolism followed by biliary excretion, while gemcitabine is inactivated by cytidine deaminase followed by urinary excretion. Pharmacokinetic interactions between Abraxane and gemcitabine have not been evaluated in humans. Abraxane is indicated as monotherapy for breast cancer, or in combination with gemcitabine for pancreatic adenocarcinoma (see section 4.1). Abraxane should not be used in combination with other anticancer agents. 4.6 Fertility, pregnancy and lactation Contraception in males and females Women of childbearing potential should use effective contraception during treatment and up to 1 month after receiving treatment with Abraxane. Male patients treated with Abraxane are advised not to father a child during and up to six months after treatment. Pregnancy There are very limited data on the use of paclitaxel in human pregnancy. Paclitaxel is suspected to cause serious birth defects when administered during pregnancy. Studies in animals have shown reproductive toxicity (see section 5.3). Abraxane should not be used in pregnancy, and in women of childbearing potential not using effective contraception, unless the clinical condition of the mother requires treatment with paclitaxel. Breast-feeding It is not known if paclitaxel is excreted in human milk. Because of potential serious adverse reactions in breast-feeding infants, Abraxane is contraindicated during lactation. Breast-feeding must be discontinued for the duration of therapy. Fertility Abraxane induced infertility in male rats (see section 5.3). Male patients should seek advice on conservation of sperm prior to treatment because of the possibility of irreversible infertility due to therapy with Abraxane. 4.7 Effects on ability to drive and use machines Abraxane has minor or moderate influence on the ability to drive and use machines. Abraxane may cause adverse reactions such as tiredness (very common) and dizziness (common) that may affect the ability to drive and use machinery. Patients should be advised not to drive and use machines if they feel tired or dizzy. 4.8 Undesirable effects Summary of the safety profile The most common clinically significant adverse reactions associated with the use of Abraxane have been neutropenia, peripheral neuropathy, arthralgia/myalgia and gastrointestinal disorders. The frequencies of adverse reactions associated with the administration of Abraxane are listed in Table 4 (Abraxane as monotherapy) and Table 5 (Abraxane in combination with gemcitabine). Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Breast cancer (Abraxane administered as monotherapy) Tabulated list of adverse reactions Table 4 lists adverse reactions associated with the administration of Abraxane to patients from studies in which Abraxane has been administered as monotherapy at any dose in any indication (N = 789). Table 4: Adverse reactions reported with Abraxane monotherapy at any dose in clinical studies Infections and infestations Common: Infection, urinary tract infection, folliculitis, upper respiratory tract infection, candidiasis, sinusitis Uncommon: Oral candidiasis, nasopharyngitis, cellulitis, herpes simplex, viral infection, pneumonia, catheter-related infection, fungal infection, herpes zoster, injection site infection, sepsis2, neutropenic sepsis2 Neoplasms benign, malignant and unspecified (including cysts and polyps) Uncommon: Metastatic pain, tumour necrosis Blood and lymphatic system disorders Very common: Neutropenia, anaemia, leukopenia, thrombocytopenia, lymphopenia, bone marrow suppression Common: Febrile neutropenia Rare: Pancytopenia Immune system disorders Uncommon1: Hypersensitivity Rare: Severe hypersensitivity Metabolism and nutrition disorders Very common: Anorexia Common: Dehydration, decreased appetite, hypokalaemia Uncommon: Hypophosphataemia, fluid retention, hypoalbuminaemia, polydipsia, hyperglycaemia, hypocalcaemia, hypoglycaemia, hyponatraemia Psychiatric disorders Common: Insomnia, depression, anxiety Uncommon: Restlessness Nervous system disorders Very common: Peripheral neuropathy, neuropathy, hypoaesthesia, paraesthesia Common: Peripheral sensory neuropathy, headache, dysgeusia, dizziness, peripheral motor neuropathy, ataxia, sensory disturbance, somnolence Uncommon: Polyneuropathy, areflexia, dyskinesia, hyporeflexia, neuralgia, sensory loss, syncope, postural dizziness, neuropathic pain, tremor Eye disorders Common: Increased lacrimation, blurred vision, dry eye, keratoconjunctivitis sicca, madarosis Uncommon: Eye irritation, eye pain, abnormal vision, reduced visual acuity, conjunctivitis, visual disturbance, eye pruritus, keratitis Rare: Cystoid macular oedema2 Ear and labyrinth disorders Common: Vertigo Uncommon: Ear pain, tinnitus Cardiac disorders Common: Tachycardia, arrhythmia, supraventricular tachycardia Rare: bradycardia, cardiac arrest, left ventricular dysfunction, congestive heart failure, atrioventricular block2 Vascular disorders Common: Flushing, hot flushes, hypertension, lymphoedema Uncommon: Hypotension, peripheral coldness, orthostatic hypotension Rare: Thrombosis Respiratory, thoracic and mediastinal disorders Common: Interstitial pneumonitis3, dyspnoea, epistaxis, pharyngolaryngeal pain, cough, rhinitis, rhinorrhoea Uncommon: Productive cough, exertional dyspnoea, sinus congestion, decreased breath sounds, pleural effusion, allergic rhinitis, hoarseness, nasal congestion, nasal dryness, wheezing, pulmonary emboli, pulmonary thromboembolism Gastrointestinal disorders Very common: Nausea, diarrhoea, vomiting, constipation, stomatitis Common: Abdominal pain, abdominal distension, upper abdominal pain, dyspepsia, gastrooesophageal reflux disease, oral hypoaesthesia Uncommon: Dysphagia, flatulence, glossodynia, dry mouth, gingival pain, loose stools, oesophagitis, lower abdominal pain, mouth ulceration, oral pain, rectal haemorrhage Hepatobiliary disorders Uncommon: Hepatomegaly Skin and subcutaneous tissue disorders Very common: Alopecia, rash Common: Nail disorder, pruritus, dry skin, erythema, nail pigmentation/discolouration, skin hyperpigmentation, onycholysis, nail changes Uncommon: Nail bed tenderness, urticaria, skin pain, photosensitivity reaction, pigmentation disorder, pruritic rash, skin disorder, hyperhidrosis, onychomadesis, erythematous rash, generalised rash, dermatitis, night sweats, maculo-papular rash, vitiligo, hypotrichosis, nail discomfort, generalized pruritus, macular rash, papular rash, skin lesion, swollen face Very rare: Stevens-Johnson syndrome2, toxic epidermal necrolysis2 Musculoskeletal and connective tissue disorders Very common: Arthralgia, myalgia. Common: Pain in extremity, bone pain, back pain, muscle cramps, limb pain Uncommon: Chest wall pain, muscular weakness, neck pain, groin pain, muscle spasms, musculoskeletal pain, flank pain, limb discomfort, muscle weakness Renal and urinary disorders Uncommon: Dysuria, pollakiuria, haematuria, nocturia, polyuria, urinary incontinence Reproductive system and breast disorders Uncommon: Breast pain General disorders and administration site conditions Very common: Fatigue, asthenia, pyrexia Common: Peripheral oedema, mucosal inflammation, pain, rigors, oedema, weakness, decreased performance status, chest pain, influenza-like illness, malaise, lethargy, hyperpyrexia Uncommon: Chest discomfort, abnormal gait, swelling, injection site reaction Rare: Extravasation Investigations Common: Decreased weight, increased alanine aminotransferase, increased aspartate aminotransferase, decreased haematocrit, decreased red blood cell count, increased body temperature, increased gamma-glutamyltransferase, increased blood alkaline phosphatase Uncommon: Increased blood pressure, increased weight, increased blood lactate dehydrogenase, increased blood creatinine, increased blood glucose, increased blood phosphorus, decreased blood potassium, increased bilirubin Injury, poisoning and procedural complications Uncommon: Contusion Rare: Radiation recall phenomenon, radiation pneumonitis MedDRA = Medical Dictionary for Regulatory Activities. SMQ = Standardized MedDRA Query; SMQ is a grouping of several MedDRA preferred terms to capture a medical concept. 1 The frequency of hypersensitivity reactions is calculated based on one definitely related case in a population of 789 patients. 2 As reported in the post-marketing surveillance of Abraxane. 3 The frequency of pneumonitis is calculated based on pooled data in 1310 patients in clinical trials receiving Abraxane monotherapy for breast cancer and for other indications using MedDRA SMQ Interstitial lung disease. See section 4.4. Description of selected adverse reactions The following are the most common and clinically relevant adverse reactions related to 229 patients with metastatic breast cancer who were treated with 260 mg/m2 Abraxane once every three weeks in the pivotal phase III clinical study. Blood and lymphatic system disorders Neutropenia was the most notable important haematological toxicity (reported in 79% of patients), and was rapidly reversible and dose dependent; leukopenia was reported in 71% of patients. Grade 4 neutropenia (< 500 cells/mm3) occurred in 9% of patients treated with Abraxane. Febrile neutropenia occurred in four patients on Abraxane. Anaemia (Hb < 10 g/dl) was observed in 46% of patients on Abraxane, and was severe (Hb < 8 g/dl) in three cases. Lymphopenia was observed in 45% of the patients. Nervous system disorders In general, the frequency and severity of neurotoxicity was dose-dependent in patients receiving Abraxane. Peripheral neuropathy (mostly Grade 1 or 2 sensory neuropathy) was observed in 68% of patients on Abraxane with 10% being Grade 3, and no cases of Grade 4. Gastrointestinal disorders Nausea occurred in 29% of the patients and diarrhoea in 25% of the patients. Skin and subcutaneous tissue disorders Alopecia was observed in >80% of the patients treated with Abraxane. The majority of alopecia events occurred less than one month after initiation of Abraxane. Pronounced hair loss ≥50% is expected for the majority of patients who experience alopecia. Musculoskeletal and connective tissue disorders Arthralgia occurred in 32% of patients on Abraxane and was severe in 6% of cases. Myalgia occurred in 24% of patients on Abraxane and was severe in 7% of cases. The symptoms were usually transient, typically occurred three days after Abraxane administration and resolved within a week. General disorders and administration site conditions Asthenia/Fatigue was reported in 40% of the patients. Pancreatic adenocarcinoma (Abraxane administered in combination with gemcitabine) Tabulated list of adverse reactions Adverse reactions were assessed in 421 patients treated with Abraxane in combination with gemcitabine and 402 gemcitabine monotherapy-treated patients receiving first-line systemic treatment for metastatic adenocarcinoma of the pancreas in a phase III randomized, controlled, open-label trial. Table 5 lists adverse reactions assessed in patients with pancreatic adenocarcinoma treated with Abraxane in combination with gemcitabine. Table 5: Adverse reactions reported with Abraxane in combination with gemcitabine (N =421) Infections and infestations Common: Sepsis, pneumonia, oral candidiasis Blood and lymphatic system disorders Very common: Neutropenia, anaemia, thrombocytopenia Common: Pancytopenia Uncommon: Thrombotic thrombocytopenic purpura Metabolism and nutrition disorders Very common: Dehydration, decreased appetite, hypokalaemia Psychiatric disorders Very common: Insomnia, depression Common: Anxiety Nervous system disorders Very common: Peripheral neuropathya, dysgeusia, headache, dizziness Uncommon: VIIth nerve paralysis Eye disorders Common: Lacrimation increased Uncommon: Cystoid macular oedema Cardiac disorders Common: Cardiac failure congestive, tachycardia Vascular disorders Common: Hypotension, hypertension Respiratory, thoracic and mediastinal disorders Very Common: Dyspnoea, epistaxis, cough Common: Pneumonitis, nasal congestion Uncommon: Dry throat, nasal dryness Gastrointestinal disorders Very Common: Nausea, diarrhoea, vomiting, constipation, abdominal pain, abdominal pain upper Common: Stomatitis, intestinal obstruction, colitis, dry mouth Hepatobiliary disorders Common: Cholangitis Skin and subcutaneous tissue disorders Very Common: Alopecia, rash Common: Pruritus, dry skin, nail disorder, flushing Musculoskeletal and connective tissue disorders Very common: Pain in extremity, arthralgia, myalgia Common: Muscular weakness, bone pain Renal and urinary disorders Common: Acute renal failure Uncommon: Haemolytic uraemic syndrome General disorders and administration site conditions Very common: Fatigue, oedema peripheral, pyrexia, asthenia, chills Common: Infusion site reaction Investigations Very common: Weight decreased, alanine aminotransferase increased Common: Aspartate aminotransferase increased, blood bilirubin increased, blood creatinine increased MedDRA = Medical Dictionary for Regulatory Activities; SMQ = Standardized MedDRA Query (a grouping of several MedDRA preferred terms to capture a medical concept). a Peripheral neuropathy evaluated using the Standardized MedDRA Query (broad scope). In this phase III randomized, controlled, open-label trial, adverse reactions resulting in death within 30 days of the last dose of study drug were reported for 4% of patients receiving Abraxane in combination with gemcitabine and for 4% of patients receiving gemcitabine monotherapy. Description of selected adverse reactions The following are the most common and important incidences of adverse reactions related to 421 patients with metastatic adenocarcinoma of the pancreas who were treated with 125 mg/m2 Abraxane in combination with gemcitabine at a dose of 1000 mg/m2 given on Days 1, 8 and 15 of each 28-day cycle in the phase III clinical study. Blood and lymphatic system disorders Table 6 provides the frequency and severity of haematologic laboratory-detected abnormalities for patients treated with Abraxane in combination with gemcitabine or with gemcitabine. Table 6: Haematologic laboratory-detected abnormalities in pancreatic adenocarcinoma trial Abraxane(125 mg/m2)/ Gemcitabine Gemcitabine Grades 1-4 (%) Grade 3-4 (%) Grades 1-4 (%) Grade 3-4 (%) Anaemiaa,b 97 13 96 12 Neutropenia a,b 73 38 58 27 Thrombocytopeniab,c 74 13 70 9 a 405 patients assessed in Abraxane/gemcitabine-treated group b 388 patients assessed in gemcitabine-treated group c 404 patients assessed in Abraxane/gemcitabine-treated group Peripheral Neuropathy For patients treated with Abraxane in combination with gemcitabine, the median time to first occurrence of grade 3 peripheral neuropathy was 140 days. The median time to improvement by at least 1 grade was 21 days, and the median time to improvement from grade 3 peripheral neuropathy to Grade 0 or 1 was 29 days. Of the patients with treatment interrupted due to peripheral neuropathy, 44% (31/70 patients) were able to resume Abraxane at a reduced dose. No patients treated with Abraxane in combination with gemcitabine had grade 4 peripheral neuropathy. Sepsis Sepsis was reported at a rate of 5% in patients with or without neutropenia who received Abraxane in combination with gemcitabine during the conduct of a trial in pancreatic adenocarcinoma. Complications due to the underlying pancreatic cancer, especially biliary obstruction or presence of biliary stent, were identified as significant contributing factors. If a patient becomes febrile (regardless of neutrophil count), initiate treatment with broad spectrum antibiotics. For febrile neutropenia, withhold Abraxane and gemcitabine until fever resolves and ANC ≥ 1500 cells/mm3, then resume treatment at reduced dose levels (see section 4.2). Pneumonitis Pneumonitis has been reported at a rate of 4% with the use of Abraxane in combination with gemcitabine. Of the 17 cases of pneumonitis reported in patients treated with Abraxane in combination with gemcitabine, 2 had a fatal outcome. Monitor patients closely for signs and symptoms of pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with Abraxane and gemcitabine and promptly initiate appropriate treatment and supportive measures (see section 4.2). Post-marketing experience Cranial nerve palsies, vocal cord paresis, and rare reports of severe hypersensitivity reactions have been reported during post-marketing surveillance of Abraxane. There have been rare reports of reduced visual acuity due to cystoid macular oedema during treatment with Abraxane. Upon diagnosis of cystoid macular oedema, treatment with Abraxane should be discontinued. In some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysaesthesiae have been reported as part of the continuing surveillance of Abraxane. Because these events have been reported voluntarily during clinical practice, true estimates of frequency cannot be made and a causal relationship to the events has not been established. 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 (Freephone 0808 100 3352). 4.9 Overdose There is no known antidote for paclitaxel overdose. In the event of an overdose, the patient should be closely monitored. Treatment should be directed at the major anticipated toxicities, which are bone marrow suppression, mucositis and peripheral neuropathy. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antineoplastic agents, plant alkaloids and other natural products, taxanes, ATC Code: L01CD01 Mechanism of action Paclitaxel is an antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilises microtubules by preventing depolymerisation. This stability results in the inhibition of the normal dynamic reorganisation of the microtubule network that is essential for vital interphase and mitotic cellular functions. In addition, paclitaxel induces abnormal arrays or “bundles” of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis. Abraxane contains human serum albumin-paclitaxel nanoparticles of approximately 130 nm in size, where the paclitaxel is present in a non-crystalline, amorphous state. Upon intravenous administration, the nanoparticles dissociate rapidly into soluble, albumin bound paclitaxel complexes of approximately 10 nm in size. Albumin is known to mediate endothelial caveolar transcytosis of plasma constituents, and in vitro studies demonstrated that the presence of albumin in Abraxane enhances transport of paclitaxel across endothelial cells. It is hypothesised that this enhanced transendothelial caveolar transport is mediated by the gp-60 albumin receptor, and that there is enhanced accumulation of paclitaxel in the area of tumour due to the albumin-binding protein Secreted Protein Acidic Rich in Cysteine (SPARC). Clinical efficacy and safety Breast cancer Data from 106 patients accrued in two single-arm open-label studies and from 454 patients treated in a randomised Phase III comparative study are available to support the use of Abraxane in metastatic breast cancer. This information is presented below. Single-arm open-label studies In one study, Abraxane was administered as a 30-minute infusion at a dose of 175 mg/m2 to 43 patients with metastatic breast cancer. The second trial utilised a dose of 300 mg/m2 as a 30 minute infusion in 63 patients with metastatic breast cancer. Patients were treated without steroid pre-treatment or planned G-CSF support. Cycles were administered at 3 week intervals. The response rates in all patients were 39.5% (95% CI: 24.9%-54.2%) and 47.6% (95% CI: 35.3%-60.0%), respectively. The median time to disease progression was 5.3 months (175 mg/m2; 95% CI: 4.6-6.2 months) and 6.1 months (300 mg/m2; 95% CI: 4.2-9.8 months). Randomised comparative study This multi-centre trial was conducted in patients with metastatic breast cancer, who were treated every 3 weeks with single-agent paclitaxel, either as solvent-based paclitaxel 175 mg/m2 given as a 3-hour infusion with premedication to prevent hypersensitivity (N = 225), or as Abraxane 260 mg/m2 given as a 30 minute infusion without premedication (N = 229). Sixty-four percent of patients had impaired performance status (ECOG 1 or 2) at study entry; 79% had visceral metastases; and 76% had > 3 sites of metastases. Fourteen percent of the patients had not received prior chemotherapy; 27% had received chemotherapy in the adjuvant setting only, 40% in the metastatic setting only, and 19% in both metastatic and adjuvant settings. Fifty-nine percent received study medicinal product as second or greater than second-line therapy. Seventy-seven percent of the patients had been previously exposed to anthracyclines. Results for overall response rate and time to disease progression, and progression-free survival and survival for patients receiving > 1st-line therapy, are shown below. Table 7: Results for overall response rate, median time to disease progression, and progression-free survival as assessed by the investigator Efficacy variable Abraxane (260 mg/m2) Solvent-based paclitaxel (175 mg/m2) p-value Response rate [95% CI] (%) > 1st-line therapy 26.5 [18.98, 34.05] (n = 132) 13.2 [7.54, 18.93] (n = 136) 0.006a *Median time to disease progression [95% CI] (weeks) > 1st-line therapy 20.9 [15.7, 25.9] (n = 131) 16.1 [15.0, 19.3] (n = 135) 0.011b *Median progression free survival [95% CI] (weeks) > 1st-line therapy 20.6 [15.6, 25.9] (n = 131) 16.1 [15.0, 18.3] (n = 135) 0.010b *Survival [95% CI] (weeks) > 1st-line therapy 56.4 [45.1, 76.9] (n = 131) 46.7 [39.0, 55.3] (n = 136) 0.020b *This data is based on Clinical Study Report: CA012-0 Addendum dated Final (23 March-2005) a Chi-squared test b Log-rank test Two hundred and twenty nine patients treated with Abraxane in the randomized, controlled clinical trial were evaluated for safety. Neurotoxicity to paclitaxel was evaluated through improvement by one grade for patients experiencing grade 3 peripheral neuropathy at any time during therapy. The natural course of peripheral neuropathy to resolution to baseline due to cumulative toxicity of Abraxane after > 6 courses of treatment was not evaluated and remains unknown. Pancreatic adenocarcinoma A multicenter, multinational, randomized, open-label study was conducted in 861 patients to compare Abraxane/gemcitabine versus gemcitabine monotherapy as first-line treatment in patients with metastatic adenocarcinoma of the pancreas. Abraxane was administered to patients (N = 431) as an intravenous infusion over 30-40 minutes at a dose of 125 mg/m2 followed by gemcitabine as an intravenous infusion over 30-40 minutes at a dose of 1000 mg/m2 given on Days 1, 8 and 15 of each 28-day cycle. In the comparator treatment arm, gemcitabine monotherapy was administered to patients (N = 430) in accordance with the recommended dose and regimen. Treatment was administered until disease progression or development of an unacceptable toxicity. Of the 431 patients with pancreatic adenocarcinoma who were randomized to receive Abraxane in combination with gemcitabine, the majority (93%) were white, 4% were black and 2% were Asian. 16% had a Karnofsky Performance Status of 100; 42% had a KPS of 90; 35% had a KPS of 80; 7% had a KPS of 70; and <1% of patients had a KPS of below 70. Patients with high cardiovascular risk, history of peripheral artery disease and/or of connective tissue disorders and/or interstitial lung disease were excluded from the study. Patients received a median treatment duration of 3.9 months in the Abraxane/gemcitabine arm and 2.8 months in the gemcitabine arm. 32% of patients in the Abraxane/gemcitabine arm compared with 15% of patients in the gemcitabine arm received 6 or more months of treatment. For the treated population, the median relative dose intensity for gemcitabine was 75% in the Abraxane/gemcitabine arm and 85% in the gemcitabine arm. The median relative dose intensity of Abraxane was 81%. A higher median cumulative dose of gemcitabine was delivered in the Abraxane/gemcitabine arm (11400 mg/m2) when compared with the gemcitabine arm (9000 mg/m2). The primary efficacy endpoint was overall survival (OS). The key secondary endpoints were progression-free survival (PFS) and overall response rate (ORR), both assessed by independent, central, blinded radiological review using RECIST guidelines (Version 1.0). Table 8: Efficacy results from randomized study in patients with pancreatic adenocarcinoma (Intent-to-treat population) Abraxane(125 mg/m2)/gemcitabine (N=431) Gemcitabine  (N=430) Overall Survival Number of deaths (%) 333 (77) 359 (83) Median Overall Survival, months (95% CI) 8.5 (7.89, 9.53) 6.7 (6.01, 7.23) HRA+G/G (95% CI)a 0.72 (0.617, 0.835) P-valueb <0.0001 Survival Rate % (95% CI) at   1 Year 35% (29.7, 39.5) 22% (18.1, 26.7) 2 Year 9% (6.2, 13.1) 4% (2.3, 7.2) 75th Percentile Overall Survival (months) 14.8 11.4 Progression-free Survival Death or progression, n (%) 277 (64) 265 (62) Median Progression-free Survival, months (95% CI) 5.5 (4.47, 5.95) 3.7 (3.61, 4.04) HRA+G/G (95% CI)a 0.69 (0.581, 0.821) P-valueb <0.0001 Overall Response Rate Confirmed complete or partial overall response, n (%) 99 (23) 31 (7) 95% CI 19.1, 27.2 5.0, 10.1 pA+G/pG (95% CI) 3.19 (2.178, 4.662) P-value (chi-square test) <0.0001 CI = confidence interval, HRA+G/G = hazard ratio of Abraxane+gemcitabine/gemcitabine, pA+G/pG=response rate ratio of Abraxane+gemcitabine/gemcitabine a stratified Cox proportional hazard model b stratified log-rank test, stratified by geographic region (North America versus others), KPS (70 to 80 versus 90 to 100), and presence of liver metastasis (yes versus no). There was a statistically significant improvement in OS for patients treated with Abraxane/gemcitabine versus gemcitabine alone, with 1.8 months increase in median OS, 28% overall reduction in risk of death, 59% improvement in 1-year survival, and 125% improvement in 2-year survival rates. Figure 1: Kaplan-Meier Curve of Overall Survival (Intent-to-treat Population) Treatment effects on OS favoured the Abraxane/gemcitabine arm across the majority of pre-specified subgroups (including gender, KPS, geographic region, primary location of pancreatic cancer, stage at diagnosis, presence of liver metastases, presence of peritoneal carcinomatosis, prior Whipple procedure, presence of biliary stent at baseline, presence of pulmonary metastases, and number of metastatic sites). For patients ≥ 75 years of age in the Abraxane/gemcitabine and gemcitabine arms the survival Hazard Ratio (HR) was 1.08 (95% CI 0.653, 1. 797). For patients with normal baseline CA 19-9 levels the survival HR was 1.07 (95% CI 0.692, 1.661). There was a statistically significant improvement in PFS for patients treated with Abraxane/gemcitabine versus gemcitabine alone, with 1.8 months increase in median PFS. Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Abraxane in all subsets of the paediatric population in the treatment of metastatic breast cancer and pancreatic adenocarcinoma (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties The pharmacokinetics of total paclitaxel following 30- and 180-minute infusions of Abraxane at dose levels of 80 to 375 mg/m2 were determined in clinical studies. The paclitaxel exposure (AUC) increased linearly from 2653 to 16736 ng.hr/ml following dosing from 80 to 300 mg/m2. Following intravenous administration of Abraxane to patients with metastatic breast cancer at the recommended clinical dose of 260 mg/m2, paclitaxel plasma concentrations declined in a multiphasic manner. The mean Cmax of paclitaxel, which occurred at the end of the infusion, was 18.7 µg/ml. The mean total clearance was 15 l/hr/m2. The terminal half-life was about 27 hours. The mean volume of distribution was 632 l/m2; the large volume of distribution indicates extensive extravascular distribution and/or tissue binding of paclitaxel. In a study in patients with advanced solid tumours, the pharmacokinetic characteristics of paclitaxel following Abraxane administered intravenously at 260 mg/m2 over 30 minutes were compared with those following 175 mg/m2 of the solvent-based paclitaxel injection administered over 3 hours. The clearance of paclitaxel with Abraxane was larger (43%) than that following a solvent-based paclitaxel injection and its volume of distribution was also higher (53%). Differences in Cmax and Cmax corrected for dose reflected differences in total dose and rate of infusion. There were no differences in terminal half-lives. In a repeat dose study with 12 patients receiving Abraxane administered intravenously at the approved dose, intrapatient variability in systemic paclitaxel exposure (AUCinf) was 19% (range = 3.21%-27.70%). There was no evidence for accumulation of paclitaxel with multiple treatment courses. An analysis of patient exposure (AUCinf) against bodyweight indicated a trend toward reduced AUC at 260 mg/m2 Abraxane, with decreased body weight. Patients weighing 50 kg had paclitaxel AUC approximately 25% lower than those weighing 75 kg. The clinical relevance of this finding is uncertain. The protein binding of paclitaxel following Abraxane was evaluated by ultrafiltration. The fraction of free paclitaxel was significantly higher with Abraxane (6.2%) than with solvent-based paclitaxel (2.3%). This resulted in significantly higher exposure to unbound paclitaxel with Abraxane compared with solvent-based paclitaxel, even though the total exposure is comparable. This is possibly due to paclitaxel not being trapped in Cremophor EL micelles as with solvent-based paclitaxel. Based on the published literature, in vitro studies of binding to human serum proteins, (using paclitaxel at 6µM) the presence of ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel. Based on the published literature, in vitro studies with human liver microsomes and tissue slices show that paclitaxel is metabolised primarily to 6α-hydroxypaclitaxel; and to two minor metabolites, 3'-p-hydroxypaclitaxel and 6α-3'-p-dihydroxypaclitaxel. The formation of these hydroxylated metabolites is catalysed by CYP2C8, -3A4, and both -2C8 and -3A4 respectively. The pharmacokinetic profile of Abraxane administered as a 30 minute infusion was evaluated in 15 out of 30 patients with three levels of hepatic impairment based on serum bilirubin and liver enzyme levels. Figure 2 shows the correlation between paclitaxel clearance and total blood bilirubin as measured just prior to dosing. Figure 2: Correlation between paclitaxel clearance and total blood bilirubin The effect of renal dysfunction on the disposition of paclitaxel has not been formally investigated. In patients with metastatic breast cancer, after a 30 minute infusion of Abraxane at 260 mg/m2, the mean value for cumulative urinary excretion of unchanged active substance accounted for 4% of the total administered dose with less than 1% as the metabolites 6α-hydroxypaclitaxel and 3'-p-hydroxypaclitaxel, indicating extensive non-renal clearance. Paclitaxel is principally eliminated by hepatic metabolism and biliary excretion. Pharmacokinetics of paclitaxel in patients aged over 65 years seems comparable to that in patients less than 65 years. However, little information in patients over 75 years is available as only 3 patients over 75 years of age where included in the pharmacokinetic analysis. 5.3 Preclinical safety data The carcinogenic potential of paclitaxel has not been studied. However, based on the published literature, paclitaxel is a potentially carcinogenic and genotoxic agent at clinical doses, based upon its pharmacodynamic mechanism of action. Paclitaxel has been shown to be clastogenic in vitro (chromosome aberrations in human lymphocytes) and in vivo (micronucleus test in mice). Paclitaxel has been shown to be genotoxic in vivo (micronucleus test in mice), but it did not induce mutagenicity in the Ames test or the Chinese hamster ovary/hypoxanthine-guanine phosphoribosyl transferase (CHO/HGPRT) gene mutation assay. Paclitaxel at doses below the human therapeutic dose was associated with low fertility and foetal toxicity in rats. Animal studies with Abraxane showed non-reversible, toxic effects on the male reproductive organs at clinically relevant exposure levels. 6. Pharmaceutical particulars 6.1 List of excipients Human albumin solution (containing sodium, sodium caprylate and N-acetyl DL tryptophanate). 6.2 Incompatibilities This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6. 6.3 Shelf life Unopened vials 3 years Stability of reconstituted suspension in the vial After first reconstitution, the suspension should be filled into an infusion bag immediately. However, chemical and physical in use stability has been demonstrated for 8 hours at 2°C-8°C in the original carton, and protected from bright light. Alternative light-protection may be used in the clean room. Stability of the reconstituted suspension in the infusion bag After reconstitution, the reconstituted suspension in the infusion bag should be used immediately. However chemical and physical in use stability has been demonstrated for 8 hours not above 25°C. 6.4 Special precautions for storage Unopened vials Keep the vial in the outer carton in order to protect from light. Reconstituted suspension For storage conditions after reconstitution of the medicinal product, see section 6.3. 6.5 Nature and contents of container 50 ml vial (type 1 glass) with a stopper (butyl rubber), with an overseal (aluminium), containing 100 mg of paclitaxel formulated as albumin bound nanoparticles. 100ml vial (type 1 glass) with a stopper (butyl rubber), with an overseal (aluminium), containing 250 mg of paclitaxel formulated as albumin bound nanoparticles. Pack size of one vial. 6.6 Special precautions for disposal and other handling Preparation and administration precautions Paclitaxel is a cytotoxic anticancer medicinal product and, as with other potentially toxic compounds, caution should be exercised in handling Abraxane. The use of gloves, goggles and protective clothing is recommended. If the suspension contacts the skin, the skin should be washed immediately and thoroughly with soap and water. If it contacts mucous membranes, the membranes should be flushed thoroughly with water. Abraxane should only be prepared and administered by personnel appropriately trained in the handling of cytotoxic agents. Pregnant staff should not handle Abraxane. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during administration of the medicinal product. Limiting the infusion of Abraxane to 30 minutes, as directed, reduces the likelihood of infusion-related reactions. Reconstitution and administration of the product Abraxane is supplied as a sterile lyophilised powder for reconstitution before use. After reconstitution, each ml of suspension contains 5 mg of paclitaxel formulated as albumin bound nanoparticles. 100mg vial: Using a sterile syringe, 20 ml of sodium chloride 9 mg/ml (0.9%) solution for infusion should slowly be injected into a vial of Abraxane over a minimum of 1 minute. 250mg vial: Using a sterile syringe, 50 ml of sodium chloride 9 mg/ml (0.9%) solution for infusion should slowly be injected into a vial of Abraxane over a minimum of 1 minute. The solution should be directed onto the inside wall of the vial. The solution should not be injected directly onto the powder as this will result in foaming. Once the addition is complete, the vial should be allowed to stand for a minimum of 5 minutes to ensure proper wetting of the solid. Then, the vial should gently and slowly be swirled and/or inverted for at least 2 minutes until complete resuspension of any powder occurs. The generation of foam must be avoided. If foaming or clumping occurs, the solution must stand for at least 15 minutes until foam subsides. The reconstituted suspension should be milky and homogenous without visible precipitates. Some settling of the reconstituted suspension may occur. If precipitates or settling are visible, the vial should be gently inverted again to ensure complete resuspension prior to use. Inspect the suspension in the vial for particulate matter. Do not administer the reconstituted suspension if particulate matter is observed in the vial. The exact total dosing volume of 5 mg/ml suspension required for the patient should be calculated and the appropriate amount of reconstituted Abraxane should be injected into an empty, sterile, PVC or non-PVC type intravenous bag. The use of medical devices containing silicone oil as a lubricant (i.e. syringes and IV bags) to reconstitute and administer Abraxane may result in the formation of proteinaceous strands. Administer Abraxane using an infusion set incorporating a 15 µm filter to avoid administration of these strands. Use of a 15 µm filter removes strands and does not change the physical or chemical properties of the reconstituted product. Use of filters with a pore size less than 15 µm may result in blockage of the filter. The use of specialized di(2-ethylhexyl)phthalate (DEHP)-free solution containers or administration sets is not necessary to prepare or administer Abraxane infusions. Any unused product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Celgene Europe Limited 1 Longwalk Road Stockley Park Uxbridge UB11 1DB United Kingdom 8. Marketing authorisation number(s) EU/1/07/428/001 EU/1/07/428/002 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 11 January 2008 Date of latest renewal: 11 January 2013 10. Date of revision of the text 20/03/2014 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu FDA批准Celgene公司Abraxane用于胰腺癌治疗 2013年9月6日美国食品和药品监督管理局(FDA)扩展批准使用Abraxane(紫杉醇[paclitaxel] 蛋白质结合颗粒注射用混悬液，白蛋白结合)治疗有晚期(转移)胰腺癌患者。 在美国胰腺癌是癌症死亡的第四大原因。按照美国国家癌症研究所估计在2013年45,220例患者将被诊断和38,460例将死于该疾病。永久去除或治愈胰腺癌的唯一选择是手术，但通常癌症被诊断时对手术已太晚 美国FDA药物评价和研究中心血液学和肿瘤学室主任Richard Pazdur，M.D.说：“有胰腺癌患者常在癌症已晚期和不能手术去除后被诊断，”“在这些情况，和在手术后进展的情况时，选择像 Abraxane可能有助于延长患者生命。” Abraxane是一种化疗药物可减慢某些肿瘤生长。Abraxane意向在有胰腺癌已播散至机体其他部位患者中与吉西他滨[gemcitabine]，另一种化疗药物使用。 FDA在监管局的优先审评程序下审评Abraxane的新使用，优先审评提供加快审评药物。Abraxane还被授予对胰腺癌孤儿产品指定因为它意向治疗一种罕见疾病或情况。 在一项临床试验有861例参加者被随机赋予接受Abraxane加吉西他滨或单独吉西他滨确定Abraxane对胰腺癌安全性和有效性。用Abraxane加吉西他滨治疗参加者活存长于单独吉西他滨治疗平均1.8个月。另外，participants who接受Abraxane加吉西他滨参加者经受肿瘤生长延缓(无进展生存)比只接受吉西他滨参加者延缓平均1.8个月。 Abraxane加吉西他滨-治疗参加者观察到常见副作用包括与感染斗争白细胞减低，血中低水平血小板，疲乏，臂和腿神经损伤，恶心，脱发，组织肿胀，腹泻，发热，呕吐，皮疹和脱水。最常见严重副作用是发热，脱水，肺炎和呕吐。其他临床上重要严重副作用包括脓毒血症和肺炎。 Abraxane也已批准治疗乳癌(2005)和非小细胞肺癌(2012)。它由总部设在新泽西州Summit的 Celgene公司上市。吉西他滨印第安纳波利斯的礼来公司上市。 ---------------------------------------- 产地国家: 德国 原产地英文商品名: Abraxane 5mg/ml 100mg/20ml Intravenous infusion solution bottle 原产地英文药品名: Paclitaxel 中文参考商品译名: Abraxane静脉输液 5毫克/毫升 100毫克/20毫升/瓶 生产厂家英文名: Celgene