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骨肉瘤最新治疗药—米伐木肽通过刺激诸如巨噬细胞等某些白细胞来杀灭肿瘤细胞，是20余年来首个获准上市治疗骨肉瘤的新药，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。
Osteosarcoma is a rare and often fatal disease, with approximately 1,200 new cases diagnosed in Europe each year; primarily children and young adults3.The standard treatment for osteosarcoma is surgical removal of the tumour (resection) with combination chemotherapy before and after surgery. Mepact is used in combination with these other anti-cancer medicines after the cancer has been removed by surgery1. Data from the largest independent clinical study ever completed in osteosarcoma (662 patients) conducted by the Children's Oncology Group in the USA, showed that when combined with chemotherapy, Mepact reduced the risk of death by almost one third compared with chemotherapy alone. In addition, 78 percent of patients survived after six years of follow-up after treatment with Mepact and chemotherapy, compared with 70 percent receiving chemotherapy alone4. "There has been a significant lack of progress during the last two decades in treating osteosarcoma," said Ian Lewis, Professor of Cancer Studies at St. James University Hospital in Leeds, England. "The availability of mifamurtide brings hope to children and young adults in need of a more positive treatment option for this devastating disease." Dr Erich Brunn, Chief Executive Officer for TPEU said, "This is an important milestone for Takeda in Europe and for the treatment of osteosarcoma. We are excited to bring this innovation to patients and physicians." Takeda anticipates that final reimbursement decisions in European countries will be completed during the course of 2010. About mifamurtide Mifamurtide is indicated for the treatment of high-grade, resectable, non-metastatic osteosarcoma after complete surgical removal of the tumour (resection) in children, adolescents and young adults between the ages of 2 and 30. "High grade" means that the cancer is a severe type. "Non-metastatic" means that there is no detectable cancer beyond the primary tumour, but in many patients there are already micro-metastases in the lung. It is these micro-metastases that are the primary targets for Mepact, preventing them from developing into metastases. Mepact is administered by intravenous infusion over the course of one hour, twice a week for 12 weeks, and then once a week for 24 additional weeks, for a total of 36 weeks of therapy or 48 doses3. Safety Information 近期，IDM生物制药公司研发的骨肉瘤治疗新药Mepact已通过欧盟的上市批准，该药用于治疗可进行手术切除的非转移性骨肉瘤患者。 -------------------------------------------------------------------------------- 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 a full list of excipients, see section 6.1. White to off-white homogeneous lyophilised powder. 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. The safety and efficacy of MEPACT have been established in children from the age of 2 years. It is not recommended for use in children below the age of 2 due to a lack of data on efficacy and safety in this age group. None of the patients treated in the osteosarcoma studies were 65 or older and in the phase III randomised study, only patients up to age 30 years were included. Therefore, there are not sufficient data to recommend the use of MEPACT in patients >30 years of age. The pharmacokinetics of mifamurtide in patients with renal or hepatic impairment have not been formally studied. Caution should be used in these patients because dose adjustment information is not available. Continued monitoring of the kidney and liver function is recommended if MEPACT is used beyond completion of chemotherapy until all therapy is completed. 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. 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). 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. If a severe respiratory reaction occurs, administration of MEPACT should be discontinued and appropriate treatment initiated. Administration of MEPACT was commonly associated with transient neutropenia, usually when used in conjunction with chemotherapy. Episodes of neutropenic fever should be monitored and managed appropriately. MEPACT 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 MEPACT should be evaluated for possible sepsis. Association of MEPACT 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 MEPACT administration, patients should be monitored for unusual signs or symptoms, such as arthritis or synovitis, suggestive of uncontrolled inflammatory reactions. Patients with a history of venous thrombosis, vasculitis or unstable cardiovascular disorders should be closely monitored during MEPACT 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. Occasional allergic reactions have been associated with MEPACT treatment, including rash, shortness of breath and Grade 4 hypertension. It may be difficult to distinguish allergic reactions from exaggerated inflammatory responses, but patients should be monitored for signs of allergic reactions. Nausea, vomiting and loss of appetite are very common adverse reactions to MEPACT. Gastrointestinal toxicity may be exacerbated when MEPACT is used in combination with high dose, multi-agent chemotherapy and was associated with an increased use of parenteral nutrition. It is recommended to separate the administration times of MEPACT and doxorubicin or other lipophilic medicinal products if used in the same chemotherapy regimen. The use of MEPACT 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 MEPACT. 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, MEPACT 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. There are no data from the use of mifamurtide in pregnant patients. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). MEPACT should not be used during pregnancy and in women not using effective contraception. 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 MEPACT therapy to the woman. 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, undesirable effects are presented in order of decreasing seriousness.
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 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 Blood and lymphatic system disorders Anaemia has most commonly been reported when MEPACT is used in conjunction with chemotherapeutic agents. In a randomised controlled trial, 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 (approximately 2.5%). Anorexia (21%) was very commonly reported in trials of MEPACT in late stage cancer patients. Consistent with other generalised symptoms, the most common nervous system disorders were headache (50%) and dizziness (17%). 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 7%, respectively) in the phase III study (see Section 5.1 for a description of the trial) 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. Mild-moderate tachycardia (50%), hypertension (26%) and hypotension (29%) were commonly reported in uncontrolled trials of MEPACT. One serious incident of subacute thrombosis was reported in early studies, but no serious cardiac events were associated with MEPACT in a large randomised controlled trial. 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 were frequently associated with MEPACT administration, including nausea (57%) and vomiting (44%) in about half of patients, constipation (17%), diarrhoea (13%) and abdominal pain. Hyperhidrosis (11%) was very common in patients receiving MEPACT in uncontrolled studies. Low grade pain was common in patients receiving MEPACT, including myalgia (31%), back pain (15%), extremity pain (12%) and arthralgia (10%). 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. Increase in blood urea and blood creatinine was associated with MEPACT use in one patient with osteosarcoma. 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. 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 MEPACT 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 tumor cells (including melanoma, ovarian, colon, and renal carcinoma), but had no toxicity towards normal cells. In vivo administration of MEPACT 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 MEPACT as adjuvant therapy. The exact mechanism by which MEPACT activation of monocytes and macrophages leads to antitumour activity in animals and humans is not yet known. 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). MEPACT 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 osetosarcoma, the addition of adjuvant MEPACT 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]). At 6 hours after injection of radiolabelled liposomes containing 6 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. 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. Data from a six month dog study of daily intravenous injections of up to 0.5 mg/kg (10 mg/m2) MEPACT 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 MEPACT 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. MEPACT 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. 1,2-Dioleoyl-sn-glycero-3-phospho-L-serine monosodium salt (OOPS) 30 months Reconstituted suspension: Chemical and physical stability has been demonstrated for 6 hours up to 25ºC. 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 25ºC. Do not store in a refrigerator and do not freeze the solution. 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. Each carton contains one vial and one single-use, non-pyrogenic, latex-free sterile Filter for MEPACT supplied in a PVC-grade blister. 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. Materials provided in each package - • MEPACT powder for suspension for infusion (vial) • Filter for MEPACT Materials required but not provided - • Sodium chloride 9 mg/ml (0.9%) solution for injection, EP/USP 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). 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). 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:
Figure 3 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). 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. No special requirements. 11-15 Quai De Dion Bouton 92816 Puteaux Cedex France | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
骨肉瘤新药-Mepact(mifamurtide)注射剂首个获准上市简介：
导读：骨肉瘤最新治疗药—米伐木肽在欧上市。米伐木肽通过刺激诸如巨噬细胞等某些白细胞来杀灭肿瘤细胞，是20余年来首个获准上市治疗骨肉瘤的新药，研究显示，米伐木肽与化学药物联合使用可使死亡率降 ... 关键字：米伐木肽脂质体注射剂
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