Patient Information Leaflet: Information for the Patient

Advagraf 0.5 mg prolonged-release hard capsules, 1 mg prolonged-release hard capsules, 3 mg prolonged-release hard capsules, 5 mg prolonged-release hard capsules

Tacrolimus
Please read this leaflet carefully before taking this medicine because it contains
important information for you.

Keep this leaflet. You may need to read it again.
If you have any questions, ask your doctor or pharmacist.
This medicine has been prescribed for you only. Do not give it to other people, even if they have the same symptoms as yours, because it could be harmful.
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. See section 4.
Contents of this leaflet:
1. What Advagraf is and what it is used for
2. What you need to know before taking Advagraf
3. How to take Advagraf
4. Possible side effects
5. How to store Advagraf
6. Contents of the pack and other information

1. What Advagraf is and what it is used for

Advagraf contains the active substance tacrolimus. It is an immunosuppressant. After an organ transplant (liver, kidney), the body's immune system will attempt to reject the new organ. Advagraf is used to control the immune response, enabling the body to accept the transplanted organ.

You may also receive Advagraf for ongoing rejection of a transplanted liver, kidney, heart or other organ when one of the treatments you were taking has proven unable to control the immune response after transplantation.

Advagraf is used in adult patients.

2. What you should know before taking Advagraf

Do not take Advagraf

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

Warnings and precautions

Prograf and Advagraf both contain the active substance tacrolimus. However, Advagraf is taken once daily, whereas Prograf is taken twice daily. This is because Advagraf capsules provide prolonged release (slower release over a longer period of time) of tacrolimus. Advagraf and Prograf are not interchangeable.

Talk to your doctor or pharmacist before taking Advagraf:

if you are taking any of the medicines listed below in section “Other medicines and Advagraf”
if you have or have had liver problems
if you have diarrhoea lasting more than one day
if you have severe abdominal pain, with or without other symptoms such as chills, fever, nausea or vomiting
if you have a disturbance in the electrical activity of the heart known as “QT prolongation”
if you have or have had damage to the smallest blood vessels, known as thrombotic microangiopathy/thrombotic thrombocytopenic purpura/hemolytic uremic syndrome. Inform your doctor if you develop fever, bruising under the skin (which may appear as small red spots), unexplained fatigue, confusion, yellowing of the skin or eyes, reduced urine output, loss of vision, or seizures (see section 4). The risk of developing these symptoms may increase when tacrolimus is taken together with sirolimus or everolimus.

Please avoid taking any herbal remedy, such as St. John’s wort (Hypericum perforatum) or any other herbal product, as it may alter the effectiveness and required dose of Advagraf. If you have any doubts, please consult your doctor before taking any herbal product or remedy.
Your doctor may need to adjust your dose of Advagraf.
You should maintain regular contact with your doctor. Periodically, your doctor may consider it necessary for you to undergo blood and urine tests, heart or eye examinations to determine the correct dose of Advagraf.
You should limit exposure to sunlight and UV (ultraviolet) rays while taking Advagraf. This is because immunosuppressive therapies may increase the risk of skin tumours. Wear protective clothing and use sunscreen with a high protection factor.

Precautions for handling
During preparation, avoid direct contact with any part of the body such as skin or eyes, or inhalation of injectable solutions, powder, or granules contained in tacrolimus-based products. In case of contact, wash skin and eyes thoroughly.

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

Other medicines and Advagraf
Inform your doctor or pharmacist if you are taking or have recently taken any other medicines, including those without a prescription and herbal products.
The use of Advagraf together with ciclosporin (another medicine used to prevent organ transplant rejection) is not recommended.
If you visit a doctor other than your transplant specialist, inform them that you are taking tacrolimus. Your doctor may need to consult with your transplant specialist if you are prescribed another medicine that could increase or decrease tacrolimus blood levels.
Blood levels of Advagraf may be affected by other medicines you are taking, and conversely, blood levels of other medicines you are taking may be altered by taking Advagraf, which may require interruption, increase, or decrease in the dose of Advagraf.
Some patients have experienced increased blood levels of tacrolimus while taking other medicines. This may cause serious side effects such as kidney problems, nervous system disorders, and heart rhythm disturbances (see section 4).
An effect on Advagraf blood levels may occur soon after starting another medicine; therefore, frequent and ongoing monitoring of Advagraf blood levels may be necessary in the first days after starting the other medicine and throughout its treatment. Some other medicines may cause a decrease in tacrolimus blood levels, which could increase the risk of organ transplant rejection. In particular, inform your doctor if you are taking or have recently taken medicines such as:

antifungal and antibiotic medicines, particularly so-called macrolide antibiotics used to treat infections, e.g. ketoconazole, fluconazole, itraconazole, posaconazole, voriconazole, clotrimazole, isavuconazole, miconazole, caspofungin, telithromycin, erythromycin, clarithromycin, josamycin, azithromycin, rifampicin, rifabutin, isoniazid, and flucloxacillin
letermovir, used to prevent a disease caused by CMV (human cytomegalovirus)
HIV protease inhibitors (e.g. ritonavir, nelfinavir, saquinavir), the booster medicine cobicistat, and tablet combinations or non-nucleoside reverse transcriptase inhibitors of HIV (efavirenz, etravirine, nevirapine) used to treat HIV infections
HCV protease inhibitors (e.g. telaprevir, boceprevir, the combination ombitasvir/paritaprevir/ritonavir with or without dasabuvir, elbasvir/grazoprevir, and glecaprevir/pibrentasvir) used to treat hepatitis C
nilotinib and imatinib, idelalisib, ceritinib, crizotinib, apalutamide, enzalutamide, or mitotane (used to treat certain types of cancer)
mycophenolic acid, used to suppress the immune system and prevent transplant rejection
medicines for stomach ulcer or acid reflux (e.g. omeprazole, lansoprazole, or cimetidine)
antiemetics used to treat nausea and vomiting (e.g. metoclopramide)
cisapride or the antacid magnesium-aluminium hydroxide, used to treat heartburn
oral contraceptive pills or other hormonal treatments containing ethinylestradiol, or hormonal treatments with danazol
medicines used to treat high blood pressure or heart problems (e.g. nifedipine, nicardipine, diltiazem, and verapamil)
antiarrhythmic medicines (amiodarone) used to control arrhythmia (irregular heartbeat)
medicines known as “statins” used to treat high cholesterol and triglycerides
carbamazepine, phenytoin, or phenobarbital, used to treat epilepsy
metamizole, used to treat pain and fever
corticosteroids prednisolone or methylprednisolone, belonging to the class of corticosteroids used to treat inflammation or suppress the immune system (e.g. in organ rejection)
nefazodone, used to treat depression
herbal preparations containing St. John’s wort (Hypericum perforatum) or extracts of Schisandra sphenanthera
cannabidiol (uses include, among others, treatment of seizures).

Inform your doctor if you are receiving treatment for hepatitis C. Pharmacological treatment for hepatitis C may alter liver function and affect tacrolimus blood levels. Tacrolimus blood levels may decrease or increase depending on the medicines prescribed for hepatitis C. Your doctor may need to closely monitor tacrolimus blood levels and make necessary dose adjustments of Advagraf after starting hepatitis C treatment.
Inform your doctor if you are taking or need to take ibuprofen (used to treat fever, inflammation, and pain), antibiotics (cotrimoxazole, vancomycin, or aminoglycoside antibiotics such as gentamicin), amphotericin B (used to treat fungal infections), or antiviral medicines (used to treat viral infections, e.g. aciclovir, ganciclovir, cidofovir, foscarnet). These may worsen kidney or nervous system problems when taken together with Advagraf.
Inform your doctor if you are taking sirolimus or everolimus. When tacrolimus is taken together with sirolimus or everolimus, the risk of developing thrombotic microangiopathy, thrombotic thrombocytopenic purpura, and hemolytic uremic syndrome may increase (see section 4).
Your doctor also needs to know if you are taking potassium supplements or certain diuretics used for heart failure, hypertension, and kidney diseases (e.g. amiloride, triamterene, or spironolactone), or the antibiotics trimethoprim or cotrimoxazole, which may increase potassium levels in the blood, non-steroidal anti-inflammatory drugs (NSAIDs, e.g. ibuprofen) used for fever, inflammation, and pain, anticoagulants (blood thinners), or oral medicines for diabetes while taking Advagraf.
If you need to be vaccinated, discuss this with your doctor first.

Advagraf with food and drinks
Avoid grapefruit (including grapefruit juice) while taking Advagraf, as it may alter its blood concentration.

Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, or are planning to become pregnant, consult your doctor before using Advagraf. In a study evaluating pregnancy outcomes in women treated with tacrolimus and those treated with other immunosuppressants, although the evidence gathered in this study is insufficient to draw definitive conclusions, higher rates of spontaneous abortion were reported among liver and kidney transplant recipients treated with tacrolimus, as well as higher rates of persistent hypertension associated with protein loss in urine developing during pregnancy or the postpartum period (a condition called pre-eclampsia) among kidney transplant recipients. No increased risk of major birth defects has been observed with the use of Advagraf.
Advagraf passes into breast milk. Breastfeeding is therefore not recommended during treatment with Advagraf.

Driving and using machines
Do not drive or operate tools or machinery if you feel dizzy or drowsy, or have problems with clear vision after taking Advagraf. These effects may be more pronounced if you also consume alcohol.

Advagraf contains lactose, sodium, and lecithin (soy)
Advagraf contains lactose (milk sugar). If your doctor has diagnosed you with an intolerance to certain sugars, contact them before taking this medicine.
This medicine contains less than 1 mmol of sodium (23 mg) per capsule, i.e. it is essentially “sodium-free”.
The printing ink used on Advagraf capsules contains soy lecithin. If you are allergic to peanuts or soy, discuss with your doctor whether you should take this medicine.

3. How to take Advagraf

Take Advagraf exactly as directed by your doctor. If you have any doubts, consult your doctor or pharmacist.
This medicine should only be prescribed by a doctor experienced in the management of transplant patients.
Always ensure that you receive the same formulation of tacrolimus when collecting your prescription, unless your transplant specialist has specifically agreed to a change in the tacrolimus formulation.
This medicine must be taken once daily. If this medicine looks different than usual, or if the dosing instructions have changed, contact your doctor or pharmacist as soon as possible to confirm that you have received the correct medicine.

The initial dose to prevent rejection of your transplanted organ will be determined by your doctor and calculated based on your body weight. The initial daily dose immediately after transplantation will generally be within the following range:
0.10–0.30 mg per kg of body weight per day,
depending on the transplanted organ. The same doses may be used for treatment of rejection.

Your dose depends on your general condition and on any other immunosuppressive medicines you are taking.
Shortly after starting treatment with Advagraf, your doctor will ask you to have frequent blood tests to determine the correct dose. Later, you will continue to have regular blood tests so that the correct dose can be established and adjusted as needed.
Your doctor will usually reduce your dose of Advagraf once your condition has stabilized. Your doctor will tell you exactly how many capsules to take.

It is essential that you take Advagraf every day for as long as you require immunosuppression to prevent rejection of your transplanted organ. You must remain in close contact with your doctor.
Advagraf must be taken once daily by mouth in the morning. Take Advagraf on an empty stomach, or 2 or 3 hours after a meal. Wait at least one hour before eating your next meal. Take the capsules immediately after removing them from the blister pack. The capsules must be swallowed whole with a glass of water. Do not swallow the desiccant contained in the aluminum packaging.

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

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

If you have any questions about how to use this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, Advagraf can cause side effects, although not everyone gets them.
Advagraf reduces the body's defence mechanisms (immune system), making it less effective in fighting infections. Therefore, you may be more susceptible to infections while taking Advagraf.
Some of these infections may be serious or fatal and may include those caused by bacteria, viruses, fungi, parasites, or other infections.
Inform your doctor immediately if you experience signs of an infection, including:

Fever, cough, sore throat, feeling weak or generally unwell
Memory loss, difficulty thinking, difficulty walking, or loss of vision – these may be due to a very rare but serious brain infection that can be fatal (Progressive Multifocal Leukoencephalopathy or PML)

Serious side effects, including allergic and anaphylactic reactions, may occur. Benign and malignant tumours have been reported following treatment with Advagraf.
Inform your doctor immediately if you have or suspect you may have any of the following serious side effects:
Serious common side effects (may affect up to 1 in 10 people):

Gastrointestinal perforation: severe abdominal pain with or without other symptoms such as chills, fever, nausea or vomiting.
Poor function of the transplanted organ.
Blurred vision.

Serious uncommon side effects (may affect up to 1 in 100 people):

Thrombotic microangiopathy (damage to the smallest blood vessels), including haemolytic uraemic syndrome, a condition with the following symptoms: reduced or no urine output (acute kidney failure), extreme fatigue, yellowing of the skin or eyes (jaundice), and appearance of bruises (ecchymoses) or abnormal bleeding, and signs of infection.

Serious rare side effects (may affect up to 1 in 1,000 people):

Thrombotic thrombocytopenic purpura: a condition involving damage to the smallest blood vessels, characterised by fever and subcutaneous bruising appearing as red spots, with or without unexplained extreme fatigue, confusion, yellowing of the skin or eyes (jaundice), symptoms of acute kidney failure (reduced or absent urine output), loss of vision, and seizures.
Toxic epidermal necrolysis: erosion and blistering of the skin or mucous membranes, red and swollen skin that may peel off large areas of the body.
Blindness.

Very rare serious side effects (may affect up to 1 in 10,000 people):

Stevens-Johnson syndrome: unexplained widespread skin pain, facial swelling, severe illness with blistering of the skin, mouth, eyes, and genitals, hives, swelling of the tongue, red or purplish skin rash that spreads, skin peeling.
Torsade de pointes: change in heart rate, which may or may not be accompanied by symptoms such as chest pain (angina), fainting, dizziness or nausea, palpitations (strong awareness of heartbeat), and difficulty breathing.

Serious side effects – frequency not known (frequency cannot be estimated from available data):

Opportunistic infections (bacterial, fungal, viral, and protozoal): prolonged diarrhoea, fever, sore throat.
Benign and malignant tumours have been reported after treatment, as a consequence of immunosuppression, including malignant skin cancers and a rare type of cancer that may include skin lesions, called Kaposi’s sarcoma. Symptoms include skin changes such as new or changing discoloration, lesions, or nodules.
Cases of pure red cell aplasia (a very severe reduction in red blood cell count), haemolytic anaemia (reduced number of red blood cells due to their abnormal destruction, accompanied by fatigue), and febrile neutropenia (a decrease in the type of white blood cells that fight infections, accompanied by fever) have been reported. It is not exactly known how often these side effects occur. You may have no symptoms, or depending on the severity of the condition, you may experience: fatigue, apathy, unusual paleness of the skin, shortness of breath, dizziness, headache, chest pain, and cold hands and feet.
Cases of agranulocytosis (a severely reduced number of white blood cells accompanied by mouth ulcers, fever, and infection(s)) have been reported. You may have no symptoms or may experience sudden fever, fever-related chills, and sore throat.
Allergic and anaphylactic reactions with the following symptoms: sudden skin rash with itching (urticaria), swelling of the hands, feet, ankles, face, lips, mouth, or throat (which may cause difficulty swallowing or breathing), and you may feel weak.
Reversible posterior encephalopathy syndrome (PRES): headache, confusion, mood swings, seizures, and visual disturbances. These may be signs of a disorder called reversible posterior encephalopathy syndrome, which has been reported in some patients treated with tacrolimus.
Optic neuropathy (abnormality of the optic nerve): vision problems, such as blurred vision, changes in colour vision, difficulty seeing details, or visual field restriction.

The following side effects may also occur after taking Advagraf and could be serious:
Very common side effects (may affect more than 1 in 10 people):
Increased blood glucose, diabetes mellitus, increased potassium in the blood.
Difficulty sleeping.
Tremor, headache.
Increased blood pressure.
Abnormal liver function test results.
Diarrhoea, nausea.
Kidney problems.
Common side effects (may affect up to 1 in 10 people):
Reduced number of blood cells (platelets, red blood cells, or white blood cells), increased number of white blood cells, abnormalities in red blood cell count (detected in blood tests).
Decreased magnesium, phosphate, potassium, calcium, or sodium in the blood, fluid retention, increased uric acid or lipids in the blood, decreased appetite, increased blood acidity, other changes in blood electrolyte balance (detected in blood tests).
Anxiety symptoms, confusion and disorientation, depression, mood swings, nightmares, hallucinations, psychiatric disorders.
Seizures, altered consciousness, tingling and numbness of hands and feet (sometimes painful), sensation of loss of balance, impaired writing ability, nervous system disorders.
Increased light sensitivity, eye disorders.
Ringing in the ears.
Reduced blood flow in heart vessels, increased heart rate.
Bleeding, complete or partial blockage of blood vessels, low blood pressure.
Shortness of breath, changes in lung tissue, fluid accumulation around the lung, inflammation of the pharynx, cough, flu-like symptoms.
Inflammations or ulcers causing abdominal pain or diarrhoea, stomach bleeding, mouth inflammation or ulcers, fluid accumulation in the stomach, vomiting, abdominal pain, indigestion, constipation, flatulence, bloating, loose stools, gastrointestinal problems.
Biliary tract disorders, yellowing of the skin due to liver problems, liver damage and inflammation.
Itching, skin rash, hair loss, acne, increased sweating.
Joint, limb, back, and foot pain, muscle cramps.
Poor kidney function, reduced urine production, reduced or painful urination.
General weakness, fever, swelling (oedema), pain and discomfort, increased alkaline phosphatase enzyme in the blood, weight gain, altered perception of temperature.
Uncommon side effects (may affect up to 1 in 100 people):
Alterations in blood clotting processes, reduced number of all types of blood cells (detected in blood tests).
Dehydration.
Reduced protein or sugar in the blood, increased phosphate in the blood.
Coma, brain haemorrhages, stroke, paralysis, brain disorders, language and expression disorders, memory problems.
Lens opacity.
Hearing impairment.
Irregular heartbeat, heartbeat cessation, reduced cardiac output, disorders of the heart muscle, thickening of the heart muscle, increased heartbeat, abnormal electrocardiogram (ECG), altered heart rhythm and rate.
Blood clot in a limb vein, shock.
Breathing difficulties, respiratory disorders, asthma.
Intestinal obstruction, increased blood levels of amylase enzyme, reflux of stomach contents into the throat, delayed gastric emptying.
Skin inflammation, burning sensation upon sun exposure.
Joint pain.
Inability to urinate, painful menstruation, abnormal menstrual bleeding.
Failure of multiple organs, flu-like illness, increased sensitivity to heat and cold, chest tightness, restlessness and discomfort, increased blood lactate dehydrogenase enzyme, weight loss.
Rare side effects (may affect up to 1 in 1,000 people):
Small skin haemorrhages caused by blood clots.
Increased muscle stiffness.
Deafness.
Fluid accumulation around the heart.
Acute respiratory distress syndrome.
Cyst formation in the pancreas.
Circulatory problems in the liver.
Increased hair growth.
Thirst, fainting, chest tightness, decreased mobility, ulcer.
Very rare side effects (may affect up to 1 in 10,000 people):
Muscle weakness.
Abnormal echocardiogram.
Liver failure.
Painful urination with blood in the urine.
Increased fatty tissue.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Advagraf

Keep this medicine out of the sight and reach of children.
Do not use Advagraf after the expiry date stated on the pack after “Exp.”. The expiry date refers to the last day of that month.
Use all extended-release capsules within 1 year after opening the aluminium foil pouch.
Store in the original packaging to protect the medicine from moisture.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer in use. This will help protect the environment.

6. Package contents and other information

What Advagraf contains

The active substance is tacrolimus. Each 0.5 mg Advagraf capsule contains 0.5 mg of tacrolimus (as monohydrate). Each 1 mg Advagraf capsule contains 1 mg of tacrolimus (as monohydrate). Each 3 mg Advagraf capsule contains 3 mg of tacrolimus (as monohydrate). Each 5 mg Advagraf capsule contains 5 mg of tacrolimus (as monohydrate).
The other components are: Capsule contents: hypromellose, ethylcellulose, lactose, magnesium stearate. Capsule shell: titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172), sodium lauryl sulfate, gelatin. Printing ink: shellac, lecithin (soy), simethicone, red iron oxide (E 172), hydroxypropylcellulose.

Description of the appearance of Advagraf and contents of the pack

Advagraf 0.5 mg prolonged-release hard capsules are hard gelatin capsules with ''0.5 mg'' printed in red on the upper light yellow part of the capsule and “ 647” on the orange body, containing white powder.
Advagraf 0.5 mg is supplied in blisters or in unit-dose divisible blisters of 10 capsules, contained within a protective wrapper with a desiccant. Packs of 30, 50 and 100 prolonged-release hard capsules in blisters and packs of 30×1, 50×1 and 100×1 prolonged-release hard capsules in unit-dose divisible blisters are available.

Advagraf 1 mg prolonged-release hard capsules are hard gelatin capsules with ''1 mg'' printed in red on the upper white part of the capsule and “ 677” on the orange body, containing white powder.
Advagraf 1 mg is supplied in blisters or in unit-dose divisible blisters of 10 capsules, contained within a protective wrapper with a desiccant. Packs of 30, 50, 60 and 100 prolonged-release hard capsules in blisters and packs of 30×1, 50×1, 60×1 and 100×1 prolonged-release hard capsules in unit-dose divisible blisters are available.

Advagraf 3 mg prolonged-release hard capsules are hard gelatin capsules with ''3 mg'' printed in red on the upper orange part of the capsule and “ 637” on the orange body, containing white powder.
Advagraf 3 mg is supplied in blisters or in unit-dose divisible blisters of 10 capsules, contained within a protective wrapper with a desiccant. Packs of 30, 50 and 100 prolonged-release hard capsules in blisters and packs of 30×1, 50×1 and 100×1 prolonged-release hard capsules in unit-dose divisible blisters are available.

Advagraf 5 mg prolonged-release hard capsules are hard gelatin capsules with ''5 mg'' printed in red on the upper greyish-red part of the capsule and “ 687” on the orange body, containing white powder.
Advagraf 5 mg is supplied in blisters or in unit-dose divisible blisters of 10 capsules, contained within a protective wrapper with a desiccant. Packs of 30, 50 and 100 prolonged-release hard capsules in blisters and packs of 30×1, 50×1 and 100×1 prolonged-release hard capsules in unit-dose divisible blisters are available.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:
Astellas Pharma Europe B.V.
Sylviusweg 62
2333 BE Leiden
The Netherlands

Manufacturer:
Astellas Ireland Co., Ltd.
Killorglin, County Kerry, V93FC86
Ireland

For further information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder:

België/Belgique/Belgien Lietuva
Astellas Pharma B.V. Branch Astellas Pharma d.o.o.
Tél/Tel: + 32 (0)2 5580710 Tel. +370 37 408 681

България Luxembourg/Luxemburg
Астелас Фарма ЕООД Astellas Pharma B.V. Branch
Tel.: + 359 2 862 53 72 Belgique/Belgien
Tél/Tel: + 32 (0)2 5580710

Česká republika Magyarország
Astellas Pharma s.r.o. Astellas Pharma Kft.
Tel: +420 221 401 500 Tel.: + 36 1 577 8200

Danmark Malta
Astellas Pharma a/s Astellas Pharmaceuticals AEBE
Tlf: + 45 43 430355 Tel.: +30 210 8189900

Deutschland Nederland
Astellas Pharma GmbH Astellas Pharma B.V.
Tel: + 49 (0)89 454401 Tel: + 31 (0)71 5455745

Eesti Norge
Astellas Pharma d.o.o. Astellas Pharma
Tel: +372 6 056 014 Tlf: + 47 66 76 46 00

Ελλάδα Österreich
Astellas Pharmaceuticals AEBE Astellas Pharma Ges.m.b.H.
Τηλ: +30 210 8189900 Tel: + 43 (0)1 8772668

España Polska
Astellas Pharma S.A. Astellas Pharma Sp.z.o.o.
Tel: + 34 91 4952700 Tel.: + 48 (0) 225451 111

France Portugal
Astellas Pharma S.A.S. Astellas Farma, Lda.
Tél: + 33 (0)1 55917500 Tel: + 351 21 4401320

Hrvatska România
Astellas d.o.o. S.C. Astellas Pharma SRL
Tel: +38516700102 Tel: +40 (0)21 361 0495

Ireland Slovenija
Astellas Pharma Co. Ltd. Astellas Pharma d.o.o.
Tel: + 353 (0)1 4671555 Tel: + 3864011400

Ísland Slovenská republika
Vistor hf Astellas Pharma s.r.o.
Sími: + 354 535 7000 Tel: +421 2 4444 2157

Italia Suomi/Finland
Astellas Pharma S.p.A. Astellas Pharma
Tel: + 39 02 921381 Puh/Tel: + 358 (0)9 85606000

Κύπρος Sverige
Astellas Pharmaceuticals AEBE Astellas Pharma AB
Ελλάδα Tel: + 46 (0)40-650 15 00
Τηλ: +30 210 8189900

Latvija
Astellas Pharma d.o.o.
Tel: + 371 67 619365

More detailed information on this medicinal product is available on the website of the European Medicines Agency: https://www.ema.europa.eu.

Annex IV

Scientific conclusions and grounds for the variation to the terms of the marketing authorisation

Scientific conclusions

Taking into account the assessment by the Pharmacovigilance Risk Assessment Committee (PRAC) of the Periodic Safety Update Reports (PSURs) for tacrolimus (systemic formulations), the PRAC's scientific conclusions are as follows:

In view of the available data on cases of Kaposi's sarcoma from clinical studies, literature and spontaneous reports, including cases with a close temporal relationship and a number of fatal outcomes, and in view of a plausible mechanism of action, the PRAC considers that a causal relationship between systemic tacrolimus and Kaposi's sarcoma is at least a reasonable possibility. The PRAC concluded that the product information for medicinal products containing systemic tacrolimus should therefore be amended accordingly.

Having reviewed the PRAC's recommendation, the Committee for Human Medicinal Products (CHMP) agrees with its general conclusions and the reasoning behind the recommendation.

Grounds for the variation to the terms of the marketing authorisation

Based on the scientific conclusions for tacrolimus (systemic formulations), the CHMP considers that the benefit-risk balance of medicinal products containing tacrolimus (systemic formulations) remains favourable, subject to the proposed amendments to the product information.

The CHMP recommends a variation to the terms of the marketing authorisation.