Chemical formula: C₅₉H₁₀₉N₆O₁₉P Molecular mass: 1,277.515 g/mol
Mifamurtide interacts in the following cases:
Because mifamurtide acts through stimulation of the immune system, the chronic or routine use of corticosteroids should be avoided during treatment with mifamurtide.
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.
Occasional allergic reactions have been associated with mifamurtide 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.
Nausea, vomiting and loss of appetite are very common adverse reactions to mifamurtide. 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.
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.
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.
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.
There are no data from the use of mifamurtide in pregnant women. Animal studies are insufficient with respect to reproductive toxicity. 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.
Mifamurtide 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 list are thought to be related to the mechanism of action of mifamurtide (see below). 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.
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 mifamurtide 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 mifamurtide 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 mifamurtide and chemotherapy (12% and 4%, respectively) in the phase III 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.
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 mifamurtide 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.
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.
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