1. Name Of The Medicinal Product
MEPACT
2. Qualitative And Quantitative Composition
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.
3. Pharmaceutical Form
Powder for suspension for infusion.
White to off-white homogeneous lyophilised powder.
4. Clinical Particulars
4.1 Therapeutic Indications
MEPACT is indicated in children, adolescents and young adults for the treatment of high
4.2 Posology And Method Of Administration
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 once.
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.
4.3 Contraindications
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 high
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
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.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
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 anti
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 high
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 non
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.
4.6 Pregnancy And Lactation
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 breast
4.7 Effects On Ability To Drive And Use Machines
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.
4.8 Undesirable Effects
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 life
Adverse reactions are classified according to system organ class and frequency. Frequency groupings are defined according to the following convention: Very common (
Table 1. Adverse reactions associated with MEPACT in
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
|
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
|
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
|
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.
4.9 Overdose
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 life
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.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
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 naturallyMycobacterium sp. It has similar immunostimulatory effects as natural MDP with the additional advantage of a longer halfin 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 newly
5.2 Pharmacokinetic Properties
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 concentration
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 half
5.3 Preclinical Safety Data
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 no2 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.
6. Pharmaceutical Particulars
6.1 List Of Excipients
1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)
1,2-Dioleoyl-sn-glycero-3-phospho-L-serine monosodium salt (OOPS)
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
6.3 Shelf Life
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 in
6.4 Special Precautions For Storage
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.
6.5 Nature And Contents Of Container
50 ml type I glass vial with a grey butyl rubber stopper, aluminium seal and plastic flip
Each carton contains one vial and one single
6.6 Special Precautions For Disposal And Other Handling
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:
Dose
|
Volume
|
1.0 mg
|
12.5 ml
|
2.0 mg
|
25 ml
|
3.0 mg
|
37.5 ml
|
4.0 mg
|
50 ml
|
Figure 3
11. The syringe should then be removed from the filter and a new needle placed on the suspension
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 in
15. From a microbiological point of view, the product should be used immediately. If not used immediately, in
16. The liposomal suspension is infused intravenously over about one hour.
Disposal
No special requirements.
7. Marketing Authorisation Holder
IDM PHARMA SAS
11-15 Quai De Dion Bouton
92816 Puteaux Cedex
France
8. Marketing Authorisation Number(S)
EU/1/08/502/001
9. Date Of First Authorisation/Renewal Of The Authorisation
06/03/2009
10. Date Of Revision Of The Text
05/01/2011
