Drug Class Description
This medicine is monitored intensively by the CHM and MHRA

Drug Description
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.

Presentation
Powder for suspension for infusion.White to off-white homogeneous lyophilised powder.

Indications
MEPACT is indicated in children, adolescents and young adults for the treatment of highgrade resectable nonmetastatic osteosarcoma after macroscopically complete surgical resection. It is used in combination with postoperative multi-agent chemotherapy. Safety and efficacy have been assessed in studies of patients 2 to 30 years of age at initial diagnosis.

Adult Dosage
MEPACT treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of osteosarcoma.PosologyThe 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 onceweekly treatments for an additional 24 weeks for a total of 48 infusions in 36 weeks.Paediatric patientsThe 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.Elderly patientsNone 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.Patients with impaired renal or hepatic functionThe 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.Method of administrationMEPACT 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.

Contra Indications
Hypersensitivity to the active substance or to any of the excipients.Concurrent use with ciclosporin or other calcineurin inhibitors.Concurrent use with highdose nonsteroidal antiinflammatory drugs (NSAIDs, cyclooxygenase inhibitors)

Special Precautions
Respiratory distressIn 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 preexisting 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.NeutropeniaAdministration 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 eva luated for possible sepsis.Inflammatory responseAssociation 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.Cardiovascular disordersPatients 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.Allergic reactionsOccasional 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.Gastrointestinal toxicityNausea, 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.

Interactions
Limited studies of the interaction of MEPACT with chemotherapy have been conducted. Although these studies are not conclusive, there is no evidence of interference of MEPACT with the antitumour effects of chemotherapy and vice versa.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.Also, it has been demonstrated in vitro that highdose NSAIDs (cyclooxygenase inhibitors) can block the macrophage activating effect of liposomal mifamurtide. Therefore the use of highdose NSAIDs is contraindicated.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 nonliposomal mifamurtide do not inhibit the metabolic activity of cytochrome P450 in pooled human liver microsomes. Liposomal and nonliposomal 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.

Adverse Reactions
Each of the 248 patients treated with MEPACT during the early phase single arm studies in patients with mostly advanced malignancies experienced at least one undesirable effect. Many of the most frequently reported undesirable effects as shown in the following summary table are thought to be related to the mechanism of action of mifamurtide. 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 undesirable effects also occurred in the large randomised study, but they were not recorded because only serious and lifethreatening adverse reactions were collected in that study.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.Table 1. Adverse reactions associated with MEPACT in 1/100 patientsInfections and infestationsCommon:Sepsis, cellulitis, nasopharyngitis, catheter site infection, upper respiratory tract infection, urinary tract infection, pharyngitis, Herpes simplex infectionNeoplasms benign, malignant and unspecified (incl cysts and polyps)Common:Cancer painBlood and lymphatic system disordersVery common:AnaemiaCommon:Leukopenia, thrombocytopenia, granulocytopeniaMetabolism and nutrition disordersVery common:AnorexiaCommon:Dehydration, hypokalaemia, decreased appetitePsychiatric disordersCommon:Confusional state, depression, insomnia, anxietyNervous system disordersVery common:Headache, dizzinessCommon:Paraesthesia, hypoaesthesia, tremor, somnolence, lethargyEye disordersCommon:Blurred visionEar and labyrinth disordersCommon:Vertigo, tinnitus, hearing lossCardiac disordersVery common:TachycardiaCommon:Cyanosis, palpitationsVascular disordersVery common:Hypertension, hypotensionCommon:Phlebitis, flushing, pallorRespiratory, thoracic and mediastinal disordersVery common:Dyspnoea, tachypnoea, coughCommon:Pleural effusion, exacerbated dyspnoea, productive cough, haemoptysis, wheezing, epistaxis, exertional dyspnoea, sinus congestion, nasal congestion, pharyngolaryngeal painGastrointestinal disordersVery common:Vomiting, diarrhoea, constipation, abdominal pain, nauseaCommon:Upper abdominal pain, dyspepsia, abdominal distension, lower abdominal painHepatobiliary disordersCommon:Hepatic painSkin and subcutaneous tissue disordersVery common:HyperhidrosisCommon:Rash, pruritis, erythema, alopecia, dry skinMusculoskeletal and connective tissue disordersVery common:Myalgia, arthralgia, back pain, pain in extremityCommon:Muscle spasms, neck pain, groin pain, bone pain, shoulder pain, chest wall pain, musculoskeletal stiffnessRenal and urinary disordersCommon:Haematuria, dysuria, pollakiuriaReproductive system and breast disordersCommon:DysmenorrhoeaGeneral disorders and administration site conditionsVery common:Fever, chills, fatigue, hypothermia, pain, malaise, asthenia, chest painCommon:Peripheral oedema, oedema, mucosal inflammation, infusion site erythema, infusion site reaction, catheter site pain, chest discomfort, feeling coldInvestigationsCommon:Weight decreasedSurgical and medical proceduresCommon:Postprocedural painBlood and lymphatic system disordersAnaemia 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%).Metabolism and nutritional disordersAnorexia (21%) was very commonly reported in trials of MEPACT in late stage cancer patients.Nervous system disordersConsistent with other generalised symptoms, the most common nervous system disorders were headache (50%) and dizziness (17%).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 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.Cardiac and vascular disordersMild-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 disordersRespiratory 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 disordersGastrointestinal 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.Skin and subcutaneous disordersHyperhidrosis (11%) was very common in patients receiving MEPACT in uncontrolled studies.Musculoskeletal and connective tissue disordersLow grade pain was common in patients receiving MEPACT, 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.InvestigationsIncrease in blood urea and blood creatinine was associated with MEPACT use in one patient with osteosarcoma.

Manufacturer
Takeda UK Ltd

Drug Availability
POM – Prescription Only Medicine

Updated
10 November 2011