Copywriter Collective - Harold - Mepact d aid


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Copywriter Collective - Harold - Mepact d aid

  1. 1. Today I just want to beat my cancer One day I want to beat the world champion Prescribing information can be found on the back cover. Recommended by NICE NICERecommendsMifamurtideForBoneCancerChildren.jsp last accessed December 2011. Approved by SMC 621_10_mifamurtide_Mepact/mifamurtide_Mepact_Resubmission last accessed December 2011.
  2. 2. Mepact is indicated for the treatment of high-grade, resectable, non-metastatic osteosarcoma following complete surgical resection in children, adolescents and young adults, aged 2-30 years, in combination with post-operative multi-agent chemotherapy.1 Mepact is a synthetic analogue of muramyl dipeptide, the smallest natural immuno- adjuvant from the mycobacterium cell wall.2 It is the only authorised product in its class which activates the body’s immune system to target micro-metastatic lung disease,3,4 the primary cause of death in osteosarcoma.5 Anti-tumour activity of Mepact is mediated by activation of host immune system Mepact enters the macrophage where it is broken down to Muramyl Di-Peptide (MDP), which then binds to the NOD-2 receptor.2,3 Intracellular pathways are activated3 which induce cytotoxic function2,7,8 and secretion of numerous cytokines and chemokines,13,17,18 which along with other recruited and activated immune cells2 directly affect the micro-metastases,2,4 producing tumour cell apoptosis.2,7,9 Background to the Phase III study The Mepact Phase III study10,11 was a National Cancer Institute (NCI)-funded Cooperative Group study conducted by the Children’s Oncology Group (COG): • 4-year enrolment (1993 – 1997) • 14-year follow-up (1993 – 2007) This was a large and extensive study carried out in newly diagnosed osteosarcoma patients (777 patients, age under 31, mean age 14 years), with independently analysed and published survival benefits. Patients and methods Six hundred and sixty two patients with osteosarcoma, without clinically detectable metastatic disease and whose disease was considered resectable, 115 with more advanced disease, received one of four prospectively randomised treatments.9,10 Having received neo- adjuvant chemotherapy, all patients underwent definitive surgical resection of their primary tumour. As part of their adjuvant chemotherapy all patients received identical cumulative doses of cisplatin, doxorubicin and methotrexate. Patients were randomly assigned to receive or not to receive ifosfamide and/or Mepact in a 2 x 2 factorial design.10,11 Study end points To determine whether the addition of a single 36-week course of Mepact to standard three- or four-drug adjuvant chemotherapy enhanced overall survival and event-free survival in newly diagnosed patients with osteosarcoma.10,11 What is Mepact? An overview of efficacy and tolerability of Mepact Adapted from references 2-4, 6-9 Adapted from references 10 and 11. Treatment Surgical resection Tumour removed but micro-metastases remain Adjuvant combination chemotherapy Combination chemotherapy + Mepact To prevent lung metastases by eradicating micro-metastases13 Patient Diagnosed At diagnosis Tumour Neo-adjuvant combination chemotherapy Combination chemotherapy to shrink tumour Almostallpatientshavemicro-metastasesatdiagnosis6 micro- metastases + Mepact macrophage micro- metastases adhesion moleculesICAM-1 LFA-1 (HLA)-DR NOD-2 ▼ RICK ▼ NF-κB ▼ cytokines IL-6 IL-8 IL-12 TNFα IL-1 cytokines Induction B Ifosfamide Doxorubicin HDMTX A Cisplatin Doxorubicin HDMTX RANDOMISATION DEFINITIVESURGERY 0 Weeks 20 27 36 Maintenance HISTOLOGICAL EVALUATION A– A+ B– B+ Cisplatin, Doxorubicin, HDMTX Cisplatin, Doxorubicin, HDMTX, Mepact Cisplatin, Ifosfamide, Doxorubicin, HDMTX, Mepact Cisplatin, Ifosfamide, Doxorubicin, HDMTX Regimens A and B: 4 courses of cisplatin 120 mg/m2 over 4 hours combined with 6 courses of doxorubicin (25 mg/m2/day x 3) and 12 courses of methotrexate 12 g/m2 Regimen B only: Ifosfamide 1.8 g/m2 /day for 5 days HDMTX: High-dose methotrexate
  3. 3. The study found that the addition of Mepact to current chemotherapy significantly improved 6-year overall survival from 70% to 78% (p=0.03)10,11 and reduced the risk of death by almost one-third (29%; relative risk=0.71, 95% CI, 0.52 to 0.96, absolute risk reduction 8%, p=0.03).10 In the Phase III study, Mepact was administered to 332 subjects (half of whom were under the age of 16) and side effects were found to be mild to moderate in nature.10,11 The most common grade-1 or grade-2 adverse events included chills, fever, fatigue, nausea, tachycardia and headache.1 The study showed no significant increased incidence of adverse events over current chemotherapy regimens10,11 and no life-threatening risks were associated with Mepact use.10,11 Most patients experienced fewer adverse events with subsequent administration.10-12 Tolerability profile Frequency groupings are defined according to the following convention: very common (≥1/10), common (≥1/100 to 1/10).1 Significantly improved overall survival Mepact tolerability Event-free survival The study also showed a trend towards better event-free survival with Mepact: 67% at 6 years compared to 61% without Mepact, with a hazard ratio of 0.8 (p=0.08, 95% CI, 0.62 to 1.0).10,11 The addition of ifosfamide to cisplatin, doxorubicin and methotrexate did not enhance overall survival or event-free survival for patients with osteosarcoma. The addition of Mepact to chemotherapy resulted in a statistically significant improvement in overall survival and a trend toward better event-free survival.6,7 Overall survival for all patients assigned to receive or not to receive Mepact independently of chemotherapy regimen received10,11 0 0.25 0.50 0.75 1.00 5 10 15 Time (years) Estimated Proportion Surviving Assigned Mepact Yes No p=0.03, HR=0.71 (95% CI: 0.52 to 0.96) Adapted from references 10 and 11. Very Common Common Infections and infestations 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) Cancer pain Blood and lymphatic system disorders Anaemia Leukopenia, thrombocytopenia, granulocytopenia Metabolism and nutrition disorders Anorexia Dehydration, hypokalaemia, decreased appetite Psychiatric disorders Confusional state, depression, insomnia, anxiety Nervous system disorders Headache, dizziness Paraesthesia, hypoaesthesia, tremor, somnolence, lethargy Eye disorders Blurred vision Ear and labyrinth disorders Vertigo, tinnitus, hearing loss Cardiac disorders Tachycardia Cyanosis, palpitations Vascular disorders Hypertension, hypotension Phlebitis, flushing, pallor Respiratory, thoracic and mediastinal disorder Dyspnoea, tachypnoea, cough Pleural effusion, exacerbated dyspnoea productive cough, haemoptysis, wheezing, epistaxis, exertional dyspnoea, sinus congestion, nasal congestion, pharyngolaryngeal pain Gastrointestinal disorders Vomiting, diarrhoea, constipation, abdominal pain, nausea Upper abdominal pain, dyspepsia, abdominal distension, lower abdominal pain Hepatobiliary disorders Hepatic pain Skin and subcutaneous tissue disorders Hyperhidrosis Rash, pruritus, erythema, alopecia, dry skin Musculoskeletal and connective tissue disorders Myalgia, arthralgia, back pain, pain in extremity Muscle spasms, neck pain, groin pain, bone pain, shoulder pain, chest wall pain, musculoskeletal stiffness Renal and urinary disorders Haematuria, dysuria, pollakiuria Reproductive system and breast disorders Dysmenorrhoea General disorders and administration site conditions Fever, chills, fatigue, hypothermia, pain, malaise, asthenia, chest pain Peripheral oedema, oedema, mucosal inflammation, infusion site erythema, infusion site reaction, catheter site pain, chest discomfort, feeling cold Investigations Weight decreased Surgical and medical procedures Post-procedural pain
  4. 4. 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. If a severe respiratory reaction occurs, administration of Mepact should be discontinued and appropriate treatment initiated.1 Neutropenia 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.1 Inflammatory response 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.1 Cardiovascular disorders 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.1 Allergic reactions 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.1 Gastrointestinal toxicity 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.1 Mepact is administered on the same day as adjuvant combination chemotherapy1 and should not be interrupted due to delays in the chemotherapy regimen.13 Mepact can be administered on an inpatient or outpatient basis.21 Mepact must not be administered as a bolus injection.1 Mepact therapy: • Should not be mixed with other drugs in the same container or iv line1 • Can be used with combination chemotherapy as long as one infusion is finished and the iv line is flushed before the next infusion is given according to the information on its product label1 • Should be separated temporally from other liposomal or lipophilic drugs (e.g. liposomal doxorubicin) if given in the same regimen1 How frequently should Mepact be administered? Mepact is given by intravenous infusion over the course of one hour, twice a week for 12 weeks, then once weekly for 24 additional weeks – a total of 36 weeks of therapy, or 48 doses.1 The recommended dose for all patients is 2 mg/m2 body surface area.1 Explaining Mepact to patients More information on this sensitive topic is presented in straightforward language at the end of this booklet. Additionally, a number of separate leaflets on Mepact have been made available for patients and their parents/carers, as well as pharmacists and nurses. These are designed to inform and educate the various groups involved with Mepact, and by increasing awareness, will ideally make your job easier when administering treatment. How is Mepact administered? First 12 weeks Next 24 weeks Twice weekly at least 3 days apart Total: 24 infusions Once weekly Total: 24 infusions Special warnings and precautions for use
  5. 5. How to order Mepact should be ordered from Unidrug Distribution Group (UDG) Amber Park, Berristow Lane, South Normanton, Derbyshire, DE55 2FH. By fax to: 01773 810644. By email to: Contact telephone: 01773 515004 or 01773 515066 Orders received by UDG before 2pm will be delivered the next day. How is Mepact administered? Mepact must be reconstituted using the filter provided and further diluted prior to administration. The reconstituted 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, Mepact is administered by intravenous infusion over a period of one hour. Mepact must not be administered as a bolus injection.1 Mepact and overdose No case of overdose has been reported with Mepact. 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.1 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,13 chills and headache and anti-emetics (other than steroids) for nausea and vomiting.1 Instructions for the preparation of Mepact for intravenous infusion2 Materials provided in each package • 1 vial of Mepact (mifamurtide) • 1 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. Step by step administration of Mepact 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 swabbedwith 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. Figure 1 How is Mepact administered?
  6. 6. 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. Figure 3 Figure 4Figure 2 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. Storing Mepact1 Unopened vial Store in a refrigerator (2°C – 8°C). Do not freeze. Keep the vial in outer carton in order to protect from light. Reconstituted suspension Once reconstituted in sodium chloride 9 mg/ml (0.9%) solution, store at room temperature (approximately 20ºC – 25ºC) and use within 6 hours. How is Mepact administered?
  7. 7. Bone Cancer Research Trust Devoted to promoting research into the causes and treatment of Primary Bone Cancer and in particular of Osteosarcoma and Ewing’s Sarcoma. The Trust is also looking to provide information, support and, in the longer term, counselling services for those suffering from Primary Bone Cancer, and their families. Website: Cancer52 An organisation that represents the less common cancers, giving member charities and those they represent a more powerful voice and the driving force of a larger group, as well as listening to the community and sharing information and experience. Website: CLIC Sargent CLIC Sargent is committed to improving the survival of children with cancer through its specialist care and by funding both clinical and social research projects. It provides individual support to children and young people with cancer and their families through clinical, emotional, psychological, social and financial services in hospital, at home and in the community across the UK. Website: Rarer Cancers Forum The Forum draws together people with rare and less common cancers, giving them a bigger collective voice to exact better services, and enabling them to support one another. It makes health professionals aware of issues related to rarer cancers and works with the Government, the NHS and Primary Care Trusts/Health Boards to ensure that people with rarer cancers have access to the best possible services across the UK. Website: Sarcoma UK Sarcoma UK publishes information about sarcoma, develops support services for patients, develops educational opportunities for professionals and patients, and empowers patients as representatives and advocates working for the benefit of all patients. Website: Some useful organisations Teenage Cancer Trust TCT’s top priority is building units in NHS hospitals specifically for teenagers with cancer. Everything the TCT does is to improve the quality of life and chances of survival for teenagers and young adults diagnosed with cancer and it provides a support network for teenagers providing individual and group counselling. Website: Other useful contacts
  8. 8. References 1. Mepact Summary of Product Characteristics ( searchresults.aspx?term =MEPACTsearchtype=QuickSearch). 2. Nardin A, Lefebvre M-L, Labroquère K, Faure O, Abastado J-P. Liposomal muramyl tripeptide phosphatidylethanolamine. Targeting and activating macrophages for adjuvant treatment of osteosarcoma. Current Cancer Drug Targets 2006;6(2):123-33. 3. Strober W, Murray PJ, Kitani A, Watanabe T. Signalling pathways and molecular interactions of NOD1 and NOD2. Nat Rev Immunol 2006;6:9-20. 4. Fidler IJ, Sone S, Fogler WE, et al. Eradication of spontaneous metastases and activation of alveolar macrophages by intravenous injection of liposomes containing muramyl dipeptide. Proc Natl Acad Sci USA 1981;78:1680-1684. 5. Meyers PA, Gorlick R. Osteosarcoma. Pediatr Clin North Am 1997; 44:973-989. 6. Kleinerman ES, Snyder JS, Jaffe N. Influence of chemotherapy administration on monocyte activation by liposomal muramyl tripeptide phosphatidyl ethanolamine in children with osteosarcoma. J Clin Oncol 1991;9:259-267. 7. Anderson P. Liposomal muramyl tripeptide phosphatidyl ethanolamine: ifosfamide-containing chemotherapy in osteosarcoma. Future Oncol. (2006) 2(3),333-343. 8. Kleinerman ES, Meyers PA, Raymond AK, et al. Combination therapy with ifosfamide and liposome- encapsulated muramyl tripeptide: Tolerability, toxicity, and immune stimulation. J Immunother Emphasis Tumor Immunol 1995;17:181-193. 9. Kleinerman ES, Erickson KL, Schroit AJ, et al. Activation of tumoricidal properties in human blood monocytes by liposomes containing lipophilic muramyl tripeptide. Cancer Res 1983:43:2010-2014. 10. Meyers PA, et al. Osteosarcoma: The Addition of Muramyl Tripeptide to Chemotherapy Improves Overall Survival – A Report From The Children’s Oncology Group. J Clin Oncol 2008;26:633-638. 11. Meyers PA, Schwartz CL, Krailo MK, et al. Osteosarcoma: A Randomized, Prospective Trial of the Addition of Ifosfamide and/or Muramyl Tripeptide to Cisplatin, Doxorubicin, and High-Dose Methotrexate. J Clin Oncol. 2005;23:2004-2011. 12. Meyers PA. Muramyl tripeptide (mifamurtide) for the treatment of osteosarcoma. Expert Rev. Anticancer Ther. 2009;9(8):1035-1049. 13. Mepact Patient Information Leaflet ( searchresults.aspx?term=MEPACT searchtype=QuickSearch). MEPACT® Prescribing Information (Refer to Summary of Product Characteristics (SmPC) before prescribing) Mifamurtide 4 mg vial. Presentation: 4 mg powder for suspension for infusion. Single vial in outer carton EU/1/08/502/001 £2375. Indication: Treatment of high-grade resectable nonmetastatic osteosarcoma after macroscopically complete surgical resection in children, adolescents and young adults (2-30 years) used in combination with post-operative multi-agent chemotherapy. Dosage Administration: Should be initiated and supervised by specialist oncologists. Powder for suspension for infusion: Mepact® should be reconstituted with 50 mL sodium chloride 9 mg/mL (0.9%) and the appropriate dose volume withdrawn and added to a sodium chloride 9 mg/mL (0.9%) infusion bag for intravenous administration over 1 hour (see SmPC). Children, adolescents young adults 2-30 years: 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. Paediatric patients (2 yrs): No data available. Elderly patients (65yrs): No data available. Patients with impaired renal or hepatic function: No data available regarding use in renal or hepatic failure. Contraindications, Warnings etc.: Contraindications: Hypersensitivity to mifamurtide or excipients. Concurrent administration with ciclosporin, other calcineurin inhibitors and high-dose non-steroidal anti- inflammatory agents (cyclooxygenase inhibitors). Precautions: In patients with asthma or other chronic obstructive pulmonary disease, consider administration of prophylactic bronchodilators. If a severe respiratory reaction occurs, administration should be discontinued and appropriate treatment initiated. Monitor and manage episodes of neutropenic fever. Fever or chills persisting more than 8 hours after administration of Mepact® should be evaluated for possible sepsis. Use Mepact® with caution in patients with a history of autoimmune, inflammatory or other collagen diseases. Monitor for signs or symptoms of arthritis or synovitis. If symptoms persist or worsen in patients with a history of thrombosis, vasculitis or unstable cardiovascular disorders, Mepact® administration should be delayed or discontinued. Monitor for signs of allergic reactions. 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. Interactions: There is no evidence of any interactions between Mepact® and the anti-tumour effects of chemotherapy and vice versa. Mepact® should be administered at a separate time to doxorubicin or other liposomal formulations. Chronic or routine use of corticosteroids should be avoided. Mifamurtide is 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 did not exacerbate the renal toxicities of cisplatin and ifosfamide or the hepatic toxicities of methotrexate and ifosfamide. Pregnancy lactation: No data available. Adverse Effects: Very common (10%): Anaemia, anorexia, headache, dizziness, tachycardia, hypertension, hypotension, dyspnoea, tachypnoea, cough, vomiting, diarrhoea, constipation, abdominal pain, nausea, hyperhidrosis, myalgia, arthralgia, back pain, pain in extremity, fever, chills, fatigue, hypothermia, pain, malaise, asthenia, chest pain. Pharmaceutical Precautions: Store in a refrigerator (2-8°C), protected from light. The reconstituted vial is stable for up to 6 hours at 25°C. PI Date: April 2011. PI Code: MEP131. Legalcategory:POMNameAddressofMarketing Authorisation Holder: IDM PHARMA SAS, 11-15 Quai De Dion Bouton, 92816 Puteaux Cedex, France Further information is available from: Takeda Pharmaceuticals Europe Ltd. Medical and Scientific Affairs. 61 Aldwych, London, WC2B 4AE, UK. +44 203 116 8879. Mepact® is a registered trademark Please refer to the summary of product characteristics for details on the full side-effects of Mepact. Adverse events should be reported. Reporting forms and information can be found at Adverse events should also be reported to Takeda UK Ltd 01628-537900
  9. 9. Date of preparation: December 2011 EU/MEP-010000