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  • Mepact
    / Takeda


    Active Ingredient
    Mifamurtide 4 mg/vial

    Status in Israel
    RX

    Presentation and Status in Health Basket

    Presentation Basket Yarpa Pharmasoft

    Vial

    1 X 50 ml

    full basket chart 20527 13701

    Related information


    Dosage

    Mifamurtide treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of osteosarcoma.
    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 mifamurtide in patients >30 years of age.
    Renal or hepatic impairment: There are no clinically meaningful effects of mild to moderate renal (creatinine clearance (CrCL) ≥ 30ml/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, 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 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 of the medicinal product before administration see prescribing information.


    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.


    Contra-Indications

    Hypersensitivity to the active substance or to any of the excipients.
    Concurrent use with cyclosporine or other calcineurin inhibitors.
    Concurrent use with high-dose NSAIDs, cyclooxygenase inhibitors.


    Special Precautions

    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 mifamurtide should be discontinued and appropriate treatment initiated.
    Neutropenia: Administration 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 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 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 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.
    Gastrointestinal toxicity: Nausea, vomiting and loss of appetite are very common adverse reactions. 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.
    MEPACT contains sodium: This medicine contains less than 1 mmol sodium (23 mg) per dosage unit.


    Side Effects

    The most frequent adverse reactions are chills, pyrexia, fatigue, nausea, tachycardia and headache. Many of the very commonly reported adverse reactions are thought to be related to the mechanism of action of mifamurtide. The majority of these events were reported as either mild or moderate.
    Very common: Anemia, anorexia, headache, dizziness, tachycardia, hypertension, hypotension, dyspnea, tachypnea, cough, vomiting, diarrhea, constipation, abdominal pain, nausea, hyperhidrosis, myalgia, arthralgia, back pain, pain in extremity, fever, chills, fatigue, hypothermia, pain, malaise, asthenia, chest pain.
    Common: Sepsis, cellulitis, nasopharyngitis, catheter site infection, upper respiratory tract infection, urinary tract infection, pharyngitis, Herpes simplex infection, Cancer pain, leukopenia, thrombocytopenia, granulocytopenia, febrile neutropenia, dehydration, hypokalemia, decreased appetite, confusional state, depression, insomnia, anxiety, paresthesia, hypoesthesia, tremor, somnolence, lethargy, blurred vision, vertigo, tinnitus, hearing loss, cyanosis, palpitations, phlebitis, flushing, pallor, pleural effusion, exacerbated dyspnea, productive cough, haemoptysis, wheezing, epistaxis, exertional dyspnea, sinus congestion, nasal congestion, pharyngolaryngeal pain, upper abdominal pain, dyspepsia, abdominal distension, lower abdominal pain, hepatic pain, rash, pruritis, erythema, alopecia, dry skin, muscle spasms, neck pain, groin pain, bone pain, shoulder pain, chest wall pain, musculoskeletal stiffness, hematuria, dysuria, pollakiuria, dysmenorrhea, peripheral oedema, oedema, mucosal inflammation, infusion site erythema, infusion site reaction, catheter site pain, chest discomfort, feeling cold, weight decreased, post-procedural pain.
    Not known: Pericardial effusion.
    See prescribing information for full details. 


    Drug interactions

    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-tumor 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 hypothesized effect on splenic macrophages and mononuclear phagocytic function.
    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.
    Because mifamurtide acts through stimulation of the immune system, the chronic or routine use of corticosteroids should be avoided during treatment.
    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.


    Pregnancy and Lactation

    Pregnancy: There are no data from the use of mifamurtide in pregnant women.  Mifamurtide is not recommended for use during pregnancy and in women of childbearing potential not using effective contraception.
    Lactation: It is unknown whether mifamurtide is excreted in human milk. 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.
    See prescribing information for full details.       


    Overdose

    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.


    Important notes

    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 after reconstitution of the medicinal product, please refer to the PI.
    Effects on ability to drive and use machines: MEPACT has a moderate influence on the ability to drive and use machines. Dizziness, vertigo, fatigue and blurred vision have shown as very common or common undesirable effects of mifamurtide treatment.


    Manufacturer
    BSP Pharmaceuticals S.P.A., Italy
    Licence holder
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