POM: Prescription only medicine
This information is intended for use by health professionals
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 once-weekly treatments for an additional 24 weeks for a total of 48 infusions in 36 weeks.
Adults >30 yearsNone 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 impairmentThere 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 yearsThe safety and efficacy of mifamurtide in children aged 0 to 2 years have not been established. No data are available.
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.For further instructions on reconstitution, filtering using the filter provided and dilution prior to administration, see section 6.6.
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 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.
NeutropeniaAdministration 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 responseAssociation 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 disordersPatients 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 reactionsOccasional 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 toxicityNausea, 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.
PregnancyThere 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-feedingIt 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.
FertilityNo dedicated fertility studies have been conducted with mifamurtide (see section 5.3).
Summary of the safety profileMifamurtide 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 reactionsAdverse 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)|
|Blood and lymphatic system disorders|
|Common||Leukopenia, Thrombocytopenia, Granulocytopenia, Febrile neutropenia|
|Metabolism and nutrition disorders|
|Common||Dehydration, Hypokalaemia, Decreased appetite|
|Common||Confusional state, Depression, Insomnia, Anxiety|
|Nervous system disorders|
|Very common||Headache, Dizziness|
|Common||Paraesthesia, Hypoaesthesia, Tremor, Somnolence, Lethargy|
|Ear and labyrinth disorders|
|Common||Vertigo, Tinnitus, Hearing loss|
|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|
|Very common||Vomiting, Diarrhoea, Constipation, Abdominal pain, Nausea|
|Common||Upper abdominal pain, Dyspepsia, Abdominal distension, Lower abdominal pain|
|Skin and subcutaneous tissue disorders|
|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|
|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|
|Surgical and medical procedures|
Description of selected adverse reactions
Blood and lymphatic system disordersAnaemia 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 disordersAnorexia (21%) was very commonly reported in phase I and II studies of mifamurtide
Nervous system disordersConsistent 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 disordersAlthough 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 disordersMild-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 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 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 disordersHyperhidrosis (11%) was very common in patients receiving mifamurtide in uncontrolled studies.
Musculoskeletal and connective tissue disordersLow 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 conditionsThe 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.
InvestigationsAn 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 disordersIn 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 reactionsReporting 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.
Mechanism of actionMifamurtide (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 efficacyThe 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]).
Renal impairmentThe 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 impairmentThe 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).
Instructions for preparation of MEPACT for intravenous infusion
Materials provided in each package -• MEPACT powder for concentrate for dispersion for infusion (vial) • Filter for MEPACTMaterials 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 needlesIt 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:
|1.0 mg||12.5 ml|
|2.0 mg||25 ml|
|3.0 mg||37.5 ml|
|4.0 mg||50 ml|
DisposalNo special requirements.