2009年8月6日，癌症新药Mozobil获欧盟批准上市，对淋巴瘤与多发性骨髓瘤患者提供重要的选项，这些患者原本需要异体干细胞移植。 作用机理 Plerixafor是CXCR4的趋化因子受体并阻断其同源配体，基质细胞衍生因子1α（SDF-1α）的结合的抑制剂。 SDF-1α和CXCR4被认为发挥贩运和人造血干细胞（HSC）的归巢作用是骨髓舱。一旦在骨髓，干细胞的CXCR4可起到帮助锚定这些细胞的骨髓基质，可以通过SDF-1α或通过其他粘附分子的诱导直接。与plerixafor治疗导致白细胞增多和海拔在小鼠，狗和人造血循环祖细胞。通过动员plerixafor CD34 +细胞能植入与长期再生能力长达一年犬移植模型。 适应症和用法 Mozobil，造血干细胞动员，指示结合粒细​​胞集落刺激因子（G-CSF），以动员造血干细胞的外周血收集和随后的自体移植的患者的非霍奇金淋巴瘤和多发性骨髓瘤。 用法用量 •启动治疗Mozobil患者接受的G-CSF后，每天一次，4天。 •重复Mozobil剂量最多连续4天。 •选择剂量以0.24毫克/公斤实际体重。 •通过单采开始大约11小时前，皮下注射辖。 •肾损害：如果肌酐清除率≤50 mL/min的剂量减少三分之一至0.16毫克/公斤。 剂型和规格 •含有20毫克/毫升溶液1.2毫升一次性使用小瓶中。 禁忌 •无。 Mozobil 20mg/ml solution for injection 1. Name of the medicinal product Mozobil 20 mg/ml solution for injection 2. Qualitative and quantitative composition One ml of solution contains 20 mg plerixafor. Each vial contains 24 mg plerixafor in 1.2 ml solution. Excipients with known effect: Each ml contains approximately 5 mg (0.2 mmol) of sodium. For the full list of excipients, see section 6.1. 3. Pharmaceutical form Solution for injection. Clear, colourless to pale yellow solution, with a pH of 6.0-7.5 and an osmolality of 260 - 320 mOsm/kg. 4. Clinical particulars 4.1 Therapeutic indications Mozobil is indicated in combination with granulocyte-colony stimulating factor (G-CSF) to enhance mobilisation of haematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in adult patients with lymphoma and multiple myeloma whose cells mobilise poorly (see section 4.2). 4.2 Posology and method of administration Mozobil therapy should be initiated and supervised by a physician experienced in oncology and/or haematology. The mobilisation and apheresis procedures should be performed in collaboration with an oncology-haematology centre with acceptable experience in this field and where the monitoring of haematopoietic progenitor cells can be correctly performed. Age over 60 and/ or prior myelosuppressive chemotherapy and/or extensive prior chemotherapy and/or a peak circulating stem cell count of less than 20 stem cells/microliter, have been identified as predictors of poor mobilization. Posology The recommended dose of plerixafor is 0.24 mg/kg body weight/day. It should be administered by subcutaneous injection 6 to 11 hours prior to initiation of each apheresis following 4 day pre-treatment with G-CSF. In clinical trials, Mozobil has been commonly used for 2 to 4 (and up to 7) consecutive days. The weight used to calculate the dose of plerixafor should be obtained within 1 week before the first dose of plerixafor. In clinical studies, the dose of plerixafor has been calculated based on body weight in patients up to 175% of ideal body weight. Plerixafor dose and treatment of patients weighing more than 175% of ideal body weight have not been investigated. Ideal body weight can be determined using the following equations: male (kg):  50 + 2.3 x ((Height (cm) x 0.394) – 60); female (kg):  45.5 + 2.3 x ((Height (cm) x 0.394) – 60). Based on increasing exposure with increasing body weight, the plerixafor dose should not exceed 40 mg/day. Recommended concomitant medicinal products In pivotal clinical studies supporting the use of Mozobil, all patients received daily morning doses of 10 μg/kg G-CSF for 4 consecutive days prior to the first dose of plerixafor and on each morning prior to apheresis. Special populations Renal impairment Patients with creatinine clearance 20-50 ml/min should have their dose of plerixafor reduced by one-third to 0.16 mg/kg/day (see section 5.2). Clinical data with this dose adjustment are limited. There is insufficient clinical experience to make alternative posology recommendations for patients with a creatinine clearance <20 ml/min, as well as to make posology recommendations for patients on haemodialysis. Based on increasing exposure with increasing body weight the dose should not exceed 27 mg/day if the creatinine clearance is lower than 50 ml/min. Paediatric population The experience in paediatric patients is limited. The safety and efficacy of Mozobil in children less than 18 years have not yet been established. Elderly patients (> 65 years old) No dose modifications are necessary in elderly patients with normal renal function. Dose adjustment in elderly patients with creatinine clearance ≤ 50 ml/min is recommended (see Renal impairment above). In general, care should be taken in dose selection for elderly patients due to the greater frequency of decreased renal function with advanced age. Method of administration Mozobil is for subcutaneous injection. Each vial is intended for single use only. Vials should be inspected visually prior to administration and not used if there is particulate matter or discolouration. Since Mozobil is supplied as a sterile, preservative-free formulation, aseptic technique should be followed when transferring the contents of the vial to a suitable syringe for subcutaneous administration (see section 6.3). 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 Potential for tumour cell mobilisation in patients with lymphoma and multiple myeloma The effect of potential re-infusion of tumour cells has not been adequately studied. When Mozobil is used in conjunction with G-CSF for haematopoietic stem cell mobilisation in patients with lymphoma or multiple myeloma‚ tumour cells may be released from the marrow and subsequently collected in the leukapheresis product. The clinical relevance of the theoretical risk of tumour cell mobilisation is not fully elucidated. In clinical studies of patients with non-Hodgkin's lymphoma and multiple myeloma, mobilisation of tumour cells has not been observed with plerixafor. Tumour cell mobilisation in leukaemia patients In a compassionate use programme, Mozobil and G-CSF have been administered to patients with acute myelogenous leukaemia and plasma cell leukaemia. In some instances, these patients experienced an increase in the number of circulating leukaemia cells. For the purpose of haematopoietic stem cell mobilisation, plerixafor may cause mobilisation of leukaemic cells and subsequent contamination of the apheresis product. Therefore, plerixafor is not recommended for haematopoietic stem cell mobilisation and harvest in patients with leukaemia. Haematological effects Hyperleukocytosis Administration of Mozobil in conjunction with G-CSF increases circulating leukocytes as well as haematopoietic stem cell populations. White blood cell counts should be monitored during Mozobil therapy. Clinical judgment should be exercised when administering Mozobil to patients with peripheral blood neutrophil counts above 50 x 109/L. Thrombocytopenia Thrombocytopenia is a known complication of apheresis and has been observed in patients receiving Mozobil. Platelet counts should be monitored in all patients receiving Mozobil and undergoing apheresis. Allergic reactions Mozobil has been uncommonly associated with potential systemic reactions related to subcutaneous injection such as urticaria, periorbital swelling, dyspnoea, or hypoxia (see section 4.8). Symptoms responded to treatments (e.g., antihistamines, corticosteroids, hydration or supplemental oxygen) or resolved spontaneously. Cases of anaphylactic reactions, including anaphylactic shock, have been reported from world-wide post-marketing experience. Appropriate precautions should be taken because of the potential for these reactions. Vasovagal reactions Vasovagal reactions, orthostatic hypotension, and/or syncope can occur following subcutaneous injections (see section 4.8). Appropriate precautions should be taken because of the potential for these reactions. Splenomegaly In preclinical studies, higher absolute and relative spleen weights associated with extramedullary haematopoiesis were observed following prolonged (2 to 4 weeks) daily plerixafor subcutaneous administration in rats at doses approximately 4 fold higher than the recommended human dose. The effect of plerixafor on spleen size in patients has not been specifically evaluated in clinical studies. The possibility that plerixafor in conjunction with G-CSF can cause splenic enlargement cannot be excluded. Due to the very rare occurrence of splenic rupture following G-CSF administration, individuals receiving Mozobil in conjunction with G-CSF who report left upper abdominal pain and/or scapular or shoulder pain should be evaluated for splenic integrity. Sodium Mozobil contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially 'sodium- free'. 4.5 Interaction with other medicinal products and other forms of interaction No interaction studies have been performed. In vitro tests showed that plerixafor was not metabolised by P450 CYP enzymes, did not inhibit or induce P450 CYP enzymes. Plerixafor did not act as a substrate or inhibitor of P-glycoprotein in an in vitro study. In clinical studies of patients with Non-Hodgkin's lymphoma, the addition of rituximab to a mobilisation regimen of plerixafor and G-CSF did not impact patient safety or CD34+ cell yield. 4.6 Fertility, pregnancy and lactation Women of childbearing potential Women of childbearing potential have to use effective contraception during treatment. Pregnancy There are no adequate data on the use of plerixafor in pregnant women. Based on the pharmacodynamic mechanism of action, plerixafor is suggested to cause congenital malformations when administered during pregnancy. Studies in animals have shown teratogenicity (see section 5.3). Mozobil should not be used during pregnancy unless the clinical condition of the woman requires treatment with plerixafor. Breast-feeding It is unknown whether plerixafor is excreted in human milk. A risk to the suckling child cannot be excluded. Breast-feeding should be discontinued during treatment with Mozobil. Fertility The effects of plerixafor on male and female fertility are not known (see section 5.3). 4.7 Effects on ability to drive and use machines Mozobil may influence the ability to drive and use machines. Some patients have experienced dizziness, fatigue or vasovagal reactions; therefore caution is advised when driving or operating machines. 4.8 Undesirable effects Summary of the safety profile Safety data for Mozobil in conjunction with G-CSF in oncology patients with lymphoma and multiple myeloma were obtained from 2 placebo-controlled Phase III studies (301 patients) and 10 uncontrolled Phase II studies (242 patients). Patients were primarily treated with daily doses of 0.24 mg/kg plerixafor by subcutaneous injection. The exposure to plerixafor in these studies ranged from 1 to 7 consecutive days (median = 2 days). In the two Phase III studies in non-Hodgkin's lymphoma and multiple myeloma patients (AMD3100-3101 and AMD3100-3102, respectively), a total of 301 patients were treated in the Mozobil and G-CSF group and 292 patients were treated in the placebo and G-CSF group. Patients received daily morning doses of G-CSF 10 μg/kg for 4 days prior to the first dose of plerixafor or placebo and on each morning prior to apheresis. Adverse reactions that occurred more frequently with Mozobil and G-CSF than placebo and G-CSF and were reported as related in ≥1% of the patients who received Mozobil, during haematopoietic stem cell mobilisation and apheresis and prior to chemotherapy/ablative treatment in preparation for transplantation are shown in Table 1. From chemotherapy/ablative treatment in preparation of transplantation through 12 months post-transplantation, no significant differences in the incidence of adverse reactions were observed across treatment groups. Tabulated list of adverse reactions Adverse reactions are listed by System Organ Class and frequency. Frequencies are defined according to the following convention: 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). Table 1. Adverse reactions occurring more frequently with Mozobil than placebo and considered related to Mozobil during mobilisation and apheresis in phase III studies Immune system disorders Uncommon Allergic reaction* Anaphylactic reactions, including anaphylactic shock (see section 4.4) ** Psychiatric disorders Common Insomnia Uncommon Abnormal dreams, nightmares Nervous system disorders Common Dizziness, headache Gastrointestinal disorders Very common Diarrhoea, nausea Common Vomiting, abdominal pain, stomach discomfort, dyspepsia, abdominal distention, constipation, flatulence, hypoaesthesia oral, dry mouth Skin and subcutaneous tissue disorders Common Hyperhidrosis, erythema Musculoskeletal and connective tissue disorders Common Arthralgia, musculoskeletal pain General disorders and administration site conditions Very common Injection and infusion site reactions Common Fatigue, malaise * The frequency of allergic reactions presented is based on adverse reactions that occurred in the oncology studies (679 patients). Events included one or more of the following: urticaria (n = 2), periorbital swelling (n = 2), dyspnoea (n = 1) or hypoxia (n = 1). These events were generally mild or moderate and occurred within approximately 30 min after Mozobil administration. ** From post-marketing experience The adverse reactions reported in patients with lymphoma and multiple myeloma who received Mozobil in the controlled Phase III studies and uncontrolled studies, including a Phase II study of Mozobil as monotherapy for haematopoietic stem cell mobilisation, are similar. No significant differences in the incidence of adverse reactions were observed for oncology patients by disease, age, or gender. Description of selected adverse reactions Myocardial infarction In clinical studies, 7 of 679 oncology patients experienced myocardial infarctions after haematopoietic stem cell mobilisation with plerixafor and G-CSF. All events occurred at least 14 days after last Mozobil administration. Additionally, two female oncology patients in the compassionate use programme experienced myocardial infarction following haematopoietic stem cell mobilisation with plerixafor and G-CSF. One of these events occurred 4 days after last Mozobil administration. Lack of temporal relationship in 8 of 9 patients coupled with the risk profile of patients with myocardial infarction does not suggest Mozobil confers an independent risk for myocardial infarction in patients who also receive G-CSF. Hyperleukocytosis White blood cell counts of 100 x 109/L or greater were observed, on the day prior to or any day of apheresis, in 7% patients receiving Mozobil and in 1% patients receiving placebo in the Phase III studies. No complications or clinical symptoms of leukostasis were observed. Vasovagal reactions In Mozobil oncology and healthy volunteer clinical studies, less than 1% of subjects experienced vasovagal reactions (orthostatic hypotension and/or syncope) following subcutaneous administration of plerixafor doses ≤0.24 mg/kg. The majority of these events occurred within 1 hour of Mozobil administration. Gastrointestinal disorders In Mozobil clinical studies of oncology patients, there have been rare reports of severe gastrointestinal events, including diarrhoea, nausea, vomiting, and abdominal pain. Paraesthesia Paraesthesia is commonly observed in oncology patients undergoing autologous transplantation following multiple disease interventions. In the placebo-controlled Phase III studies, the incidence of paraesthesia was 20.6% and 21.2% in the plerixafor and placebo groups, respectively. Elderly patients In the two placebo-controlled clinical studies of plerixafor, 24% of patients were ≥ 65 years old. No notable differences in the incidence of adverse reactions were observed in these elderly patients when compared with younger ones. 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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard. 4.9 Overdose No case of overdose has been reported. Based on limited data at doses above the recommended dose and up to 0.48 mg/kg the frequency of gastrointestinal disorders, vasovagal reactions, orthostatic hypotension, and/or syncope may be higher. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Other immunostimulants; ATC code: L03AX16 Mechanism of action Plerixafor is a bicyclam derivative, a selective reversible antagonist of the CXCR4 chemokine receptor and blocks binding of its cognate ligand, stromal cell-derived factor-1α (SDF-1α), also known as CXCL12. Plerixafor-induced leukocytosis and elevations in circulating haematopoietic progenitor cell levels are thought to result from a disruption of CXCR4 binding to its cognate ligand, resulting in the appearance of both mature and pluripotent cells in the systemic circulation. CD34+ cells mobilised by plerixafor are functional and capable of engraftment with long-term repopulating capacity. Pharmacodynamic effects In pharmacodynamic studies in healthy volunteers of plerixafor alone, peak mobilisation of CD34+ cells was observed from 6 to 9 hours after administration. In pharmacodynamic studies in healthy volunteers of plerixafor in conjunction with G-CSF administered at identical dose regimen to that in studies in patients, a sustained elevation in the peripheral blood CD34+ count was observed from 4 to 18 hours after plerixafor administration with peak response between 10 and 14 hours. Clinical efficacy and safety In two Phase III randomised-controlled studies patients with non-Hodgkin's lymphoma or multiple myeloma received Mozobil 0.24 mg/kg or placebo on each evening prior to apheresis. Patients received daily morning doses of G-CSF 10 μg/kg for 4 days prior to the first dose of plerixafor or placebo and on each morning prior to apheresis. Optimal (5 or 6 x 106 cells/kg) and minimal (2 x 106 cells/kg) numbers of CD34+ cells/kg within a given number of days, as well as the primary composite endpoints which incorporated successful engraftment are presented in Tables 2 and 4; the proportion of patients reaching optimal numbers of CD34+ cells/kg by apheresis day are presented in Tables 3 and 5. Table 2. Study AMD3100-3101 efficacy results - CD34+ cell mobilisation in non-Hodgkin's lymphoma patients Efficacy endpointb Mozobil and G-CSF (n = 150) Placebo and G-CSF (n = 148) p-value a Patients achieving ≥ 5 x 106 cells/kg in ≤ 4 apheresis days and successful engraftment 86 (57.3%) 28 (18.9%) <0.001 Patients achieving ≥ 2 x 106 cells/kg in ≤ 4 apheresis days and successful engraftment 126 (84.0%) 64 (43.2%) < 0.001 a p-value calculated using Pearson's Chi-Squared test bStatistically significantly more patients achieved ≥ 5 x 106 cells/kg in ≤ 4 apheresis days with Mozobil and G-CSF (n=89; 59.3%) than with placebo and G-CSF (n=29; 19.6%), p<0.001; statistically significantly more patients achieved ≥ 2 x 106 cells/kg in ≤ 4 apheresis days with Mozobil and G-CSF (n=130; 86.7%) than with placebo and G-CSF (n=70; 47.3%), p<0.001. Table 3. Study AMD3100-3101 – Proportion of patients who achieved ≥ 5 x 106 CD34+ cells/kg by apheresis day in non-Hodgkin's lymphoma patients Days Proportiona in Mozobil and G-CSF (n=147b) Proportiona in Placebo and G-CSF (n=142b) 1 27.9% 4.2% 2 49.1% 14.2% 3 57.7% 21.6% 4 65.6% 24.2% aPercents determined by Kaplan Meier method b n includes all patients who received at least one day of apheresis Table 4. Study AMD3100-3102 efficacy results – CD34+ cell mobilisation in multiple myeloma patients Efficacy endpointb Mozobil and G-CSF (n = 148) Placebo and G-CSF (n = 154) p-value a Patients achieving ≥ 6 x 106 cells/kg in ≤ 2 apheresis days and successful engraftment 104 (70.3%) 53 (34.4%) <0.001 ap-value calculated using Cochran-Mantel-Haenszel statistic blocked by baseline platelet count bStatistically significantly more patients achieved ≥ 6 x 106 cells/kg in ≤ 2 apheresis days with Mozobil and G-CSF (n=106; 71.6%) than with placebo and G-CSF (n=53; 34.4%), p<0.001; statistically significantly more patients achieved ≥ 6 x 106 cells/kg in ≤ 4 apheresis days with Mozobil and G-CSF (n=112; 75.7%) than with placebo and G-CSF (n=79; 51.3%), p<0.001; statistically significantly more patients achieved ≥ 2 x 106 cells/kg in ≤ 4 apheresis days with Mozobil and G-CSF (n=141; 95.3%) than with placebo and G-CSF (n=136; 88.3%), p=0.031. Table 5. Study AMD3100-3102 – Proportion of patients who achieved ≥ 6 x 106 CD34+ cells/kg by apheresis day in multiple myeloma patients Days Proportiona in Mozobil and G-CSF (n=144b) Proportiona in Placebo and G-CSF (n=150b) 1 54.2% 17.3% 2 77.9% 35.3% 3 86.8% 48.9% 4 86.8% 55.9% aPercents determined by Kaplan Meier method b n includes all patients who received at least one day of apheresis Rescue patients In study AMD3100-3101, 62 patients (10 in the Mozobil + G-CSF group and 52 in the placebo + G-CSF group), who could not mobilise sufficient numbers of CD34+ cells and thus could not proceed to transplantation, entered into an open-label Rescue procedure with Mozobil and G-CSF. Of these patients, 55 % (34 out of 62) mobilised ≥ 2 x106/kg CD34+ cells and had successful engraftment. In study AMD3100-3102, 7 patients (all from the placebo + G-CSF group) entered the Rescue procedure. Of these patients, 100% (7 out of 7) mobilised ≥ 2 x106/kg CD34+ cells and had successful engraftment. The dose of haematopoietic stem cells used for each transplant was determined by the investigator and all haematopoietic stem cells that were collected were not necessarily transplanted. For transplanted patients in the Phase III studies, median time to neutrophil engraftment (10-11 days), median time to platelet engraftment (18-20 days) and graft durability up to 12 months post-transplantation were similar across the Mozobil and placebo groups. Mobilisation and engraftment data from supportive Phase II studies (plerixafor 0.24 mg/kg dosed on the evening or morning prior to apheresis) in patients with non-Hodgkin's lymphoma, Hodgkin's disease, or multiple myeloma were similar to those data for the Phase III studies. In the placebo-controlled studies, fold increase in peripheral blood CD34+ cell count (cells/μl) over the 24-hour period from the day prior to the first apheresis to just before the first apheresis was evaluated (Table 6). During that 24-hour period, the first dose of plerixafor 0.24 mg/kg or placebo was administered 10-11 hours prior to apheresis. Table 6. Fold increase in peripheral blood CD34+ cell count following Mozobil administration Study Mozobil and G-CSF Placebo and G-CSF Median Mean (SD) Median Mean (SD) AMD3100-3101 5.0 6.1 (5.4) 1.4 1.9 (1.5) AMD3100-3102 4.8 6.4 (6.8) 1.7 2.4 (7.3) Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Mozobil in children aged 0 to 1 year in myelosuppression caused by chemotherapy to treat malignant disorders, which requires an autologous haematopoietic stem cell transplant (see section 4.2 for information on paediatric use). The European Medicines Agency has deferred the obligation to submit the results of studies with Mozobil in children aged 1 to 18 years in myelosuppression caused by chemotherapy to treat malignant disorders, which requires an autologous haematopoietic stem cell transplant (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties The pharmacokinetics of plerixafor have been evaluated in lymphoma and multiple myeloma patients at the clinical dose level of 0.24 mg/kg following pre-treatment with G-CSF (10 μg/kg once daily for 4 consecutive days). Absorption Plerixafor is rapidly absorbed following subcutaneous injection, reaching peak concentrations in approximately 30-60 minutes (tmax). Following subcutaneous administration of a 0.24 mg/kg dose to patients after receiving 4-days of G-CSF pre-treatment, the maximal plasma concentration (Cmax) and systemic exposure (AUC0-24) of plerixafor were 887 ± 217 ng/ml and 4337 ± 922 ng·hr/ml, respectively. Distribution Plerixafor is moderately bound to human plasma proteins up to 58%. The apparent volume of distribution of plerixafor in humans is 0.3 l/kg demonstrating that plerixafor is largely confined to, but not limited to, the extravascular fluid space. Biotransformation Plerixafor is not metabolised in vitro using human liver microsomes or human primary hepatocytes and does not exhibit inhibitory activity in vitro towards the major drug-metabolising CYP450 enzymes (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4/5). In in vitro studies with human hepatocytes, plerixafor does not induce CYP1A2, CYP2B6, and CYP3A4 enzymes. These findings suggest that plerixafor has a low potential for involvement in P450-dependent drug-drug interactions. Elimination The major route of elimination of plerixafor is urinary. Following a 0.24 mg/kg dose in healthy volunteers with normal renal function, approximately 70% of the dose was excreted unchanged in urine during the first 24 hours following administration. The elimination half-life (t1/2) in plasma is 3-5 hours. Plerixafor did not act as a substrate or inhibitor of P-glycoprotein in an in vitro study with MDCKII and MDCKII-MDR1 cell models. Special populations Renal impairment Following a single dose of 0.24 mg/kg plerixafor, clearance was reduced in subjects with varying degrees of renal impairment and was positively correlated with creatinine clearance (CrCl). Mean values of AUC0-24 of plerixafor in subjects with mild (CrCl 51-80 ml/min), moderate (CrCl 31-50 ml/min) and severe (CrCl ≤ 30 ml/min) renal impairment were 5410, 6780, and 6990 ng.hr/ml, respectively, which were higher than the exposure observed in healthy subjects with normal renal function (5070 ng·hr/ml). Renal impairment had no effect on Cmax.. Gender A population pharmacokinetic analysis showed no effect of gender on pharmacokinetics of plerixafor. Elderly A population pharmacokinetic analysis showed no effect of age on pharmacokinetics of plerixafor. Paediatric population There are limited pharmacokinetic data in paediatric patients. 5.3 Preclinical safety data The results from single dose subcutaneous studies in rats and mice showed plerixafor can induce transient but severe neuromuscular effects (uncoordinated movement), sedative-like effects (hypoactivity), dyspnoea, ventral or lateral recumbency, and/or muscle spasms. Additional effects of plerixafor consistently noted in repeated dose animal studies included increased levels of circulating white blood cells and increased urinary excretion of calcium and magnesium in rats and dogs, slightly higher spleen weights in rats, and diarrhoea and tachycardia in dogs. Histopathology findings of extramedullary haematopoiesis were observed in the liver and spleen of rats and/or dogs. One or more of these findings were usually observed at systemic exposures in the same order of magnitude or slightly higher than the human clinical exposure. An in vitro general receptor activity screen showed that plerixafor, at a concentration (5 µg/ml) several fold higher than the maximum human systemic level, has moderate or strong binding affinity for a number of different receptors predominantly located on pre-synaptic nerve endings in the central nervous system (CNS) and/or the peripheral nervous system (PNS) (N-type calcium channel, potassium channel SKCA, histamine H3, acetylcholine muscarinic M1 and M2, adrenergic α1B and α2C, neuropeptide Y/Y1 and glutamate NMDA polyamine receptors). The clinical relevance of these findings is not known. Safety pharmacology studies with intravenously administered plerixafor in rats showed respiratory and cardiac depressant effects at systemic exposure slightly above the human clinical exposure, whilst subcutaneous administration elicited respiratory and cardiovascular effects only at higher systemic levels. SDF-1α and CXCR4 play major roles in embryo-foetal development. Plerixafor has been shown to cause increased resorptions, decreased foetal weights, retarded skeletal development and increased foetal abnormalities in rats and rabbits. Data from animal models also suggest modulation of foetal haematopoiesis, vascularisation, and cerebellar development by SDF-1α and CXCR4. Systemic exposure at No Observed Adverse Effect Level for teratogenic effects in rats and rabbits was of the same magnitude or lower as found at therapeutic doses in patients. This teratogenic potential is likely due to its pharmacodynamic mechanism of action. In rat distribution studies concentrations of radiolabelled plerixafor was detected in reproductive organs (testes, ovaria, uterus) two weeks after single or 7 daily repeated doses in males and after 7 daily repeated doses in females. The elimination rate from tissues was slow. The potential effects of plerixafor on male and female fertility and post-natal development have not been evaluated in non-clinical studies. Carcinogenicity studies with plerixafor have not been conducted.Plerixafor was not genotoxic in an adequate battery of genotoxicity tests. Plerixafor inhibited tumour growth in in vivo models of non-Hodgkin's lymphoma, glioblastoma, medulloblastoma, and acute lymphoblastic leukaemia when dosed intermittently. An increase of non-Hodgkin's lymphoma growth was noted after a continuous administration of plerixafor for 28 days. The potential risk associated with this effect is expected to be low for the intended short term duration of dosing plerixafor in humans. 6. Pharmaceutical particulars 6.1 List of excipients Sodium chloride Hydrochloric acid, concentrated (pH adjustment) Sodium hydroxide (pH adjustment) Water for injections 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life Unopened vial 3 years. After opening From a microbiological point of view the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user. 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container Clear type I glass 2 ml vial with a chlorobutyl/butyl rubber stopper and aluminium seal with a plastic flip-off cap. Each vial contains 1.2 ml solution. Pack size of 1 vial. 6.6 Special precautions for disposal and other handling Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Genzyme Europe B.V., Gooimeer 10, NL-1411 DD Naarden, The Netherlands. 8. Marketing authorisation number(s) EU/1/09/537/001 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 31 July 2009 Date of latest renewal: 31 July 2014 10. Date of revision of the text 24 March 2015. Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. 普乐沙福（plerixafor）注射液-被批准作为罕用药 基因酶（Genzyme）公司产品（商品名：Mozobil），与粒细胞集落刺激因子（G-CSF）联合用药来促进红细胞生成素干细胞进入非霍奇金淋巴瘤（NHL）和多发性骨髓瘤（MM）患者血流以收集、随后自体移植。 本品还被获准作为罕用药物。 剂量规格:普乐沙福20 mg/mL。 普乐沙福系一新颖的小分子CXCR4趋化因子受体拮抗剂，多项早期研究显示可快速有效地增加NHL和MM患者血液循环中的干细胞数。 普乐沙福治疗需干细胞移植的某些类型癌症患者是一重大进展。由于本品有益于患者、医生和移植治疗中心将成为干细胞移植治疗方案的整体部分。 普乐沙福调动红细胞生成素干细胞从骨髓进入血流，收集、为需干细胞移植的某些类型癌症患者进行移植。以往，移植前患者需接受处方药化疗和（或）生长因子类药物来帮助其调动红细胞生成素干细胞进入血流。一旦此细胞进入血流，它们被收集用于移植制备。 为了完成干细胞移植，按体重必需收集约200万个干细胞/kg。许多患者需3-4小时至数日来完成此过程。甚至一些患者调动不了足够的干细胞，因而不能进行移植。对许多癌症患者来说，调动干细胞是缩小癌症或治愈的唯一希望。 在普乐沙福注射剂关键的临床研究中，59％的NHL患者接受Mozobil和G-CSF联合用药治疗旨在4个或更少的单采血液成分术期间内按体重至少收集的目标数为500万个干细胞/kg，与20％接受安慰剂的患者进行比较。 Mozobil治疗组达到目标细胞数的平均天数为3日，安慰剂组未作评价。72％的MM患者接受Mozobil与G-CSF联合用药治疗旨在2个或更少的单采血液成分术期间内按体重至少收集的目标数为600万个干细胞/kg，与28％使用安慰剂患者进行对照。Mozobil治疗组达到靶细胞数的平均天数为1日，安慰剂组为4日。在关键的临床研究中选择的干细胞目标数是依据达到这些目标数有助于促进移植的文献资料。 Mozobil除了有益于NHL和MM患者外，还为移植治疗中心带来了经济效益。本品可减少单采血液成分术的天数，可向移植中心提供可预测的结果和有效地利用单采血液成分术中心。 Mozobil还可减少原先单一采用G-CSF治疗不能调动足够细胞数需第2次治疗的患者人数。 ------------------------------------------------------- 产地国家：荷兰 原产地英文商品名： Mozobil solution for injection 20mg/ml 1.2ml/vial 原产地英文药品名： PLERIXAFOR 中文参考商品译名： MOZOBIL注射溶液 20毫克/毫升 1.2毫升/瓶 中文参考药品译名： 普乐沙福 生产厂家英文名： SANOFI（Genzyme Europe B.V.） 生产厂家中文参考译名： SANOFI（持卡人：健赞公司 B.V.）