Advagraf 0.5 mg prolonged-release hard capsules

Advagraf is an immunosuppressant. Following your organ transplant (liver, kidney), your body?s immune system will try to reject the new organ. Advagraf is used to control your body?s immune response, enabling your body to accept the transplanted organ.

You may also be given Advagraf for an ongoing rejection of your transplanted liver, kidney, heart or other organ when any previous treatment you were taking was unable to control this immune response after your transplantation.

Prograf and Advagraf contain both the active substance, tacrolimus. However, Advagraf is taken once daily, whereas Prograf is taken twice daily. This is because Advagraf capsules allow for a prolonged release of tacrolimus.

Do not take Advagraf

• if you are allergic (hypersensitive) to tacrolimus or any of the other ingredients of Advagraf (see section 6).
• if you are allergic to sirolimus or to any macrolide-antibiotic (e.g. erythromycin, clarithromycin, josamycin).

Take special care with Advagraf

Tell your doctor if any of the following apply to you:

• if you are taking any medicines mentioned below under ?Using other medicines?.
• if you have or have had liver problems
• if you have diarrhoea for more than one day
• if you need to receive any vaccinations Your doctor may need to adjust your dose of Advagraf.

You should keep in regular contact with your doctor. From time to time, your doctor may need to do blood, urine, heart, eye tests, to set the right dose of Advagraf.

The use of Advagraf is not recommended in children and adolescents under 18 years.

You should limit your exposure to the sun and UV (ultraviolet) light whilst taking Advagraf. This is because immunosuppressants could increase the risk of skin cancer. Wear appropriate protective clothing and use a sunscreen with a high sun protection factor.

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 and herbal preparations.

It is not recommended that Advagraf is taken with ciclosporin.

Advagraf blood levels can be affected by other medicines you take, and blood levels of other medicines can be affected by taking Advagraf, which may require an increase or decrease in Advagraf dose. In particular, you should tell your doctor if you are taking or have recently taken medicines like:

• antifungal medicines and antibiotics, particularly so-called macrolide antibiotics, used to treat infections e.g. ketoconazole, fluconazole, itraconazole, voriconazole, clotrimazole, erythromycin, clarithromycin, josamycin, and rifampicin
• HIV protease inhibitors (e.g ritonavir), used to treat HIV infection
• medicines for stomach ulcer and acid reflux (e.g. omeprazol, lansoprazol or cimetidine)
• antiemetics, used to treat nausea and vomiting (e.g. metoclopramide)
• cisapride or the antacid magnesium-aluminium-hydroxide, used to treat heartburn
• the contraceptive pill or other hormone treatments with ethinylestradiol, hormone treatments with danazol
• medicines used to treat high blood pressure or heart problems (e.g. nifedipine, nicardipine, diltiazem and verapamil)
• medicines known as ?statins? used to treat elevated cholesterol and triglycerides
• phenytoin or phenobarbital, used to treat epilepsy
• the corticosteroids prednisolone and methylprednisolone, belonging to the class of corticosteroids used to treat inflammations or suppress the immune system (e.g. in transplant rejection)
• nefazodone, used to treat depression
• Herbal preparations containing St. John?s Wort ( Hypericum perforatum)

Tell your doctor if you are taking or need to take ibuprofen, amphotericin B or antivirals (e.g. aciclovir). These may worsen kidney or nervous system problems when taken together with Advagraf.

Your doctor also needs to know if you are taking potassium supplements or certain diuretics used for heart failure, hypertension and kidney disease, (e.g. amiloride, triamterene, or spironolactone), non-steroidal anti-inflammatory drugs (NSAIDs, e.g. ibuprofen) used for fever, inflammation and pain, anticoagulants (blood thinners), or oral medicines for diabetes, while you take Advagraf.

If you need to have any vaccinations, please tell your doctor before.

Taking Advagraf with food and drink
Take Advagraf on an empty stomach or 2 to 3 hours after a meal. Wait at least 1 hour until the next meal. Avoid grapefruit (also as juice) while on treatment with Advagraf, since it can affect its levels

Pregnancy and breast-feeding

If you are, think you might be or are planning to become pregnant, ask your doctor for advice before using Advagraf.
Advagraf passes into breast milk. Therefore, you should not breast-feed whilst using Advagraf.

Driving and using machines
Do not drive or use any tools or machines if you feel dizzy or sleepy, or have problems seeing clearly after taking Advagraf. These effects are more frequent if you also drink alcohol.

Important information about some of the ingredients of Advagraf

Advagraf contains lactose (milk sugar). If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.
The printing ink used on Advagraf capsules contains soya lecithin. If you are allergic to peanut or soya, talk to your doctor to determine whether you should use this medicine.

Always take Advagraf exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

Make sure that you receive the same tacrolimus medicine every time you collect your prescription, unless your transplant specialist has agreed to change to a different tacrolimus medicine. This medicine should be taken once a day. If the appearance of this medicine is not the same as usual, or if dosage instructions have changed, speak to your doctor or pharmacist as soon as possible to make sure that you have the right medicine.

The starting dose to prevent the rejection of your transplanted organ will be determined by your doctor calculated according to your body weight. Initial daily doses just after transplantation will generally be in the range of 0.10 ? 0.30 mg per kg body weight per day

depending on the transplanted organ.

Your dose depends on your general condition and on which other immunosuppressive medication you are taking.

Following the initiation of your treatment with Advagraf, frequent blood tests will be taken by your doctor to define the correct dose. Afterwards regular blood tests by your doctor will be required to define the correct dose and to adjust the dose from time to time. Your doctor will usually reduce your Advagraf dose once your condition has stabilised. Your doctor will tell you exactly how many capsules to take.

You will need to take Advagraf every day as long as you need immunosuppression to prevent rejection of your transplanted organ. You should keep in regular contact with your doctor.

Advagraf is taken orally once daily in the morning. Take the capsules immediately following removal from the blister. The capsules should be swallowed whole with a glass of water. Do not swallow the desiccant contained in the foil wrapper.

If you take more Advagraf than you should
If you have accidentally taken too much Advagraf, contact your doctor or nearest hospital emergency department immediately.

If you forget to take Advagraf
If you have forgotten to take your Advagraf capsules in the morning, take them as soon as possible on the same day. Do not take a double dose the next morning.

If you stop taking Advagraf

Stopping your treatment with Advagraf may increase the risk of rejection of your transplanted organ. Do not stop your treatment unless your doctor tells you to do so.

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

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

Advagraf reduces your body?s defence mechanism (immune system), which will not be as good at fighting infections. Therefore, you may be more prone to infections while you are taking Advagraf.

Severe effects may occur, including allergic and anaphylactic reactions. Benign and malignant tumours have been reported following Advagraf treatment.

Possible side effects are listed according to the following categories:
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:

• Increased blood sugar, diabetes mellitus, increased potassium in the blood
• Difficulty in sleeping
• Trembling, headache
• Increased blood pressure
• Liver function tests abnormal
• Diarrhoea, nausea
• Kidney problems

Common side effects:

• Reduction in blood cell counts (platelets, red or white blood cells), increase in white blood cell counts, changes in red blood cell counts (seen in blood tests)
• Reduced magnesium, phosphate, potassium, calcium or sodium in the blood, fluid overload, increased uric acid or lipids in the blood, decreased appetite, increased acidity of the blood, other changes in the blood salts (seen in blood tests)
• Anxiety symptoms, confusion and disorientation, depression, mood changes, nightmare, hallucination, mental disorders
• Fits, disturbances in consciousness, tingling and numbness (sometimes painful) in the hands and feet, dizziness, impaired writing ability, nervous system disorders
• Blurred vision, increased sensitivity to light, eye disorders
• Ringing sound in your ears
• Reduced blood flow in the heart vessels, faster heartbeat
• Bleeding, partial or complete blocking of blood vessels, reduced blood pressure
• Shortness in breath, changes in the lung tissue, collection of liquid around the lung, inflammation of the pharynx, cough, flu-like symptoms
• Stomach problems such as inflammation or ulcer causing abdominal pain or diarrhoea, bleeding in the stomach, inflammation or ulcer in the mouth, collection of fluid in the belly, vomiting, abdominal pain, indigestion, constipation, passing wind, bloating, loose stools
• Bile duct disorders, yellowing of the skin due to liver problems, liver tissue damage and inflammation of the liver
• Itching, rash, hair loss, acne, increased sweating
• Pain in joints, limbs or back, muscle cramps
• Insufficient function of the kidneys, reduced production of urine, impaired or painful urination
• General weakness, fever, collection of fluid in your body, pain and discomfort, increase of the enzyme alkaline phosphatase in your blood, weight gain, feeling of temperature disturbed
• Insufficient function of your transplanted organ

Uncommon side effects:

• Changes in blood clotting, reduction in the number of all types of blood cells (seen in blood tests)
• Dehydration, inability to urinate
• Abnormal blood test results: reduced protein or sugar, increased phosphate, increase of the enzyme lactate dehydrogenase
• Coma, bleeding in the brain, stroke, paralysis, brain disorder, speech and language abnormalities, memory problems
• Clouding of the eye lens, impaired hearing
• Irregular heartbeat, stop of heartbeat, reduced performance of your heart, disorder of the heart muscle, enlargement of the heart muscle, stronger heartbeat, abnormal ECG, heart rate and pulse abnormal
• Blood clot in a vein of a limb, shock
• Difficulties in breathing, respiratory tract disorders, asthma
• Obstruction of the gut, increased blood level of the enzyme amylase, reflux of stomach content in your throat, delayed emptying of the stomach
• Inflammation of the skin, burning sensation in the sunlight
• Joint disorders
• Painful menstruation and abnormal menstrual bleeding
• Failure of some organs, flu-like illness, increased sensitivity to heat and cold, feeling of pressure on your chest, jittery or abnormal feeling, weight loss

Rare side effects:

• Small bleedings in your skin due to blood clots
• Increased muscle stiffness
• Blindness, deafness
• Collection of fluid around the heart
• Acute breathlessness
• Cyst formation in your pancreas
• Problems with blood flow in the liver
• Serious illness with blistering of skin, mouth, eyes and genitals; increased hairiness
• Thirst, fall, feeling of tightness in your chest, decreased mobility, ulcer

Very rare side effects:

• Muscular weakness
• Abnormal heart scan
• Liver failure
• Painful urination with blood in the urine
• Increase of fat tissue

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 Advagraf after the expiry date which is stated on the carton after ?Exp?. The expiry date refers to the last day of that month. Use all the prolonged-release hard capsules within 1 year of opening the aluminium wrapping.

Store in the original package in order to protect from moisture.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

What Advagraf contains

• The active substance is tacrolimus.Each capsule of Advagraf 0.5 mg contains 0.5 mg of tacrolimus. Each capsule of Advagraf 1 mg contains 1 mg of tacrolimus. Each capsule of Advagraf 3 mg contains 3 mg of tacrolimus. Each capsule of Advagraf 5 mg contains 5 mg of tacrolimus.
• The other ingredients are: Capsule content: Hypromellose, ethylcellulose, lactose, magnesium stearate. Capsule shell: Titanium dioxide (E171), yellow iron oxide (E 172), red iron oxide (E 172), sodium laurilsulfate, gelatin. Printing ink: Shellac, lecithin (soya), simeticone, red iron oxide (E 172), hydroxypropylcellulose.

What Advagraf looks like and contents of the pack

Advagraf 0.5 mg prolonged-release hard capsules are hard gelatin capsules imprinted in red with ?0.5 mg? on the light yellow capsule cap and ? 647? on the orange capsule body, containing white powder.
Advagraf 0.5 mg is supplied in blisters or perforated unit-dose blisters containing 10 capsules within a protective foil wrapper, including a desiccant. Packs of 30, 50 and 100 prolonged-release capsules are available in blisters and packs of 30×1, 50×1 and 100×1 prolonged-release capsules are available in perforated unit-dose blisters.

Advagraf 1 mg prolonged-release hard capsules are hard gelatin capsules imprinted in red with ?1 mg? on the white capsule cap and ? 677? on the orange capsule body, containing white powder. Advagraf 1 mg is supplied in blisters or perforated unit-dose blisters containing 10 capsules within a protective foil wrapper, including a desiccant. Packs of 30, 50, 60 and 100 prolonged-release capsules are available in blisters and packs of 30×1, 50×1, 60×1 and 100×1 prolonged-release capsules are available in perforated unit-dose blisters.

Advagraf 3 mg prolonged-release hard capsules are hard gelatin capsules imprinted in red with ?3 mg? on the orange capsule cap and ? 637? on the orange capsule body, containing white powder. Advagraf 3 mg is supplied in blisters or perforated unit-dose blisters containing 10 capsules within a protective foil wrapper, including a desiccant. Packs of 30, 50 and 100 prolonged-release capsules are available in blisters and packs of 30×1, 50×1 and 100×1 prolonged-release capsules are available in perforated unit-dose blisters.

Advagraf 5 mg prolonged-release hard capsules are hard gelatin capsules imprinted in red with ?5 mg? on the greyish red capsule cap and ? 687? on the orange capsule body, containing white powder. Advagraf 5 mg is supplied in blisters or perforated unit-dose blisters containing 10 capsules within a protective foil wrapper, including a desiccant. Packs of 30, 50 and 100 prolonged-release hard capsules are available in blisters and packs of 30×1, 50×1 and 100×1 prolonged-release capsules are available in perforated unit-dose blisters.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:

Astellas Pharma Europe B.V.
Elisabethhof 19
2353 EW Leiderdorp
Netherlands

Manufacturer:
Astellas Ireland Co., Ltd.
Killorglin, County Kerry
Ireland

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

BelgiëBelgiqueBelgien Astellas Pharma B.V. Branch Erasmus ParkParc Erasme Square Marie Curie 50 B-1070 BrüsselBruxelles TélTel 32 02 5580710 LuxembourgLuxemburg Astellas Pharma B.V.Branch Erasmus ParkParc Erasme Square Marie Curie 50 B-1070 BrüsselBruxelles BelgiqueBelgien TélTel 32 02 5580710

. 6 1407 Te. 359 2 862 53 72 Magyarország Astellas Pharma Kft. Kelenhegyi út 43 H-1118 Budapest Tel. 36 061 3614673

eská republika Astellas Pharma s.r.o. Sokolovská 10094 CZ 18600 Praha 8 Tel 420 236 080300 Malta E.J. Busuttil Ltd Niche, 1, Triq ix-Xorrox BKara BKR 1633 Tel 356 2144 7184

Danmark Astellas Pharma as Naverland 4 DK-2600 Glostrup Tlf 45 43 430355 Nederland Astellas Pharma B.V. Elisabethhof 19 NL-2353 EW Leiderdorp Tel 31 071 5455745

Deutschland Astellas Pharma GmbH Georg-Brauchle-Ring 64 66 D-80992 München Tel 49 089 454401 Norge Astellas Pharma Solbråveien 47 N-1383 Asker Tlf 47 66 76 46 00

Österreich Astellas Pharma Ges.m.b.H. Linzer Straße 221E02 A-1140 Wien Tel 43 01 8772668 Eesti PharmaSwiss Eesti OÜ Tammsaare tee 47 11316 Tallinn Tel. 372 682 7403 Fax 372 682 7401

Astellas Pharmaceuticals AEBE 1 GR-14565 30 210 8189900 Polska Astellas Pharma Sp.z.o.o. ul. Poleczki 21 PL 02-822 Warszawa Tel. 48 0 225451 111

España Astellas Pharma S.A. Paseo del Club Deportivo n 1 Bloque 14-2aE-28223 Pozuelo de Alarcón, Madrid Tel 34 91 4952700 Portugal Astellas Farma, Lda. Edifício Cinema Rua José Fontana, n.1, 1Andar P-2770101 Paço de Arcos Tel 351 21 4401320

France Astellas Pharma S.A.S. 114 rue Victor Hugo F-92300 Levallois Perret Tél 33 01 55917500 România S.C.Astellas Pharma SRL Detalii de contact pentru România oseaua Bucureti-Ploieti 42-44, Cldire 1, Parter, 013696-Bucureti Tel 40 021 361 0495

Ireland Astellas Pharma Co. Ltd. 25, The Courtyard Kilcarbery Business Park, Clondalkin IRL Dublin 22 Tel 353 01 4671555 Slovenija Astellas Pharma Europe B.V. Elisabethhof 19 NL-2353 EW Leiderdorp Nizozemska Tel 31 071 5455745

Ísland Vistor hf Hörgatúni 2 IS-210 Garðabæ Sími 354 535 7000 Slovenská republika Astellas Pharma s.r.o., organizaná zloka Galvániho 15C SK-821 04 Bratislava 2 Tel 421 2 4444 2157

Italia Astellas Pharma S.p.A. Via delle Industrie 1 I-20061 Carugate Milano Tel 39 02 921381 SuomiFinland Astellas Pharma Algol Pharma Oy Ab PLBox 13 FIN-02611 EspooEsbo PuhTel 358 9 50991

Astellas Pharmaceuticals AEBE 1 GR-14565 30 210 8189900 Sverige Astellas Pharma AB Per Albin Hanssons väg 41 S-205 12 Malmö Tel 46 040-650 15 00

Latvija United Kingdom

SIA PharmaSwiss Latvia Astellas Pharma Ltd.
-ertr-des iela 54 ? 5 Lovett House
R-ga, LV 1011 Lovett Road, Staines
Tel: + 371 67502 185 Middlesex TW18 3AZ ? UK Fakss: + 371 67502 190 Tel: + 44 (0) 1784 419615

Lietuva

UAB ?PharmaSwiss?
?eimyni?ki- g. 21b
LT-09200, Vilnius
Tel.: +370 5 279 0762
Faks.: +370 5 279 0702

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