I just want
to beat my
I want to beat
Prescribing information can be found on the back cover.
Recommended by NICE
last accessed December 2011.
Approved by SMC
last accessed December 2011.
Mepact is indicated for the treatment of high-grade, resectable, non-metastatic
osteosarcoma following complete surgical resection in children, adolescents and young
adults, aged 2-30 years, in combination with post-operative multi-agent chemotherapy.1
Mepact is a synthetic analogue of muramyl dipeptide, the smallest natural immuno-
adjuvant from the mycobacterium cell wall.2
It is the only authorised product in its class
which activates the body’s immune system to target micro-metastatic lung disease,3,4
the primary cause of death in osteosarcoma.5
Anti-tumour activity of Mepact is mediated by activation of host immune system
Mepact enters the macrophage where it is broken down to Muramyl Di-Peptide (MDP),
which then binds to the NOD-2 receptor.2,3
Intracellular pathways are activated3
induce cytotoxic function2,7,8
and secretion of numerous cytokines and chemokines,13,17,18
which along with other recruited and activated immune cells2
directly affect the
producing tumour cell apoptosis.2,7,9
Background to the Phase III study
The Mepact Phase III study10,11
was a National Cancer Institute (NCI)-funded Cooperative
Group study conducted by the Children’s Oncology Group (COG):
• 4-year enrolment (1993 – 1997)
• 14-year follow-up (1993 – 2007)
This was a large and extensive study carried out in newly diagnosed osteosarcoma patients
(777 patients, age under 31, mean age 14 years), with independently analysed and
published survival benefits.
Patients and methods
Six hundred and sixty two patients with osteosarcoma, without clinically detectable
metastatic disease and whose disease was considered resectable, 115 with more advanced
disease, received one of four prospectively randomised treatments.9,10
Having received neo-
adjuvant chemotherapy, all patients underwent definitive surgical resection of their primary
tumour. As part of their adjuvant chemotherapy all patients received identical cumulative
doses of cisplatin, doxorubicin and methotrexate. Patients were randomly assigned to
receive or not to receive ifosfamide and/or Mepact in a 2 x 2 factorial design.10,11
Study end points
To determine whether the addition of a single 36-week course of Mepact to standard
three- or four-drug adjuvant chemotherapy enhanced overall survival and event-free
survival in newly diagnosed patients with osteosarcoma.10,11
What is Mepact? An overview of efficacy and tolerability of Mepact
Adapted from references 2-4, 6-9
Adapted from references 10 and 11.
Tumour removed but
To prevent lung metastases by
20 27 36
Cisplatin, Doxorubicin, HDMTX
Cisplatin, Doxorubicin, HDMTX, Mepact
Cisplatin, Ifosfamide, Doxorubicin, HDMTX, Mepact
Cisplatin, Ifosfamide, Doxorubicin, HDMTX
Regimens A and B: 4 courses of cisplatin 120 mg/m2
over 4 hours combined with 6 courses of doxorubicin (25 mg/m2/day x 3)
and 12 courses of methotrexate 12 g/m2
Regimen B only: Ifosfamide 1.8 g/m2
/day for 5 days
HDMTX: High-dose methotrexate
The study found that the addition of Mepact to current chemotherapy significantly
improved 6-year overall survival from 70% to 78% (p=0.03)10,11
and reduced the risk of
death by almost one-third (29%; relative risk=0.71, 95% CI, 0.52 to 0.96, absolute risk
reduction 8%, p=0.03).10
In the Phase III study, Mepact was administered to 332 subjects (half of whom were under
the age of 16) and side effects were found to be mild to moderate in nature.10,11
most common grade-1 or grade-2 adverse events included chills, fever, fatigue, nausea,
tachycardia and headache.1
The study showed no significant increased incidence of adverse events over current
and no life-threatening risks were associated with
Most patients experienced fewer adverse events with subsequent administration.10-12
Frequency groupings are defined according to the following convention: very common
(≥1/10), common (≥1/100 to 1/10).1
Significantly improved overall survival Mepact tolerability
The study also showed a trend towards better event-free survival with Mepact:
67% at 6 years compared to 61% without Mepact, with a hazard ratio of 0.8
(p=0.08, 95% CI, 0.62 to 1.0).10,11
The addition of ifosfamide to cisplatin, doxorubicin and methotrexate did not
enhance overall survival or event-free survival for patients with osteosarcoma.
The addition of Mepact to chemotherapy resulted in a statistically significant
improvement in overall survival and a trend toward better event-free survival.6,7
Overall survival for all patients assigned to receive or not to receive
Mepact independently of chemotherapy regimen received10,11
5 10 15
Estimated Proportion Surviving
(95% CI: 0.52 to 0.96)
Adapted from references 10 and 11.
Very Common Common
Infections and infestations 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)
Blood and lymphatic system disorders Anaemia Leukopenia, thrombocytopenia, granulocytopenia
Metabolism and nutrition disorders Anorexia Dehydration, hypokalaemia, decreased appetite
Psychiatric disorders Confusional state, depression, insomnia, anxiety
Nervous system disorders Headache, dizziness Paraesthesia, hypoaesthesia, tremor, somnolence, lethargy
Eye disorders Blurred vision
Ear and labyrinth disorders Vertigo, tinnitus, hearing loss
Cardiac disorders Tachycardia Cyanosis, palpitations
Vascular disorders Hypertension, hypotension Phlebitis, flushing, pallor
Respiratory, thoracic and mediastinal
Dyspnoea, tachypnoea, cough Pleural effusion, exacerbated dyspnoea productive cough, haemoptysis,
wheezing, epistaxis, exertional dyspnoea, sinus congestion, nasal
congestion, pharyngolaryngeal pain
Gastrointestinal disorders Vomiting, diarrhoea, constipation,
abdominal pain, nausea
Upper abdominal pain, dyspepsia, abdominal distension,
lower abdominal pain
Hepatobiliary disorders Hepatic pain
Skin and subcutaneous tissue disorders Hyperhidrosis Rash, pruritus, erythema, alopecia, dry skin
Musculoskeletal and connective tissue
Myalgia, arthralgia, back pain,
pain in extremity
Muscle spasms, neck pain, groin pain, bone pain, shoulder pain,
chest wall pain, musculoskeletal stiffness
Renal and urinary disorders Haematuria, dysuria, pollakiuria
Reproductive system and breast disorders Dysmenorrhoea
General disorders and administration site
Fever, chills, fatigue, hypothermia,
pain, malaise, asthenia, chest pain
Peripheral oedema, oedema, mucosal inflammation, infusion site
erythema, infusion site reaction, catheter site pain, chest discomfort,
Investigations Weight decreased
Surgical and medical procedures Post-procedural pain
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
Mepact should be discontinued and appropriate treatment initiated.1
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.1
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.1
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
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.1
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
Mepact is administered on the same day as adjuvant combination chemotherapy1
should not be interrupted due to delays in the chemotherapy regimen.13
Mepact can be administered on an inpatient or outpatient basis.21
Mepact must not be
administered as a bolus injection.1
• Should not be mixed with other drugs in the same container or iv line1
• Can be used with combination chemotherapy as long as one infusion is finished and
the iv line is flushed before the next infusion is given according to the information on
its product label1
• Should be separated temporally from other liposomal or lipophilic drugs (e.g. liposomal
doxorubicin) if given in the same regimen1
How frequently should Mepact be administered?
Mepact is given by intravenous infusion over the course of one hour, twice a week for
12 weeks, then once weekly for 24 additional weeks – a total of 36 weeks of therapy,
or 48 doses.1
The recommended dose for all patients is 2 mg/m2
body surface area.1
Explaining Mepact to patients
More information on this sensitive topic is presented in straightforward language at the
end of this booklet.
Additionally, a number of separate leaflets on Mepact have been made available for
patients and their parents/carers, as well as pharmacists and nurses. These are designed
to inform and educate the various groups involved with Mepact, and by increasing
awareness, will ideally make your job easier when administering treatment.
How is Mepact administered?
First 12 weeks Next 24 weeks
Twice weekly at least 3 days apart
Total: 24 infusions
Total: 24 infusions
Special warnings and precautions for use
How to order
Mepact should be ordered from Unidrug Distribution Group (UDG)
Amber Park, Berristow Lane, South Normanton, Derbyshire, DE55 2FH.
By fax to: 01773 810644.
By email to: email@example.com. Contact telephone: 01773 515004 or 01773 515066
Orders received by UDG before 2pm will be delivered the next day.
How is Mepact administered?
Mepact must be reconstituted using the filter provided and further diluted prior to
administration. The reconstituted 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, Mepact is administered by intravenous infusion over a
period of one hour. Mepact must not be administered as a bolus injection.1
Mepact and overdose
No case of overdose has been reported with Mepact. 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.1
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,13
chills and headache and
anti-emetics (other than steroids) for nausea and vomiting.1
Instructions for the preparation of Mepact for intravenous infusion2
Materials provided in each package
• 1 vial of Mepact (mifamurtide)
• 1 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.
Step by step administration of Mepact
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 swabbedwith 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
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.
How is Mepact administered?
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
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:
1.0 mg 12.5 ml
2.0 mg 25 ml
3.0 mg 37.5 ml
4.0 mg 50 ml
11. The syringe should then be removed from the filter and a new needle placed on the
suspension-filled 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
12. The bag should be gently swirled to mix the solution.
Figure 3 Figure 4Figure 2
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-use 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, in-use 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.
No special requirements.
Store in a refrigerator (2°C – 8°C). Do not freeze.
Keep the vial in outer carton in order to protect from light.
Once reconstituted in sodium chloride 9 mg/ml (0.9%) solution, store at room
temperature (approximately 20ºC – 25ºC) and use within 6 hours.
How is Mepact administered?
Bone Cancer Research Trust
Devoted to promoting research into the causes and treatment of Primary Bone Cancer and
in particular of Osteosarcoma and Ewing’s Sarcoma. The Trust is also looking to provide
information, support and, in the longer term, counselling services for those suffering from
Primary Bone Cancer, and their families.
An organisation that represents the less common cancers, giving member charities and
those they represent a more powerful voice and the driving force of a larger group, as well
as listening to the community and sharing information and experience.
CLIC Sargent is committed to improving the survival of children with cancer through
its specialist care and by funding both clinical and social research projects. It provides
individual support to children and young people with cancer and their families through
clinical, emotional, psychological, social and financial services in hospital, at home and in
the community across the UK.
Rarer Cancers Forum
The Forum draws together people with rare and less common cancers, giving them a
bigger collective voice to exact better services, and enabling them to support one another.
It makes health professionals aware of issues related to rarer cancers and works with the
Government, the NHS and Primary Care Trusts/Health Boards to ensure that people with
rarer cancers have access to the best possible services across the UK.
Sarcoma UK publishes information about sarcoma, develops support services for patients,
develops educational opportunities for professionals and patients, and empowers patients
as representatives and advocates working for the benefit of all patients.
Some useful organisations
Teenage Cancer Trust
TCT’s top priority is building units in NHS hospitals specifically for teenagers with cancer.
Everything the TCT does is to improve the quality of life and chances of survival for
teenagers and young adults diagnosed with cancer and it provides a support network for
teenagers providing individual and group counselling.
Other useful contacts
1. Mepact Summary of Product Characteristics (http://www.medicines.org.uk/EMC/ searchresults.aspx?term
2. Nardin A, Lefebvre M-L, Labroquère K, Faure O, Abastado J-P. Liposomal muramyl tripeptide
phosphatidylethanolamine. Targeting and activating macrophages for adjuvant treatment of
osteosarcoma. Current Cancer Drug Targets 2006;6(2):123-33.
3. Strober W, Murray PJ, Kitani A, Watanabe T. Signalling pathways and molecular interactions of NOD1
and NOD2. Nat Rev Immunol 2006;6:9-20.
4. Fidler IJ, Sone S, Fogler WE, et al. Eradication of spontaneous metastases and activation of alveolar
macrophages by intravenous injection of liposomes containing muramyl dipeptide. Proc Natl Acad Sci
5. Meyers PA, Gorlick R. Osteosarcoma. Pediatr Clin North Am 1997; 44:973-989.
6. Kleinerman ES, Snyder JS, Jaffe N. Influence of chemotherapy administration on monocyte activation by
liposomal muramyl tripeptide phosphatidyl ethanolamine in children with osteosarcoma. J Clin Oncol
7. Anderson P. Liposomal muramyl tripeptide phosphatidyl ethanolamine: ifosfamide-containing
chemotherapy in osteosarcoma. Future Oncol. (2006) 2(3),333-343.
8. Kleinerman ES, Meyers PA, Raymond AK, et al. Combination therapy with ifosfamide and liposome-
encapsulated muramyl tripeptide: Tolerability, toxicity, and immune stimulation. J Immunother Emphasis
Tumor Immunol 1995;17:181-193.
9. Kleinerman ES, Erickson KL, Schroit AJ, et al. Activation of tumoricidal properties in human blood
monocytes by liposomes containing lipophilic muramyl tripeptide. Cancer Res 1983:43:2010-2014.
10. Meyers PA, et al. Osteosarcoma: The Addition of Muramyl Tripeptide to Chemotherapy Improves Overall
Survival – A Report From The Children’s Oncology Group. J Clin Oncol 2008;26:633-638.
11. Meyers PA, Schwartz CL, Krailo MK, et al. Osteosarcoma: A Randomized, Prospective Trial of the
Addition of Ifosfamide and/or Muramyl Tripeptide to Cisplatin, Doxorubicin, and High-Dose
Methotrexate. J Clin Oncol. 2005;23:2004-2011.
12. Meyers PA. Muramyl tripeptide (mifamurtide) for the treatment of osteosarcoma. Expert Rev. Anticancer
13. Mepact Patient Information Leaflet (http://www.medicines.org.uk/EMC searchresults.aspx?term=MEPACT
(Refer to Summary of Product Characteristics (SmPC)
Mifamurtide 4 mg vial. Presentation: 4 mg powder
for suspension for infusion. Single vial in outer carton
EU/1/08/502/001 £2375. Indication: Treatment of
high-grade resectable nonmetastatic osteosarcoma
after macroscopically complete surgical resection in
children, adolescents and young adults (2-30 years)
used in combination with post-operative multi-agent
chemotherapy. Dosage Administration: Should be
initiated and supervised by specialist oncologists.
Powder for suspension for infusion: Mepact®
reconstituted with 50 mL sodium chloride 9 mg/mL
(0.9%) and the appropriate dose volume withdrawn
and added to a sodium chloride 9 mg/mL (0.9%)
infusion bag for intravenous administration over 1 hour
(see SmPC). Children, adolescents young adults 2-30
years: 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.
Paediatric patients (2 yrs): No data available. Elderly
patients (65yrs): No data available. Patients with
impaired renal or hepatic function: No data available
regarding use in renal or hepatic failure.
Contraindications, Warnings etc.: Contraindications:
Hypersensitivity to mifamurtide or excipients.
Concurrent administration with ciclosporin, other
calcineurin inhibitors and high-dose non-steroidal anti-
inflammatory agents (cyclooxygenase inhibitors).
Precautions: In patients with asthma or other chronic
obstructive pulmonary disease, consider administration
of prophylactic bronchodilators. If a severe respiratory
reaction occurs, administration should be discontinued
and appropriate treatment initiated. Monitor and
manage episodes of neutropenic fever. Fever or chills
persisting more than 8 hours after administration of
should be evaluated for possible sepsis. Use
with caution in patients with a history of
autoimmune, inflammatory or other collagen diseases.
Monitor for signs or symptoms of arthritis or synovitis.
If symptoms persist or worsen in patients with a history
of thrombosis, vasculitis or unstable cardiovascular
administration should be delayed
or discontinued. Monitor for signs of allergic reactions.
Gastrointestinal toxicity may be exacerbated when
is used in combination with high dose, multi-
agent chemotherapy and was associated with an
increased use of parenteral nutrition. Interactions:
There is no evidence of any interactions between
and the anti-tumour effects of chemotherapy
and vice versa. Mepact®
should be administered at a
separate time to doxorubicin or other liposomal
formulations. Chronic or routine use of corticosteroids
should be avoided. Mifamurtide is 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 did not exacerbate
the renal toxicities of cisplatin and ifosfamide or the
hepatic toxicities of methotrexate and ifosfamide.
Pregnancy lactation: No data available. Adverse
Effects: Very common (10%): Anaemia, anorexia,
headache, dizziness, tachycardia, hypertension,
hypotension, dyspnoea, tachypnoea, cough, vomiting,
diarrhoea, constipation, abdominal pain, nausea,
hyperhidrosis, myalgia, arthralgia, back pain, pain in
extremity, fever, chills, fatigue, hypothermia, pain,
malaise, asthenia, chest pain. Pharmaceutical
Precautions: Store in a refrigerator (2-8°C), protected
from light. The reconstituted vial is stable for up to 6
hours at 25°C. PI Date: April 2011. PI Code: MEP131.
Authorisation Holder: IDM PHARMA SAS, 11-15
Quai De Dion Bouton, 92816 Puteaux Cedex, France
Further information is available from: Takeda
Pharmaceuticals Europe Ltd. Medical and Scientific
Affairs. 61 Aldwych, London, WC2B 4AE, UK.
+44 203 116 8879.
is a registered trademark
Please refer to the summary of product
characteristics for details on the full
side-effects of Mepact. Adverse events
should be reported. Reporting forms and
information can be found at
Adverse events should also be reported to
Takeda UK Ltd 01628-537900
Date of preparation: December 2011 EU/MEP-010000