4.1. Therapeutic indications

Mifamurtide 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 (see section 5.1).

4.2. Posology and method of administration

Mifamurtide treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of osteosarcoma.

Posology

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.

Special populations

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) ≥ 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 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

Mifamurtide is administered by intravenous infusion over a period of 1 hour.

Mifamurtide 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 section 6.6.

4.3. Contraindications

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).

4.4. Special warnings and precautions for use

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 (see section 4.8). If a severe respiratory reaction occurs, administration of mifamurtide should be discontinued and appropriate treatment initiated.

Neutropenia

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.

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 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 reactions

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.

Gastrointestinal toxicity

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.

Mifamurtide contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per dosage unit.

4.5. Interaction with other medicinal products and other forms of interaction

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.

4.6. Fertility, pregnancy and lactation

Pregnancy

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.

Breast-feeding

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.

Fertility

No dedicated fertility studies have been conducted with mifamurtide (see section 5.3).

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

Summary of the safety profile

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.

Tabulated list of adverse reactions

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

System organ class

Frequency category

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)

Common

Cancer pain

Blood and lymphatic system disorders

Very Common

Anaemia

Common

Leukopenia, Thrombocytopenia, Granulocytopenia, Febrile neutropenia

Metabolism and nutrition disorders

Very common

Anorexia

Common

Dehydration, Hypokalaemia, Decreased appetite

Psychiatric disorders

Common

Confusional state, Depression, Insomnia, Anxiety

Nervous system disorders

Very common

Headache, Dizziness

Common

Paraesthesia, Hypoaesthesia, Tremor, Somnolence, Lethargy

Eye disorders

Common

Blurred vision

Ear and labyrinth disorders

Common

Vertigo, Tinnitus, Hearing loss

Cardiac disorders

Very common

Tachycardia

Common

Cyanosis, Palpitations

Not known

Pericardial effusion

Vascular disorders

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

Gastrointestinal disorders

Very common

Vomiting, Diarrhoea, Constipation, Abdominal pain, Nausea

Common

Upper abdominal pain, Dyspepsia, Abdominal distension, Lower abdominal pain

Hepatobiliary disorders

Common

Hepatic pain

Skin and subcutaneous tissue disorders

Very common

Hyperhidrosis

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

Common

Dysmenorrhoea

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

Investigations

Common

Weight decreased

Surgical and medical procedures

Common

Post-procedural pain

Description of selected adverse reactions

Blood and lymphatic system disorders

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%).

Metabolism and nutritional disorders

Anorexia (21%) was very commonly reported in phase I and II studies of mifamurtide

Nervous system disorders

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.

Ear and labyrinth disorders

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 (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 disorders

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

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

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).

Skin and subcutaneous disorders

Hyperhidrosis (11%) was very common in patients receiving mifamurtide in uncontrolled studies.

Musculoskeletal and connective tissue disorders

Low 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 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.

Investigations

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.

Immune system disorders

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 of suspected adverse reactions

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 Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. 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.