artesunate: package leaflet

Artesunate Amivas contains the active substance artesunate. Artesunate Amivas is used to treat severe malaria in adults and children.

After treatment with Artesunate Amivas your doctor will complete your treatment for malaria with a course of anti-malarial medicine that can be taken by mouth.

Do not use Artesunate Amivas
- if you are allergic to artesunate, to any other antimalarial treatment that contains an artemisinin (e.g. artemether or dihydroartemisinin) or any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions
Talk to your doctor or nurse before using Artesunate Amivas.

You may develop anaemia, a reduced number of red blood cells, or other blood changes after treatment with this medicine. Some changes to numbers of blood cells can occur while you are being treated and usually recover after stopping treatment for malaria. However, some individuals develop severe anaemia that can occur up to several weeks after completing treatment for malaria. In most cases, the anaemia recovers without any specific treatment. In a small number of cases the anaemia may be severe and require blood transfusion. Your doctor will carry out regular blood tests that can include a direct antiglobulin test to determine if treatment, e.g. with corticosteroids, is necessary and monitor your recovery for 4 weeks after you have completed your treatment for malaria. It is important you attend appointments for these check-ups.

Other medicines and Artesunate Amivas
Tell your doctor if you are taking, have recently taken or might take any other medicines.

Some medicines should not be taken with artesunate because they could reduce its effect on malaria.
Some examples include:
- rifampicin (to treat bacterial infections)
- ritonavir, nevirapine (anti-HIVmedicine)
- carbamazepine, phenytoin (to treat epilepsy)

Some medicines may increase blood levels of artesunate and may increase the risk of side effects.
Some examples include:
- diclofenac (to treat pain or inflammation)
- axitinib, vandetanib and imatinib (used in the treatment of certain cancers)

Artesunate may increase or decrease the blood levels of some other medicines. Your doctor will advise you on taking any medicines during artesunate treatment.

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, you should talk to your doctor before being given this medicine.

Pregnancy
Your doctor will discuss with you the potential risk of taking Artesunate Amivas during pregnancy.
Use in the first trimester of pregnancy is not recommended unless your doctor decides that the benefit of treatment for you outweighs the risk to your unborn child. In the later stages of pregnancy, you should only take Artesunate Amivas if your doctor feels that there are no suitable alternative medicines.

Pregnancy registry
If you are or become pregnant during treatment with this medicine, the doctor will report your pregnancy to the manufacturer, who is keeping a record in order to understand any effects that the treatment may have on the pregnancy and the baby.

Breast-feeding
Traces of this medicine may be present in your breast milk. It is not known if these could have any effect on a breastfed baby. If you are planning to breastfeed, discuss with your doctor whether the benefits of breastfeeding to you and your baby outweigh the potential risk.

Infants under 6 months
Talk to your doctor for more information.

Elderly
Talk to your doctor for more information.

Driving and using machines
You should not drive or use machines if you feel tired or dizzy.

Artesunate Amivas contains sodium
This medicine contains 193 mg sodium (main component of cooking/table salt) in each single dose.
This is equivalent to just under 10 % of the recommended maximum daily dietary intake of sodium for an adult.
As the first and second doses are recommended 12 hours apart, this would supply 386 mg sodium (nearly 20% of your maximum daily intake).

Always use this medicine exactly as your doctor has told you. Check with your doctor if you are not sure.

This medicine will be given to you by a slow injection directly into a vein. Your doctor or nurse will inject this medicine for you.

The dose of the medicine you are given is based on your weight and your doctor or nurse will work out the right amount to give you. The recommended dose is 2.4 mg for each kg of body weight. The dose per kg is the same for adults and children of all ages.

You will be given at least three doses of Artesunate Amivas, each dose given 12 hours apart. After three doses, if you still cannot take medicines by mouth, you will be given one dose of Artesunate Amivas every 24 hours (once a day) until you are able to take a different malaria treatment by mouth.

It is very important that you complete a full course of antimalarial treatment taken by mouth after you have had at least three doses of Artesunate Amivas by injection.

If you are given more Artesunate Amivas than you should
As this medicine will be given to you in a hospital, it is unlikely that you will be given too much. Tell your doctor if you have any concerns. Signs of an overdose include seizures, dark coloured stools, a blood test showing low blood cell counts, weakness, fatigue, fever and nausea. Your doctor will help to treat these symptoms if you are given too much of this medicine.

If a dose of Artesunate Amivas is forgotten
As this medicine will be given to you in a hospital, your doctor or nurse will manage your treatment and it is unlikley a dose will be forgotten. Should a dose be delayed, your doctor or nurse will give the required dose at the earliest opportunity and continue to give future doses 12 or 24 hours apart.

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

Like all medicines, this medicine can cause side effects, although not everybody gets them.

If you experience any of the following side effects seek medical help immediately:
- difficulty breathing or swallowing, swelling of your face, mouth or throat. These are signs you may be having a severe allergic reaction. The frequency of very severe allergic reactions leading to loss of consciousness is unknown.

Very common side effects (may affect more than 1 in 10 people)
- a lack of healthy red blood cells, which can make you feel tired and weak (anaemia); this can develop at least 7 days or sometimes several weeks after treatment has finished.

Common side effects (may affect up to 1 in 10 people)
- inflammation of a vein
- altered sense of taste
- raised body temperature or fever
- very dark yellow or reddish brown coloured urine
- reduced kidney function, including low urine output
- bruising easily or slow clotting of any cuts or wounds.
- abnormal levels of liver enzyme levels detected in blood tests
- yellowing of the skin (jaundice)
- diarrhoea
- abdominal pain

• vomiting
• slow heart rate
• low blood pressure
• cough
• rhinitis (blocked and/or runny nose)
• feeling dizzy or weak
• headache

Uncommon (affecting less than 1 in 100 patients)
- tiredness
- feeling sick
- constipation
- pain at injection site
- painful widespread rash with blisters especially near mouth, nose, eyes and genitals, flu-like symptoms for several days (Stevens-Johnson syndrome or SJS)
- loss of appetite
- rash
- itching
- swelling and reddening of the face
- flushing

Not known (frequency cannot be estimated from the available data)
- a lack of healthy red blood cells caused by your immune system (immune haemolytic anaemia)
- abnormal electrical activity of the heart that affects its rhythm (Prolonged electrocardiogram QT)

Reporting of side effects
If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the label on the carton after EXP. The expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

The reconstituted solution must be used within 1.5 hours of preparation.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

What Artesunate Amivas contains
- The active substance is artesunate.
Each vial of powder contains 110 mg of artesunate.
Each vial of solvent for reconstitution contains 12 mL of 0.3 M sodium phosphate buffer.
- The other ingredients in the 0.3 M sodium phosphate buffer solvent are monosodium phosphate monohydrate, disodium phosphate dihydrate (see section 2 “Artesunate Amivas contains

sodium”) and phosphoric acid, concentrated (for pH adjustment), sodium hydroxide (for pH adjustment) and water for injections.

After reconstitution with 11 mL of the solvent provided, the solution for injection contains 10 mg of artesunate per mL.

What Artesunate Amivas looks like and contents of the pack
Artesunate Amivas 110 mg powder and solvent for solution for injection.
The powder is white or almost white, fine crystalline powder in a glass vial.
The solvent is a clear, colourless liquid in a glass vial.

Each pack contains 2 or 4 vials of Artesunate Amivas powder and 2 or 4 vials of sodium phosphate buffer solvent.

Not all pack sizes may be marketed.

Marketing Authorisation Holder
Amivas Ireland Ltd, Suite 5, Second Floor, Station House, Railway Square, Waterford, Ireland

Manufacturer
MIAS Pharma Limited, Suite 1, Stafford House, Strand Road, Portmarnock, Co. Dublin, Ireland

This leaflet was last revised in

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu

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The following information is intended for healthcare professionals only:

Preparation and Administration

The required dose of Artesunate Amivas should be calculated prior to reconstitution:

Dose mg = patient’s weight in kg x 2.4

Only the required number of vials of Artesunate Amivas should be reconstituted when preparing the dose. Remaining unopened vials can be stored in the carton ready for use at the next scheduled dose.

To reconstitute, withdraw 11 mL of the supplied solvent (0.3 M sodium phosphate buffer) with a needle and syringe. Inject into the vial containing the artesunate powder (the final concentration of artesunate is 10 mg/mL when reconstituted). Swirl gently for 5 to 6 minutes until the powder is fully dissolved. Do not shake.

Visually inspect the solution within the vial to ensure that no visible particles remain and there is no discolouration. Do not administer if solution is discoloured or contains visible particles.

Inject the reconstituted medicinal product solution intravenous as a slow bolus over 1-2 minutes. Do not administer via continuous intravenous infusion.

The recommended dosage schedule is at 0, 12, and 24 hours, then once daily until alternative oral anti- malarial medicine can be tolerated.

Artesunate Amivas also contains 193 mg sodium per the recommended single dose in a 60 kg adult, equivalent to 9.6 % of the WHO recommended maximum daily intake of 2 g sodium for an adult. As the first and second doses are recommended 12 hours apart, on days when two doses are given in a 24 hour period, then the dose would be 386 mg sodium per day, equivalent to 19.2 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Storage of reconstituted Artesunate Amivas solution

Once reconstituted, the Artesunate Amivas solution should be administered within 1.5 hours of preparation. Discard any unusued solution in accordance with local guidelines.

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