Tacrolimus: package leaflet

For patients

Package leaflet, verbatim

Advagraf

Package leaflet: Advagraf 0.5 mg prolonged-release hard capsules / Advagraf 1 mg prolonged-release hard capsules / Advagraf 3 mg prolonged-release hard capsules / Advagraf 5 mg prolonged-release hard capsules

1. What Advagraf is and what it is used for

Advagraf contains the active substance tacrolimus. It 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.

Advagraf is used in adults.

2. What you need to know before you take Advagraf

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).
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 allow for a prolonged release (more slow release over a longer period) of tacrolimus. Advagraf and Prograf are not interchangeable.

Talk to your doctor or pharmacist before taking Advagraf:
- if you are taking any medicines mentioned below under ‘Other medicines and Advagraf’.
- if you have or have had liver problems.
- if you have diarrhoea for more than one day.

if you feel strong abdominal pain accompanied or not with other symptoms, such as chills, fever, nausea or vomiting.
if you have an alteration of the electrical activity of your heart called “QT prolongation”.
if you have or have had damage to the smallest blood vessels, known as thrombotic microangiopathy/thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome. Tell your doctor if you develop fever, bruising under the skin (which may appear as red dots), unexplained tiredness, confusion, yellowing of the skin or eyes, reduced urine output, vision loss 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, e.g., St. John’s wort (Hypericum perforatum) or any other herbal products as this may affect the effectiveness and the dose of Advagraf that you need to receive.
If in doubt please consult your doctor prior to taking any herbal products or remedies.

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.

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.

Precaution for handling:
Direct contact with any part of your body like your skin or eyes, or breathing in of injection solutions, powder or granules contained in tacrolimus products should be avoided during preparation. If such contact occurs, wash the skin and eyes.
Children and adolescents
The use of Advagraf is not recommended in children and adolescents under 18 years.
Other medicines and Advagraf
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 (another medicine used for the prevention of transplant organ rejection).

If you need to attend a doctor other than your transplant specialist, tell the doctor that you are taking tacrolimus. Your doctor may need to consult your transplant specialist if you should use another medicine that could increase or decrease your tacrolimus blood level.

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 interruption, an increase or a decrease in Advagraf dose.

clotrimazole, isavuconazole, miconazole, caspofungin, telithromycin, erythromycin, clarithromycin, josamycin, azithromycin, rifampicin, rifabutin, isoniazid and flucloxacillin
- letermovir, used to prevent illness caused by CMV (human cytomegalovirus)
- HIV protease inhibitors (e.g., ritonavir, nelfinavir, saquinavir), the booster medicine cobicistat, and combination tablets, or HIV non-nucleoside reverse transcriptase inhibitors (efavirenz, etravirine, nevirapine) used to treat HIV infection
- 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 infection
- nilotinib and imatinib, idelalisib, ceritinib, crizotinib, apalutamide, enzalutamide, or mitotane (used to treat certain cancers)
- mycophenolic acid, used to suppress the immune system to prevent transplant rejection
- medicines for stomach ulcer and 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
- 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)
- anti-arrhythmic drugs (amiodarone) used to control arrhythmia (uneven beating of the heart)
- medicines known as “statins” used to treat elevated cholesterol and triglycerides
- carbamazepine, phenytoin or phenobarbital, used to treat epilepsy
- metamizole, used to treat pain and fever
- 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) or extracts of Schisandra sphenanthera
- cannabidiol (uses amongst others include treatment of seizures).

Tell your doctor if you are receiving treatment for hepatitis C. The drug treatment for hepatitis C may change your liver function and may affect blood levels of tacrolimus. Tacrolimus blood levels may fall or may increase depending on the medicines prescribed for hepatitis C. Your doctor may need to closely monitor tacrolimus blood levels and make necessary adjustments of Advagraf dose after you start 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) or antivirals (used to treat viral infections e.g.
acyclovir, ganciclovir, cidofovir, foscarnet). These may worsen kidney or nervous system problems when taken together with Advagraf.

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 haemolytic uraemic 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 disease, (e.g. amiloride, triamterene, or spironolactone), or the antibiotics trimethoprim or cotrimoxazole that may increase levels of potassium in your 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 you take Advagraf.

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

Advagraf with food and drink
Avoid grapefruit (also as juice) while on treatment with Advagraf, since it can affect its levels in the blood.
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. One study assessed pregnancy outcomes in women treated with tacrolimus and those treated with other immunosuppressants. While there was insufficient evidence in this study to draw conclusions, higher rates of miscarriage were reported among liver and kidney transplant patients treated with tacrolimus, as well as higher rates among kidney transplant patients of persistent hypertension associated with protein loss in the urine that develops during pregnancy or the postpartum period (a condition called pre-eclampsia). No increased risk of major birth defects associated with Advagraf use was found.
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.
Advagraf contains lactose, sodium and lecithin (soya)
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.
This medicine contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially ‘sodium-free’.
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.

3. How to take Advagraf

Always take Advagraf exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure. This medicine should only be prescribed to you by a doctor with experience in the treatment of transplant patients.

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. When treating rejection, these same doses may be used.

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 Advagraf on an empty stomach or 2 to 3 hours after a meal. Wait at least 1 hour until the next meal. 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.

4. Possible side effects

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

Advagraf reduces your body’s defense 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.

Some infections could be serious or fatal and may include infections caused by bacteria, viruses, fungi, parasites, or other infections.
Tell your doctor immediately if you get signs of an infection including:
- Fever, cough, sore throat, feeling weak or generally unwell
- Memory loss, trouble thinking, difficulty walking or loss of vision - these may be due to a very rare, serious brain infection, which can be fatal (Progressive Multifocal Leukoencephalopathy or PML)

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

Tell 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: strong abdominal pain accompanied or not with other symptoms, such as chills, fever, nausea or vomiting.
- Insufficient function of your 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: low or no urine output (acute renal failure), extreme tiredness, yellowing of the skin or eyes (jaundice) and abnormal bruising or 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 and characterised by fever and bruising under the skin that may appear as red pinpoint dots, with or without unexplained extreme tiredness, confusion, yellowing of the skin or eyes (jaundice), with symptoms of acute renal failure (low or no urine output), vision loss and seizures.
- Toxic epidermal necrolysis: erosion and blistering of skin or mucous membranes, red swollen skin that can detach in large parts of the body.
- Blindness.

Serious very rare side effects (may affect up to 1 in 10,000 people):
- Stevens-Johnson syndrome: unexplained widespread skin pain, facial swelling, serious illness with blistering of skin, mouth, eyes and genitals, hives, tongue swelling, red or purple skin rash that spreads, skin shedding.
- Torsades de pointes: change in the heart frequency that can be accompanied or not of symptoms, such as chest pain (angina), faint, vertigo or nausea, palpitations (feeling the heartbeat) and difficulty breathing.

Serious side effects – frequency not known (frequency cannot be estimated from the available data):
- Opportunistic infections (bacterial, fungal, viral and protozoal): prolonged diarrhea, fever and sore throat.
- Benign and malignant tumours have been reported following treatment as a result of immunosuppression, including malignant skin cancers and a rare type of cancer that may include skin lesions known as Kaposi’s sarcoma. Symptoms include skin changes such as new or changing discoloration, lesions or lumps.
- Cases of pure red cell aplasia (a very severe reduction in red blood cell counts), haemolytic anaemia (decreased number of red blood cells due to abnormal breakdown accompanied with tiredness) and febrile neutropenia (a decrease in the type of white blood cells which fight infection, 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 feel: fatigue, apathy, abnormal paleness of the skin (pallor), shortness of breath, dizziness, headache, chest pain and coldness in hands and feet.
- Cases of agranulocytosis (a severely lowered number of white blood cells accompanied with ulcers in the mouth, fever and infection(s)). You may have no symptoms or you may feel sudden fever, rigors and sore throat.
- Allergic and anaphylactic reactions with the following symptoms: a sudden itchy rash (hives), swelling of hands, feet, ankle, face, lips, mouth or throat (which may cause difficulty in swallowing or breathing) and you may feel you are going to faint.
- Posterior Reversible Encephalopathy Syndrome (PRES): headache, confusion, mood changes, fits, and disturbances of your vision. These could be signs of a disorder known as posterior reversible encephalopathy syndrome, which has been reported in some patients treated with tacrolimus.
- Optic neuropathy (abnormality of the optic nerve): problems with your vision such as blurred vision, changes in colour vision, difficulty in seeing detail or restriction of your field of vision.

The side effects listed below may also occur after receiving Advagraf and could be serious:

Very common side effects (may affect more than 1 in 10 people):
- 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 (may affect up to 1 in 10 people):
- 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.
- 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.
- Inflammations or ulcers causing abdominal pain or diarrhoea, bleeding in the stomach, inflammations or ulcers in the mouth, collection of fluid in the belly, vomiting, abdominal pains, indigestion, constipation, flatulence, bloating, loose stools, stomach problems.
- 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, back and feet, muscle spasms.
- 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.

Uncommon side effects (may affect up to 1 in 100 people):
- Changes in blood clotting, reduction in the number of all types of blood cells (seen in blood tests).
- Dehydration.
- Reduced protein or sugar in the blood, increased phosphate in the blood.
- Coma, bleeding in the brain, stroke, paralysis, brain disorder, speech and language abnormalities, memory problems.
- Opacity 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.
- Inability to urinate, painful menstruation and abnormal menstrual bleeding.
- Multiple organ failure, flu-like illness, increased sensitivity to heat and cold, feeling of pressure on your chest, jittery or abnormal feeling, increase of the enzyme lactate dehydrogenase in your blood, weight loss.

Problems with blood flow in the liver.
Increased hairiness.
Thirst, fall, feeling of tightness in your chest, decreased mobility, ulcer.

Very rare side effects (may affect up to 1 in 10,000 people):
- Muscular weakness.
- Abnormal heart scan.
- Liver failure.
- Painful urination with blood in the urine.
- Increase of fat tissue.

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. 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.

5. How to store Advagraf

Keep this medicine out of the sight and reach 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.

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.

6. Contents of the pack and other information

What Advagraf contains
- The active substance is tacrolimus.
Each capsule of Advagraf 0.5 mg contains 0.5 mg of tacrolimus (as monohydrate).
Each capsule of Advagraf 1 mg contains 1 mg of tacrolimus (as monohydrate).
Each capsule of Advagraf 3 mg contains 3 mg of tacrolimus (as monohydrate).
Each capsule of Advagraf 5 mg contains 5 mg of tacrolimus (as monohydrate).

- 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.
Sylviusweg 62
2333 BE Leiden
Netherlands

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

For any information about this medicine, please 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

Česká republika
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
Tel: +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: + 385 1 670 01 02

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 (0)2 921381

Κύπρος
Astellas Pharmaceuticals AEBE
Ελλάδα
Τηλ: +30 210 8189900
Suomi/Finland
Astellas Pharma
Puh/Tel: + 358 9 85606000

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

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

This leaflet was last revised in
Detailed information on this medicine is available on the European Medicines Agency website:
https://www.ema.europa.eu.

Annex IV
Scientific conclusions and grounds for the variation to the terms of the marketing authorisation(s)

Scientific conclusions
Taking into account the PRAC Assessment Report on the PSUR(s) for tacrolimus (systemic formulations), the scientific conclusions of PRAC are as follows:
In view of available data on cases of Kaposi sarcoma from clinical trial data, literature and spontaneous reports, including cases with a close temporal relationship and a number of cases with a fatal outcome, and in view of a plausible mechanism of action, the PRAC considers a causal relationship between systemic tacrolimus and Kaposi sarcoma is at least a reasonable possibility.
The PRAC concluded that the product information of products containing systemic tacrolimus should be amended accordingly.
Having reviewed the PRAC recommendation, the CHMP agrees with the PRAC overall conclusions and grounds for recommendation.
Grounds for the variation to the terms of the marketing authorisation(s)
On the basis of the scientific conclusions for tacrolimus (systemic formulations) the CHMP is of the opinion that the benefit-risk balance of the medicinal product(s) containing tacrolimus (systemic formulations) is unchanged subject to the proposed changes to the product information.
The CHMP recommends that the terms of the marketing authorisation(s) should be varied.

Envarsus

Package leaflet: Envarsus 0.75 mg prolonged-release tablets / Envarsus 1 mg prolonged-release tablets / Envarsus 4 mg prolonged-release tablets

1. What Envarsus is and what it is used for

Envarsus contains the active substance tacrolimus. It is an immunosuppressant. Following your kidney or liver transplant, your body’s immune system will try to reject the new organ.

Envarsus is used to control your body’s immune response, enabling your body to accept the transplanted organ.

You may also be given Envarsus 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.

Envarsus is used in adults.

2. What you need to know before you take Envarsus

Do not take Envarsus
- if you are allergic to tacrolimus or any of the other ingredients of this medicine (listed in section 6).
- if you are allergic to sirolimus or to any macrolide-antibiotic (e.g., erythromycin, clarithromycin, josamycin).

Warnings and precautions
Envarsus contains the active substance tacrolimus presented in a prolonged release formulation.
Envarsus is taken once daily and is not interchangeable with other existing medicines containing tacrolimus (immediate release or prolonged release) on an equal dose by dose basis.

Talk to your doctor or pharmacist before taking Envarsus:
- if you have, or have had, liver problems.
- if you have diarrhoea for more than one day.
- if you are taking any medicines mentioned below under “Other medicines and Envarsus”.
- if you have an alteration of the electrical activity of your heart called “QT prolongation”.
- if you feel strong abdominal pain accompanied or not with other symptoms, such as chills, fever, nausea or vomiting
- an infection, leading to problems with your kidney or neurological symptoms
- headache, altered mental status, seizures and visual disturbances
- weakness, change in skin or eye colour, easy bruising, infection, cough, anaemia
- if you have or have had damage to the smallest blood vessels, known as thrombotic microangiopathy/thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome. Tell your doctor if you develop fever, bruising under the skin (which may appear as red dots), unexplained tiredness, confusion, yellowing of the skin or eyes, reduced urine output, vision loss 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, e.g., St. John’s wort (Hypericum perforatum) or any other herbal products as this may affect the effectiveness and the dose of Envarsus that you need to receive.
If in doubt, please consult your doctor prior to taking any herbal products or remedies.

Your doctor may need to adjust your dose of Envarsus or will decide to stop treatment with tacrolimus.

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

You should limit your exposure to the sun and UV (ultraviolet) light whilst taking Envarsus. 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.

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

Other medicines and Envarsus
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including medicines obtained without a prescription and herbal preparations.

It is not recommended that Envarsus is taken with ciclosporin (another medicine used for the prevention of transplant organ rejection).

Envarsus blood levels can be affected by other medicines you take, and blood levels of other medicines can be affected by taking Envarsus, which may require interruption, an increase or a decrease in Envarsus dose.

An effect on the Envarsus blood levels may occur very soon after starting the use of another medicine, therefore frequent continued monitoring of your Envarsus blood level may be needed within the first few days of starting another medicine and frequently while treatment with the other medicine continues. Some other medicines may cause tacrolimus blood levels to decrease, which could increase the risk of rejecting the transplanted organ. 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, posaconazole, voriconazole, clotrimazole, isavuconazole, miconazole, caspofungin, telithromycin, erythromycin, clarithromycin, josamycin, azithromycin, rifampicin, rifabutin, isoniazid and flucloxacillin)
- letermovir, used to prevent illness caused by CMV (human cytomegalovirus)
- HIV protease inhibitors (e.g., ritonavir, nelfinavir, saquinavir), the booster medicine cobicistat and combination tablets, or HIV non‐nucleoside reverse transcriptase inhibitors (efavirenz, etravirine, nevirapine) used to treat HIV infection
- 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 cancers)
- mycophenolic acid, used to suppress the immune system to prevent transplant rejection
- medicines for stomach ulcer and 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
- 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)
- anti-arrhythmic substances (e.g., amiodarone) used to control arrhythmia (uneven beating of the heart)
- medicines known as “statins”, used to treat elevated cholesterol and triglycerides
- carbamazepine, phenytoin or phenobarbital, used to treat epilepsy
- metamizole, used to treat pain and fever
- the corticosteroids prednisolone and methylprednisolone, belonging to the class of corticosteroids and 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) or extracts of Schisandra sphenanthera
- cannabidiol (uses amongst others include treatment of seizures)

Tell your doctor if you are receiving treatment for hepatitis C. The drug treatment for hepatitis C may change your liver function and may affect blood levels of tacrolimus. Tacrolimus blood levels may fall or may increase depending on the medicines prescribed for hepatitis C. Your doctor may need to closely monitor tacrolimus blood levels and make adjustments to the dose after you start 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) or antivirals (used to treat viral infections, e.g., acyclovir, ganciclovir, cidofovir, foscarnet). These may worsen kidney or nervous system problems when taken together with Envarsus.

While you take Envarsus 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), or the antibiotics trimethoprim or cotrimoxazole that may increase levels of potassium in your blood, nonsteroidal anti-inflammatory substances (NSAIDs, e.g., ibuprofen) used for fever, inflammation and pain, anticoagulants (blood thinners), or oral medicines for diabetes.

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

Envarsus with food and drink
Avoid grapefruit (also as juice) while on treatment with Envarsus, since it can affect its levels in the blood.

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. One study assessed pregnancy outcomes in women treated with tacrolimus and those treated with other immunosuppressants. While there was insufficient evidence in this study to draw conclusions, higher rates of miscarriage were reported among liver and kidney transplant patients treated with tacrolimus, as well as higher rates among kidney transplant patients of persistent hypertension associated with protein loss in the urine that develops during pregnancy or the postpartum period (a condition called pre-eclampsia). No increased risk of major birth defects associated with Envarsus use was found.
Tacrolimus passes into breast milk. Therefore, you should not breast-feed whilst taking Envarsus.

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 Envarsus. These effects are more frequent if you also drink alcohol.

Envarsus contains lactose
Envarsus contains lactose (milk sugar).
- Envarsus 0.75 mg tablets: 41.7 mg
- Envarsus 1 mg tablets:
41.7 mg
- Envarsus 4 mg tablets:
104 mg
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

3. How to take Envarsus

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.
This medicine should only be prescribed for you by a doctor with experience in the treatment of transplant patients.

Important information
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 doe instructions have changed, speak to your doctor or pharmacist as soon as possible to make sure that you have the right medicine.

How much Envarsus do I have to take
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:
0.11 - 0.17 mg per kg body weight per day depending on the transplanted organ. When treating rejection, the same doses may be used.

Your dose depends on your general condition and on which other immunosuppressive medicines you are taking. Following the initiation of your treatment with this medicine, 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 Envarsus dose once your condition has stabilised.

How should I take the Envarsus tablets
Envarsus is taken orally once daily, generally on an empty stomach.

Take the tablets immediately following removal from the blister. The tablets should be swallowed whole with a glass of water. Do not swallow the desiccant contained in the foil wrapper.

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

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

If you forget to take Envarsus
Do not take a double dose to make up for a forgotten tablet. Take the tablet as soon as possible on the same day.

If you stop taking Envarsus
Stopping your treatment with Envarsus 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.

4. Possible side effects

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

Tacrolimus 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 Envarsus.
Some infections could be serious or fatal and may include infections caused by bacteria, viruses, fungi, parasites, or other infections.
Tell your doctor immediately if you get signs of an infection including:
- fever, cough, sore throat, feeling weak or generally unwell
- memory loss, trouble thinking, difficulty walking or loss of vision - these may be due to a very rare, serious brain infection, which can be fatal (Progressive Multifocal Leukoencephalopathy (PML)) Please contact your doctor immediately, should you experience severe effects.
Severe effects may occur, including allergic and anaphylactic reactions. Benign and malignant tumours have been reported following Envarsus treatment.

Tell your doctor immediately if you have or suspect you may have any of the following serious side effects:

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: low or no urine output (acute renal failure), extreme tiredness, yellowing of the skin or eyes (jaudince) and abnormal bruising or 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 and characterised by fever and bruising under the skin that may appear as red pinpoint dots, with or without unexplained extreme tiredness, confusion, yellowing of the skin or eyes (jaundice), with symptoms of acute renal failure (low or no urine output), vision loss and seizures.
- Toxic epidermal necrolysis: erosion and blistering of skin or mucous membranes, red swollen skin that can detach in large parts of the body.
- Blindness.

Serious very rare side effects (may affect up to 1 in 10 000 people):
- Stevens-Johnson syndrome: unexplained widespread skin pain, facial swelling, serious illness with blistering of skin, mouth, eyes and genitals, hives, tongue swelling, red or purple skin rash that spreads, skin shedding.
- Torsades de pointes: change in the heart frequency that can be accompanied or not of symptoms, such as chest pain (angina), faint, vertigo or nausea, palpitations (feeling the heartbeat) and difficulty breathing.

Serious side effects – frequency not known (frequency cannot be estimated from the available data):
- Opportunistic infections (bacterial, fungal, viral and protozoal): prolonged diarrhoea, fever and sore throat.
- Benign and malignant tumours have been reported following treatment as a result of immunosuppression, including malignant skin cancers and a rare type of cancer that may include skin lesions known as Kaposi’s sarcoma. Symptoms include skin changes such as new or changing discoloration, lesions or lumps.
- Cases of pure red cell aplasia (a very severe reduction in red blood cell counts), haemolytic anaemia (decreased number of red blood cells due to abnormal breakdown accompanied with tiredness) and febrile neutropenia (a decrease in the type of white blood cells which fight infection, 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 feel: fatigue, apathy, abnormal paleness of the skin (pallor), shortness of breath, dizziness, headache, chest pain and coldness in hands and feet.
- Cases of agranulocytosis (a severely lowered number of white blood cells accompanied with ulcers in the mouth, fever and infection(s)). You may have no symptoms or you may feel sudden fever, rigors and sore throat.
- Allergic and anaphylactic reactions with the following symptoms: a sudden itchy rash (hives), swelling of hands, feet, ankle, face, lips, mouth or throat (which may cause difficulty in swallowing or breathing) and you may feel you are going to faint.
- Posterior Reversible Encephalopathy Syndrome (PRES): headache, confusion, mood changes, fits, and disturbances of your vision. These could be signs of a disorder known as posterior reversible encephalopathy syndrome, which has been reported in some patients treated with tacrolimus.
- Optic neuropathy (abnormality of the optic nerve): problems with your vision such as blurred vision, changes in colour vision, difficulty in seeing detail or restriction of your field of vision.

The side effects listed below may also occur after receiving Envarsus and could be serious:

Very common side effects (may affect more than 1 in 10 people):
- 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 (may affect up to 1 in 10 people):
- 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, loss of 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
- 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
- Inflammations or ulcers causing abdominal pain or diarrhoea, bleeding in the stomach, inflammations or ulcers in the mouth, collection of fluid in the belly, vomiting, abdominal pain, indigestion, constipation, flatulence, bloating, loose stools, stomach problems
- 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

Uncommon side effects (may affect up to 1 in 100 people):
- Changes in blood clotting, reduction in the number of all types of blood cells (seen in blood tests)
- Dehydration
- Psychotic behaviour, such as delusions, hallucinations, and confusion
- Reduced protein or sugar in the blood, increased phosphate in the blood
- Coma, bleeding in the brain, stroke, paralysis, brain disorder, speech and language abnormalities, memory problems
- Opacity of the eye lens, partial or total inability to hear
- 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
- Acute or chronic inflammation of the pancreas, inflammation of the lining of the inner wall of the abdomen, obstruction of the gut, increased blood level of the enzyme amylase, reflux of stomach contents in your throat, delayed emptying of the stomach
- Inflammation of the skin, burning sensation in the sunlight

Joint disorders
Inability to urinate, painful menstruation and abnormal menstrual bleeding
Multiple organ failure, flu-like illness, increased sensitivity to heat and cold, feeling of pressure on your chest, jittery or abnormal feeling, increase of the enzyme lactate dehydrogenase in your blood, weight loss

Rare side effects (may affect up to 1 in 1 000 people):
- Small bleedings in your skin due to blood clots
- Increased muscle stiffness
- Deafness
- Collection of fluid around the heart
- Acute breathlessness
- Cyst formation in your pancreas, pre-stage of a blockage in your bowel
- 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 (may affect up to 1 in 10 000 people):
- Muscular weakness
- Impaired hearing
- Abnormal heart scan
- Liver failure
- Painful urination with blood in the urine
- Increase of fat tissue

5. How to store Envarsus

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 carton, blister and wrapper after ‘EXP’. The expiry date refers to the last day of that month.

Do not store above 25°C.
Store in the original aluminium foil wrapper in order to protect from light.

Use all the prolonged-release tablets within 45 days of opening the aluminium wrapping.

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.

6. Contents of the pack and other information

What Envarsus contains
- The active substance is tacrolimus.

Envarsus 0.75 mg prolonged-release tablets
Each prolonged-release tablet contains 0.75 mg tacrolimus (as monohydrate).

Envarsus 1 mg prolonged-release tablets
Each prolonged-release tablet contains 1.0 mg tacrolimus (as monohydrate).

Envarsus 4 mg prolonged-release tablets
Each prolonged-release tablet contains 4.0 mg tacrolimus (as monohydrate).

The other excipients are hypromellose, lactose monohydrate, macrogol 6000, poloxamer 188, magnesium stearate, tartaric acid (E334), butylated hydroxytoluene (E321), dimethicone 350.

What Envarsus looks like and contents of the pack
Envarsus 0.75 mg prolonged-release tablets are oval, white to off-white uncoated tablet, debossed with “0.75” on one side and “TCS” on the other side.
Envarsus 1 mg prolonged-release tablets are oval, white to off-white uncoated tablet, debossed with “1” on one side and “TCS” on the other side Envarsus 4 mg prolonged-release tablets are oval, white to off-white uncoated tablet, debossed with “4” on one side and “TCS” on the other side.

Envarsus is supplied in PVC/alu blisters containing 10 tablets. 3 blisters are packed together within a protective aluminium foil wrapper, including a desiccant. Packs of 30, 60 and 90 prolonged-release tablets are available.

Not all pack sizes may be marketed.

Marketing Authorisation Holder
Chiesi Farmaceutici S.p.A.
Via Palermo, 26/A
43122 Parma
Italy

Manufacturer
Rottendorf Pharma GmbH
Ostenfelder Straβe 51 - 61
59320 Ennigerloh
Germany or
Chiesi Farmaceutici S.p.A.
Via San Leonardo 96
43122 Parma
Italy or
Chiesi Pharmaceuticals GmbH
Gonzagagasse 16/16
1010 Wien
Austria

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

België/Belgique/Belgien
Chiesi sa/nv
Tél/Tel: +32 (0)2 788 42 00

Lietuva
Chiesi Pharmaceuticals GmbH
Tel: +43 1 4073919

България
Chiesi Bulgaria EOOD
Teл.: +359 29201205

Luxembourg/Luxemburg
Chiesi sa/nv
Tél/Tel: +32 (0)2 788 42 00

Česká republika
Chiesi CZ s.r.o.
Tel: +420 261221745

Magyarország
Chiesi Hungary Kft.
Tel.: +36-1-429 1060

Danmark
Chiesi Pharma AB
Tlf: +46 8 753 35 20

Malta
Chiesi Farmaceutici S.p.A.
Tel: +39 0521 2791

Deutschland
Chiesi GmbH
Tel: +49 40 89724-0

Nederland
Chiesi Pharmaceuticals B.V.
Tel: +31 0 88 5016400

Eesti
Chiesi Pharmaceuticals GmbH
Tel: +43 1 4073919

Norge
Chiesi Pharma AB
Tlf: +46 8 753 35 20

Ελλάδα
Chiesi Hellas AEBE
Τηλ: +30 210 6179763

Österreich
Chiesi Pharmaceuticals GmbH
Tel: +43 1 4073919

España
Chiesi España, S.A.U.
Tel: +34 93 494 8000

Polska
Chiesi Poland Sp. z.o.o.
Tel.: +48 22 620 1421

France
Chiesi S.A.S
Tél: +33 1 47688899

Portugal
Chiesi Farmaceutici S.p.A.
Tel: +39 0521 2791

Hrvatska
Chiesi Pharmaceuticals GmbH
Tel: +43 1 4073919

România
Chiesi Romania S.R.L.
Tel: +40 212023642

Ireland
Chiesi Farmaceutici S.p.A.
Tel: +39 0521 2791
Slovenija
CHIESI SLOVENIJA, d.o.o.
Tel: +386-1-43 00 901

Ísland
Chiesi Pharma AB
Tlf: +46 8 753 35 20

Slovenská republika
Chiesi Slovakia s.r.o.
Tel: +421 259300060

Italia
Chiesi Italia S.p.A.
Tel: +39 0521 2791

Suomi/Finland
Chiesi Pharma AB
Puh/Tel: +46 8 753 35 20

Κύπρος
Chiesi Farmaceutici S.p.A.
Τηλ: +39 0521 2791

Sverige
Chiesi Pharma AB
Tlf: +46 8 753 35 20

Latvija
Chiesi Pharmaceuticals GmbH
Tel: +43 1 4073919

United Kingdom (Northern Ireland)
Chiesi Farmaceutici S.p.A.
Tel: +39 0521 2791

This leaflet was last revised in.

Other sources of information

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

ANNEX IV
SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS
OF THE MARKETING AUTHORISATION(S)

Modigraf

Package leaflet: Modigraf 0.2 mg, granules for oral suspension / Modigraf 1 mg, granules for oral suspension

1. What Modigraf is and what it is used for

Modigraf contains the active substance tacrolimus. It is an immunosuppressant. Following your organ transplant (e.g., liver, kidney, heart), your body’s immune system will try to reject the new organ.
Modigraf is used to control your body’s immune response enabling your body to accept the transplanted organ.

You may also be given Modigraf for an ongoing rejection of your transplanted liver, kidney, heart or other organ or if any previous treatment you were taking was unable to control this immune response after your 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 any of the other ingredients of this medicine (listed in section 6).
- If you are allergic to sirolimus (another substance used to prevent rejection of your transplanted organ) or to any macrolide antibiotic (e.g., erythromycin, clarithromycin, josamycin).
Warnings and precautions
Talk to your doctor or pharmacist before taking Modigraf

if you have or have had liver problems.
if you have diarrhoea for more than one day.
if you feel strong abdominal pain accompanied or not with other symptoms, such as chills, fever, nausea or vomiting.
if you have an alteration of the electrical activity of your heart called “QT prolongation”.
if you have or have had damage to the smallest blood vessels, known as thrombotic microangiopathy/thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome. Tell your doctor if you develop fever, bruising under the skin (which may appear as red dots), unexplained tiredness, confusion, yellowing of the skin or eyes, reduced urine output, vision

loss 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, e.g., St. John’s wort (Hypericum perforatum) or any other herbal products as this may affect the effectiveness and the dose of Modigraf that you need to receive.
If in doubt please consult your doctor prior to taking any herbal products or remedies.

Your doctor may need to adjust your dose of Modigraf.

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 Modigraf.

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

It is not recommended that Modigraf is taken with ciclosporin (another medicine used for the prevention of transplant organ rejection).

Modigraf blood levels can be affected by other medicines you take, and blood levels of other medicines can be affected by taking Modigraf, which may require interruption, an increase or a decrease in Modigraf dose.

Some patients have experienced increases in tacrolimus blood levels while taking other medicines.
This could lead to serious side effects, such as kidney problems, nervous system problems, and heart rhythm disturbances (see section 4).
An effect on the Modigraf blood levels may occur very soon after starting the use of another medicine, therefore frequent continued monitoring of your Modigraf blood level may be needed within the first few days of starting another medicine and frequently while treatment with the other medicine continues. Some other medicines may cause tacrolimus blood levels to decrease, which could increase the risk of rejecting the transplanted organ. 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, posaconazole, voriconazole, clotrimazole, isavuconazole, miconazole, caspofungin, telithromycin, erythromycin, clarithromycin, josamycin, azithromycin, rifampicin, rifabutin, isoniazid and flucloxacillin
- letermovir, used to prevent illness caused by CMV (human cytomegalovirus)
- HIV protease inhibitors (e.g., ritonavir, nelfinavir, saquinavir), the booster medicine cobicistat, and combination tablets, or HIV non-nucleoside reverse transcriptase inhibitors (efavirenz, etravirine, nevirapine) used to treat HIV infection
- 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 infection

nilotinib and imatinib, idelalisib, ceritinib, crizotinib, apalutamide, enzalutamide, or mitotane (used to treat certain cancers)
mycophenolic acid, used to suppress the immune system to prevent transplant rejection
medicines for stomach ulcer and 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
the contraceptive pill, hormone treatments with ethinylestradiol, or hormone treatments with danazol
medicines used to treat high blood pressure or heart problems (e.g., nifedipine, nicardipine, diltiazem and verapamil)
anti-arrhythmic medicines (amiodarone) used to control arrhythmia (uneven beating of the heart)
medicines known as “statins” used to treat elevated cholesterol and triglycerides
carbamazepine, phenytoin or phenobarbital, used to treat epilepsy
metamizole, used to treat pain and fever
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) or extracts of Schisandra sphenanthera.
cannabidiol (uses amongst others include treatment of seizures)

Tell your doctor if you are receiving treatment for hepatitis C. The drug treatment for hepatitis C may change your liver function and may affect blood levels of tacrolimus. Tacrolimus blood levels may fall or may increase depending on the medicines prescribed for hepatitis C. Your doctor may need to closely monitor tacrolimus blood levels and make necessary adjustments of Modigraf dose after you start treatment for hepatitis C.

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), or the antibiotics trimethoprim or cotrimoxazole that may increase levels of potassium in your 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 you take Modigraf.

If you need to have any vaccinations, please tell your doctor before.
Modigraf with food and drink
You should generally take Modigraf on an empty stomach or at least 1 hour before or 2 to 3 hours after a meal. Grapefruit and grapefruit juice should be avoided while taking Modigraf, since it can affect its levels in the blood.
Pregnancy and breast-feeding
If you take Modigraf during pregnancy, it may pass into your baby through the placenta. It could potentially influence the health of the baby or adversely influence the course of the pregnancy.
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. One study assessed pregnancy outcomes in women

treated with tacrolimus and those treated with other immunosuppressants. While there was insufficient evidence in this study to draw conclusions, higher rates of miscarriage were reported among liver and kidney transplant patients treated with tacrolimus, as well as higher rates among kidney transplant patients of persistent hypertension associated with protein loss in the urine that develops during pregnancy or the postpartum period (a condition called pre-eclampsia). No increased risk of major birth defects associated with Modigraf use was found.
Modigraf passes into breast milk. Therefore, you should not breast-feed whilst using Modigraf.
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 Modigraf. These effects are more frequent if you also drink alcohol.
Modigraf contains lactose and sodium
Modigraf 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.
This medicine contains less than 1 mmol sodium (23 mg) per sachet, that is to say essentially ‘sodium-free’.

3. How to take Modigraf

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. Modigraf should be prescribed by doctors trained to treat transplant patients and experienced in the use of medicines that control the body’s immune system (immunosuppressants).

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 twice a day. If the physical appearance has changed from the normal white granules, or if dose 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 doses just after transplantation will generally be in the range of 0.075 - 0.30 mg per kg body weight per day depending on the transplanted organ. When treating rejection, these same doses may be used.

Your dose depends on your general condition and on which other immunosuppressive medicines you are taking.
Children and adolescents
Children and adolescents will receive doses of Modigraf calculated in the same way as adults. In general children need higher doses per kg of body weight to achieve the same effective levels in the blood as adults.

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

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

Modigraf is taken orally twice daily, usually in the morning and evening. Take Modigraf on an empty stomach or 2 to 3 hours after a meal. Wait at least 1 hour until the next meal.

How to prepare the Modigraf sachets for use?
Your doctor will advise you on the number of sachets that you need to open and the volume of water that is required to make a suspension. For accurate measuring the volume of water you can use a syringe or graduated cylinder.

Pour the prescribed volume of water (at room temperature) into a glass or cup, up to a maximum of 50 ml. Place the cup with water on a stable surface. Do not use cups or spoons that are made of PVC (polyvinylchloride) to take Modigraf because the active substance in Modigraf may stick to PVC.
Carefully open the prescribed number of sachets, e.g. with a pair of scissors at the point indicated with an arrow. Hold the opened sachet between thumb and index finger above the cup with the open side of the sachet facing downwards. Gently tap on the closed end of the sachet and pour the contents of each sachet into the glass or cup containing the water. Do not use any utensils or liquids to empty the sachet. If you follow these instructions, you will get the right amount of granules from the sachet. It is normal that some granules stay behind; the sachet was designed that way.
Stir, or swirl gently until the granules have been suspended completely. The suspension can be drawn up with a syringe or swallowed directly by the patient. The liquid has a sweet taste. Rinse the glass or cup once with the same amount of water and drink this, too. The liquid should be drunk immediately after preparation.
If you take more Modigraf than you should
If you have accidentally taken too much Modigraf, contact your doctor or nearest hospital emergency department immediately.
If you forget to take Modigraf
Do not take a double dose to make up for forgotten individual doses.
If you have forgotten to take your Modigraf, wait until it is time for the next dose, and then continue as before.
If you stop taking Modigraf
Stopping your treatment with Modigraf 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.

4. Possible side effects

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

Modigraf reduces your body’s defense mechanism (immune system), which will not be as good at fighting infections. Therefore, you may be more prone to infections while you are taking Modigraf.
Some infections could be serious or fatal and may include infections caused by bacteria, viruses, fungi, parasites, or other infections.
Tell your doctor immediately if you get signs of an infection including:
- Fever, cough, sore throat, feeling weak or generally unwell
- Memory loss, trouble thinking, difficulty walking or loss of vision - these may be due to a very rare, serious brain infection, which can be fatal (Progressive Multifocal Leukoencephalopathy or PML)

Severe effects may occur, including allergic and anaphylactic reactions (a very serious type of allergic reaction with fainting and difficulty breathing, which needs immediate medical attention). Benign and malignant tumours have been reported following Modigraf treatment.

Tell your doctor immediately if you have or suspect you may have any of the following serious side effects:

Serious side effects - frequency not known (frequency cannot be estimated from the available data):
- Opportunistic infections (bacterial, fungal, viral and protozoal): prolonged diarrhea, fever and sore throat.
- Benign and malignant tumours have been reported following treatment as a result of immunosuppression, including malignant skin cancers and a rare type of cancer that may include skin lesions known as Kaposi’s sarcoma. Symptoms include skin changes such as new or changing discoloration, lesions or lumps.
- Cases of pure red cell aplasia (a very severe reduction in red blood cell counts), haemolytic anaemia (decreased number of red blood cells due to abnormal breakdown accompanied with tiredness) and febrile neutropenia (a decrease in the type of white blood cells which fight infection, 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 feel: fatigue, apathy, abnormal paleness of the skin (pallor), shortness of breath, dizziness, headache, chest pain and coldness in hands and feet.
- Cases of agranulocytosis (a severely lowered number of white blood cells accompanied with ulcers in the mouth, fever and infection(s)). You may have no symptoms or you may feel sudden fever, rigors and sore throat.
- Allergic and anaphylactic reactions with the following symptoms: a sudden itchy rash (hives), swelling of hands, feet, ankle, face, lips, mouth or throat (which may cause difficulty in swallowing or breathing) and you may feel you are going to faint.
- Posterior Reversible Encephalopathy Syndrome (PRES): headache, confusion, mood changes, fits, and disturbances of your vision. These could be signs of a disorder known as posterior reversible encephalopathy syndrome, which has been reported in some patients treated with tacrolimus.

Optic neuropathy (abnormality of the optic nerve): problems with your vision such as blurred vision, changes in colour vision, difficulty in seeing detail or restriction of your field of vision.

The side effects listed below may also occur after receiving Modigraf and could be serious:

Common side effects (may affect up to 1 in 10 people):
- 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.
- 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 throat, cough, flu-like symptoms.
- Inflammations or ulcers causing abdominal pain or diarrhoea, bleeding in the stomach, inflammations or ulcers in the mouth, collection of fluid in the belly, vomiting, abdominal pains, indigestion, constipation, flatulence, bloating, loose stools, stomach problems.
- 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, back and feet, muscle spasms.
- 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.

Inflammation of the skin, burning sensation in the sunlight.
Joint disorders.
Inability to urinate, painful menstruation and abnormal menstrual bleeding.
Multiple organ failure, flu-like illness, increased sensitivity to heat and cold, feeling of pressure on your chest, jittery or abnormal feeling, increase of the enzyme lactate dehydrogenase in your blood, weight loss.

Rare side effects (may affect up to 1 in 1,000 people):
- Small bleedings in your skin due to blood clots.
- Increased muscle stiffness.
- Deafness.
- Collection of fluid around the heart.
- Acute breathlessness.
- Cyst formation in your pancreas.
- Problems with blood flow in the liver.
- Increased hairiness.
- Thirst, fall, feeling of tightness in your chest, decreased mobility, ulcer.

Very rare side effects (may affect up to 1 in 10,000 people):
- Muscular weakness.
- Abnormal heart scan.
- Liver failure.
- Painful urination with blood in the urine.
- Increase of fat tissue.

Children and adolescents
Children and adolescents may experience the same side effects as adults.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. 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.

5. How to store Modigraf

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 carton and sachet after EXP. The expiry date refers to the last day of that month.

This medicine does not require any special temperature storage conditions.

After preparation, the suspension should be taken immediately.

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.

6. Contents of the pack and other information

What Modigraf contains
- The active substance 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 croscarmellose sodium (E468).

What Modigraf looks like and contents of the pack
Modigraf granules for oral suspension are white granules supplied in sachets.
Packs containing 50 sachets are available.
Marketing Authorisation Holder
Astellas Pharma Europe B.V.
Sylviusweg 62
2333 BE Leiden
Netherlands

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

For any information about this medicine, please 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

Česká republika
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
Tel: +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: + 385 1 670 01 02
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

This leaflet was last revised in:
Detailed information on this medicine is available on the European Medicines Agency website:
https://www.ema.europa.eu.

Annex IV
Scientific conclusions and grounds for the variation to the terms of the marketing authorisation(s)

Protopic

Package leaflet: Protopic 0.03% ointment / tacrolimus monohydrate

1. What Protopic is and what it is used for

The active substance of Protopic, tacrolimus monohydrate, is an immunomodulating agent.

Protopic 0.03% ointment is used to treat moderate to severe atopic dermatitis (eczema) in adults who are not adequately responsive to or are intolerant of conventional therapies such as topical corticosteroids and in children (2 years of age and older) who failed to respond adequately to conventional therapies such as topical corticosteroids.

Once moderate to severe atopic dermatitis is cleared or almost cleared after up to 6 weeks treatment of a flare, and if you are experiencing frequent flares (i.e. 4 or more per year), it may be possible to prevent flares coming back or prolong the time you are free from flares by using Protopic 0.03% ointment twice weekly.

In atopic dermatitis, an over-reaction of the skin’s immune system causes skin inflammation (itchiness, redness, dryness). Protopic alters the abnormal immune response and relieves the skin inflammation and the itch.

2. What you need to know before you use Protopic

Do not use Protopic
- If you are allergic to tacrolimus or any of the other ingredients of this medicine (listed in section 6) or to macrolide antibiotics (e.g. azithromycin, clarithromycin, erythromycin).

Warnings and precautions
Talk to your doctor before using Protopic:
- If you have liver failure.
- If you have any skin malignancies (tumours) or if you have a weakened immune system (immuno-compromised) whatever the cause.
- If you have an inherited skin barrier disease such as Netherton’s syndrome, lamellar ichthyosis (extensive scaling of the skin due to a thickening of the outer layer of the skin), or if eDoc-000593873 - Version 19. 0

you have an inflammatory skin disease such as pyoderma gangrenosum, or if you suffer from generalised erythroderma (inflammatory reddening and scaling of the entire skin).
- If you have a cutaneous Graft Versus Host Disease (an immune reaction of the skin which is a common complication in patients who have undergone a bone marrow transplant).
- If you have swollen lymph nodes at initiation of treatment. If your lymph nodes become swollen during treatment with Protopic, consult your doctor.
- If you have infected lesions. Do not apply the ointment to infected lesions.
- If you notice any change to the appearance of your skin, please inform your physician.
- Based on the results of long-term studies and experience, a link between Protopic ointment treatment and the development of malignancies has not been confirmed, but definitive conclusions cannot be drawn.
- Avoid exposing the skin to long periods of sunlight or artificial sunlight such as tanning beds. If you spend time outdoors after applying Protopic, use a sunscreen and wear loose fitting clothing that protects the skin from the sun. In addition, ask your doctor for advice on other appropriate sun protection methods. If you are prescribed light therapy, inform your doctor that you are using Protopic as it is not recommended to use Protopic and light therapy at the same time.
- If your doctor tells you to use Protopic twice weekly to keep your atopic dermatitis cleared, your condition should be reviewed by your doctor at least every 12 months, even if it remains under control. In children, maintenance treatment should be suspended after 12 months, to assess whether the need for continued treatment still exists.
- It is recommended to use Protopic ointment at the lowest possible strength, at the lowest frequency and for the shortest possible duration necessary. This decision should be based on your doctor’s assessment of how your eczema responds to Protopic ointment.

Children
- Protopic ointment is not approved for children younger than 2 years of age. Therefore it should not be used in this age group. Please consult your doctor.
- The effect of treatment with Protopic on the developing immune system in children, especially the young, has not been established.

Other medicines, cosmetics and Protopic
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines.

You may use moisturising creams and lotions during treatment with Protopic but these products should not be used within two hours of applying Protopic.

The use of Protopic at the same time as other preparations to be used on the skin or while taking oral corticosteroids (e.g. cortisone) or medicines which affect the immune system has not been studied.

Protopic with alcohol
While using Protopic, drinking alcohol may cause the skin or face to become flushed or red and feel hot.

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Protopic contains butylhydroxytoluene (E321)
Protopic contains butylhydroxytoluene (E321), which may cause local skin reactions (e.g. contact dermatitis), or irritation to the eyes and mucous membranes.

3. How to use Protopic

Always use this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.
eDoc-000593873 - Version 19. 0

Apply Protopic as a thin layer to affected areas of your skin.
Protopic may be used on most parts of the body, including the face and neck and in the creases of your elbows and knees.
Avoid using the ointment inside your nose or mouth or in your eyes. If the ointment gets on any of these areas, it should be thoroughly wiped off and/or rinsed off with water.
Do not cover the skin being treated with bandages or wraps.
Wash your hands after applying Protopic unless your hands are also being treated.
Before applying Protopic after a bath or shower, be sure your skin is completely dry.

Children (2 years of age and older)
Apply Protopic 0.03 % ointment twice a day for up to three weeks, once in the morning and once in the evening. Afterwards the ointment should be used once a day on each affected region of the skin until the eczema has gone away.

Adults (16 years of age and older)
Two strengths of Protopic (Protopic 0.03% and Protopic 0.1% ointment) are available for adult patients (16 years of age and older). Your doctor will decide which strength is best for you.

Usually, treatment is started with Protopic 0.1% ointment twice a day, once in the morning and once in the evening, until the eczema has cleared. Depending on the response of your eczema your doctor will decide if the frequency of application can be reduced or the lower strength, Protopic 0.03% ointment, can be used.

Treat each affected region of your skin until the eczema has gone away. Improvement is usually seen within one week. If you do not see any improvement after two weeks, see your doctor about other possible treatments.

You may be told by your doctor to use Protopic ointment twice weekly once your atopic dermatitis has cleared or almost cleared (Protopic 0.03% for children and Protopic 0.1% for adults). Protopic ointment should be applied once a day twice weekly (e.g. Monday and Thursday) to areas of your body commonly affected by atopic dermatitis. There should be 2–3 days without Protopic treatment between applications.
If symptoms reappear you should use Protopic twice daily as outlined above and arrange to see your doctor to review your treatment.

If you accidentally swallow some ointment
If you accidentally swallow the ointment, consult your doctor or pharmacist as soon as possible. Do not try to induce vomiting.

If you forget to use Protopic
If you forget to apply the ointment at the scheduled time, do it as soon as you remember and then continue as before.

If you have any further questions on the use of 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.

Very common (may affect more than 1 in 10 people):
- burning sensation and itching
These symptoms are usually mild to moderate and generally go away within one week of using Protopic.

Common (may affect up to 1 in 10 people):
eDoc-000593873 - Version 19. 0

redness
feeling of warmth
pain
increased skin sensitivity (especially to hot and cold)
skin tingling
rash
local skin infection regardless of specific cause including but not limited to: inflamed or infected hair follicles, cold sores, generalised herpes simplex infections
facial flushing or skin irritation after drinking alcohol is also common

Uncommon (may affect fewer than 1 in 100 people):
- acne

Following twice-weekly treatment application site infections have been reported in children and adults. Impetigo, a superficial bacterial skin infection that usually produces blisters or sores on skin, has been reported in children.

Rosacea (facial redness), rosacea-like dermatitis, lentigo (presence of flat brown spots on the skin), oedema at the application site and herpes eye infections have been reported during post-marketing experience.

5. How to store Protopic

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 tube and carton after EXP. The expiry date refers to the last day of that month.
Do not store above 25ºC.

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.

6. Contents of the pack and other information

What Protopic contains
- The active substance is tacrolimus monohydrate.
One gram of Protopic 0.03% ointment contains 0.3 mg tacrolimus (as tacrolimus monohydrate).
- The other ingredients are white soft paraffin, liquid paraffin, propylene carbonate, white beeswax, hard paraffin, butylhydroxytoluene (E321) and all-rac-α-tocopherol.

What Protopic looks like and contents of the pack
Protopic is a white to slightly yellowish ointment. It is supplied in tubes containing 10, 30 or 60 grams of ointment. Not all pack sizes may be marketed. Protopic is available in two strengths (Protopic 0.03% and Protopic 0.1% ointment).

Marketing Authorisation Holder
LEO Pharma A/S
Industriparken 55 eDoc-000593873 - Version 19. 0

2750 Ballerup
Denmark

Manufacturer
LEO Laboratories Ltd.
285 Cashel Road
Crumlin, Dublin 12
Ireland

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

België/Belgique/Belgien
LEO Pharma N.V./S.A
Tél/Tel: +32 3 740 7868

Lietuva
LEO Pharma A/S
Tel: +45 44 94 58 88
Danija

България
LEO Pharma A/S
Teл.: +45 44 94 58 88
Дания

Luxembourg/Luxemburg
LEO Pharma N.V./S.A
Tél/Tel: +32 3 740 7868

Česká republika
LEO Pharma s.r.o.
Tel: +420 734 575 982

Magyarország
LEO Pharma A/S
Tel: +45 44 94 58 88
Dánia

Danmark
LEO Pharma AB
Tlf: +45 70 22 49 11

Malta
LEO Pharma A/S
Tel: +45 44 94 58 88
Id-Danimarka

Deutschland
LEO Pharma GmbH
Tel: +49 6102 2010

Nederland
LEO Pharma B.V.
Tel: +31 205104141

Eesti
LEO Pharma A/S
Tel: +45 44 94 58 88
Taani

Norge
LEO Pharma AS
Tlf: +47 22514900

Ελλάδα
LEO Pharmaceutical Hellas S.A.
Τηλ: +30 210 68 34322

Österreich
LEO Pharma GmbH
Tel: +43 1 503 6979

España
Laboratorios LEO Pharma, S.A.
Tel: +34 93 221 3366

Polska
LEO Pharma Sp. z o.o.
Tel: +48 22 244 18 40

France
Laboratoires LEO
Tél: +33 1 3014 40 00

Portugal
LEO Farmacêuticos Lda.
Tel: +351 21 711 0760

eDoc-000593873 - Version 19. 0

Hrvatska
LEO Pharma A/S
Tel: +45 44 94 58 88
Danska

România
LEO Pharma A/S
Tel: +45 44 94 58 88
Danemarca
Ireland
LEO Laboratories Ltd
Tel: +353 (0) 1 490 8924

Slovenija
LEO Pharma A/S
Tel: +45 44 94 58 88
Danska

Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
LEO Pharma s.r.o.
Tel: +420 734 575 982

Italia
LEO Pharma S.p.A.
Tel: +39 06 52625500

Suomi/Finland
LEO Pharma Oy
Puh./Tel: +358 20 721 8440

Κύπρος
The Star Medicines Importers Co. Ltd.
Τηλ: +357 2537 1056

Sverige
LEO Pharma AB
Tel: +46 40 3522 00

Latvija
LEO Pharma A/S
Tel: +45 44 94 58 88
Dānija

This leaflet was last revised in.

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

eDoc-000593873 - Version 19. 0

Package leaflet: Protopic 0.1% ointment / tacrolimus monohydrate

1. What Protopic is and what it is used for

The active substance of Protopic, tacrolimus monohydrate, is an immunomodulating agent.

Protopic 0.1% ointment is used to treat moderate to severe atopic dermatitis (eczema) in adults who are not adequately responsive to or are intolerant of conventional therapies such as topical corticosteroids.

2. What you need to know before you use Protopic

If you have a cutaneous Graft Versus Host Disease (an immune reaction of the skin which is a common complication in patients who have undergone a bone marrow transplant).
If you have swollen lymph nodes at initiation of treatment. If your lymph nodes become swollen during treatment with Protopic, consult your doctor.
If you have infected lesions. Do not apply the ointment to infected lesions.
If you notice any change to the appearance of your skin, please inform your physician.
Based on the results of long-term studies and experience, a link between Protopic ointment treatment and the development of malignancies has not been confirmed, but definitive conclusions cannot be drawn.
Avoid exposing the skin to long periods of sunlight or artificial sunlight such as tanning beds. If you spend time outdoors after applying Protopic, use a sunscreen and wear loose fitting clothing that protects the skin from the sun. In addition, ask your doctor for advice on other appropriate sun protection methods. If you are prescribed light therapy, inform your doctor that you are using Protopic as it is not recommended to use Protopic and light therapy at the same time.
If your doctor tells you to use Protopic twice weekly to keep your atopic dermatitis cleared, your condition should be reviewed by your doctor at least every 12 months, even if it remains under control. In children, maintenance treatment should be suspended after 12 months, to assess whether the need for continued treatment still exists.
It is recommended to use Protopic ointment at the lowest possible strength, at the lowest frequency and for the shortest possible duration necessary. This decision should be based on your doctor’s assessment of how your eczema responds to Protopic ointment.

Children
- Protopic 0.1 % ointment is not approved for children younger than 16 years of age.
Therefore it should not be used in this age group. Please consult your doctor.
- The effect of treatment with Protopic on the developing immune system in children, especially the young, has not been established.

Other medicines, cosmetics and Protopic
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines.

You may use moisturising creams and lotions during treatment with Protopic but these products should not be used within two hours of applying Protopic.

Protopic with alcohol
While using Protopic, drinking alcohol may cause the skin or face to become flushed or red and feel hot.

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

3. How to use Protopic

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

- Apply Protopic as a thin layer to affected areas of your skin.
eDoc-000593873 - Version 19. 0

Protopic may be used on most parts of the body, including the face and neck and in the creases of your elbows and knees.
Avoid using the ointment inside your nose or mouth or in your eyes. If the ointment gets on any of these areas, it should be thoroughly wiped off and/or rinsed off with water.
Do not cover the skin being treated with bandages or wraps.
Wash your hands after applying Protopic unless your hands are also being treated.
Before applying Protopic after a bath or shower, be sure your skin is completely dry.

You may be told by your doctor to use Protopic 0.1% ointment twice weekly once your atopic dermatitis has cleared or almost cleared. Protopic 0.1 % ointment should be applied once a day twice weekly (e.g. Monday and Thursday) to areas of your body commonly affected by atopic dermatitis.
There should be 2–3 days without Protopic treatment between applications.
If symptoms reappear you should use Protopic twice daily as outlined above and arrange to see your doctor to review your treatment.

If you accidentally swallow some ointment
If you accidentally swallow the ointment, consult your doctor or pharmacist as soon as possible. Do not try to induce vomiting.

If you forget to use Protopic
If you forget to apply the ointment at the scheduled time, do it as soon as you remember and then continue as before.

If you have any further questions on the use of 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.

Very common (may affect more than 1 in 10 people):
- burning sensation and itching
These symptoms are usually mild to moderate and generally go away within one week of using Protopic.

Common (may affect up to 1 in 10 people):
- redness
- feeling of warmth
- pain
- increased skin sensitivity (especially to hot and cold)
- skin tingling
- rash eDoc-000593873 - Version 19. 0

local skin infection regardless of specific cause including but not limited to: inflamed or infected hair follicles, cold sores, generalised herpes simplex infections
facial flushing or skin irritation after drinking alcohol is also common

Uncommon (may affect fewer than 1 in 100 people):
- acne

Following twice-weekly treatment application site infections have been reported in adults.
Rosacea (facial redness), rosacea-like dermatitis, lentigo (presence of flat brown spots on the skin), oedema at the application site and herpes eye infections have been reported during post-marketing experience.

5. How to store Protopic

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 tube and carton after EXP. The expiry date refers to the last day of that month.
Do not store above 25ºC.

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.

6. Contents of the pack and other information

What Protopic contains
- The active substance is tacrolimus monohydrate.
One gram of Protopic 0.1% ointment contains 1.0 mg tacrolimus (as tacrolimus monohydrate).
- The other ingredients are white soft paraffin, liquid paraffin, propylene carbonate, white beeswax, hard paraffin, butylhydroxytoluene (E321) and all-rac-α-tocopherol.

Marketing Authorisation Holder
LEO Pharma A/S
Industriparken 55
2750 Ballerup
Denmark

Manufacturer
LEO Laboratories Ltd.
285 Cashel Road
Crumlin, Dublin 12
Ireland

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

België/Belgique/Belgien
LEO Pharma N.V./S.A
Tél/Tel: +32 3 740 7868

Lietuva
LEO Pharma A/S
Tel: +45 44 94 58 88
Danija

България
LEO Pharma A/S
Teл.: +45 44 94 58 88
Дания

Luxembourg/Luxemburg
LEO Pharma N.V./S.A
Tél/Tel: +32 3 740 7868

Česká republika
LEO Pharma s.r.o.
Tel: +420 734 575 982

Magyarország
LEO Pharma A/S
Tel: +45 44 94 58 88
Dánia

Danmark
LEO Pharma AB
Tlf: +45 70 22 49 11

Malta
LEO Pharma A/S
Tel: +45 44 94 58 88
Id-Danimarka

Deutschland
LEO Pharma GmbH
Tel: +49 6102 2010

Nederland
LEO Pharma B.V.
Tel: +31 205104141

Eesti
LEO Pharma A/S
Tel: +45 44 94 58 88
Taani

Norge
LEO Pharma AS
Tlf: +47 22514900

Ελλάδα
LEO Pharmaceutical Hellas S.A.
Τηλ: +30 210 68 34322

Österreich
LEO Pharma GmbH
Tel: +43 1 503 6979

España
Laboratorios LEO Pharma, S.A.
Tel: +34 93 221 3366

Polska
LEO Pharma Sp. z o.o.
Tel: +48 22 244 18 40

France
Laboratoires LEO
Tél: +33 1 3014 40 00

Portugal
LEO Farmacêuticos Lda.
Tel: +351 21 711 0760

Hrvatska
LEO Pharma A/S
Tel: +45 44 94 58 88
Danska

România
LEO Pharma A/S
Tel: +45 44 94 58 88
Danemarca
Ireland
LEO Laboratories Ltd
Tel: +353 (0) 1 490 8924

Slovenija
LEO Pharma A/S
Tel: +45 44 94 58 88
Danska

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Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
LEO Pharma s.r.o.
Tel: +420 734 575 982

Italia
LEO Pharma S.p.A.
Tel: +39 06 52625500

Suomi/Finland
LEO Pharma Oy
Puh./Tel: +358 20 721 8440

Κύπρος
The Star Medicines Importers Co. Ltd.
Τηλ: +357 2537 1056

Sverige
LEO Pharma AB
Tel: +46 40 3522 00

Latvija
LEO Pharma A/S
Tel: +45 44 94 58 88
Dānija

This leaflet was last revised in.

Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu.
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Source: European Medicines Agency (EMA), product information. Not advertising, not a treatment recommendation. For questions about your own treatment, ask your doctor or pharmacist.