Xigris 5 mg powder for solution for infusion

Xigris is very similar to a protein that occurs naturally in your blood. This protein helps to control blood clotting and inflammation. When your body has a severe infection, clots can form in your blood. These can block the blood supply to important parts of your body such as the kidneys and lungs. This causes an illness called severe sepsis which can make you very ill. Some people will die from this illness. Xigris helps your body to get rid of the clots and also reduces the inflammation caused by the infection.

Xigris is used to treat adults with severe sepsis.

You should not be given :

• if you are allergic (hypersensitive) to drotrecogin alfa (activated) or any of the other ingredients of Xigris, or bovine (cattle-derived) thrombin (protein)
• if you are a child below the age of 18
• if you have internal bleeding
• if you have a brain tumour, or pressure on the brain
• if you are being given heparin at the same time (? 15 International Units/kg/hr)
• if you have a bleeding tendency which is not related to sepsis
• if you have a long-standing, severe problem with your liver
• if your platelet (a type of cell in your blood) count is low, even if this has been increased by a transfusion
• if you are at high risk of bleeding (for example):

a) you have had surgery within the last twelve hours before you receive Xigris, or you are bleeding from a previous surgery, or you might have surgery while you receive Xigris

b) you have been in hospital with a severe injury to your head, or you have had surgery on your brain or spine, or you have had a bleed in your brain (haemorrhagic stroke) within

the past three months, or you have abnormal blood vessels in your brain, or a mass in your head; you have an epidural catheter (a tube in your spine)

c) you have been born with bleeding tendencies

d) you have bled from your bowels within the last six weeks, unless treated adequately

e) you have had a major accident and are at increased risk of bleeding

Special care should be taken with Xigris if you are at risk of bleeding, for example:

• if you are taking other medicines which affect how your blood clots (for example medicines that dissolve blood clots, thin the blood, or medicines that inhibit platelets such as aspirin)
• if within the last three months, you have had a stroke caused by a blood clot
• if you have a known problem with bleeding

Xigris should not be used if you have a less severe form of sepsis (only one organ failure) and have recently had a surgical operation.

Using other medicines:
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. Caution should be employed when Xigris is used with other medicines that affect how your blood clots (for example medicines that dissolve blood clots, thin the blood, or medicines that inhibit platelets such as aspirin, non-steroidal anti-inflammatory medicines, or clopidogrel).

Pregnancy and breast-feeding
It is not known whether drotrecogin alfa (activated) causes damage to an unborn child or affects your ability to have babies. If you are pregnant your doctor will only give you Xigris if necessary. It is not known whether drotrecogin alfa (activated) appears in human milk and therefore you should not breast-feed whilst treated with Xigris.

Important information about some of the ingredients of Xigris
This medicinal product contains approximately 17 mg sodium per vial. To be taken into consideration by patients on a controlled sodium diet.

The recommended dose of Xigris is 24 micrograms (?g) per kilogram (kg) of body weight each hour for 96 hours.

A hospital pharmacist, nurse or doctor will have dissolved the Xigris powder in water for injection and sodium chloride solution. This liquid is then passed from a bag through a tube into one of your veins for a period of 96 hours.

Like all medicines, Xigris can cause side effects, although not everybody gets them. Xigris increases the risk of bleeding which can be serious or life-threatening. Serious bleeding during the infusion period occurred in 1% (1 in 100) of patient with severe sepsis and in 2.4% (roughly 1 in 40) of patients treated with Xigris, with most bleeding in both groups occurring in the stomach and bowel. Bleeding into the brain was uncommon, occurring in 0.2% (1 in 500) of patients treated with Xigris.

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

Keep out of the reach and sight of children.

Do not use after the expiry date stated on the label.

Store in a refrigerator (2°C ? 8°C).
Keep the vial in the carton in order to protect it from light.

What Xigris contains

• The active substance is 5 mg of drotrecogin alfa (activated) in each vial. Drotrecogin alfa (activated) is a version of a natural protein in the blood called Activated Protein C and it is produced by recombinant technology.
• The other ingredients are sucrose, sodium chloride, sodium citrate, citric acid, hydrochloric acid and sodium hydroxide.

What Xigris looks like and contents of the pack

Xigris is presented as a powder for solution for infusion in a vial.

A vial contains 5 mg of drotrecogin alfa (activated). After reconstitution with 2.5 ml of Water for Injection each ml contains 2 mg of Drotrecogin alfa (activated).

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder: Eli Lilly Nederland B.V., Grootslag 1-5, 3991 RA, Houten, The Netherlands
Manufacturer: Lilly Pharma Fertigung und Distribution GmbH & Co. KG, Teichweg 3, D- 35396 Giessen, Germany.

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder.

BelgiqueBelgiëBelgien Eli Lilly Benelux S.A.N.V. TélTel 32-02 548 84 84 .. - . 359 2 491 41 40 eská republika ELI LILLY R, s.r.o. Tel 420 234 664 111 Danmark Eli Lilly Danmark AS Tlf 45 45 26 60 00 Deutschland Lilly Deutschland GmbH Tel. 49-0 6172 273 2222 Eesti Eli Lilly Holdings Limited Eesti filiaal Tel 3726441100 - .... 30 210 629 4600 LuxembourgLuxemburg Eli Lilly Benelux S.A.N.V. TélTel 32-02 548 84 84 Magyarország Lilly Hungária Kft. Tel 36 1 328 5100 Malta Charles de Giorgio Ltd. Tel 356 25600 500 Nederland Eli Lilly Nederland B.V. Tel 31-0 30 60 25 800 Norge Eli Lilly Norge A.S. Tlf 47 22 88 18 00 Österreich Eli Lilly Ges. m.b.H. Tel 43-0 1 711 780 Polska Eli Lilly Polska Sp. z o.o. Tel. 48 0 22 440 33 00

Portugal Lilly Portugal Produtos Farmacêuticos, Lda Tel 351-21-4126600 România Eli Lilly România S.R.L. Tel 40 21 4023000 Slovenija Eli Lilly farmacevtska druba, d.o.o. Tel 386 01 580 00 10 Slovenská republika Eli Lilly Slovakia, s.r.o. Tel 421 220 663 111 SuomiFinland Oy Eli Lilly Finland Ab PuhTel 358-0 9 85 45 250 Sverige Eli Lilly Sweden AB Tel 46-0 8 7378800 United Kingdom Eli Lilly and Company Limited Tel 44-0 1256 315999 España Lilly S.A. Tel 34- 91 749 76 98 France Lilly France SAS Tél 33-0 1 55 49 34 34 Ireland Eli Lilly and Company Ireland Limited Tel 353-0 1 661 4377 Ísland Eli Lilly Danmark AS, Útibú á Íslandi Sími 354 520 34 00 Italia Eli Lilly Italia S.p.A. Tel 39- 055 42571 Phadisco Ltd 357 22 715000 Latvija Eli Lilly Holdings Limited prstvniecba Latvij Tel 371 7364000 Lietuva Eli Lilly Holdings Limited atstovyb Tel. 370 5 2649600

This leaflet was last approved on {date}

This medicine has been authorised under ?Exceptional Circumstances?. This means that for scientific reasons it has been impossible to get complete information on this medicine. The European Medicines Agency (EMEA) will review any new information on the medicine every year and this leaflet will be updated as necessary.

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

Instructions for use and handling

1. Use appropriate aseptic technique during the preparation of Xigris for intravenous administration.

2. Calculate the dose and the number of Xigris vials needed.

Each Xigris vial contains 5 mg of drotrecogin alfa (activated).

The vial contains an excess of drotrecogin alfa (activated) to facilitate delivery of the label amount.

3. Prior to administration, 5 mg vials of Xigris must be reconstituted with 2.5 ml of Sterile Water for Injection, resulting in a solution with a concentration of approximately 2 mg/ml drotrecogin alfa (activated).

Slowly add the Sterile Water for Injection to the vial and avoid inverting or shaking the vial. Gently swirl each vial until the powder is completely dissolved.

4. The solution of reconstituted Xigris must be further diluted with sterile 0.9% Sodium Chloride Injection. Slowly withdraw the appropriate amount of reconstituted drotrecogin alfa (activated) solution from the vial. Add the reconstituted drotrecogin alfa (activated) into a prepared infusion bag of sterile 0.9% Sodium Chloride Injection. When adding the reconstituted drotrecogin alfa (activated) into the infusion bag, direct the stream to the side of the bag to minimise the agitation of the solution. Gently invert the infusion bag to obtain a homogeneous solution. Do not transport the infusion bag between locations using mechanical delivery systems.

5. After reconstitution, immediate use is recommended. However, the reconstituted solution in the vial may be held for up to 3 hours at room temperature (15 to 30ºC). After preparation, the intravenous infusion solution can be used at room temperature (15 to 30ºC) for a period up to 14 hours.

6. Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration.

7. It is recommended that Xigris be infused with an infusion pump to accurately control the infusion rate. The solution of reconstituted Xigris should be diluted into an infusion bag containing sterile 0.9% Sodium Chloride Injection to a final concentration of between 100 ?g/ml and 200 ?g/ml.

8. When administering drotrecogin alfa (activated) at low flow rates (less than approximately 5 ml/hr), the infusion set must be primed for approximately 15 minutes at a flow rate of approximately 5 ml/hr.

9. Xigris should be administered via a dedicated intravenous line or a dedicated lumen of a multilumen central venous catheter. The ONLY other solutions that can be administered through the same line are 0.9% Sodium Chloride Injection, Lactated Ringer?s Injection, Dextrose or Dextrose and Saline mixtures.

10. Avoid exposing drotrecogin alfa (activated) solutions to heat and/or direct sunlight. No incompatibilities have been observed between drotrecogin alfa (activated) and glass infusion bottles or infusion bags made of polyvinylchloride, polyethylene, polypropylene, or polyolefin.

The use of other types of infusion sets could have a negative impact on the amount and potency of drotrecogin alfa (activated) administered.

11. Care should be taken to administer Xigris at the appropriate rate, calculated based on kg of bodyweight and infused for the correct duration. It is recommended that the bag be labelled accordingly.