MODIGRAF 0.2 MG Гранулы для пероральной суспензии

Содержание инструкции

1. Modigraf 0.2 mg, granules for oral suspension, 1 mg, granules for oral suspension
   1. What is Modigraf and what it is used for
   2. What you need to know before you take Modigraf
   3. How to take Modigraf
   4. Possible side effects
   5. How to store Modigraf
   6. Package contents and other information

Modigraf 0.2 mg, granules for oral suspension, 1 mg, granules for oral suspension

Tacrolimus

Read this leaflet carefully before you start taking this medicine as 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 pass it on to others, even if their symptoms are the same as yours, as it could be harmful.
• If you get any side effects, even those not listed in this leaflet, tell your doctor or pharmacist. See section 4. Contents of this leaflet:
• 1. What Modigraf is and what it is used for
• 2. What you need to know before you take Modigraf
• 3. How to take Modigraf
• 4. Possible side effects
• 5. How to store Modigraf
• 6. Contents of the pack and other information

1. What is Modigraf and what it is used for

Modigraf contains the active substance tacrolimus. It is an immunosuppressant. Following organ transplantation (e.g. liver, kidney, heart), the body's immune system will attempt to reject the new organ. Modigraf is used to control the immune response by enabling the body to accept the transplanted organ.
You may also receive Modigraf for an ongoing rejection of the liver, kidney, heart or other transplanted organ, or if one of the treatments you were taking has not proven able to control this immune response after transplantation.
Modigraf is used in adults and children.

2. What you need to know before you take Modigraf

Do not take Modigraf

• if you are allergic to tacrolimus or to any of the other ingredients of this medicine (listed in section 6).
• if you are allergic to sirolimus (another substance used to prevent organ rejection after transplantation) or to any macrolide antibiotic (e.g. erythromycin, clarithromycin, josamycin). Warnings and precautionsTalk to your doctor or pharmacist before taking Modigraf.
• if you have or have had liver problems
• if you have had diarrhoea for 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 an alteration of the electrical activity of the heart defined as “prolongation QT”
• if you have or have had damage to the small blood vessels, known as thrombotic microangiopathy/thrombotic thrombocytopenic purpura/hemolytic uremic syndrome. Tell your doctor if you develop fever, bruises under the skin (which may appear as red dots), unexplained fatigue, confusion, yellowing of the skin or eyes, decreased urine production,

loss of vision and seizures (see section 4). When tacrolimus is taken
together with sirolimus or everolimus, the risk of developing these symptoms may increase.
Please avoid taking any herbal remedies, such as St John's Wort (Hypericum perforatum) or any other herbal product, as it
may change the effectiveness and dose of Modigraf you need to receive. If you have any doubts, please consult
your doctor before taking any herbal product or remedy. The doctor may need to adjust the dose of Modigraf.
You should maintain regular contact with your doctor. From time to time, your doctor may feel it necessary
for you to have blood tests, urine tests, heart or eye checks to establish the correct dose of
Modigraf.
You should limit your exposure to the sun and UV (ultraviolet) rays while taking Modigraf. This is
because immunosuppressive therapies like Modigraf can increase the risk of skin cancer. If exposed to sunlight, wear protective clothing and use a sunscreen with a high protection factor.
Precautions for handling:
During preparation, you should avoid direct contact with any part of the body such as the skin or
eyes or inhalation of the injectable solutions, powder or granules contained in
tacrolimus-based products. If contact occurs, wash the skin and eyes.

Other medicines and Modigraf
Tell your doctor or pharmacist if you are taking, have recently taken or might take
any other medicine.
The use of Modigraf together with cyclosporine (another drug used to prevent organ rejection) is not recommended.

If you visit a doctor other than the transplant specialist, tell them that you are taking
tacrolimus. The doctor may need to consult the transplant specialist if you
need to use another medicine that can increase or decrease tacrolimus concentrations
in the blood.
The concentrations of Modigraf in the blood can be affected by other medicines you are
taking and vice versa, the concentrations in the blood of other medicines can be altered
by taking Modigraf, which may require interruption, an increase or a decrease
in the dose of Modigraf.
Some patients have shown increases in tacrolimus concentrations in the blood while
taking other medicines. This can cause serious side effects, such as kidney problems, nervous system problems and heart rhythm disturbances (see section 4).
An effect on Modigraf concentrations in the blood can occur very soon after the start
of using another medicine, so frequent and continuous monitoring of Modigraf concentration in the blood may be necessary in the first days after starting the other medicine and
frequently during treatment with the other medicine. Some other medicines can cause
a decrease in tacrolimus concentrations in the blood, which can increase the risk of organ rejection. In particular, you should tell your doctor if you are taking or have recently taken
medicines such as:

• antifungal and antibiotic medicines, especially the so-called macrolide antibiotics, used to treat infections, for example ketoconazole, fluconazole, itraconazole, posaconazole, voriconazole, clotrimazole, isavuconazole, miconazole, caspofungin, telitromycin, 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 potentiator cobicistat, and 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 inhibit the immune system and prevent transplant rejection
• medicines for stomach ulcers or acid reflux (e.g. omeprazole, lansoprazole or cimetidine)
• anti-emetics used to treat nausea and vomiting (e.g. metoclopramide)
• cisapride or magnesium-aluminium hydroxide antacid, used to treat heartburn
• the contraceptive pill or other hormonal treatments with ethinylestradiol, hormonal treatments with danazol
• medicines used to treat high blood pressure or heart problems (e.g. nifedipine, nicardipine, diltiazem and verapamil)
• antiarrhythmic drugs (amiodarone) used to control arrhythmias (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 to suppress the immune system (for example 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, also, the treatment of seizures).

Tell your doctor if you are receiving treatment for hepatitis C. Pharmacological treatment for
hepatitis C can change liver function and affect tacrolimus concentrations in the
blood. Tacrolimus concentrations in the blood may decrease or increase depending on
the medicines prescribed for hepatitis C. Your doctor may need to carefully monitor
tacrolimus concentrations in the blood and make the necessary dose adjustments of Modigraf
after starting treatment for hepatitis C.
Tell 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), antiviral drugs (used to treat viral infections, for example acyclovir, ganciclovir, cidofovir, foscarnet).
These can worsen kidney or nervous system problems when taken together with Modigraf.
Tell 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).
The doctor also needs to know if, while taking Modigraf, you are taking potassium supplements or those diuretics used for heart failure, high blood pressure and for
kidney diseases (for example amiloride, triamterene or spironolactone), or the antibiotics trimethoprim or
cotrimoxazole which can increase potassium levels in the blood, non-steroidal anti-inflammatory drugs (NSAIDs, for example ibuprofen), used against fever, to treat inflammatory states
and pain, anticoagulants (blood thinners), or medicines for diabetes taken orally.
If you need to be vaccinated, talk to your doctor first.

Modigraf with food and drink
Take Modigraf generally on an empty stomach or at least 1 hour before or 2 to 3 hours after meals.
Avoid grapefruit and grapefruit juice while using Modigraf, as it can
vary its concentration in the blood.

Pregnancy and breastfeeding
If you take Modigraf during pregnancy, it can reach the baby through the placenta. It
can potentially affect the health of the baby or conversely, affect the course of
pregnancy.
If you are pregnant, suspect you are pregnant, are planning a pregnancy, or are breastfeeding, ask your doctor for advice before taking this medicine.
In a study, the outcomes of pregnancy were assessed in women treated with tacrolimus and
in women treated with other immunosuppressants. Although the evidence collected in this study is not
sufficient to draw conclusions, higher rates of miscarriage have been reported among patients
receiving liver and kidney transplant treated with tacrolimus; as higher rates, among patients
receiving kidney transplant, of persistent hypertension associated with protein loss in the urine, which
develops during pregnancy or in the postpartum period (a condition called pre-eclampsia). No
increased risk of major birth defects associated with the use of Modigraf has been detected.
Modigraf passes into breast milk. Therefore, you should not breastfeed while taking Modigraf.

Driving and using machines
Do not drive and do not use tools or machinery if you feel a loss of balance or drowsiness,
or have problems seeing clearly after taking Modigraf. These effects have been
more pronounced if you also drink alcohol.

Modigraf contains lactose and sodium
Modigraf 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 (23 mg) of sodium per sachet, i.e. it is essentially
‘sodium-free’.

3. How to take Modigraf

Take this medicine following exactly the instructions of your doctor. If you have any doubts, ask your
doctor or pharmacist. Modigraf must be prescribed by a doctor specializing in the care of
transplant patients and experienced in the use of drugs that control the immune system
(immunosuppressants).
Make sure you always receive the same formulation of tacrolimus when you pick up the prescription, unless
the transplant specialist has agreed to change the formulation of tacrolimus.
This medicine must be taken twice a day. If the appearance of this medicine is not
that of normal white granules, or if the dosage instructions have changed, contact your doctor or
pharmacist as soon as possible to make sure you have received the correct medicine.
The initial dose to prevent organ rejection will be established by the doctor
and calculated based on weight. The daily dose shortly after transplantation will generally be within
the range of 0.075 – 0.30 mg per kg of body weight per day depending on the transplanted organ. The same
dosages should be used when treating a rejection.
The dose depends on your general condition and what other immunosuppressive medicine you are
taking.

Children and adolescents
Children and adolescents will receive doses of Modigraf calculated using the same procedure as that
of adults. In general, children need higher doses per kg of body weight to be able to
achieve the same effective plasma levels as adults.
Shortly after starting treatment with Modigraf, your doctor will ask you to undergo frequent
blood tests to determine the correct dose and to adjust that dose from time to time. The doctor
will generally reduce the dose of Modigraf once the condition has stabilized. The doctor will
tell you exactly how many sachets to take.
It is essential that you take Modigraf every day as long as you need immunosuppression to
prevent rejection of the transplanted organ. You must remain in close contact with your doctor.
Modigraf must be taken twice a day orally, usually in the morning and evening.
Take Modigraf on an empty stomach or 2 or 3 hours after a meal. Wait at least 1 hour before
taking the next meal.
How to prepare Modigraf sachets for use?
The doctor will inform you about the number of sachets that will need to be opened and the amount of water
required for preparing the suspension. For an accurate measurement of the water volume
you can use a syringe or a graduated cylinder.
Pour the expected volume of water (at room temperature), up to a maximum of 50 ml, into a
glass or cup. Place the cup with water on a stable surface. Do not use cups or
spoons made of PVC (polyvinyl chloride) to take Modigraf because the active substance contained in
Modigraf may adhere to PVC. Carefully open the prescribed number of sachets, for example with a
pair of scissors at the point indicated by an arrow. Hold the open sachet between your thumb and index finger above
the cup with the open part of the sachet facing downwards. Gently tap the bottom of the
sachet and pour the contents of each sachet into the glass or cup containing the water. Do not
use any utensils or any liquid to empty the sachet. If you follow these instructions you will obtain
the correct amount of granules from the sachet. It is normal for some granules to remain in the sachet;
the sachet has been specially designed.
Mix or rotate gently until the granules are completely in suspension. The suspension can
be drawn up with a syringe or ingested directly by the patient. The liquid has a sweet taste.
Rinse the glass or cup with the same amount of water and drink it. The liquid must be
taken immediately after preparation.

If you take more Modigraf than you should
If you have accidentally taken too much Modigraf, contact your doctor or the Emergency
Room of your nearest hospital immediately.

If you forget to take Modigraf
Do not take a double dose to make up for missed doses.
If you have forgotten to take Modigraf, wait until the time of the next dose and then continue
as before.

If you stop taking Modigraf
Stopping treatment with Modigraf may increase the risk of rejection of the organ that has been
transplanted to you. Do not stop treatment unless your doctor tells you to do so.
If you have any doubts about using this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
Modigraf reduces the body's defense mechanisms (immune system) which will no longer be as
efficient at fighting infections. Therefore, you may be more susceptible to infections while
taking Modigraf.
Some infections may be serious or fatal and can include infections 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 and serious brain infection, which can be fatal (Progressive Multifocal Leukoencephalopathy or PML)

Serious side effects can occur, including allergic and anaphylactic reactions (a very serious type of
allergic reaction with loss of consciousness and difficulty breathing requiring immediate medical
attention). Benign and malignant tumors have been reported following
treatment with Modigraf.

Inform your doctor immediately if you have or suspect you may have any of the following
serious side effects:
Common serious 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.
• Insufficient function of the transplanted organ.
• Blurred vision.

Uncommon serious side effects (may affect up to 1 in 100 people):

• Thrombotic microangiopathy (damage to small blood vessels), including hemolytic uremic syndrome, a condition with the following symptoms: reduced or absent urine output (acute kidney failure), extreme fatigue, yellowing of the skin or eyes (jaundice), and abnormal bruising (ecchymosis) or bleeding and signs of infection.

Rare serious side effects (may affect up to 1 in 1000 people):

• Thrombotic thrombocytopenic purpura: a condition that includes damage to small blood vessels and is characterized by fever and skin bruising that may appear as red spots, with or without extreme unjustified fatigue, confusion, yellowing of the skin or eyes (jaundice), with 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, reddened and swollen skin that may detach from 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, a severe illness with blistering on the skin, mouth, eyes, and genitals, hives, swelling of the tongue, red or purple skin rash that spreads, and skin peeling.
• Torsades de pointes: a change in heart rate that may or may not be accompanied by symptoms such as chest pain (angina), fainting, dizziness, nausea, palpitations (a strong awareness of your heartbeat), and difficulty breathing.

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

• Opportunistic infections (bacterial, fungal, viral, and protozoal): prolonged diarrhea, fever, and sore throat.
• Following treatment, the occurrence of benign and malignant tumors has been reported, resulting from immunosuppression, including skin cancers and a rare type of cancer that can include skin lesions, called Kaposi's sarcoma. Symptoms include changes in the skin, such as new or changing discoloration, lesions, or nodules.
• Cases of pure red cell aplasia (a very severe decrease in red blood cell count), hemolytic anemia (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 known exactly how often these side effects occur. You may have no symptoms, or depending on the severity of the condition, you may experience: fatigue, apathy, abnormal paleness of the skin, shortness of breath, headache, chest pain, and cooling of the hands and feet.
• Cases of agranulocytosis (a strongly 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 fevers, chills, and sore throat.
• Allergic and anaphylactic reactions with the following symptoms: sudden itchy rash (hives), swelling of the hands, feet, ankles, face, lips, mouth, or throat (which can cause difficulty swallowing or breathing) and you may feel weak.
• Posterior reversible encephalopathy syndrome (PRES): headache, confusion, mood swings, seizures, and visual disturbances. These can be signs of a condition called posterior reversible 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 color vision, difficulty seeing details, or restriction of the visual field.

The following side effects can also occur after taking Modigraf 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.
Diarrhea, 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 the number of red blood cells (highlighted
in blood tests).
Decreased magnesium, phosphate, potassium, calcium, or sodium in the blood, increased
fluid, increased uric acid or lipids in the blood, decreased appetite, increased
blood acidity, other changes in blood salt balance (highlighted in
blood tests).
Symptoms of anxiety, confusion and disorientation, depression, mood swings, nightmares,
hallucinations, mental disorders.
Seizures, altered consciousness, tingling and numbness in hands and feet (sometimes
painful), feeling of loss of balance, impaired ability to write, nervous system disorders.
Increased sensitivity to light, eye disorders.
Ringing in the ears.
Reduced blood flow in the 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 throat, cough, flu-like symptoms.
Inflammation or ulcers causing abdominal pain or diarrhea, bleeding in the
stomach, inflammation or ulcers in the mouth, accumulation of fluid in the stomach, vomiting, abdominal
pain, indigestion, constipation, flatulence, bloating, soft stools, stomach problems.
Bile duct disorders, yellowing of the skin due to liver problems, liver damage and
inflammation.
Itching, skin rash, hair loss, acne, increased sweating.
Joint pain, limb pain, back pain, and foot pain, muscle cramps.
Impaired kidney function, reduced urine production, painful or reduced urination.
General weakness, fever, swelling (edema), pain and discomfort, increased alkaline phosphatase
in the blood, weight gain, feeling of altered temperature perception.
Uncommon side effects (may affect up to 1 in 100)
Alterations in blood clotting processes, reduction in the number of all types of blood cells
(highlighted in blood tests).
Dehydration.
Decreased proteins or sugar in the blood, increased phosphate in the blood.
Coma, brain hemorrhages, stroke, paralysis, brain disorders, speech and
expression disorders, memory problems.
Cataract opacity.
Hearing impairment.
Irregular heartbeat, heart stoppage, reduced heart output, heart muscle disorders,
thickening of the heart muscle, increased heartbeat, abnormal ECG, altered
heart rate and rhythm.
Thrombosis in a vein in the limbs, shock.
Difficulty breathing, respiratory disorders, asthma.
Intestinal blockage, increased levels of the enzyme amylase in the blood, reflux of stomach contents
into the throat, delayed gastric emptying.
Skin inflammation, burning sensation during sun exposure.
Joint pain.
Inability to urinate, painful menstruation and abnormal menstrual bleeding.
Multiple organ failure, flu-like illness, increased sensitivity to heat and
cold, feeling of tightness in the chest, feeling of restlessness and discomfort,
increased lactate dehydrogenase in the blood, weight loss.
Rare side effects (may affect up to 1 in 1000)
Small hemorrhages in the skin caused by blood clots.
Increased muscle stiffness.
Deafness.
Fluid accumulation around the heart.
Acute respiratory distress syndrome.
Cyst formation in the pancreas.
Problems with blood circulation in the liver.
Increased hair growth.
Thirst, fainting, feeling of constriction in the chest, decreased mobility, ulcer.
Very rare side effects (may affect up to 1 in 10,000)
Muscle weakness.
Abnormal echocardiogram.
Liver failure.
Painful urination with blood in the urine.
Increased adipose tissue.

Children and adolescents
The same side effects as adults can occur in children and adolescents.

Reporting of side effects
If you get any side effects, even those not listed in this leaflet, tell your
doctor or pharmacist. You can also report side effects directly through the
national reporting system detailed in Annex V.
By reporting side effects you can help provide more information on the safety of
this medicine.

5. How to store Modigraf

Keep Modigraf out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and the sachet after
“Exp.”. The expiry date refers to the last day of the month.
This medicine does not require any particular storage temperature.
After preparation, the suspension must be taken immediately.
Do not dispose of any medicine in wastewater or household waste. Ask your pharmacist how to
dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Modigraf contains

• The active ingredient is tacrolimus. Each sachet of Modigraf 0.2 mg granules contains 0.2 mg of tacrolimus (as monohydrate). Each sachet of Modigraf 1 mg granules contains 1 mg of tacrolimus (as monohydrate).
• The other ingredients are: Lactose monohydrate, hypromellose (E464) and sodium croscarmellose (E468). Description of the appearance ofModigraf and contents of the packModigraf granules for oral suspension consists of white granules contained in a sachet. A pack containing 50 sachets is available. Marketing authorisation holderAstellas Pharma Europe B.V. Sylviusweg 62 2333 BE Leiden Netherlands

Manufacturer
Astellas Ireland Co., Ltd.
Killorglin, County Kerry, V93FC86
Ireland
For further information on this medicinal product, contact the local representative of the marketing authorisation holder:

België/Belgique/Belgien
Astellas Pharma B.V. Branch
Tél/Tel: + 32 (0)2 5580710

Lietuva
Astellas Pharma d.o.o.
Tel: +370 37 408 681

България
Астелас Фарма ЕООД
Teл.: + 359 2 862 53 72

Luxembourg/Luxemburg
Astellas Pharma B.V.Branch
Belgique/Belgien
Tél/Tel: + 32 (0)2 5580710

Českárepublika
Astellas Pharma s.r.o.
Tel: +420 221 401 500

Magyarország
Astellas Pharma Kft.
Tel.: + 36 1 577 8200

Danmark
Astellas Pharma a/s
Tlf: + 45 43 430355

Malta
Astellas Pharmaceuticals AEBE
Τ el: +30 210 8189900

Deutschland
Astellas Pharma GmbH
Tel: + 49 (0)89 454401

Nederland
Astellas Pharma B.V.
Tel: + 31 (0)71 5455745

Eesti
Astellas Pharma d.o.o.
Tel: +372 6 056 014

Norge
Astellas Pharma
Tlf: + 47 66 76 46 00

Ελλάδα
Astellas Pharmaceuticals AEBE
Τηλ : +30 210 8189900

Österreich
Astellas Pharma Ges.m.b.H.
Tel: + 43 (0)1 8772668

España
Astellas Pharma S.A.
Tel: + 34 91 4952700

Polska
Astellas Pharma Sp.z.o.o.
Tel.: + 48 225451 111

France
Astellas Pharma S.A.S.
Tél: + 33 (0)1 55917500

Portugal
Astellas Farma, Lda.
Tel: + 351 21 4401320

Hrvatska
Astellas d.o.o.
Tel: +38516700102

România
S.C.Astellas Pharma SRL
Tel: +40 (0)21 361 04 95

Ireland
Astellas Pharma Co. Ltd.
Tel: + 353 (0)1 4671555

Slovenija
Astellas Pharma d.o.o.
Tel: +386 (0) 14011 400

Ísland
Vistor hf
Sími: + 354 535 7000

Slovenská republika
Astellas Pharma s.r.o.
Tel: +421 2 4444 2157

Italia
Astellas Pharma S.p.A.
Tel: + 39 02 921381

Suomi/Finland
Astellas Pharma
Puh/Tel: + 358 (0)9 85606000

Κύπρος
Astellas Pharmaceuticals AEBE
Ελλάδα
Τηλ : +30 210 8189900

Sverige
Astellas Pharma AB
Tel: + 46 (0)40-650 15 00

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 justifications for the variation of the terms of the marketing authorisation
Scientific conclusions
Taking into account the assessment of the Pharmacovigilance and Risk Assessment Committee (PRAC) of the Periodic Safety Update Reports (PSUR) for tacrolimus (systemic formulations), the scientific conclusions of the PRAC are as follows:
In light of the available data on cases of Kaposi's sarcoma from clinical studies, the literature and spontaneous reports, including cases with a close temporal association and a number of fatal cases, and in light 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 products containing systemic tacrolimus should be amended accordingly.
Having examined the PRAC recommendation, the Committee for Human Medicinal Products (CHMP) agrees with the overall conclusions and with the justifications for the recommendation.

Justifications for the variation of the terms of the marketing authorisation
Based on the scientific conclusions on tacrolimus (systemic formulations), the CHMP considers that the benefit-risk ratio of medicinal products containing tacrolimus (systemic formulations) remains unchanged, subject to the proposed changes to the product information.
The CHMP recommends the variation of the terms of the marketing authorisation.