MEPACT 4 mg powder for suspension for infusion

MEPACT contains the active substance mifamurtide, similar to a component of the cell wall of certain bacteria. It stimulates your immune system to help your body kill tumour cells.

MEPACT is used to treat osteosarcoma (bone cancer) in children, adolescents and young adults. It is used after you have had surgery to remove the tumour and together with chemotherapy to kill remaining cancer cells to reduce the risk of cancer coming back.

Do not use MEPACT

• if you are allergic (hypersensitive) to mifamurtide or any of the other ingredients of MEPACT.
• if you are taking medicines containing ciclosporin or tacrolimus or high doses of NSAIDs (see ?Using other medicines? below).

Take special care with MEPACT

You should tell your doctor before using MEPACT if any of the following applies to you:

• if you have or have had problems with your heart or blood vessels, like blood clots (thrombosis), bleeding (haemorrhage) or inflammation of the veins (vasculitis). You should be more closely monitored while receiving MEPACT treatment. If you have long-lasting or worsening symptoms, you should contact your doctor, as MEPACT administration may need to be delayed or discontinued.
• if you have a history of asthma or other breathing disorders. Before using MEPACT, you should discuss with your doctor whether you should take medicine for your asthma when using MEPACT.
• if you have a history of inflammatory or autoimmune disease or have been treated with corticosteroids or other medicines that may affect your immune system.

Using other medicines Please tell your doctor if you are taking or have recently taken any other medicines, including medicines that may be obtained without a prescription. It is especially important to tell your doctor if you are taking medicines containing any of the following active substances:

• ciclosporin, tacrolimus, used after a transplant to prevent rejection of transplanted organs, or other immunosuppressants used e.g. to treat psoriasis (a skin disease).
• non-steroidal-anti-inflammatory drugs (NSAIDs), such as acetylsalicylic acid, ibuprofen, or diclofenac, used for treatment of headaches, fever or pain. You must not use MEPACT with high doses of NSAIDs.
• corticosteroids, used to treat inflammations, allergies or asthma. You must not use MEPACT with regular use of corticosteroids.

It is recommended to separate the times of administration of MEPACT and doxorubicin or other medicines if used in the same chemotherapy treatment regimen.

Pregnancy and breast-feeding MEPACT has not been tested in pregnant women. Therefore, MEPACT should not be used during pregnancy and in women not using effective contraception. You should use effective contraception if you are being treated with MEPACT. It is important to tell your doctor if you are pregnant, think you may be pregnant, or are planning to get pregnant.

It is not known whether MEPACT passes to human milk. If you are breast-feeding, you should discuss with your doctor.

Driving and using machines
Some very common and common side effects of MEPACT treatment (such as dizziness, vertigo, fatigue and blurred vision) may affect your ability to drive and use machines.

Dose and schedule The safety and efficacy of MEPACT have been established in patients aged 2 to 30 years. The

dose of MEPACT is 2 mg mifamurtide/m 2 body surface area. It will be given to you twice a week (at least three days apart) for the first 12 weeks, then once a week for 24 more weeks.

The schedule of your MEPACT treatments can be adjusted to fit with your chemotherapy schedule. It is not necessary to interrupt your schedule of MEPACT if your chemotherapy is delayed; you should complete 36 weeks (9 months) of treatment with MEPACT without an interruption.

How MEPACT is given

The freeze-dried powder has to be reconstituted into a liquid suspension, filtered using the filter provided and further diluted before use. MEPACT is then infused directly into your vein (intravenous) over about one hour. This is done by your doctor or a nurse, who will also monitor you during that time. You do not need to be hospitalised to receive MEPACT. It can also be administered as an outpatient.

If you use more MEPACT than you should
You may experience more severe side effects, including fever, chills, fatigue, nausea, vomiting, headache and hypo- or hypertension. In the event of such an overdose, contact your doctor or nearest hospital.

If you have any other questions on the use of this medicine, ask your doctor.

Like all medicines, MEPACT can cause side effects, although not everybody gets them. The majority of patients experience chills, fever and fatigue. These are typically mild to moderate and transient and can usually be treated by your doctor, e.g., with paracetamol for fever.

Contact your doctor immediately:

• if you have continuing fever or chills more than 8 hours after your dose of MEPACT, because this may be a sign of an infection or
• if you experience rash or have any problems breathing (wheezing).

Side effects may occur with certain frequencies, which are defined as follows: very common: affects more than 1 user in 10
common: affects 1 to 10 users in 100
uncommon: affects 1 to 10 users in 1,000
rare: affects 1 to 10 users in 10,000
very rare: affects less than 1 user in 10,000
not known: frequency cannot be estimated from the available data.

Very common side effects:

• fever, shaking/shivering, weakness, tiredness or general discomfort
• nausea and/or vomiting, diarrhoea or constipation
• headache or dizziness
• rapid beating of the heart
• high blood pressure or low blood pressure
• no appetite for food
• sweating
• pain, including general pain, pain in your muscles and/or joints and pain in back, chest, abdomen, arm or leg
• cough, trouble breathing or rapid breathing
• low body temperature
• low number of red blood cells

Common side effects:

• blue colour of tissues such as the skin or gums caused by too little oxygen
• perceptible increase in frequency or force of heartbeat
• swelling in arms or legs or other swelling
• chest discomfort
• upset stomach, decreased appetite or weight loss
• injection site or catheter site redness, swelling, infection or other local reaction
• rash or redness, inflammation of the skin, itching, dry skin, pale or transient red appearance
• inflammation of skin, tendons, muscles or similar tissues that support body structure
• inflammation of a vein
• upper abdominal or chest wall pain; abdominal bloating or pain
• other pain, including neck, shoulder or throat pain
• muscle spasms or stiffness
• feeling cold
• tired feeling, drowsiness or sleepiness
• burning, pricking/tingling sensation or diminished sensitivity to sensation
• involuntary shaking movement
• dehydration
• mucosal inflammation
• nose, throat, or sinus congestion or inflammation
• infections of the upper respiratory tract (such as a cold) or the urinary tract (such as a bladder infection)
• generalised infection
• Herpes simplex (virus) infection
• productive cough, wheezing or exertional or exacerbated shortness of breath
• spitting of blood or nosebleed
• fluid in the lung cavity
• blood in urine, difficulty or pain in urination or frequent urination
• difficulty sleeping, depression, anxiety or confusion
• dizziness
• ears ringing
• blurred vision
• hair loss
• difficult, painful menstruation
• hearing loss

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor.

Keep out of the reach and sight of children.
Do not use MEPACT after the expiry date which is stated on the vial label and the carton.

Unopened vial
Store in a refrigerator (2°C ? 8°C). Do not freeze.
Keep the vial in outer carton in order to protect from light.

Reconstituted suspension
Once reconstituted in sodium chloride 9 mg/ml (0.9%) solution, store at room temperature (approximately 20ºC - 25ºC) and use within 6 hours.

What MEPACT contains

• The active substance is mifamurtide. Each vial contains 4 mg of mifurtamide. After reconstitution with 50 ml sodium chloride 9 mg/ml (0.9%) solution for injection, each ml of suspension contains 0.08 mg of mifamurtide.
• The other ingredients are 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and 1,2-Dioleoyl-sn-glycero-3-phospho-L-serine monosodium salt (OOPS).

What MEPACT looks like and contents of the pack

MEPACT is a white to off-white homogeneousfreeze-dried powder for suspension for infusion.

MEPACT is supplied in a carton that contains

• One 50 ml vial with a grey butyl stopper, aluminium seal and plastic flip-off cap.
• One sterile Filter for MEPACT supplied in a blister.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:
IDM PHARMA SAS
11-15 Quai De Dion Bouton
92816 Puteaux Cedex
France

Manufacturer:
Takeda Ireland Ltd
Bray Business Park
Kilruddery
Co. Wicklow
Ireland

Takeda Italia Farmaceutici S.p.A
Via Crosa, 86
28065 Cerano (NO)

Italy

This leaflet was last approved in

---------------------------------------------------------------------------------------------------------------------- The following information is intended for medical or healthcare professionals only:

Instructions for preparation of MEPACT for intravenous infusion

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.

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 thefilter 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-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 (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 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.

Disposal
No special requirements.