Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Takeda France SAS, 112 avenue Kléber, 75116, Paris, France
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
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 (see section 4.8). If a severe respiratory reaction occurs, administration of mifamurtide should be discontinued and appropriate treatment initiated.
Administration 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.
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.
Patients 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.
Occasional 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.
Nausea, 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.
This medicine contains less than 1 mmol sodium (23 mg) per dosage unit.
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-tumour 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 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 mifamurtide.
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.
There 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.
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 mifamurtide therapy to the woman.
No dedicated fertility studies have been conducted with mifamurtide (see section 5.3).
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.
Mifamurtide 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 are chills, pyrexia, fatigue, nausea, tachycardia 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.
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), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 1. Adverse reactions:
Common: Sepsis, Cellulitis, Nasopharyngitis, Catheter site infection, Upper respiratory tract infection, Urinary tract infection, Pharyngitis, Herpes simplex infection
Common: Cancer pain
Very Common: Anaemia
Common: Leukopenia, Thrombocytopenia, Granulocytopenia, Febrile neutropenia
Very common: Anorexia
Common: Dehydration, Hypokalaemia, Decreased appetite
Common: Confusional state, Depression, Insomnia, Anxiety
Very common: Headache, Dizziness
Common: Paraesthesia, Hypoaesthesia, Tremor, Somnolence, Lethargy
Common: Blurred vision
Common: Vertigo, Tinnitus, Hearing loss
Very common: Tachycardia
Common: Cyanosis, Palpitations
Not known: Pericardial effusion
Very common: Hypertension, Hypotension
Common: Phlebitis, Flushing, Pallor
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
Common: Hepatic pain
Very common: Hyperhidrosis
Common: Rash, Pruritis, Erythema, Alopecia, Dry skin
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
Common: Haematuria, Dysuria, Pollakiuria
Common: Dysmenorrhoea
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
Common: Weight decreased
Common: Post-procedural pain
Anaemia 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%).
Anorexia (21%) was very commonly reported in phase I and II studies of mifamurtide
Consistent 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.
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 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.
Mild-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 disorders, including dyspnoea (21%), cough (18%) and tachypnoea (13%) were very commonly reported, and 2 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 mifamurtide administration, including nausea (57%) and vomiting (44%) in about half of patients, constipation (17%), diarrhoea (13%) and abdominal pain (see section 4.4).
Hyperhidrosis (11%) was very common in patients receiving mifamurtide in uncontrolled studies.
Low grade pain was very common in patients receiving mifamurtide, 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.
An 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.
In 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 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 national reporting system listed in Appendix V.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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