MEPACT 4 mg powder for suspension for infusion.

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.

For a full list of excipients, see section 6.1.

Powder for suspension for infusion.

White to off-white homogeneous lyophilised powder.

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 (see section 5.1).

MEPACT 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 onceweekly treatments for an additional 24 weeks for a total of 48 infusions in 36 weeks.

Paediatric patients

The 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 patients

None 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 function

The 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 administration

MEPACT 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.

Hypersensitivity to the active substance or to any of the excipients.

Concurrent use with ciclosporin or other calcineurin inhibitors (see section 4.5).

Concurrent use with highdose nonsteroidal antiinflammatory drugs (NSAIDs, cyclooxygenase inhibitors) (see section 4.5).

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 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.

Neutropenia

Administration 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 evaluated for possible sepsis.

Inflammatory response

Association 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 disorders

Patients 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 reactions

Occasional 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 toxicity

Nausea, 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.

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 (see section 4.3).

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 (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 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.

Pregnancy

There are no data from the use of mifamurtide in pregnant patients. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). MEPACT should not be used during pregnancy and in women not using effective contraception.

Lactation

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 breastfeeding or to continue/discontinue therapy should be made taking into account the benefit of breastfeeding to the child and the benefit of MEPACT therapy to the woman.

No studies of the effects on the ability to drive and use machines have been performed. Some very common or common undesirable effects of MEPACT treatment (such as dizziness, vertigo, fatigue and blurred vision) may have an effect on the ability to drive and use machines.

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 patients

Blood and lymphatic system disorders

Anaemia 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 disorders

Anorexia (21%) was very commonly reported in trials of MEPACT in late stage cancer patients.

Nervous system disorders

Consistent 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 disorders

Mild-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 disorders

Respiratory 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 disorders

Gastrointestinal 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 disorders

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

Musculoskeletal and connective tissue disorders

Low 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.

Investigations

Increase in blood urea and blood creatinine was associated with MEPACT use in one patient with osteosarcoma.

No case of overdose has been reported. 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 lifethreatening, and included fever, chills, fatigue, nausea, vomiting, headache and hypo- or hypertension.

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.

Pharmacotherapeutic group: Other cytokines and immunomodulators, ATC code: L03AX15

Mechanism of action

Mifamurtide (muramyl tripeptide phosphatidyl ethanolamine, MTP-PE) is a fully synthetic derivative of muramyl dipeptide (MDP), the smallest naturallyoccurring immune stimulatory component of cell walls from Mycobacterium sp. It has similar immunostimulatory effects as natural MDP with the additional advantage of a longer halflife 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 MEPACT 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 tumor cells (including melanoma, ovarian, colon, and renal carcinoma), but had no toxicity towards normal cells.

In vivo administration of MEPACT 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 MEPACT as adjuvant therapy. The exact mechanism by which MEPACT activation of monocytes and macrophages leads to antitumour activity in animals and humans is not yet known.

Clinical safety and efficacy

The 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).

MEPACT significantly increased the overall survival of patients with newlydiagnosed resectable highgrade 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 newlydiagnosed resectable highgrade osetosarcoma, the addition of adjuvant MEPACT 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]).

After intravenous administration in 21 healthy adult subjects mifamurtide was cleared rapidly from plasma (minutes), resulting in a very low plasma concentration of total (liposomal and free) mifamurtide. The mean AUC was 17.0 +/- 4.71 h x nM and Cmax was 15.7 +/- 3.72 nM. In separate study in 14 patients, mean serum concentrationtime curves of total and free mifamurtide that were assessed after the first infusion of MEPACT and after a last infusion 11 or 12 weeks later, were almost superimposable and the mean AUC values of the free mifamurtide after the first and last infusion were similar. These data indicate that neither total nor free mifamurtide accumulated during the treatment period.

At 6 hours after injection of radiolabelled liposomes containing 6 mg mifamurtide, radioactivity was found in liver, spleen, nasopharynx, thyroid, and, to a lesser extent, in lung. The liposomes were phagocytosed by cells of the reticuloendothelial system. In 2 of 4 patients with lung metastases, radioactivity was associated with lung metastases. Mean halflife of radiolabelled material was biphasic with an α phase of about 15 minutes and a terminal halflife of approximately 18 hours.

In sensitive species (rabbit and dog) the highest daily dose of liposomal mifamurtide that did not cause adverse effects was 0.1 mg/kg, corresponding to 1.2 and 2 mg/m², respectively. The noadverseeffect level for MEPACT in animals corresponds roughly to the 2 mg/m² recommend dose for humans.

Data from a six month dog study of daily intravenous injections of up to 0.5 mg/kg (10 mg/m²) MEPACT provide an 8- to 19-fold cumulative exposure safety margin for overt toxicity for the intended clinical dose in humans. Major toxic effects associated with these high daily and cumulative doses of MEPACT were mainly exaggerated pharmacological effects: pyrexia, signs of pronounced inflammatory response manifested as synovitis, bronchopneumonia, pericarditis and inflammatory necrosis of the liver and bone marrow. The following events were also observed: haemorrhage and prolongation of coagulation times, infarcts, morphological changes in the wall of small arteries, oedema and congestion of the central nervous system, minor cardiac effects, and slight hyponatraemia. MEPACT was not mutagenic and did not cause teratogenic effects in rats and rabbits. Embryotoxic effects were observed only at maternal toxic levels.

There were no results from general toxicity studies that suggested harmful effects on male or female reproductive organs. Specific studies addressing reproductive function, perinatal toxicity and carcinogenic potential have not been performed.

1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)

1,2-Dioleoyl-sn-glycero-3-phospho-L-serine monosodium salt (OOPS)

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Unopened vial of powder:

30 months

Reconstituted suspension:

Chemical and physical stability has been demonstrated for 6 hours up to 25ºC.

From a microbiological point of view, immediate use is recommended. If not used immediately, the reconstituted, filtered and diluted solution inuse storage times and conditions prior to use of the reconstituted product are the responsibility of the user and must not be longer than 6 hours at 25ºC. Do not store in a refrigerator and do not freeze the solution.

Store in a refrigerator (2°C – 8°C). Do not freeze.

Keep the vial in the outer carton in order to protect from light.

For storage conditions of the reconstituted medicinal product, see section 6.3.

50 ml type I glass vial with a grey butyl rubber stopper, aluminium seal and plastic flipoff cap, containing 4 mg of mifamurtide.

Each carton contains one vial and one singleuse, nonpyrogenic, latexfree sterile Filter for MEPACT supplied in a PVCgrade blister.

MEPACT must be reconstituted, filtered using the filter provided and further diluted using aseptic technique.

Each vial should be reconstituted with 50 ml of sodium chloride 9 mg/ml (0.9 %) solution for injection. After reconstitution, each ml suspension in the vial contains 0.08 mg mifamurtide. The volume of reconstituted suspension corresponding to the calculated dose is extracted through the filter provided and further diluted with additional 50 ml sodium chloride 9 mg/ml (0.9 %) solution for injection according to the detailed instructions shown below.

Instructions for preparation of MEPACT for intravenous infusion

Materials provided in each package -

• MEPACT powder for suspension for infusion (vial)

• Filter for MEPACT

Materials required but not provided -

• Sodium chloride 9 mg/ml (0.9%) solution for injection, EP/USP 100 ml bag

• One single use 60 or 100 ml sterile syringe with luer lock

• Two medium (18) gauge sterile injection needles

It 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).

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).

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:

Figure 3

11. The syringe should then be removed from the filter and a new needle placed on the suspensionfilled syringe. The bag injection site should be wiped with an alcohol pad and the suspension in the syringe should be injected into the original bag containing the remaining 50 ml of sodium chloride 9 mg/ml (0.9%) solution for injection (Figure 4).

Figure 4

12. The bag should be gently swirled to mix the solution.

13. Patient identification, time and date should be added to the label on the bag containing the reconstituted, filtered and diluted liposomal suspension.

14. Chemical and physical inuse stability has been demonstrated for 6 hours at room temperature (between approximately 20°C – 25°C).

15. From a microbiological point of view, the product should be used immediately. If not used immediately, inuse storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 6 hours at room temperature.

16. The liposomal suspension is infused intravenously over about one hour.

Disposal

No special requirements.

IDM PHARMA SAS

11-15 Quai De Dion Bouton

92816 Puteaux Cedex

France

EU/1/08/502/001

06/03/2009

05/01/2011