米伐木肽注射剂(mifamurtide,L-MTP-PE,:Mepact)-全球第一个改善骨肉瘤长期存活的新药 IDM制药公司产品(商品名:Mepact) ,用于治疗非转移性、可切除的骨肉瘤(少见但是主要造成儿童和青年死亡的骨瘤)。 米伐木肽是20余年来首个获准上市用于改善骨肉瘤患者长期存活的新药 患者术前化疗,随后手术切除骨瘤,而后再化疗。在患者接受术后化疗的同时,静脉注射给予本品进行免疫治疗(一周2次共3个月,随后一周1次共6个月) 。化疗摧毁肿瘤,而米伐木肽可彻底清除残留肿瘤。 米伐木肽通过刺激巨噬细胞等某些白细胞来杀灭肿瘤细胞。该药制成球形脂质体, 囊泡内是胞壁酰三肽(MTP) 。此脂质触发巨噬细胞去消耗米伐木肽。一旦消耗完,MTP就刺激巨噬细胞去寻找肿瘤并杀灭之。 米伐木肽注射剂获准上市是基于Ⅲ期临床研究结果。国立癌症研究所建立协作组,由儿童肿瘤组(COG)进行研究,在册患者数约800例。研究评价了米伐木肽与3～4种辅助化疗药(顺铂、多柔比星、甲氨蝶呤、有或无异环磷酰胺)联合用药的结果。研究显示,米伐木肽与化学药物联合使用可使死亡率降低约30% , 78%经治疗的患者存活长达6年以上。 Mepact 4 mg powder for suspension for infusion 1. Name of the medicinal product MEPACT 4 mg powder for concentrate for dispersion for infusion 2. Qualitative and quantitative composition One vial contains 4 mg mifamurtide*. After reconstitution, each ml of suspension in the vial contains 0.08 mg mifamurtide. *fully synthetic analogue of a component of Mycobacterium sp. cell wall. For the full list of excipients, see section 6.1. 3. Pharmaceutical form Powder for concentrate for dispersion for infusion. White to off-white homogeneous cake or powder. 4. Clinical particulars 4.1 Therapeutic indications MEPACT is indicated in children, adolescents and young adults for the treatment of high-grade resectable non-metastatic osteosarcoma after macroscopically complete surgical resection. It is used in combination with post-operative multi-agent chemotherapy. Safety and efficacy have been assessed in studies of patients 2 to 30 years of age at initial diagnosis (see section 5.1). 4.2 Posology and method of administration Mifamurtide treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of osteosarcoma. Posology The recommended dose of mifamurtide for all patients is 2 mg/m2 body surface area. It should be administered as adjuvant therapy following resection: twice weekly at least 3 days apart for 12 weeks, followed by once-weekly treatments for an additional 24 weeks for a total of 48 infusions in 36 weeks. Adults >30 years None of the patients treated in the osteosarcoma studies were 65 years or older and in the phase III randomised study, only patients up to the age of 30 years were included. Therefore, there are not sufficient data to recommend the use of MEPACT in patients >30 years of age. Renal or hepatic impairment There are no clinically meaningful effects of mild to moderate renal (creatinine clearance (CrCL) ≥ 30 ml/min) or hepatic impairment (Child-Pugh class A or B) on the pharmacokinetics of mifamurtide; therefore, dose adjustments are not necessary for these patients. However, as the variability in pharmacokinetics of mifamurtide is greater in subjects with moderate hepatic impairment (see section 5.2), and safety data in patients with moderate hepatic impairment is limited, caution when administering mifamurtide to patients with moderate hepatic impairment is recommended. As no pharmacokinetic data of mifamurtide is available in patients with severe renal or hepatic impairment, caution when administering mifamurtide to these patients is recommended. Continued monitoring of the kidney and liver function is recommended if mifamurtide is used beyond completion of chemotherapy until all therapy is completed. Paediatric population <2 years The safety and efficacy of mifamurtide in children aged 0 to 2 years have not been established. No data are available. Method of administration MEPACT must be reconstituted, filtered using the filter provided and further diluted prior to administration. The reconstituted, filtered and diluted suspension for infusion is a homogenous, white to off-white, opaque liposomal suspension, free of visible particles and free of foam and lipid lumps. After reconstitution, filtering using the filter provided and further dilution, MEPACT is administered by intravenous infusion over a period of 1 hour. MEPACT must not be administered as a bolus injection. For further instructions on reconstitution, filtering using the filter provided and dilution prior to administration, see section 6.6. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Concurrent use with ciclosporin or other calcineurin inhibitors (see section 4.5). Concurrent use with high-dose non-steroidal anti-inflammatory drugs (NSAIDs, cyclooxygenase inhibitors) (see section 4.5). 4.4 Special warnings and precautions for use Respiratory distress In patients with a history of asthma or other chronic obstructive pulmonary disease, consideration should be given to administration of bronchodilators on a prophylactic basis. Two patients with pre-existing asthma developed mild to moderate respiratory distress associated with the treatment (see section 4.8). If a severe respiratory reaction occurs, administration of mifamurtide should be discontinued and appropriate treatment initiated. Neutropenia Administration of mifamurtide was commonly associated with transient neutropenia, usually when used in conjunction with chemotherapy. Episodes of neutropenic fever should be monitored and managed appropriately. Mifamurtide may be given during periods of neutropenia, but subsequent fever attributed to the treatment should be monitored closely. Fever or chills persisting for more than 8 hours after administration of mifamurtide should be evaluated for possible sepsis. Inflammatory response Association of mifamurtide with signs of pronounced inflammatory response, including pericarditis and pleuritis, was uncommon. It should be used with caution in patients with a history of autoimmune, inflammatory or other collagen diseases. During mifamurtide administration, patients should be monitored for unusual signs or symptoms, such as arthritis or synovitis, suggestive of uncontrolled inflammatory reactions. Cardiovascular disorders Patients with a history of venous thrombosis, vasculitis or unstable cardiovascular disorders should be closely monitored during mifamurtide administration. If symptoms are persistent and worsening, administration should be delayed or discontinued. Haemorrhage was observed in animals at very high doses. These are not expected at the recommended dose, however monitoring of clotting parameters after the first dose and once again after several doses is recommended. Allergic reactions Occasional allergic reactions have been associated with mifamurtide treatment, including rash, shortness of breath and Grade 4 hypertension (see section 4.8). It may be difficult to distinguish allergic reactions from exaggerated inflammatory responses, but patients should be monitored for signs of allergic reactions. Gastrointestinal toxicity Nausea, vomiting and loss of appetite are very common adverse reactions to mifamurtide (see section 4.8). Gastrointestinal toxicity may be exacerbated when mifamurtide is used in combination with high dose, multi-agent chemotherapy and was associated with an increased use of parenteral nutrition. 4.5 Interaction with other medicinal products and other forms of interaction Limited studies of the interaction of mifamurtide with chemotherapy have been conducted. Although these studies are not conclusive, there is no evidence of interference of mifamurtide with the anti-tumour effects of chemotherapy and vice versa. It is recommended to separate the administration times of mifamurtide and doxorubicin or other lipophilic medicinal products if used in the same chemotherapy regimen. The use of mifamurtide concurrently with ciclosporin or other calcineurin inhibitors is contraindicated due to their hypothesised effect on splenic macrophages and mononuclear phagocytic function (see section 4.3). Also, it has been demonstrated in vitro that high-dose NSAIDs (cyclooxygenase inhibitors) can block the macrophage activating effect of liposomal mifamurtide. Therefore, the use of high-dose NSAIDs is contraindicated (see section 4.3). Because mifamurtide acts through stimulation of the immune system, the chronic or routine use of corticosteroids should be avoided during treatment with mifamurtide. In vitro interaction studies showed that liposomal and non-liposomal mifamurtide do not inhibit the metabolic activity of cytochrome P450 in pooled human liver microsomes. Liposomal and non-liposomal mifamurtide do not induce the metabolic activity or the transcription of cytochrome P450 in primary cultures of freshly isolated human hepatocytes. Mifamurtide is, therefore, not expected to interact with the metabolism of substances that are hepatic cytochrome P450 substrates. In a large controlled randomised study, mifamurtide used at the recommended dose and schedule with other medicinal products that have known renal (cisplatin, ifosfamide) or hepatic (high-dose methotrexate, ifosfamide) toxicities did not exacerbate those toxicities and there was no need to adjust mifamurtide dose. 4.6 Fertility, pregnancy and lactation Pregnancy There are no data from the use of mifamurtide in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Mifamurtide is not recommended for use during pregnancy and in women of childbearing potential not using effective contraception. Breast-feeding It is unknown whether mifamurtide is excreted in human milk. The excretion of mifamurtide in milk has not been studied in animals. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy should be made taking into account the benefit of breast-feeding to the child and the benefit of mifamurtide therapy to the woman. Fertility No dedicated fertility studies have been conducted with mifamurtide (see section 5.3). 4.7 Effects on ability to drive and use machines No studies of the effects on the ability to drive and use machines have been performed. The very common or common undesirable effects of mifamurtide treatment (such as dizziness, vertigo, fatigue and blurred vision) may have an effect on the ability to drive and use machines. 4.8 Undesirable effects Summary of the safety profile Mifamurtide was studied as a single agent in 248 patients with mostly advanced malignancies during the early, single arm phase I and II clinical studies. The most frequent adverse reactions, occurring in >50% of patients, were chills, pyrexia, fatigue, nausea, tachychardia and headache. Many of the very commonly reported adverse reactions as shown in the following summary table are thought to be related to the mechanism of action of mifamurtide (see Table 1). The majority of these events were reported as either mild or moderate. This profile is consistent whether summarising all early studies (n=248) or only those studies in osteosarcoma (n=51). It is likely that these adverse reactions also occurred in the large randomised study, but they were not recorded because only serious and life-threatening adverse reactions were collected in that study. Tabulated list of adverse reactions Adverse reactions are classified according to system organ class and frequency. Frequency groupings are defined according to the following convention: Very common (≥1/10), common (≥1/100 to <1/10). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 1. Adverse reactions associated with MEPACT in ≥ 1/100 patients System Organ Class Adverse Reaction (Preferred Term) Infections and infestations Common Sepsis, Cellulitis, Nasopharyngitis, Catheter site infection, Upper respiratory tract infection, Urinary tract infection, Pharyngitis, Herpes simplex infection Neoplasms benign, malignant and unspecified (incl cysts and polyps) Common Cancer pain Blood and lymphatic system disorders Very Common Anaemia Common Leukopenia, Thrombocytopenia, Granulocytopenia, Febrile neutropenia Metabolism and nutrition disorders Very common Anorexia Common Dehydration, Hypokalaemia, Decreased appetite Psychiatric disorders Common Confusional state, Depression, Insomnia, Anxiety Nervous system disorders Very common Headache, Dizziness Common Paraesthesia, Hypoaesthesia, Tremor, Somnolence, Lethargy Eye disorders Common Blurred vision Ear and labyrinth disorders Common Vertigo, Tinnitus, Hearing loss Cardiac disorders Very common Tachycardia Common Cyanosis, Palpitations Vascular disorders Very common Hypertension, Hypotension Common Phlebitis, Flushing, Pallor Respiratory, thoracic and mediastinal disorders Very common Dyspnoea, Tachypnoea, Cough Common Pleural effusion, Exacerbated Dyspnoea, Productive cough, Haemoptysis, Wheezing, Epistaxis, Exertional dyspnoea, Sinus congestion, Nasal congestion, Pharyngolaryngeal pain Gastrointestinal disorders Very common Vomiting, Diarrhoea, Constipation, Abdominal pain, Nausea Common Upper abdominal pain, Dyspepsia, Abdominal distension, Lower abdominal pain Hepatobiliary disorders Common Hepatic pain Skin and subcutaneous tissue disorders Very common Hyperhidrosis Common Rash, Pruritis, Erythema, Alopecia, Dry skin Musculoskeletal and connective tissue disorders Very common Myalgia, Arthralgia, Back pain, Pain in extremity Common Muscle spasms, Neck pain, Groin pain, Bone pain, Shoulder pain, Chest wall pain, Musculoskeletal stiffness Renal and urinary disorders Common Haematuria, Dysuria, Pollakiuria Reproductive system and breast disorders Common Dysmenorrhoea General disorders and administration site conditions Very common Fever, Chills, Fatigue, Hypothermia, Pain, Malaise, Asthenia, Chest pain Common Peripheral oedema, Oedema, Mucosal inflammation, Infusion site erythema, Infusion site reaction, Catheter site pain, Chest discomfort, Feeling cold Investigations Common Weight decreased Surgical and medical procedures Common Post-procedural pain Description of selected adverse reactions Blood and lymphatic system disorders Anaemia has very commonly been reported when mifamurtide is used in conjunction with chemotherapeutic agents. In a randomised controlled study, the incidence of myeloid malignancy (acute myeloid leukaemia/myelodysplastic syndrome) was the same in patients receiving MEPACT plus chemotherapy as in patients receiving only chemotherapy (2.1%). Metabolism and nutritional disorders Anorexia (21%) was very commonly reported in phase I and II studies of mifamurtide Nervous system disorders Consistent with other generalised symptoms, the very common nervous system disorders were headache (50%) and dizziness (17%). One patient in the phase III study experienced 2 episodes of Grade 4 seizure while on study therapy with chemotherapy and mifamurtide. The second episode involved multiple grand mal seizures over the course of days. Mifamurtide treatment was continued for the remainder of the study without seizure recurrence. Ear and labyrinth disorders Although hearing loss may be attributable to ototoxic chemotherapy, like cisplatin, it is unclear whether MEPACT in conjunction with multi-agent chemotherapy may increase hearing loss. A higher percentage of objective and subjective hearing loss was observed overall in patients who received MEPACT and chemotherapy (12 % and 4%, respectively) in the phase III study (see Section 5.1 for a description of the study) compared to those patients that received only chemotherapy (7% and 1%). All patients received a total dose of cisplatin of 480 mg/m2 as part of their induction (neoadjuvant) and/or maintenance (adjuvant) chemotherapy regimen. Cardiac and vascular disorders Mild-moderate tachycardia (50%), hypertension (26%) and hypotension (29%) were very commonly reported in uncontrolled studies of mifamurtide. One serious incident of subacute thrombosis was reported in early studies, but no serious cardiac events were associated with mifamurtide in a large randomised controlled study (see section 4.4). Respiratory disorders Respiratory disorders, including dyspnoea (21%), cough (18%) and tachypnoea (13%) were very commonly reported, and two patients with pre-existing asthma developed mild to moderate respiratory distress associated with MEPACT treatment in a phase II study. Gastrointestinal disorders Gastrointestinal disorders were frequently associated with mifamurtide administration, including nausea (57%) and vomiting (44%) in about half of patients, constipation (17%), diarrhoea (13%) and abdominal pain (see section 4.4). Skin and subcutaneous disorders Hyperhidrosis (11%) was very common in patients receiving mifamurtide in uncontrolled studies. Musculoskeletal and connective tissue disorders Low grade pain was very common in patients receiving mifamurtide, including myalgia (31%), back pain (15%), extremity pain (12%) and arthralgia (10%). General disorders and administration site conditions The majority of patients experience chills (89%), fever (85%) and fatigue (53%). These are typically mild to moderate, transient in nature and generally respond to palliative treatment (e.g., paracetamol for fever). Other generalised symptoms that were typically mild to moderate and very common included hypothermia (23%), malaise (13%), pain (15%), asthenia (13%) and chest pain (11%). Oedema, chest discomfort, local infusion or catheter site reactions and 'feeling cold' were less frequently reported in these patients, mostly with late stage malignant disease. Investigations An osteosarcoma patient in a phase II study who had high creatinine level at enrolment showed an increase in blood urea and blood creatinine which was associated with mifamurtide use. Immune system disorders In a phase I study, there was one report of severe allergic reaction occurring after the first infusion of mifamurtide at 6 mg/m2 dose level. The patient experienced shaking, chills, fever, nausea, vomiting, uncontrollable coughing, shortness of breath, cyanotic lips, dizziness, weakness, hypotension, tachycardia, hypertension and hypothermia leading to study discontinuation. There was also one report of a grade 4 allergic reaction (hypertension) requiring hospitalization in the phase III study (see section 4.4). 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 No case of overdose has been reported within the approved indication. The maximum tolerated dose in phase I studies was 4-6 mg/m2 with a high variability of adverse reactions. Signs and symptoms that were associated with higher doses and/or were dose limiting were not life-threatening, and included fever, chills, fatigue, nausea, vomiting, headache and hypo- or hypertension. A healthy adult volunteer accidentally received a single dose of 6.96 mg mifamurtide and experienced a reversible treatment-related event of orthostatic hypotension. In the event of an overdose, it is recommended that appropriate supportive treatment be initiated. Supportive measures should be based on institutional guidelines and the clinical symptoms observed. Examples include paracetamol for fever, chills and headache and anti-emetics (other than steroids) for nausea and vomiting. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Immunostimulants, Other immunostimulants, ATC code: L03AX15 Mechanism of action Mifamurtide (muramyl tripeptide phosphatidyl ethanolamine, MTP-PE) is a fully synthetic derivative of muramyl dipeptide (MDP), the smallest naturally-occurring immune stimulatory component of cell walls from Mycobacterium sp. It has similar immunostimulatory effects as natural MDP with the additional advantage of a longer half-life in plasma. MEPACT is a liposomal formulation specifically designed for in vivo targeting to macrophages by intravenous infusion. MTP-PE is a specific ligand of NOD2, a receptor found primarily on monocytes, dendritic cells and macrophages. MTP-PE is a potent activator of monocytes and macrophages. Activation of human macrophages by mifamurtide is associated with production of cytokines, including tumour necrosis factor (TNF-α), interleukin-1 (IL-1β), IL-6, IL-8, and IL-12 and adhesion molecules, including lymphocyte function-associated antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1). In vitro-treated human monocytes killed allogeneic and autologous tumour cells (including melanoma, ovarian, colon, and renal carcinoma), but had no toxicity towards normal cells. In vivo administration of mifamurtide resulted in the inhibition of tumour growth in mouse and rat models of lung metastasis, skin and liver cancer, and fibrosarcoma. Significant enhancement of disease-free survival was also demonstrated in the treatment of dog osteosarcoma and hemangiosarcoma with mifamurtide as adjuvant therapy. The exact mechanism by which mifamurtide activation of monocytes and macrophages leads to antitumour activity in animals and humans is not yet known. Clinical safety and efficacy The safety of liposomal mifamurtide has been assessed in more than 700 patients with various kinds and stages of cancer and in 21 healthy adult subjects (see section 4.8). Mifamurtide significantly increased the overall survival of patients with newly-diagnosed resectable high-grade osteosarcoma when used in conjunction with combination chemotherapy when compared to chemotherapy alone. In a randomised phase III study of 678 patients (age range from 1.4 to 30.6 years) with newly-diagnosed resectable high-grade osteosarcoma, the addition of adjuvant mifamurtide to chemotherapy either doxorubicin cisplatin and methotrexate with or without ifosfamide, resulted in a relative reduction in the risk of death of 28% (p = 0.0313, hazard ratio (HR) = 0.72 [95% confidence interval (CI): 0.53, 0. 97]). 5.2 Pharmacokinetic properties The pharmacokinetics of mifamurtide have been characterized in healthy adult subjects following a 4 mg intravenous infusion and in paediatric and adult patients with osteosarcoma following a 2 mg/m2 intravenous infusion. In 21 healthy adult subjects mifamurtide was cleared rapidly from serum (minutes) with a half-life of 2.05 ± 0.40 hours, resulting in a very low serum concentration of total (liposomal and free) mifamurtide. The mean AUC was 17.0 ± 4.86 h x nM and Cmax was 15.7 ± 3.72 nM. In 28 osteosarcoma patients aged 6 to 39 years serum total (liposomal and free) mifamurtide concentrations declined rapidly with a mean half-life of 2.04 ± 0.456 hours. BSA-normalized clearance and half-life were similar across the age range and consistent with that determined in healthy adult subjects, supporting the recommended dose of 2 mg/m2. In a separate study in 14 patients, mean serum concentration-time curves of total and free mifamurtide that were assessed after the first infusion of mifamurtide and after a last infusion 11 or 12 weeks later, were almost superimposable and the mean AUC values of the free mifamurtide after the first and last infusion were similar. These data indicate that neither total nor free mifamurtide accumulated during the treatment period. At 6 hours after injection of radiolabelled liposomes containing 1 mg mifamurtide, radioactivity was found in liver, spleen, nasopharynx, thyroid, and, to a lesser extent, in lung. The liposomes were phagocytosed by cells of the reticuloendothelial system. In 2 of 4 patients with lung metastases, radioactivity was associated with lung metastases. Metabolism of liposomal MTP-PE has not been studied in humans. After injection of radiolabelled liposomes containing mifamurtide, mean half-life of radiolabelled material was biphasic with an α-phase of about 15 minutes and a terminal half-life of approximately 18 hours. Special populations Renal impairment The pharmacokinetics of a single 4mg dose of mifamurtide following a 1 hour intravenous infusion were evaluated in adult volunteers with mild (n=9) or moderate (n=8) renal impairment and in age- , sex-, and weight-matched healthy adults with normal renal function (n=16). There was no effect of mild (50 mL/min ≤ CLcr ≤80 mL/min) or moderate (30 mL/min ≤ CLcr < 50 mL/min) renal insufficiency on the clearance of total MTP-PE, when compared with that observed in healthy adult subjects with normal renal function (CLcr > 80 mL/min). Additionally, the systemic exposures (AUCinf) of free (non-liposome associated) MTP-PE in mild or moderate renal insufficiency were similar to those observed in healthy adult subjects with normal renal function. Hepatic impairment The pharmacokinetics of a single 4 mg dose of mifamurtide following a 1 hour intravenous infusion were evaluated in adult volunteers with mild (Child-Pugh class A; n=9) or moderate (Child-Pugh class B; n=8) hepatic impairment and in age- ,sex-, and weight-matched healthy adults with normal hepatic function (n=19). There was no effect of mild hepatic impairment on the systemic exposure (AUCinf) of total MTP-PE. Moderate hepatic impairment resulted in a small increase in AUCinf of total MTP-PE, with the geometric least square mean ratio (expressed as %) for moderate hepatic impairment in reference to the matched normal hepatic function group being 119% (90% CI: 94.1%-151%). Pharmacokinetic variability was higher in the moderate hepatic impairment group (co-efficient of variation in systemic exposure [AUCinf] was 50% versus <30% in the other hepatic function groups). Mean half-lives of total and free MTP-PE in mild hepatic impairment were 2.02 hours and 1.99 hours, respectively, and were comparable to those in subjects with normal hepatic function (2.15 hours and 2.26 hours, respectively). Mean half-lives of total and free MTP-PE in moderate hepatic impairment were 3.21 hours and 3.15 hours, respectively. Additionally, the geometric mean plasma AUCinf of free (non-liposome associated) MTP-PE in mild and moderate hepatic impairment were 47% higher than the corresponding values in the matched normal hepatic function groups. These changes were not considered to be clinically meaningful as the maximum tolerated dose (4-6 mg/m2) of mifamurtide is 2-3 times the recommended dose (2 mg/m2). 5.3 Preclinical safety data In sensitive species (rabbit and dog) the highest daily dose of liposomal mifamurtide that did not cause adverse effects was 0.1 mg/kg, corresponding to 1.2 and 2 mg/m2, respectively. The no-adverse-effect level for mifamurtide in animals corresponds roughly to the 2 mg/m2 recommend dose for humans. Data from a six month dog study of daily intravenous injections of up to 0.5 mg/kg (10 mg/m2) mifamurtide provide an 8- to 19-fold cumulative exposure safety margin for overt toxicity for the intended clinical dose in humans. Major toxic effects associated with these high daily and cumulative doses of mifamurtide were mainly exaggerated pharmacological effects: pyrexia, signs of pronounced inflammatory response manifested as synovitis, bronchopneumonia, pericarditis and inflammatory necrosis of the liver and bone marrow. The following events were also observed: haemorrhage and prolongation of coagulation times, infarcts, morphological changes in the wall of small arteries, oedema and congestion of the central nervous system, minor cardiac effects, and slight hyponatraemia. Mifamurtide was not mutagenic and did not cause teratogenic effects in rats and rabbits. Embryotoxic effects were observed only at maternal toxic levels. There were no results from general toxicity studies that suggested harmful effects on male or female reproductive organs. Specific studies addressing reproductive function, perinatal toxicity and carcinogenic potential have not been performed. 6. Pharmaceutical particulars 6.1 List of excipients 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) 1,2-Dioleoyl-sn-glycero-3-phospho-L-serine monosodium salt (OOPS) 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 vial of powder: 30 months Reconstituted suspension: Chemical and physical stability has been demonstrated for 6 hours up to 25°C. From a microbiological point of view, immediate use is recommended. If not used immediately, the reconstituted, filtered and diluted solution in-use storage times and conditions prior to use of the reconstituted product are the responsibility of the user and must not be longer than 6 hours at 25°C. Do not refrigerate or freeze the solution. 6.4 Special precautions for storage Store in a refrigerator (2°C – 8°C). Do not freeze. Keep the vial in the outer carton in order to protect from light. For storage conditions of the reconstituted medicinal product, see section 6.3. 6.5 Nature and contents of container 50 ml type I glass vial with a grey butyl rubber stopper, aluminium seal and plastic flip-off cap, containing 4 mg of mifamurtide. Each carton contains one vial and one single-use, non-pyrogenic, sterile filter for MEPACT supplied in a PVC-grade blister. 6.6 Special precautions for disposal and other handling MEPACT must be reconstituted, filtered using the filter provided and further diluted using aseptic technique. Each vial should be reconstituted with 50 ml of sodium chloride 9 mg/ml (0.9 %) solution for injection. After reconstitution, each ml suspension in the vial contains 0.08 mg mifamurtide. The volume of reconstituted suspension corresponding to the calculated dose is extracted through the filter provided and further diluted with additional 50 ml sodium chloride 9 mg/ml (0.9 %) solution for injection according to the detailed instructions shown below. Instructions for preparation of MEPACT for intravenous infusion Materials provided in each package - • MEPACT powder for concentrate for dispersion for infusion (vial) • Filter for MEPACT Materials required but not provided - • Sodium chloride 9 mg/ml (0.9%) solution for injection, 100 ml bag • One single use 60 or 100 ml sterile syringe with luer lock • Two medium (18) gauge sterile injection needles It is recommended that the reconstitution of the liposomal suspension should be performed in a laminar flow cabinet utilising sterile gloves using aseptic technique. The lyophilised powder should be allowed to reach a temperature between approximately 20°C – 25°C prior to reconstitution, filtering using the filter provided and dilution. This should take approximately 30 minutes. 1. The cap of the vial should be removed and the stopper cleaned using an alcohol pad. 2. The filter should be removed from the blister pack, and the cap removed from the filter spike. The spike should then be inserted into the vial septum firmly until seated. The filter luer connector cap should not be removed at this time. 3. The 100 ml sodium chloride 9 mg/ml (0.9%) solution for injection bag, needle and syringe should be unpacked (not provided in the pack). 4. The site of the sodium chloride 9 mg/ml (0.9%) solution for injection bag where the needle is going to be inserted should be swabbed with an alcohol pad. 5. Using the needle and syringe, 50 ml of sodium chloride 9 mg/ml (0.9%) solution for injection should be withdrawn from the bag. 6. After removing the needle from the syringe, the syringe should be attached to the filter by opening the filter luer connector cap (Figure 1). 7. The sodium chloride 9 mg/ml (0.9%) solution for injection is added to the vial by slow, firm depression of the syringe plunger. The filter and syringe must not be removed from the vial. 8. The vial should be allowed to stand undisturbed for one minute to ensure thorough hydration of the dry substance. 9. The vial should then be shaken vigorously for one minute while keeping the filter and syringe attached. During this time the liposomes are formed spontaneously (Figure 2). 10. The desired dose may be withdrawn from the vial by inverting the vial and slowly pulling back on the syringe plunger (Figure 3). Each ml reconstituted suspension contains 0.08 mg mifamurtide. The volume of suspension to be withdrawn for dose quantities is calculated as follows: Volume to withdraw = [12.5 x calculated dose (mg)] ml For convenience, the following table of concordance is provided: Dose Volume 1.0 mg 12.5 ml 2.0 mg 25 ml 3.0 mg 37.5 ml 4.0 mg 50 ml 11. The syringe should then be removed from the filter and a new needle placed on the suspension-filled syringe. The bag injection site should be wiped with an alcohol pad and the suspension in the syringe should be injected into the original bag containing the remaining 50 ml of sodium chloride 9 mg/ml (0.9%) solution for injection (Figure 4). 12. The bag should be gently swirled to mix the solution. 13. Patient identification, time and date should be added to the label on the bag containing the reconstituted, filtered and diluted liposomal suspension. 14. Chemical and physical in-use stability has been demonstrated for 6 hours at room temperature (between approximately 20°C – 25°C). 15. 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 and would normally not be longer than 6 hours at room temperature. 16. The liposomal suspension is infused intravenously over about one hour. Disposal No special requirements. 7. Marketing authorisation holder Takeda France SAS Immeuble Pacific 11-13 Cours Valmy 92800 - Puteaux France 8. Marketing authorisation number(s) EU/1/08/502/001 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 6 March 2009 Date of latest renewal: 18 December 2013 10. Date of revision of the text 18 December 2013 Detailed information on this product is available on the website of the European Medicines Agency (EMA) http://www.ema.europa.eu/ 包装规格 德国和韩国上市（厂家：Takeda） 法国上市厂家：IDM制药公司（IDM Pharma S.A.） 한국다케다, 골육종 치료제 ‘미팩트’ 식약청 승인 지난 11일 골육종 치료제 ‘미팩트’가 아시아 최초로 국내에서 승인됐다. 한국다케다제약(대표 이춘엽)은 자사의 골육종 치료제 미팩트(Mepact, 성분명 마이파머티드)가 지난 6월 5일 식품의약품안전청의 승인을 받았다고 밝혔다. 미팩트는 2009년 유럽 의약품청(EMEA) 승인을 받은 골육종 치료제로 영국, 스위스, 독일 등 유럽 다수 국가에서 시판되고 있으며 아시아에서는 국내 식약청 승인이 최초다. ‘뼈암’으로 불리는 골육종은 뼈에 발생하는 악성 희귀암으로, 보통 인구 10만명 당 1명 정도 발생하며, 어린이 및 청소년, 젊은 성인에게서 주로 나타나는 암이다. 우리나라에서는 연간 약 100~150명 정도의 신규 환자가 발생하는 것으로 보고되고 있다. 악성도가 높은 골육종의 경우 종양제거술만으로는 약 80%의 재발율을 보이며 암 진단일로부터 2~3년 이내에 사망에 이를 수 있다. 물론 종양제거술과 더불어 집중적 항암화학요법이 생존율 향상에 도움이 돼왔지만 이조차도 약 30~40%는 재발한다. 한국다케다제약의 미팩트는 20년 만에 새로 나온 골육종 치료제로서, 식약청으로부터 어린이와 청소년(만 15세 이하)의 절제가능한 고악성 및 비전이성 골육종에 대해 완전절제 후 다른 항암화학요법제와 병용하는 보조요법으로 승인 받았으며 희귀의약품으로 지정됐다. 미팩트는 골육종 환자들의 가장 주요한 사망 원인인 골육종에서의 미세 전이성 폐 질환을 표적으로 하는 새로운 계열의 면역 조절제로, 면역세포인 대식세포를 강력하게 활성화하여 직접적인 항암 효과를 나타낸다. 수술 후 보조병용 항암화학요법에 미팩트를 추가 투여한 연구에서 496명의 15세 이하 골육종 암환자를 대상으로 한 분석결과, 1세 이상 15세 이하 골육종 암 환자들의 재발률은 기존 치료 대비 약 33% 감소, 사망률은 약 44% 감소되는 등 장기적으로 현저한 생존 혜택이 입증된 바 있다. 한국다케다제약 항암제사업부 이지형 상무는 “다케다제약 한국법인 출범 후 국내 출시하는 첫 신약으로 우리나라의 희귀성, 특히 소아암 환자를 위한 미팩트가 승인돼 의미가 더 크다”며 “앞으로도 한국다케다제약은 연구개발 중심 글로벌 제약사로서 국내 암 환자 치료에 필요한 신약을 지속적으로 공급하겠다”고 말했다. 다케다제약은 글로벌 그룹 차원에서 지난 2009년 항암제 전문기관 밀레니움을 인수한 바 있다. 밀레니움은 다케다그룹 내에서 항암 분야 R&D 및 항암제 개발에만 집중하고 있으며, 미팩트를 비롯해 벨케이드(다발성골수종) 등의 항암제를 전세계에 공급하고 있다. 한국다케다제약은 작년 4월 출범한 이래 첫 신약으로 올해 골육종 치료제 미팩트를 출시하고, 향후 5년 이내에 항암, 당뇨, 호흡기계, 중추신경계 등에서 10개 이상의 혁신적인 신약을 차례로 선보일 예정이다. 다케다제약은 일본에 본사를 둔 세계 12위의 글로벌 제약회사이자 일본 1위 제약사로, 전세계 90개국 이상에 신약을 수출하며 지난해 매출 26조원을 올렸다. 아시아 제약기업 중에서는 유일하게 글로벌 최상위권 다국적제약사로 성장한 회사다.